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Sample records for bleomycin

  1. Bleomycin clinical pharmacology by radioimmunoassay

    Energy Technology Data Exchange (ETDEWEB)

    Hall, S.W.; Strong, J.E.; Broughton, A.; Frazier, M.L.; Benjamin, R.S.

    1982-01-01

    Bleomycin pharmacokinetics were studied by radioimmunoassay in 11 patients who received 7-30 U intravenously (IV) and eight patients who received 4-30 U subcutaneously (SC). For patients who received IV bleomycin plasma disappearance was biphasic, with a mean initial half-life of 0.26 h and a terminal half-life of 2.3 h. Mean plasma drug clearance was 67.8 ml/min/m/sup 2/ and the volume of distribution was 13.2 l/m/sup 2/. Urinary excretion accounted for 63.9% of the drug in 24 h. After SC administration peak plasma levels occurred in 1.1 h, with a mean elimination half-life of 4.3 h. Mean plasma drug clearance was 60.5 ml/min/m/sup 2/ and the volume of distribution was 19.2 l/m/sup 2/. Bleomycin plasma clearance correlated well with serum creatinine (r/sup 2/=0.72). Bleomycin has a rapid plasma elimination and urinary excretion. Bleomycin bioavailability after SC administration appears comparable to that seen after IV administration as determined by the areas under the plasma disappearance curves. Prolonged plasma levels are seen after SC injection, suggesting this route of administration can produce plasma concentrations comparable to those attained with continuous IV infusions.

  2. Bleomycin-Induced Lung Injury

    Directory of Open Access Journals (Sweden)

    Tomás Reinert

    2013-01-01

    Full Text Available Bleomycin is a chemotherapeutic agent commonly used to treat curable diseases such as germinative tumors and Hodgkin’s lymphoma. The major limitation of bleomycin therapy is pulmonary toxicity, which can be life threatening in up to 10% of patients receiving the drug. The mechanism of bleomycin-induced pneumonitis (BIP involves oxidative damage, relative deficiency of the deactivating enzyme bleomycin hydrolase, genetic susceptibility, and the elaboration of inflammatory cytokines. Ultimately, BIP can progress to lung fibrosis. The diagnosis of BIP is established by the combination of systemic symptoms, radiological and histological findings, and respiratory function tests abnormalities, while other disorders should be excluded. Although the diagnosis and pathophysiology of this disease have been better characterized over the past few years, there is no effective therapy for the disease. In general, the clinical picture is extremely complex. A greater understanding of the BIP pathogenesis may lead to the development of new agents capable of preventing or even treating the injury already present. Physicians who prescribe bleomycin must be aware of the potential pulmonary toxicity, especially in the presence of risk factors. This review will focus on BIP, mainly regarding recent advances and perspectives in diagnosis and treatment.

  3. Labeled bleomycin as a tumor localizing agent

    International Nuclear Information System (INIS)

    The antitumor antibiotics bleomycins labeled with 57Co are known to possess excellent tumor localizing properties but the rather long halflife of 57Co prevents its use in clinical routine. It is therefore desirable to label cobalt-bleomycin with a more suitable radionuclide, e.g. 123I. This thesis reports on further studies on cobalt-bleomycin. It appears from the studies on the structure of cobalt-bleomycin described in this thesis (Chapter B), that cobalt is able to form different complexes with bleomycin (the forms I and II). The difference in structure is not clear, but the biological behavior of both forms is studied (Chapter C). In Chapter D the iodination of cobalt-bleomycin is described. Iodination of free bleomycin yields a product with bad tumor localizing properties, and straight-on iodination of cobalt-bleomycin is prevented by the presence of cobalt. To retain the good tumor-localizing properties of cobalt-bleomycin, possibilities were explored to incorporate the iodine in the terminal amine (a side chain, not involved in complexation). Alkylation of cobalt-bleomycin demethyl A2 with N-bromoacetyl-3-iodoaniline yielded a product; unfortunately this product possessed bad tumor localizing properties and moreover, was not stable in vivo. The structure of a possibly successful iodinated cobalt-bleomycin is outlined but could not be realized during this research. (Auth.)

  4. Bleomycin treatment of brain tumors: an evaluation

    DEFF Research Database (Denmark)

    Linnert, Mette; Gehl, Julie

    2009-01-01

    Bleomycin has been used in the treatment of brain tumors for over 30 years. Currently, we are evaluating electrochemotherapy (the use of electric pulses to enhance uptake of bleomycin) for patients with secondary brain tumors. We, therefore, reviewed the literature with specific reference...... to the tolerability and toxicity of bleomycin. Using the keywords 'brain' and 'bleomycin', a database search without date restriction was performed and over 500 articles were found. Twenty-five articles were used for this study based on relevance determined by: (i) clinical studies, (ii) use of bleomycin, and (iii......) direct injection into brain tissue or cysts. There were two main indications for the use of bleomycin directly into the brain: (i) cystic tumors in the form of craniopharyngiomas and (ii) solid brain tumors such as glioblastomas and astrocytomas. The most frequent adverse effects reported were transient...

  5. Bleomycin cardiotoxicity during chemotherapy for an ovarian germ cell tumor

    OpenAIRE

    Didagelos, M; Boutis, A; Diamantopoulos, N; Sotiriadou, M; Fotiou, C

    2013-01-01

    Introduction: Platinum-based chemotherapeutic regimens, including BEP (bleomycin, etoposide, cisplatin) represent the standard of care, first line therapy in non-epithelial ovarian tumours. Cardiovascular toxicity is a rare adverse effect of bleomycin.

  6. Photochemical internalization of bleomycin for glioma treatment

    Science.gov (United States)

    Mathews, Marlon S.; Blickenstaff, Joseph W.; Shih, En-Chung; Zamora, Genesis; Vo, Van; Sun, Chung-Ho; Hirschberg, Henry; Madsen, Steen J.

    2012-05-01

    We study the use of photochemical internalization (PCI) for enhancing chemotherapeutic response to malignant glioma cells in vitro. Two models are studied: monolayers consisting of F98 rat glioma cells and human glioma spheroids established from biopsy-derived glioma cells. In both cases, the cytotoxicity of aluminum phthalocyanine disulfonate (AlPcS2a)-based PCI of bleomycin was compared to AlPcS2a-photodynamic therapy (PDT) and chemotherapy alone. Monolayers and spheroids were incubated with AlPcS2a (PDT effect), bleomycin (chemotherapy effect), or AlPcS2a+bleomycin (PCI effect) and were illuminated (670 nm). Toxicity was evaluated using colony formation assays or spheroid growth kinetics. F98 cells in monolayer/spheroids were not particularly sensitive to the effects of low radiant exposure (1.5 J/cm2 @ 5 mW/cm2) AlPcS2a-PDT. Bleomycin was moderately toxic to F98 cells in monolayer at relatively low concentrations-incubation of F98 cells in 0.1 μg/ml for 4 h resulted in 80% survival, but less toxic in human glioma spheroids respectively. In both in vitro systems investigated, a significant PCI effect is seen. PCI using 1.5 J/cm2 together with 0.25 μg/ml bleomycin resulted in approximately 20% and 18% survival of F98 rat glioma cells and human glioma spheroids, respectively. These results show that AlPcS2a-mediated PCI can be used to enhance the efficacy of chemotherapeutic agents such as bleomycin in malignant gliomas.

  7. Tumor scanning with 57Co-bleomycin

    International Nuclear Information System (INIS)

    The clinical application of 57Co-bleomycin as a tumor scanning radiopharmaceutical was firstly reported by Nouel and Maeda respectively. The authors conducted studies on the diagnostic significance of this tumor scanning agent and presented the results obtained in 40 patients with malignant and non malignant lesions. Six hours and 24 hours after the injection of 500 μCi of 57Co-bleomycin, scintigrams were taken with a 3-inch scintiscanner. Positive scans were found in 20 out of 36 patients with various malignant tumors. Of 20 patients with lung cancer, positive scans were obtained in 17 cases (85%) and of 6 with breast cancer, 3 cases showed positive scans. False negative scans were obtained in another 10 cases of malignant tumors (3 cases of thyroid carcinoma, 4 cases of hepatoma, and 1 case each of gastric carcinoma, peritoneal carcinomatosis, and reticulum cell sarcoma). Of 4 patients with non malignant disease, one case of pulmonary tuberculosis showed a positive scan. In 8 cases of lung cancer and 6 of breast cancer, the relationship between the size of the excised tumor and the scintigram findings was studied. The smallest tumors detected by scintigram were 2 cm in lung cancer and 3.2 cm in breast cancer. (author)

  8. Simvastatin attenuates bleomycin-induced pulmonary fibrosis in mice

    Institute of Scientific and Technical Information of China (English)

    OU Xue-mei; FENG Yu-lin; WEN Fu-qiang; HUANG Xiang-yang; XIAO Jun; WANG Ke; WANG Tao

    2008-01-01

    Background Bleomycin-induced fibrosis is extensively used to model aspects of the pathogenesis of interstitial pulmonary fibrosis. This study aimed to determine the benefic effects and mechanisms of simvastatin on bleomycin-induced pulmonary fibrosis in mice.Methods Bleomycin-induced pulmonary fibrosis mice were administered with simvastatin in different doses for 28 days.We measured inflammatory response, fibrogenic cytokines and profibrogenic markers in both bleomycin-stimulated and control lungs, and correlated these parameters with pulmonary fibrosis.Results Simvastatin attenuated the histopathological change of bleomycin-induced pulmonary fibrosis and prevented the increase of lung hydroxyproline content and collagen (Ⅰand Ⅲ) mRNA expression induced by bleomycin. Moreover,simvastatin down-regulated the increased expression of transforming growth factor-β1 (TGF-β1) and connective tissue growth factor (CTGF) induced by bleomycin at both gene and protein levels. Simultaneously, the accumulation of neutrophils and lymphocytes and the increased production of tumor necrosis factor-(] (TNF-a) in bronchial alveolar lavage fluid were inhibited by simvastatin in early inflammatory phase after bleomycin infusion. The higher dose of simvastatin was associated with a more significant reduction in these inflammatory and fibrotic parameters. Furthermore,the inactivation of p38, RhoA and Smad2/3 signaling pathways was observed during simvastatin administration.Conclusions Simvastatin attenuated bleomycin-induced pulmonary fibrosis, as indicated by decreases in Ashcroft score and lung collagen accumulation. The inhibitory effect of simvastatin on the progression of pulmonary fibrosis may be demonstrated by reducing inflammatory response and production of TGF-βI and CTGF. These findings indicate that simvastatin may be used in the treatment of pulmonary fibrosis.

  9. Synthetic liposomes are protective from bleomycin-induced lung toxicity

    OpenAIRE

    Gwinn, William M.; Kapita, Mayanga C.; Wang, Ping M.; Cesta, Mark F.; Martin, William J.

    2011-01-01

    Idiopathic pulmonary fibrosis is a devastating disease characterized by a progressive, irreversible, and ultimately lethal form of lung fibrosis. Except for lung transplantation, no effective treatment options currently exist. The bleomycin animal model is one of the best studied models of lung injury and fibrosis. A previous study using mouse tumor models observed that liposome-encapsulated bleomycin exhibited reduced lung toxicity. Therefore, we hypothesized that airway delivery of syntheti...

  10. Repetitive intratracheal bleomycin models several features of idiopathic pulmonary fibrosis

    OpenAIRE

    Degryse, Amber L.; Tanjore, Harikrishna; Xu, Xiaochuan C.; Polosukhin, Vasiliy V.; Jones, Brittany R.; McMahon, Frank B.; Gleaves, Linda A.; Blackwell, Timothy S.; Lawson, William E.

    2010-01-01

    Single-dose intratracheal bleomycin has been instrumental for understanding fibrotic lung remodeling, but fails to recapitulate several features of idiopathic pulmonary fibrosis (IPF). Since IPF is thought to result from recurrent alveolar injury, we aimed to develop a repetitive bleomycin model that results in lung fibrosis with key characteristics of human disease, including alveolar epithelial cell (AEC) hyperplasia. Wild-type and cell fate reporter mice expressing β-galactosidase in cells...

  11. Cells containing factor XIIIa and pulmonary fibrosis induced by bleomycin.

    OpenAIRE

    Toida, M; Y. Okumura; Takami, T.

    1991-01-01

    To show the clinical importance of cells containing FXIIIa in pulmonary fibrosis induced by bleomycin, the distributions of FXIIIa and collagenous components were investigated immunohistochemically in both normal lung tissues and those affected by bleomycin. In the normal tissues FXIIIa-containing cells were sparse, but they were numerous in the pulmonary fibrotic tissues, especially in the subpleural area and around the blood vessels of alveolar septa, where slight to moderate fibrosis was s...

  12. Elastase modifies bleomycin-induced pulmonary fibrosis in mice.

    Science.gov (United States)

    Trajano, Larissa Alexsandra Silva Neto; Trajano, Eduardo Tavares Lima; Lanzetti, Manuella; Mendonça, Morena Scopel Amorim; Guilherme, Rafael Freitas; Figueiredo, Rodrigo Tinoco; Benjamim, Cláudia Farias; Valenca, Samuel Santos; Costa, Andréa Monte Alto; Porto, Luís Cristóvão

    2016-04-01

    Pulmonary fibrosis (PF) is characterized by excessive accumulation of collagen in the lungs. Emphysema is characterized by loss of the extracellular matrix (ECM) and alveolar enlargement. We studied the co-participation of elastase-induced mild emphysema in bleomycin-induced PF in mice by analyzing oxidative stress, inflammation and lung histology. C57BL/6 mice were divided into four groups: control; bleomycin (0.1U/mouse); elastase (using porcine pancreatic elastase (PPE)+bleomycin (3U/mouse 14 days before 0.1U/mouse of bleomycin; PPE+B); elastase (3U/mouse). Mice were humanely sacrificed 7, 14 and 21 days after treatment with bleomycin or vehicle. PF was observed 14 days and 21 days after bleomycin treatment but was observed after 14 days only in the PPE+B group. In the PPE+B group at 21 days, we observed many alveoli and alveolar septa with few PF areas. We also observed marked and progressive increases of collagens 7, 14 and 21 days after bleomycin treatment whereas, in the PPE+B group, collagen deposition was observed only at 14 days. There was a reduction in activities of the antioxidant enzymes superoxide dismutase (p<0.05), catalase (p<0.01) and glutathione peroxidase (p<0.01) parallel with an increase in nitrite (p<0.01) 21 days after bleomycin treatment compared with the control group. These endpoints were also reduced (p<0.05, p<0.05 and p<0.01, respectively) and increased (p<0.01) in the PPE+B group at 21 days compared with the control group. Interleukin (IL)-1β expression was upregulated (p<0.01) whereas IL-6 was downregulated (p<0.05) in the PPE+B group at 21 days compared with the control group. PF and emphysema did not coexist in our model of lung disease and despite increased levels of oxidative stress and inflammatory markers after combined stimulus (elastase and bleomycin) overall histology was improved to that of the nearest control group. PMID:26852294

  13. Induction of tumor necrosis factor-alpha as a cause of bleomycin-related toxicity

    NARCIS (Netherlands)

    Sleijfer, S; Vujaskovic, Z; Limburg, PC; Mulder, NH; Schraffordt Koops, H.

    1998-01-01

    BACKGROUND, The application of bleomycin is characterized by acute side effects, such as fever, chills, and sometimes hypotension and tachypnea. Furthermore, bleomycin is known to induce pneumonitis. There are several indications that the induction of cytokines by bleomycin is involved in the develo

  14. The Protective Effect of Naringin against Bleomycin-Induced Pulmonary Fibrosis in Wistar Rats

    OpenAIRE

    Turgut, Nergiz H.; Kara, Haki; Elagoz, Sahende; Deveci, Koksal; Gungor, Huseyin; Arslanbas, Emre

    2016-01-01

    The aim of the current study was to investigate the protective effect of naringin on bleomycin-induced pulmonary fibrosis in rats. Twenty-four Wistar rats randomly divided into four groups (control, bleomycin alone, bleomycin + naringin 40, and bleomycin + naringin 80) were used. Rats were administered a single dose of bleomycin (5 mg/kg; via the tracheal cannula) alone or followed by either naringin 40 mg/kg (orally) or naringin 80 mg/kg (orally) or water (1 mL, orally) for 14 days. Rats and...

  15. Irradiation and bleomycin in the treatment of inoperable vulval carcinoma

    Energy Technology Data Exchange (ETDEWEB)

    Iversen, T. (The Norwegian Radium Hospital, Oslo (Norway). Dept. of Gynecology)

    1982-01-01

    Fifteen patients with inoperable squamous cell carcinoma of the vulva were treated with Bleomycin and irradiation. Only 2 patients were also treated with vulvectomy and bilateral lymphadenectomy 2 weeks later. One patient survived more than 4 years without signs of recurrence, another survived 2 1/2 years and 2 more 18 and 12 months respectively. The rest died less than 6 months after the treatment. Three patients developed signs of lung fibrosis. Bleomycin and irradiation may render a tumor operable, but in most cases this regime merely aims at palliation.

  16. Bleomycin effect on L5178Y cells

    International Nuclear Information System (INIS)

    We analyzed the effects of treatment with bleomycin (BLM) in 2 sublines of L5178Y (LY) murine lymphoma, LY-R, radioresistant, and LY-S, radiosensitive. LY-S cells were 2 times more sensitive to BLM than LY-R cells, similarly as in the case of X rays. Since there was no difference in the activity of drug transport system, this different susceptibility to BLM probably was due to the DNA repair defect in LY-S cells. Growth was impaired proportionally to the lethal effect and continued (days 3-6 after treatment with 50 microM BLM) until the elimination of dead cells from the cell population; 24 h after treatment cell cycle distributions indicated the presence of block in S phase (proportional to the dose of BLM). Contrarily to X or gamma-irradiation, BLM did not induce any block in the G2 phase. Initial DNA damage, estimated by the single cell gel electrophoresis, was linearly related to the dose of BLM in LY-S cells; in LY-R cells the damage level was significantly higher than in LY-S cells. In the higher (>10 microM BLM) dose range both dose - effect curves became identical. In gamma-irradiated LY-R and LY-S cells the dose - effect curves were identical. DNA damage distribution in BLM treated LY cells was much less uniform than in the gamma-irradiated ones; it indicated the presence of heavily damaged cells, a feature typical for BLM action. (author). 29 refs, 28 figs

  17. Elimination of multicopy plasmid R6K by bleomycin.

    OpenAIRE

    Attfield, P V; Pinney, R. J.

    1985-01-01

    Bleomycin eliminated multicopy plasmid R6K from growing cells of Escherichia coli AB1157 but failed to cure either of the low-copy plasmids R1 or R46. Measurements of R6K-encoded beta-lactamase and of covalently closed plasmid DNA indicated that the drug causes a progressive reduction in plasmid copy number.

  18. Doxycycline Attenuated Pulmonary Fibrosis Induced by Bleomycin in Mice

    OpenAIRE

    Fujita, Masaki; Ye, Qing; Ouchi, Hiroshi; Harada, Eiji; Inoshima, Ichiro; Kuwano, Kazuyoshi; Nakanishi, Yoichi

    2006-01-01

    The administration of doxycycline prior to bleomycin in mice attenuated pulmonary fibrosis. Bronchoalveolar neutrophil influx and gelatinase activity, but not caseinolytic activity, were attenuated by doxycycline. Established fibrosis was not affected by doxycycline. Thus, doxycycline might be useful for slowing down pulmonary fibrosis by biological activity other than antibacterial activity.

  19. Gefitinib attenuates murine pulmonary fibrosis induced by bleomycin

    Institute of Scientific and Technical Information of China (English)

    WANG Ping; TIAN Qing; LIANG Zhi-xin; YANG Zhen; XU Shu-feng; SUN Ji-ping; CHEN Liang-an

    2010-01-01

    Background Gefitinib, an inhibitor of epidermal growth factor receptor (EGFR) tyrosine kinase, is an effective treatment for epithelial tumors, including non-small cell lung cancer (NSCLC), and is generally well tolerated.However, some clinical trials revealed that gefitinib exposure caused lung fibrosis, a severe adverse reaction.This study investigated the effect of gefitinib on lung fibrosis in mice.Methods We generated a mouse model of lung fibrosis induced by bleomycin to investigate the fibrotic effect of gefitinib.C57BL/6 mice were injected intratracheally with bleomycin or saline, with intragastric administration of gefitinib or saline.Lung tissues were harvested on day 14 or 21 for histology and genetic analysis.Results The histological results showed that bleomycin successfully induced lung fibrosis in mice, and gefitinib prevented lung fibrosis and suppressed the proliferation of S100A4-positive fibroblast cells.In addition, Western blotting analysis revealed that gefitinib decreased the expression of phosphorylated EGFR (p-EGFR).Furthermore, quantitative real-time PCR (qRT-PCR) demonstrated that gefitinib inhibited the accumulation of collagens Ⅰ and Ⅲ.Conclusions These results reveal that gefitinib reduces pulmonary fibrosis induced by bleomycin in mice and suggest that administration of small molecule EGFR tyrosine kinase inhibitors has the potential to prevent pulmonary fibrosis by inhibiting the proliferation of mesenchymal cells, and that targeting tyrosine kinase receptors might be useful for the treatment of pulmonary fibrosis in humans.

  20. Acute respiratory failure induced by bleomycin and hyperoxia

    International Nuclear Information System (INIS)

    Bleomycin, a chemotherapeutic agent, and oxygen at concentrations greater than 20%, induce acute pulmonary damage separately and when administered together. The interaction of 5 U/kg intratracheal bleomycin and 24 hours of exposure to 80% oxygen in hamsters produces delayed onset acute respiratory distress syndrome three days after treatment. As little as 12 hours of 80% O2 exposure, after intratracheal bleomycin, induces severe pulmonary damage. Lung lesions are characterized as diffuse alveolar damage. Significantly pulmonary edema, measured by iodine-125-bovine serum albumin and technetium-99m-diethylenetriaminepentaacetate, occurs 72 hours after treatment. Lesions progress from focal mild alveolar interstitial and air-space macrophage and granulocyte infiltrates at 24 hours to marked infiltrates and severe interstitial and air space edema with hemorrhages and hyaline membranes at 96 hours. Significant changes measured by electron microscopy morphometry are increases in volume fractions of neutrophils, alveolar tissue and mononuclear leukocytes. Surfactant assay of bronchoalveolar lavage fluid shows a marked decrease in the lecithin/sphingomyelin ratio at 72 hours. Proposed mechanisms of bleomycin and hyperoxia synergism include enhanced production of superoxide radicals either directly or indirectly by increasing neutrophil activity or numbers, or by alteration of cell mediators. The pulmonary edema, without evidence of severe morphological changes, may be secondary to alterations of transalveolar transport mechanisms

  1. [Consortium for detection and management of lung damage induced by bleomycin].

    Science.gov (United States)

    Biya, Josette; Stoclin, Annabelle; Dury, Sandra; Le Pavec, Jérôme; Mir, Olivier; Lazarovici, Julien; Fermé, Christophe; Annereau, Maxime; Ekpe, Kenneth; Massard, Christophe; Michot, Jean-Marie

    2016-01-01

    Bleomycin is a cytotoxic antibiotic and a component of chemotherapy regimens of germ cell tumors and lymphoma. Bleomycin lung injuries occur in 10% of patients, and lead to severe interstitial pneumonia in 3% of patients. Pulmonary toxicity is related to endothelial cells injury induce by free radicals and inflammatory cytokines. Diagnosis of bleomycin-induced lung toxicity is based on the combination of clinical and radiological features, and requires to rule out differential diagnoses including pneumocystis. "Bleomycin-induced pneumonitis" is the most frequent pattern; eosinophilic pneumonitis and organizing pneumonia are rarer. Occurrence of bleomycin lung toxicity requires an immediate and often permanent discontinuation. Treatment is based on steroid. Regular clinical and pulmonary function tests monitoring are mandatory for early detection of bleomycin-induced lung toxicity. PMID:27241272

  2. Pulmonary platelet trapping induced by bleomycin: correlation with fibrosis and involvement of the beta 2 integrins.

    OpenAIRE

    Piguet, P F; Vesin, C

    1994-01-01

    Platelet trapping was explored during the course of bleomycin induced pulmonary fibrosis by the injection of indium-111 labelled platelets and by light and electron microscopy (EM) of the alveolar capillaries. An i.v. injection of bleomycin markedly increased the localization of labelled platelets in the lung (but not in other organs) for about 3 weeks. On day 7 after bleomycin injection, a significant increase in the number of platelets in contact with the alveolar endothelium was seen with ...

  3. Effects of bleomycin and antioxidants on the fatty acid profile of testicular cancer cell membranes.

    Science.gov (United States)

    Cort, A; Ozben, T; Melchiorre, M; Chatgilialoglu, C; Ferreri, C; Sansone, A

    2016-02-01

    Bleomycin is used in chemotherapy regimens for the treatment of patients having testicular germ-cell tumor (TGCT). There is no study in the literature investigating the effects of bleomycin on membrane lipid profile in testicular cancer cells. We investigated membrane fatty acid (FA) profiles isolated, derivatized and analyzed by gas chromatography of NTera-2 testicular cancer cells incubated with bleomycin (Bleo) for 24 h in the absence and presence of N-Acetyl-L-Cysteine (NAC) and curcumin (Cur) as commonly used antioxidant adjuvants. At the same time the MAPK pathway and EGFR levels were followed up. Bleomycin treatment increased significantly saturated fatty acids (SFA) of phospholipids at the expense of monounsaturated (MUFA) and polyunsaturated fatty acids (PUFA). Bleomycin also led to a significant increase in the trans lipid isomers of oleic and arachidonic acids due to its free radical producing effect. Incubation with bleomycin increased the p38 MAPK and JNK levels and downregulated EGFR pathway. Coincubation of bleomycin with NAC reversed effects caused by bleomycin. Our results highlight the important role of membrane fatty acid remodeling occurring during the use of bleomycin and its concurrent use with antioxidants which can adjuvate the cytotoxic effects of the chemotherapeutic agents. PMID:26656160

  4. Carbon Monoxide Suppresses Bleomycin-Induced Lung Fibrosis

    OpenAIRE

    Zhou, Zhihong; Song, Ruiping; Fattman, Cheryl L.; Greenhill, Sara; Alber, Sean; Oury, Tim D.; Augustine M K Choi; Morse, Danielle

    2005-01-01

    Idiopathic pulmonary fibrosis is an incurable fibrosing disorder that progresses relentlessly to respiratory failure. We hypothesized that a product of heme oxygenase activity, carbon monoxide (CO), may have anti-fibrotic effects. To test this hypothesis, mice treated with intratracheal bleomycin were exposed to low-concentration inhaled CO or ambient air. Lungs of mice treated with CO had significantly lower hydroxyproline accumulation than controls. Fibroblast proliferation, thought to play...

  5. Bleomycin-associated Lung Toxicity in Childhood Cancer Survivors.

    Science.gov (United States)

    Zorzi, Alexandra P; Yang, Connie L; Dell, Sharon; Nathan, Paul C

    2015-11-01

    Pulmonary disease is a significant morbidity among childhood cancer survivors. The aim of this study was to characterize the pulmonary dysfunction experienced by childhood cancer survivors treated with bleomycin. A cross-sectional analysis of pulmonary function testing (PFT) in survivors treated with bleomycin was preformed. The most recent posttherapy PFT was assessed. Spirometry and lung volumes were categorized as normal, restrictive, obstructive, or mixed. Diffusing capacity of carbon monoxide (DLCO) was categorized as normal or abnormal. PFT data of 143 survivors was analyzed. PFTs were performed a median of 2.3 years (interquartile range, 1.4 to 4.9) from completion of therapy. Spirometry was abnormal in 58 (41%), only 5 (9%) had respiratory symptoms. Forty-two (70%) had obstructive, 11 (18%) restrictive, and 5 (9%) mixed ventilatory defects. The majority of abnormalities were mild (91%). DLCO was abnormal in 27. Reductions were mild in 96%. Patients with a history of relapse were more likely to develop abnormalities in spirometry and/or DLCO (odds ratio=5.02, 95% confidence interval: 1.3-19.4, P=0.01; odds ratio=3.47, 95% confidence interval: 1.01-11.9, P=0.03). Asymptomatic abnormalities of PFT are common among childhood cancer survivors treated with bleomycin and associated with a history of relapse. Research studying the risk for clinical progression of this dysfunction is warranted. PMID:26422284

  6. Radiologic-pathologic correlation of experimental bleomycin-induced pneumonitis

    International Nuclear Information System (INIS)

    Radiologic-pathologic correlative study of bleomycin-induced pneumonitis was performed using inflated and fixed lung specimens. Sixteen male Japanese white rabbits (body weight: 2.0-2.5 kg) were given a single intratracheal injection of 10 mg/kg bleomycin. On day 3, 10, 21, and 42 after bleomycin administration, 4 rabbits were killed, and each lung was inflated and fixed for radiologic-pathologic correlation. Early pathologic change involved a markedly exudative lesion like DAD, corresponding to the finding of markedly increased density on soft X-ray. As intraalveolar organization progressed, fibrotic changes of the alveolar septum, and atelectatic change evolved pathologically, the finding of markedly increased density developed the nature of contraction, and finally the finding of an abnormal linear shadow and air space dilatation were formed. The finding of markedly increased density and slightly increased density, respectively, did not simply correspond to the alveolar lesion and interstitial lesion pathologically. We considered that the degree of increased density depended on the degree of air content in the alveoli of the lesion. The finding of an abnormal linear shadow corresponded to the band of fibrotic tissue, and band-shaped atelectasis of alveoli. The finding of air space dilatation corresponded to the dilatation of respiratory bronchioli and alveolar ducts in the fibrotic stage, and this may show the mechanism of honeycomb lung formation. The finding of a clearly demarcated shadow with linear margins could be recognized as a lobular lesion and disappeared as fibrotic change evolved. (author)

  7. Protective mechanisms against homocysteine toxicity: the role of bleomycin hydrolase.

    Science.gov (United States)

    Zimny, Jaroslaw; Sikora, Marta; Guranowski, Andrzej; Jakubowski, Hieronim

    2006-08-11

    Homocysteine (Hcy) editing by methionyl-tRNA synthetase results in the formation of Hcy-thiolactone and initiates a pathway that has been implicated in human disease. In addition to being cleared from the circulation by urinary excretion, Hcy-thiolactone is detoxified by the serum Hcy-thiolactonase/paraoxonase carried on high density lipoprotein. Whether Hcy-thiolactone is detoxified inside cells was unknown. Here we show that Hcy-thiolactone is hydrolyzed by an intracellular enzyme, which we have purified to homogeneity from human placenta and identified by proteomic analyses as human bleomycin hydrolase (hBLH). We have also purified an Hcy-thiolactonase from the yeast Saccharomyces cerevisiae and identified it as yeast bleomycin hydrolase (yBLH). BLH belongs to a family of evolutionarily conserved cysteine aminopeptidases, and its only known biologically relevant function was deamidation of the anticancer drug bleomycin. Recombinant hBLH or yBLH, expressed in Escherichia coli, exhibits Hcy-thiolactonase activity similar to that of the native enzymes. Active site mutations, C73A for hBLH and H369A for yBLH, inactivate Hcy-thiolactonase activities. Yeast blh1 mutants are deficient in Hcy-thiolactonase activity in vitro and in vivo, produce more Hcy-thiolactone, and exhibit greater sensitivity to Hcy toxicity than wild type yeast cells. Our data suggest that BLH protects cells against Hcy toxicity by hydrolyzing intracellular Hcy-thiolactone. PMID:16769724

  8. Vascular damage in testicular cancer patients : A study on endothelial activation by bleomycin and cisplatin in vitro

    NARCIS (Netherlands)

    Nuver, Janine; De Haas, Esther C.; Van Zweeden, Martine; Gietema, Jourik A.; Meijer, Coby

    2010-01-01

    Following treatment with bleomycin- and cisplatin-containing chemotherapy, testicular cancer patients frequently develop vascular complications, which may result from damage to endothelial cells. Understanding bleomycin- and cisplatin-induced endothelial alterations may help to develop strategies to

  9. Deglycosylated bleomycin has the antitumor activity of bleomycin without pulmonary toxicity.

    Science.gov (United States)

    Burgy, Olivier; Wettstein, Guillaume; Bellaye, Pierre S; Decologne, Nathalie; Racoeur, Cindy; Goirand, Françoise; Beltramo, Guillaume; Hernandez, Jean-François; Kenani, Abderraouf; Camus, Philippe; Bettaieb, Ali; Garrido, Carmen; Bonniaud, Philippe

    2016-02-17

    Bleomycin (BLM) is a potent anticancer drug used to treat different malignancies, mainly lymphomas, germ cell tumors, and melanomas. Unfortunately, BLM has major, dose-dependent, pulmonary toxicity that affects 20% of treated individuals. The most severe form of BLM-induced pulmonary toxicity is lung fibrosis. Deglyco-BLM is a molecule derived from BLM in which the sugar residue d-mannosyl-l-glucose disaccharide has been deleted. The objective of this study was to assess the anticancer activity and lung toxicity of deglyco-BLM. We compared the antitumor activity and pulmonary toxicity of intraperitoneally administrated deglyco-BLM and BLM in three rodent models. Pulmonary toxicity was examined in depth after intratracheal administration of both chemotherapeutic agents. The effect of both drugs was further studied in epithelial alveolar cells in vitro. We demonstrated in rodent cancer models, including a human Hodgkin's lymphoma xenograft and a syngeneic melanoma model, that intraperitoneal deglyco-BLM is as effective as BLM in inducing tumor regression. Whereas the antitumor effect of BLM was accompanied by a loss of body weight and the development of pulmonary toxicity, deglyco-BLM did not affect body weight and did not engender lung injury. Both molecules induced lung epithelial cell apoptosis after intratracheal administration, but deglyco-BLM lost the ability to induce caspase-1 activation and the production of ROS (reactive oxygen species), transforming growth factor-β1, and other profibrotic and inflammatory cytokines in the lungs of mice and in vitro. Deglyco-BLM should be considered for clinical testing as a less toxic alternative to BLM in cancer therapy. PMID:26888428

  10. N-acetyl-L-cysteine inhibits bleomycin induced apoptosis in malignant testicular germ cell tumors.

    Science.gov (United States)

    Kucuksayan, Ertan; Cort, Aysegul; Timur, Mujgan; Ozdemir, Evrim; Yucel, Suleyman Gultekin; Ozben, Tomris

    2013-07-01

    Antioxidants may prevent apoptosis of cancer cells via inhibiting reactive oxygen species (ROS). However, to date no study has been carried out to elucidate the effects of strong antioxidant N-acetylcysteine (NAC) on Bleomycin induced apoptosis in human testicular cancer (NTERA-2, NT2) cells. For this reason, we studied the effects of Bleomycin and NAC alone and in combination on apoptotic signaling pathways in NT2 cell line. We determined the cytotoxic effect of bleomycin on NT2 cells and measured apoptosis markers such as Caspase-3, -8, -9 activities and Bcl-2, Bax, Cyt-c, Annexin V-FTIC and PI levels in NT2 cells incubated with different agents for 24 h. Early apoptosis was determined using FACS assay. We found half of the lethal dose (LD50) of Bleomycin on NT2 cell viability as 400, 100, and 20 µg/ml after incubations for 24, 48, and 72 h, respectively. Incubation with bleomycin (LD50 ) and H2O2 for 24 h increased Caspase-3, -8, -9 activities, Cyt-c and Bax levels and decreased Bcl-2 levels. The concurrent incubation of NT2 cells with bleomycin/H2O2 and NAC (5 mM) for 24 h abolished bleomycin/H2O2-dependent increases in Caspase-3, -8, -9 activities, Bax and Cyt-c levels and bleomycin/H2O2-dependent decrease in Bcl-2 level. Our results indicate that bleomycin/H2O2 induce apoptosis in NT2 cells by activating mitochondrial pathway of apoptosis, while NAC diminishes bleomycin/H2O2 induced apoptosis. We conclude that NAC has antagonistic effects on Bleomycin-induced apoptosis in NT2 cells and causes resistance to apoptosis which is not a desired effect in eliminating cancer cells. PMID:23386420

  11. Bleomycin induced epithelial–mesenchymal transition (EMT) in pleural mesothelial cells

    International Nuclear Information System (INIS)

    Idiopathic pulmonary fibrosis (IPF) is a chronic progressive lung disease characterized by the development of subpleural foci of myofibroblasts that contribute to the exuberant fibrosis. Recent studies revealed that pleural mesothelial cells (PMCs) undergo epithelial–mesenchymal transition (EMT) and play a pivotal role in IPF. In animal model, bleomycin induces pulmonary fibrosis exhibiting subpleural fibrosis similar to what is seen in human IPF. It is not known yet whether bleomycin induces EMT in PMCs. In the present study, PMCs were cultured and treated with bleomycin. The protein levels of collagen-I, mesenchymal phenotypic markers (vimentin and α-smooth muscle actin), and epithelial phenotypic markers (cytokeratin-8 and E-cadherin) were measured by Western blot. PMC migration was evaluated using wound-healing assay of culture PMCs in vitro, and in vivo by monitoring the localization of PMC marker, calretinin, in the lung sections of bleomycin-induced lung fibrosis. The results showed that bleomycin induced increases in collagen-I synthesis in PMC. Bleomycin induced significant increases in mesenchymal phenotypic markers and decreases in epithelial phenotypic markers in PMC, and promoted PMC migration in vitro and in vivo. Moreover, TGF-β1-Smad2/3 signaling pathway involved in the EMT of PMC was demonstrated. Taken together, our results indicate that bleomycin induces characteristic changes of EMT in PMC and the latter contributes to subpleural fibrosis. - Highlights: • Bleomycin induces collagen-I synthesis in pleural mesothelial cells (PMCs). • Bleomycin induces increases in vimentin and α-SMA protein in PMCs. • Bleomycin induces decreases in cytokeratin-8 and E-cadherin protein in PMCs • TGF-β1-Smad2/3 signaling pathway is involved in the PMC EMT induced by bleomycin

  12. Bleomycin induced epithelial–mesenchymal transition (EMT) in pleural mesothelial cells

    Energy Technology Data Exchange (ETDEWEB)

    Chen, Li-Jun [Department of Respiratory and Critical Care Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei (China); Ye, Hong [Department of Pathophysiology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei (China); Key Laboratory of Pulmonary Diseases, Ministry of Health of China, Wuhan, Hubei (China); Zhang, Qian; Li, Feng-Zhi; Song, Lin-Jie; Yang, Jie; Mu, Qing [Department of Respiratory and Critical Care Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei (China); Rao, Shan-Shan [Department of Pathophysiology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei (China); Cai, Peng-Cheng [Department of Clinical Laboratory, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei (China); Xiang, Fei; Zhang, Jian-Chu [Department of Respiratory and Critical Care Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei (China); Key Laboratory of Pulmonary Diseases, Ministry of Health of China, Wuhan, Hubei (China); Su, Yunchao [Department of Pharmacology and Toxicology, Medical College of Georgia, Georgia Regents University, Augusta, GA (United States); Xin, Jian-Bao, E-mail: 814643835@qq.com [Department of Respiratory and Critical Care Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei (China); Key Laboratory of Pulmonary Diseases, Ministry of Health of China, Wuhan, Hubei (China); Ma, Wan-Li, E-mail: whmawl@aliyun.com [Department of Respiratory and Critical Care Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei (China); Key Laboratory of Pulmonary Diseases, Ministry of Health of China, Wuhan, Hubei (China)

    2015-03-01

    Idiopathic pulmonary fibrosis (IPF) is a chronic progressive lung disease characterized by the development of subpleural foci of myofibroblasts that contribute to the exuberant fibrosis. Recent studies revealed that pleural mesothelial cells (PMCs) undergo epithelial–mesenchymal transition (EMT) and play a pivotal role in IPF. In animal model, bleomycin induces pulmonary fibrosis exhibiting subpleural fibrosis similar to what is seen in human IPF. It is not known yet whether bleomycin induces EMT in PMCs. In the present study, PMCs were cultured and treated with bleomycin. The protein levels of collagen-I, mesenchymal phenotypic markers (vimentin and α-smooth muscle actin), and epithelial phenotypic markers (cytokeratin-8 and E-cadherin) were measured by Western blot. PMC migration was evaluated using wound-healing assay of culture PMCs in vitro, and in vivo by monitoring the localization of PMC marker, calretinin, in the lung sections of bleomycin-induced lung fibrosis. The results showed that bleomycin induced increases in collagen-I synthesis in PMC. Bleomycin induced significant increases in mesenchymal phenotypic markers and decreases in epithelial phenotypic markers in PMC, and promoted PMC migration in vitro and in vivo. Moreover, TGF-β1-Smad2/3 signaling pathway involved in the EMT of PMC was demonstrated. Taken together, our results indicate that bleomycin induces characteristic changes of EMT in PMC and the latter contributes to subpleural fibrosis. - Highlights: • Bleomycin induces collagen-I synthesis in pleural mesothelial cells (PMCs). • Bleomycin induces increases in vimentin and α-SMA protein in PMCs. • Bleomycin induces decreases in cytokeratin-8 and E-cadherin protein in PMCs • TGF-β1-Smad2/3 signaling pathway is involved in the PMC EMT induced by bleomycin.

  13. Bleomycin-Induced Flagellate Erythema in a Patient Diagnosed with Ovarian Yolk Sac Tumor

    Directory of Open Access Journals (Sweden)

    Stergios Boussios

    2015-01-01

    Full Text Available Flagellate linear hyperpigmentation can rarely be caused by the chemotherapy agent, bleomycin. Herein, we describe the case of a 20-year-old woman treated with bleomycin for an ovarian yolk sac tumor and review the prominent features of this form of dermatitis.

  14. Bleomycin resistance : a new dominant selectable marker for plant cell transformation

    NARCIS (Netherlands)

    Hille, Jacques; Verheggen, Frank; Roelvink, Peter; Franssen, Henk; Kammen, Ab van; Zabel, Pim

    1986-01-01

    Plant cells are sensitive to the antibiotic bleomycin, a DNA damaging glycopeptide. A bleomycin resistance determinant, located on transposon Tn5 and functional in bacteria, has been cloned in a plant expression vector and introduced into Nicotiana plumbaginifolia using Agrobacterium tumefaciens. Th

  15. Bleomycin-Induced Flagellate Erythema in a Patient Diagnosed with Ovarian Yolk Sac Tumor.

    Science.gov (United States)

    Boussios, Stergios; Moschetta, Michele; McLachlan, Jennifer; Banerjee, Susana

    2015-01-01

    Flagellate linear hyperpigmentation can rarely be caused by the chemotherapy agent, bleomycin. Herein, we describe the case of a 20-year-old woman treated with bleomycin for an ovarian yolk sac tumor and review the prominent features of this form of dermatitis. PMID:26798532

  16. Bleomycin-Induced Flagellate Erythema in a Patient Diagnosed with Ovarian Yolk Sac Tumor

    OpenAIRE

    Stergios Boussios; Michele Moschetta; Jennifer McLachlan; Susana Banerjee

    2015-01-01

    Flagellate linear hyperpigmentation can rarely be caused by the chemotherapy agent, bleomycin. Herein, we describe the case of a 20-year-old woman treated with bleomycin for an ovarian yolk sac tumor and review the prominent features of this form of dermatitis.

  17. DNA sequence and structure recognition by Fe(II)[center dot]bleomycin

    Energy Technology Data Exchange (ETDEWEB)

    Kane, S.A.

    1993-01-01

    The bleomycins (BLMs) are a family of clinically-important antitumor antibiotics whose chemotherapeutic effects are believed to be expressed at the level of DNA degradation. Bleomycin-mediated DNA strand scission is sequence-selective, resulting in cleavage predominantly at [sup 5[prime

  18. Intralesional bleomycin for the treatment of periocular capillary hemangiomas

    Directory of Open Access Journals (Sweden)

    Derrick P Smit

    2012-01-01

    Full Text Available Periocular infantile capillary hemangiomas do not always respond well to conventional treatment modalities such as systemic or intralesional corticosteroids, radiotherapy or debulking surgery. The authors describe the use of intralesional bleomycin injections (IBIs to treat potentially amblyogenic lesions in two cases where other modalities have failed. In both cases monthly IBIs successfully cleared the visual axis of the affected eye before the age of 1 year thus preventing permanent sensory deprivation amblyopia. A total of five and nine injections, respectively, were used and no significant side effects were noted. IBI appears to be a useful alternative in the treatment of periocular capillary hemangiomas refractory to more conventional modalities.

  19. Protective effects of a bacterially expressed NIF-KGF fusion protein against bleomycin-induced acute lung injury in mice.

    Science.gov (United States)

    Li, Xinping; Li, Shengli; Zhang, Miaotao; Li, Xiukun; Zhang, Xiaoming; Zhang, Wenlong; Li, Chuanghong

    2010-08-01

    Current evidence suggests that the keratinocyte growth factor (KGF) and the polymorphonuclear leukocyte may play key roles in the development of lung fibrosis. Here we describe the construction, expression, purification, and identification of a novel NIF (neutrophil inhibitory factor)-KGF mutant fusion protein (NKM). The fusion gene was ligated via a flexible octapeptide hinge and expressed as an insoluble protein in Escherichia coli BL21 (DE3). The fusion protein retained the activities of KGF and NIF, as it inhibited both fibroblast proliferation and leukocyte adhesion. Next, the effects of NKM on bleomycin-induced lung fibrosis in mice were examined. The mice were divided into the following four groups: (i) saline group; (ii) bleomycin group (instilled with 5 mg/kg bleomycin intratracheally); (iii) bleomycin plus dexamethasone (Dex) group (Dex was given intraperitoneally (i.p.) at 1 mg/kg/day 2 days prior to bleomycin instillation and daily after bleomycin instillation until the end of the treatment); and (iv) bleomycin plus NKM group (NKM was given i.p. at 2 mg/kg/day using the same protocol as the Dex group). NKM significantly improved the survival rates of mice exposed to bleomycin. The marked morphological changes and increased hydroxyproline levels resulted from the instillation of bleomycin (on Day 17) in the lungs were significantly inhibited by NKM. These results revealed that NKM can attenuate bleomycin-induced lung fibrosis, suggesting that NKM could be used to prevent bleomycin-induced lung damage or other interstitial pulmonary fibrosis.

  20. Radiosensitising effect of electrochemotherapy with bleomycin in LPB sarcoma cells and tumors in mice

    International Nuclear Information System (INIS)

    Bleomycin is poorly permeant but potent cytotoxic and radiosensitizing drug. The aim of the study was to evaluate whether a physical drug delivery system – electroporation can increase radiosensitising effect of bleomycin in vitro and in vivo. LPB sarcoma cells and tumors were treated either with bleomycin, electroporation or ionizing radiation, and combination of these treatments. In vitro, response to different treatments was determined by colony forming assay, while in vivo, treatment effectiveness was determined by local tumor control (TCD50). Time dependence of partial oxygen pressure in LPB tumors after application of electric pulses was measured by electron paramagnetic oxyimetry. Electroporation of cells in vitro increased radiosensitising effect of bleomycin for 1.5 times, in vivo radiation response of tumors was enhanced by 1.9 fold compared to response of tumors that were irradiated only. Neither treatment of tumors with bleomycin nor application of electric pulses only, affected radiation response of tumors. Application of electric pulses to the tumors induced profound but transient reduction of tumor oxygenation. Although tumor oxygenation after electroporation partially restored at the time of irradiation, it was still reduced at the level of radiobiologically relevant hypoxia. Our study shows that application of electric pulses to cells and tumors increases radiosensitising effect of bleomycin. Furthermore, our results demonstrate that the radiobiologically relevant hypoxia induced by electroporation of tumors did not counteract the pronounced radiosensitising effect of electrochemotherapy with bleomycin

  1. Radiosensitising effect of electrochemotherapy with bleomycin in LPB sarcoma cells and tumors in mice

    Directory of Open Access Journals (Sweden)

    Sentjurc Marjeta

    2005-09-01

    Full Text Available Abstract Background Bleomycin is poorly permeant but potent cytotoxic and radiosensitizing drug. The aim of the study was to evaluate whether a physical drug delivery system – electroporation can increase radiosensitising effect of bleomycin in vitro and in vivo. Methods LPB sarcoma cells and tumors were treated either with bleomycin, electroporation or ionizing radiation, and combination of these treatments. In vitro, response to different treatments was determined by colony forming assay, while in vivo, treatment effectiveness was determined by local tumor control (TCD50. Time dependence of partial oxygen pressure in LPB tumors after application of electric pulses was measured by electron paramagnetic oxyimetry. Results Electroporation of cells in vitro increased radiosensitising effect of bleomycin for 1.5 times, in vivo radiation response of tumors was enhanced by 1.9 fold compared to response of tumors that were irradiated only. Neither treatment of tumors with bleomycin nor application of electric pulses only, affected radiation response of tumors. Application of electric pulses to the tumors induced profound but transient reduction of tumor oxygenation. Although tumor oxygenation after electroporation partially restored at the time of irradiation, it was still reduced at the level of radiobiologically relevant hypoxia. Conclusion Our study shows that application of electric pulses to cells and tumors increases radiosensitising effect of bleomycin. Furthermore, our results demonstrate that the radiobiologically relevant hypoxia induced by electroporation of tumors did not counteract the pronounced radiosensitising effect of electrochemotherapy with bleomycin.

  2. Increased and prolonged pulmonary fibrosis in surfactant protein C-deficient mice following intratracheal bleomycin.

    Science.gov (United States)

    Lawson, William E; Polosukhin, Vasiliy V; Stathopoulos, Georgios T; Zoia, Ornella; Han, Wei; Lane, Kirk B; Li, Bo; Donnelly, Edwin F; Holburn, George E; Lewis, Kenneth G; Collins, Robert D; Hull, William M; Glasser, Stephan W; Whitsett, Jeffrey A; Blackwell, Timothy S

    2005-11-01

    Recent reports have linked mutations in the surfactant protein C gene (SFTPC) to familial forms of pulmonary fibrosis, but it is uncertain whether deficiency of mature SP-C contributes to disease pathogenesis. In this study, we evaluated bleomycin-induced lung fibrosis in mice with genetic deletion of SFTPC. Compared with wild-type (SFTPC+/+) controls, mice lacking surfactant protein C (SFTPC-/-) had greater lung neutrophil influx at 1 week after intratracheal bleomycin, greater weight loss during the first 2 weeks, and increased mortality. At 3 and 6 weeks after bleomycin, lungs from SFTPC-/- mice had increased fibroblast numbers, augmented collagen accumulation, and greater parenchymal distortion. Furthermore, resolution of fibrosis was delayed. Although remodeling was near complete in SFTPC+/+ mice by 6 weeks, SFTPC-/- mice did not return to baseline until 9 weeks after bleomycin. By terminal dUTP nick-end labeling staining, widespread cell injury was observed in SFTPC-/- and SFTPC+/+ mice 1 week after bleomycin; however, ongoing apoptosis of epithelial and interstitial cells occurred in lungs of SFTPC-/- mice, but not SFTPC+/+ mice, 6 weeks after bleomycin. Thus, SP-C functions to limit lung inflammation, inhibit collagen accumulation, and restore normal lung structure after bleomycin. PMID:16251411

  3. Synthesis of samarium binding bleomycin - a possible NCT radiosensitizer

    International Nuclear Information System (INIS)

    Bleomycin (BLM) is a drug that has attractive features for the development of a new radiopharmaceutical, particularly with regard to neutron capture therapy (NCT) sensitized by Sm-149. It has the ability to chelate many metal ions. In vitro studies have shown that up to 78% of BLM present in a cell is accumulated inside the nucleus or in the nuclear membrane. In addition, this drug has higher affinity for tumor tissues than for normal tissues. Radioactive isotopes carried by this antibiotic would be taken preferentially to one important cellular targets DNA. Besides, BLM displays intrinsic anti-tumor activity - it is a chemotherapic antibiotic clinically used against some cancers. This study aimed to obtain bleomycin molecules bound to samarium (BLM-Sm) for NCT studies in vitro and in vivo. The binding technique employed in this work has great simplicity and low cost. Thin layer chromatography, high performance liquid chromatography, fast protein liquid chromatography and analysis by ICP-AES were applied to verify the binding molecule. ICP-AES results showed the presence of samarium in the sample peaks related to BLM-Sm. However, efficiency and stability of this bond needs to be investigated. (author)

  4. Synthesis of samarium binding bleomycin - a possible NCT radiosensitizer

    Energy Technology Data Exchange (ETDEWEB)

    Mendes, B.M., E-mail: bmm@cdtn.b [Centro de Desenvolvimento da Tecnologia Nuclear (CDTN/CNEN-MG), Belo Horizonte, MG (Brazil); Mendes, T.M.; Campos, T.P.R., E-mail: campos@nuclear.ufmg.b [Universidade Federal de Minas Gerais (UFMG), Belo Horizonte, MG (Brazil)

    2011-07-01

    Bleomycin (BLM) is a drug that has attractive features for the development of a new radiopharmaceutical, particularly with regard to neutron capture therapy (NCT) sensitized by Sm-149. It has the ability to chelate many metal ions. In vitro studies have shown that up to 78% of BLM present in a cell is accumulated inside the nucleus or in the nuclear membrane. In addition, this drug has higher affinity for tumor tissues than for normal tissues. Radioactive isotopes carried by this antibiotic would be taken preferentially to one important cellular targets DNA. Besides, BLM displays intrinsic anti-tumor activity - it is a chemotherapic antibiotic clinically used against some cancers. This study aimed to obtain bleomycin molecules bound to samarium (BLM-Sm) for NCT studies in vitro and in vivo. The binding technique employed in this work has great simplicity and low cost. Thin layer chromatography, high performance liquid chromatography, fast protein liquid chromatography and analysis by ICP-AES were applied to verify the binding molecule. ICP-AES results showed the presence of samarium in the sample peaks related to BLM-Sm. However, efficiency and stability of this bond needs to be investigated. (author)

  5. Pingyangmycin and Bleomycin Share the Same Cytotoxicity Pathway

    Directory of Open Access Journals (Sweden)

    Yanli He

    2016-06-01

    Full Text Available Pingyangmycin is an anticancer drug known as bleomycin A5 (A5, discovered in the Pingyang County of Zhejiang Province of China. Bleomycin (BLM is a mixture of mainly two compounds (A2 and B2, which is on the World Health Organization’s list of essential medicines. Both BLM and A5 are hydrophilic molecules that depend on transporters or endocytosis receptors to get inside of cells. Once inside, the anticancer activities rely on their abilities to produce DNA breaks, thus leading to cell death. Interestingly, the half maximal inhibitory concentration (IC50 of BLMs in different cancer cell lines varies from nM to μM ranges. Different cellular uptake, DNA repair rate, and/or increased drug detoxification might be some of the reasons; however, the molecules and signaling pathways responsible for these processes are largely unknown. In the current study, we purified the A2 and B2 from the BLM and tested the cytotoxicities and the molecular mechanisms of each individual compound or in combination with six different cell lines, including a Chinese hamster ovary (CHO cell line defective in glycosaminoglycan biosynthesis. Our data suggested that glycosaminoglycans might be involved in the cellular uptake of BLMs. Moreover, both BLM and A5 shared similar signaling pathways and are involved in cell cycle and apoptosis in different cancer cell lines.

  6. Complete Resolution of Cystic Hygroma with Single Session of Intralesional Bleomycin

    Directory of Open Access Journals (Sweden)

    Fadi Atwan

    2012-07-01

    Full Text Available Intralesional sclerotherapy as a primary modality of management for cystic hygroma is successfully described in literature. It has many benefits over surgical approach; recurrence being the concern of as much as 20% of patients in which apparent complete excision has been performed. Bleomycin is one of sclerosing agents used as intralesional therapy in cystic hygroma. Complete response usually occurs in multiple sessions of sclerotherapy. Rarely, complete resolution occurs with single session of bleomycin sclerotherapy. We share our experience of managing a case of cystic hygroma of neck that completely resolved with single session of bleomycin sclerotherapy.

  7. The genome-wide DNA sequence specificity of the anti-tumour drug bleomycin in human cells.

    Science.gov (United States)

    Murray, Vincent; Chen, Jon K; Tanaka, Mark M

    2016-07-01

    The cancer chemotherapeutic agent, bleomycin, cleaves DNA at specific sites. For the first time, the genome-wide DNA sequence specificity of bleomycin breakage was determined in human cells. Utilising Illumina next-generation DNA sequencing techniques, over 200 million bleomycin cleavage sites were examined to elucidate the bleomycin genome-wide DNA selectivity. The genome-wide bleomycin cleavage data were analysed by four different methods to determine the cellular DNA sequence specificity of bleomycin strand breakage. For the most highly cleaved DNA sequences, the preferred site of bleomycin breakage was at 5'-GT* dinucleotide sequences (where the asterisk indicates the bleomycin cleavage site), with lesser cleavage at 5'-GC* dinucleotides. This investigation also determined longer bleomycin cleavage sequences, with preferred cleavage at 5'-GT*A and 5'- TGT* trinucleotide sequences, and 5'-TGT*A tetranucleotides. For cellular DNA, the hexanucleotide DNA sequence 5'-RTGT*AY (where R is a purine and Y is a pyrimidine) was the most highly cleaved DNA sequence. It was striking that alternating purine-pyrimidine sequences were highly cleaved by bleomycin. The highest intensity cleavage sites in cellular and purified DNA were very similar although there were some minor differences. Statistical nucleotide frequency analysis indicated a G nucleotide was present at the -3 position (relative to the cleavage site) in cellular DNA but was absent in purified DNA.

  8. Fluorescence properties of several chemotherapy drugs: doxorubicin, paclitaxel and bleomycin.

    Science.gov (United States)

    Motlagh, Najme Sadat Hosseini; Parvin, Parviz; Ghasemi, Fatemah; Atyabi, Fatemeh

    2016-06-01

    Several chemo-drugs act as the biocompatible fluorophores. Here, the laser induced fluorescence (LIF) properties of doxorubicin, paclitaxel and bleomycin are investigated. The absorption lines mostly lie over UV range according to the UV-VIS spectra. Therefore, a single XeCl laser provokes the desired transitions of the chemo-drugs of interest at 308 nm. It is shown that LIF spectra are strongly dependent on the fluorophore concentration giving rise to the sensible red shift. This happens when large overlapping area appears between absorption and emission spectra accordingly. The red shift is taken into account as a characteristic parameter of a certain chemo-drug. The fluorescence extinction (α) and self-quenching (k) coefficients are determined based on the best fitting of the adopted Lambert-Beer equation over experimental data. The quantum yield of each chemo-drug is also measured using the linearity of the absorption and emission rates. PMID:27375954

  9. Comparison of bleomycin-induced pulmonary apoptosis between NMRI mice and C57BL/6 mice

    OpenAIRE

    Safaeian, L.; Jafarian-Dehkordi, A.; Rabbani, M.; Sadeghi, H.M.; Afshar-Moghaddam, N.; Sarahroodi, S.

    2013-01-01

    Apoptosis has a critical role in the pathogenesis of bleomycin induced-pulmonary fibrosis. The severity of fibrosis varies among different strains of mice. Recent studies have indicated that expression of apoptotic regulatory genes may be specific in different cell types in various strains. In this study, bleomycin-induced pulmonary apoptosis in NMRI (Naval Medical Research Institute, USA) albino mice were compared with C57BL/6 black mice. Pulmonary fibrosis induced by single intratracheal ad...

  10. Increased and Prolonged Pulmonary Fibrosis in Surfactant Protein C-Deficient Mice Following Intratracheal Bleomycin

    OpenAIRE

    Lawson, William E.; Polosukhin, Vasiliy V.; Stathopoulos, Georgios T.; Zoia, Ornella; Han, Wei; Kirk B. Lane; Li, Bo; Donnelly, Edwin F.; Holburn, George E.; Lewis, Kenneth G.; Collins, Robert D.; Hull, William M.; Glasser, Stephan W.; Jeffrey A Whitsett; Blackwell, Timothy S.

    2005-01-01

    Recent reports have linked mutations in the surfactant protein C gene (SFTPC) to familial forms of pulmonary fibrosis, but it is uncertain whether deficiency of mature SP-C contributes to disease pathogenesis. In this study, we evaluated bleomycin-induced lung fibrosis in mice with genetic deletion of SFTPC. Compared with wild-type (SFTPC+/+) controls, mice lacking surfactant protein C (SFTPC−/−) had greater lung neutrophil influx at 1 week after intratracheal bleomycin, greater weight loss d...

  11. Extracellular superoxide dismutase attenuates release of pulmonary hyaluronan from the extracellular matrix following bleomycin exposure

    OpenAIRE

    Zelko, Igor N.; Folz, Rodney J

    2010-01-01

    The major pulmonary antioxidant enzyme involved in the protection of the lung interstitium from oxidative stress is extracellular superoxide dismutase (EC-SOD). It has been previously shown that EC-SOD knockout mice are more susceptible to bleomycin induced lung injury, however, the molecular mechanism(s) remains unclear. We report here that bleomycin-induced lung damage, in EC-SOD KO mice, is associated with increased hyaluronan release into alveolar fluid. Analysis of hyaluronan synthase ge...

  12. Preventing cleavage of Mer promotes efferocytosis and suppresses acute lung injury in bleomycin treated mice

    Energy Technology Data Exchange (ETDEWEB)

    Lee, Ye-Ji [Department of Physiology, School of Medicine, Ewha Womans University, Seoul (Korea, Republic of); Tissue Injury Defense Research Center, School of Medicine, Ewha Womans University, Seoul (Korea, Republic of); Lee, Seung-Hae [Department of Physiology, School of Medicine, Ewha Womans University, Seoul (Korea, Republic of); Youn, Young-So; Choi, Ji-Yeon [Department of Physiology, School of Medicine, Ewha Womans University, Seoul (Korea, Republic of); Tissue Injury Defense Research Center, School of Medicine, Ewha Womans University, Seoul (Korea, Republic of); Song, Keung-Sub [Department of Physiology, School of Medicine, Ewha Womans University, Seoul (Korea, Republic of); Cho, Min-Sun [Department of Pathology, School of Medicine, Ewha Womans University, Seoul (Korea, Republic of); Kang, Jihee Lee, E-mail: jihee@ewha.ac.kr [Department of Physiology, School of Medicine, Ewha Womans University, Seoul (Korea, Republic of); Tissue Injury Defense Research Center, School of Medicine, Ewha Womans University, Seoul (Korea, Republic of)

    2012-08-15

    Mer receptor tyrosine kinase (Mer) regulates macrophage activation and promotes apoptotic cell clearance. Mer activation is regulated through proteolytic cleavage of the extracellular domain. To determine if membrane-bound Mer is cleaved during bleomycin-induced lung injury, and, if so, how preventing the cleavage of Mer enhances apoptotic cell uptake and down-regulates pulmonary immune responses. During bleomycin-induced acute lung injury in mice, membrane-bound Mer expression decreased, but production of soluble Mer and activity as well as expression of disintegrin and metalloproteinase 17 (ADAM17) were enhanced . Treatment with the ADAM inhibitor TAPI-0 restored Mer expression and diminished soluble Mer production. Furthermore, TAPI-0 increased Mer activation in alveolar macrophages and lung tissue resulting in enhanced apoptotic cell clearance in vivo and ex vivo by alveolar macrophages. Suppression of bleomycin-induced pro-inflammatory mediators, but enhancement of hepatocyte growth factor induction were seen after TAPI-0 treatment. Additional bleomycin-induced inflammatory responses reduced by TAPI-0 treatment included inflammatory cell recruitment into the lungs, levels of total protein and lactate dehydrogenase activity in bronchoalveolar lavage fluid, as well as caspase-3 and caspase-9 activity and alveolar epithelial cell apoptosis in lung tissue. Importantly, the effects of TAPI-0 on bleomycin-induced inflammation and apoptosis were reversed by coadministration of specific Mer-neutralizing antibodies. These findings suggest that restored membrane-bound Mer expression by TAPI-0 treatment may help resolve lung inflammation and apoptosis after bleomycin treatment. -- Highlights: ►Mer expression is restored by TAPI-0 treatment in bleomycin-stimulated lung. ►Mer signaling is enhanced by TAPI-0 treatment in bleomycin-stimulated lung. ►TAPI-0 enhances efferocytosis and promotes resolution of lung injury.

  13. [Local injection of bleomycin A 5 in children with hemangiomas. Analysis of 210 cases].

    Science.gov (United States)

    Zheng, Q T

    1991-05-01

    210 children with hemangiomas were treated by local injection of Bleomycin A5. Bleomycin A5 was effective in all patients with strawberry and mixed hemangiomas, 91.2% of patients with cavernous hemangiomas, 44.4% of patients with port-wine stain. There was no response in pampiniform hemangioma. The therapeutic mechanism, indications and complications of the new method for treatment of hemangioma are discussed. PMID:1717207

  14. Rat lung fibroblast collagen metabolism in bleomycin-induced pulmonary fibrosis.

    OpenAIRE

    Phan, S. H.; Varani, J.; Smith, D.

    1985-01-01

    Endotracheal bleomycin administration in rats and other animal species causes rapid development of pulmonary fibrosis, characterized by increased lung collagen synthesis and deposition. To clarify the mechanism, lung fibroblasts from bleomycin-treated rats (BRF) were isolated and maintained in tissue culture. They were then compared with those from normal untreated control animals, with respect to several key parameters of collagen metabolism. BRF synthesized collagen at a rate 35-82% above n...

  15. Preventing cleavage of Mer promotes efferocytosis and suppresses acute lung injury in bleomycin treated mice

    International Nuclear Information System (INIS)

    Mer receptor tyrosine kinase (Mer) regulates macrophage activation and promotes apoptotic cell clearance. Mer activation is regulated through proteolytic cleavage of the extracellular domain. To determine if membrane-bound Mer is cleaved during bleomycin-induced lung injury, and, if so, how preventing the cleavage of Mer enhances apoptotic cell uptake and down-regulates pulmonary immune responses. During bleomycin-induced acute lung injury in mice, membrane-bound Mer expression decreased, but production of soluble Mer and activity as well as expression of disintegrin and metalloproteinase 17 (ADAM17) were enhanced . Treatment with the ADAM inhibitor TAPI-0 restored Mer expression and diminished soluble Mer production. Furthermore, TAPI-0 increased Mer activation in alveolar macrophages and lung tissue resulting in enhanced apoptotic cell clearance in vivo and ex vivo by alveolar macrophages. Suppression of bleomycin-induced pro-inflammatory mediators, but enhancement of hepatocyte growth factor induction were seen after TAPI-0 treatment. Additional bleomycin-induced inflammatory responses reduced by TAPI-0 treatment included inflammatory cell recruitment into the lungs, levels of total protein and lactate dehydrogenase activity in bronchoalveolar lavage fluid, as well as caspase-3 and caspase-9 activity and alveolar epithelial cell apoptosis in lung tissue. Importantly, the effects of TAPI-0 on bleomycin-induced inflammation and apoptosis were reversed by coadministration of specific Mer-neutralizing antibodies. These findings suggest that restored membrane-bound Mer expression by TAPI-0 treatment may help resolve lung inflammation and apoptosis after bleomycin treatment. -- Highlights: ►Mer expression is restored by TAPI-0 treatment in bleomycin-stimulated lung. ►Mer signaling is enhanced by TAPI-0 treatment in bleomycin-stimulated lung. ►TAPI-0 enhances efferocytosis and promotes resolution of lung injury.

  16. The Protective Effect of Naringin against Bleomycin-Induced Pulmonary Fibrosis in Wistar Rats.

    Science.gov (United States)

    Turgut, Nergiz H; Kara, Haki; Elagoz, Sahende; Deveci, Koksal; Gungor, Huseyin; Arslanbas, Emre

    2016-01-01

    The aim of the current study was to investigate the protective effect of naringin on bleomycin-induced pulmonary fibrosis in rats. Twenty-four Wistar rats randomly divided into four groups (control, bleomycin alone, bleomycin + naringin 40, and bleomycin + naringin 80) were used. Rats were administered a single dose of bleomycin (5 mg/kg; via the tracheal cannula) alone or followed by either naringin 40 mg/kg (orally) or naringin 80 mg/kg (orally) or water (1 mL, orally) for 14 days. Rats and lung tissue were weighed to determine the lung index. TNF-α and IL-1β levels, hydroxyproline content, and malondialdehyde (MDA) levels were assayed. Glutathione peroxidase (GSH-Px) and superoxide dismutase (SOD) activities were determined. Tissue sections were stained with hematoxylin-eosin, Masson's trichrome, and 0.1% toluidine blue. TNF-α, IL-1β, and MDA levels and hydroxyproline content significantly increased (p Naringin at a dose of 80 mg/kg body weight significantly decreased TNF-α and IL-1β activity, hydroxyproline content, and MDA level (p naringin has the potential of reducing the toxic effects of bleomycin and may provide supportive therapy for conventional treatment methods for idiopathic pulmonary fibrosis. PMID:26977316

  17. Bleomycin induced flagellate erythema in a patient with thalamic mixed germ cell tumour: Report of a rare adverse effect

    OpenAIRE

    Ahitagni Biswas; Pramod Kumar Julka

    2016-01-01

    Bleomycin induced flagellate dermatitis is an uncommon and unique adverse effect. With the declining use of bleomycin, this complication is becoming increasingly infrequent in day-to-day clinical practice. We herein describe a case of a 13 year old male patient with left thalamic mixed germ cell tumour treated by multimodality approach, who developed flagellate erythema after two cycles of combination chemotherapy with bleomycin, etoposide and cisplatin (BEP). This brief report highlights the...

  18. Localization of bleomycin in a single living cell using three-photon excitation microscopy

    Science.gov (United States)

    Abraham, Anil T.; Brautigan, David L.; Hecht, Sidney M.; Periasamy, Ammasi

    2001-04-01

    Bleomycin has been used in the clinic as a chemotherapeutic agent for the treatment of several neoplasms, including non-Hodgkins lymphomas, squamous cell carcinomas, and testicular tumors. The effectiveness of bleomycin is believed to be derived from its ability to bind and oxidatively cleave DNA in the presence of a iron cofactor in vivo. A substantial amount of data on BLM has been collected, there is little information concerning the effects of bleomycin in living cells. In order to obtain data pertinent to the effects of BLM in intact cells, we have exploited the intrinsic fluorescence property of bleomycin to monitor the uptake of the drug in mammalian cells. We employed two light microscopy techniques, a wide-field and three-photon excitation (760 nm) fluorescence microscopy. Treatment of HeLa cells with bleomycin resulted in rapid to localization within the cells. In addition data collected from the wide field experiments, three-photon excitation of BLM which considerably reduced the phototoxic effect compared with UV light excitation in the wide-field microscopy indicated co-localization of the drug to regions of the cytoplasm occupied by the endoplasmic reticulum probe, DiOC5. The data clearly indicates that the cellular uptake of bleomycin after one minute includes the nucleus as well as in cytoplasm. Contrary to previous studies, which indicate chromosomal DNA as the target of bleomycin, the current findings suggest that the drug is distributed to many areas within the cell, including the endoplasmic reticulum, an organelle that is known to contain ribonucleic acids.

  19. The Protective Effect of Naringin against Bleomycin-Induced Pulmonary Fibrosis in Wistar Rats

    Directory of Open Access Journals (Sweden)

    Nergiz H. Turgut

    2016-01-01

    Full Text Available The aim of the current study was to investigate the protective effect of naringin on bleomycin-induced pulmonary fibrosis in rats. Twenty-four Wistar rats randomly divided into four groups (control, bleomycin alone, bleomycin + naringin 40, and bleomycin + naringin 80 were used. Rats were administered a single dose of bleomycin (5 mg/kg; via the tracheal cannula alone or followed by either naringin 40 mg/kg (orally or naringin 80 mg/kg (orally or water (1 mL, orally for 14 days. Rats and lung tissue were weighed to determine the lung index. TNF-α and IL-1β levels, hydroxyproline content, and malondialdehyde (MDA levels were assayed. Glutathione peroxidase (GSH-Px and superoxide dismutase (SOD activities were determined. Tissue sections were stained with hematoxylin-eosin, Masson’s trichrome, and 0.1% toluidine blue. TNF-α, IL-1β, and MDA levels and hydroxyproline content significantly increased (p<0.01 and GPx and SOD activities significantly decreased in bleomycin group (p<0.01. Naringin at a dose of 80 mg/kg body weight significantly decreased TNF-α and IL-1β activity, hydroxyproline content, and MDA level (p<0.01 and increased GPx and SOD activities (p<0.05. Histological evidence supported the results. These results show that naringin has the potential of reducing the toxic effects of bleomycin and may provide supportive therapy for conventional treatment methods for idiopathic pulmonary fibrosis.

  20. Randomized phase III study comparing paclitaxel-bleomycin, etoposide, and cisplatin (BEP) to standard BEP in intermediate-prognosis germ-cell cancer

    DEFF Research Database (Denmark)

    de Wit, Ronald; Skoneczna, Iwona; Daugaard, Gedske;

    2012-01-01

    To compare the efficacy of four cycles of paclitaxel-bleomycin, etoposide, and cisplatin (T-BEP) to four cycles of bleomycin, etoposide, and cisplatin (BEP) in previously untreated patients with intermediate-prognosis germ-cell cancer (GCC).......To compare the efficacy of four cycles of paclitaxel-bleomycin, etoposide, and cisplatin (T-BEP) to four cycles of bleomycin, etoposide, and cisplatin (BEP) in previously untreated patients with intermediate-prognosis germ-cell cancer (GCC)....

  1. Static and dynamic mechanics of the murine lung after intratracheal bleomycin

    Directory of Open Access Journals (Sweden)

    Papiris Spyridon

    2011-05-01

    Full Text Available Abstract Background Despite its widespread use in pulmonary fibrosis research, the bleomycin mouse model has not been thoroughly validated from a pulmonary functional standpoint using new technologies. Purpose of this study was to systematically assess the functional alterations induced in murine lungs by fibrogenic agent bleomycin and to compare the forced oscillation technique with quasi-static pressure-volume curves in mice following bleomycin exposure. Methods Single intratracheal injections of saline (50 μL or bleomycin (2 mg/Kg in 50 μL saline were administered to C57BL/6 (n = 40 and Balb/c (n = 32 mice. Injury/fibrosis score, tissue volume density (TVD, collagen content, airway resistance (RN, tissue damping (G and elastance coefficient (H, hysteresivity (η, and area of pressure-volume curve (PV-A were determined after 7 and 21 days (inflammation and fibrosis stage, respectively. Statistical hypothesis testing was performed using one-way ANOVA with LSD post hoc tests. Results Both C57BL/6 and Balb/c mice developed weight loss and lung inflammation after bleomycin. However, only C57BL/6 mice displayed cachexia and fibrosis, evidenced by increased fibrosis score, TVD, and collagen. At day 7, PV-A increased significantly and G and H non-significantly in bleomycin-exposed C57BL/6 mice compared to saline controls and further increase in all parameters was documented at day 21. G and H, but not PV-A, correlated well with the presence of fibrosis based on histology, TVD and collagen. In Balb/c mice, no change in collagen content, histology score, TVD, H and G was noted following bleomycin exposure, yet PV-A increased significantly compared to saline controls. Conclusions Lung dysfunction in the bleomycin model is more pronounced during the fibrosis stage rather than the inflammation stage. Forced oscillation mechanics are accurate indicators of experimental bleomycin-induced lung fibrosis. Quasi-static PV-curves may be more sensitive than

  2. Rapamycin Regulates Bleomycin-Induced Lung Damage in SP-C-Deficient Mice

    Directory of Open Access Journals (Sweden)

    Satish K. Madala

    2011-01-01

    Full Text Available Injury to the distal respiratory epithelium has been implicated as an underlying cause of idiopathic lung diseases. Mutations that result in SP-C deficiencies are linked to a small subset of spontaneous and familial cases of interstitial lung disease (ILD and interstitial pulmonary fibrosis (IPF. Gene-targeted mice that lack SP-C (−/− develop an irregular ILD-like disease with age and are a model of the human SP-C related disease. In the current study, we investigated whether rapamycin could ameliorate bleomycin-induced fibrosis in the lungs of −/− mice. +/+ and −/− mice were exposed to bleomycin with either preventative administration of rapamycin or therapeutic administration beginning eight days after the bleomycin injury. Rapamycin-treatment increased weight loss and decreased survival of bleomycin-treated +/+ and −/− mice. Rapamycin did not reduce the fibrotic disease in the prophylactic or rescue experiments of either genotype of mice. Further, rapamycin treatment augmented airway resistance and reduced lung compliance of bleomycin-treated −/− mice. Rapamycin treatment was associated with an increased expression of profibrotic Th2 cytokines and reduced expression of INF-γ. These findings indicate that novel therapeutics will be required to treat individuals with SP-C deficient ILD/IPF.

  3. Rapamycin Regulates Bleomycin-Induced Lung Damage in SP-C-Deficient Mice.

    Science.gov (United States)

    Madala, Satish K; Maxfield, Melissa D; Davidson, Cynthia R; Schmidt, Stephanie M; Garry, Daniel; Ikegami, Machiko; Hardie, William D; Glasser, Stephan W

    2011-01-01

    Injury to the distal respiratory epithelium has been implicated as an underlying cause of idiopathic lung diseases. Mutations that result in SP-C deficiencies are linked to a small subset of spontaneous and familial cases of interstitial lung disease (ILD) and interstitial pulmonary fibrosis (IPF). Gene-targeted mice that lack SP-C (Sftpc(-/-)) develop an irregular ILD-like disease with age and are a model of the human SP-C related disease. In the current study, we investigated whether rapamycin could ameliorate bleomycin-induced fibrosis in the lungs of Sftpc(-/-) mice. Sftpc(+/+) and -/- mice were exposed to bleomycin with either preventative administration of rapamycin or therapeutic administration beginning eight days after the bleomycin injury. Rapamycin-treatment increased weight loss and decreased survival of bleomycin-treated Sftpc(+/+) and Sftpc(-/-) mice. Rapamycin did not reduce the fibrotic disease in the prophylactic or rescue experiments of either genotype of mice. Further, rapamycin treatment augmented airway resistance and reduced lung compliance of bleomycin-treated Sftpc(-/-) mice. Rapamycin treatment was associated with an increased expression of profibrotic Th2 cytokines and reduced expression of INF-γ. These findings indicate that novel therapeutics will be required to treat individuals with SP-C deficient ILD/IPF. PMID:21660239

  4. A Highly Sensitive Spectrophotometric Assay of Bleomycins Based on the Fading Reaction of Some Halofluorescein Dyes

    Institute of Scientific and Technical Information of China (English)

    LIU,Jiang-Tao; LIU,Zhong-Fang; HU,Xiao-Li; Kong,Ling; LIU,Shao-Pu

    2007-01-01

    In weak acidic medium, anticancer antibiotics bleomycin A5 (BLMA5) and bleomycin A2 (BLMA2) can react with halofluorescein dyes such as erythrosin (Ery), eosin Y (EY), eosin B (EB) and rose bengal (RB) by virtue of electrostatic attraction and hydrophobic force to form the ion-association complexes, which can result in the fading reactions of four halofluorescein dyes. The maximum fading wavelengths of these four dyes were located at 527 nm for Ery, 515 nm for EY, 517 nm for EB and 546 nm for RB, respectively. The decrements of absorbance (△A) were directly proportional to the concentrations of bleomycin in a certain range. A new method for the determination of bleomycins anticancer drugs based on fading reactions of halofluorescein dyes has been developed. The method was not only highly sensitive but also simple and rapid. The molar absorptivities (ε) ranged from 1.5 × 105 to 7.5 ×105 L·mol-1·cm-1. It was applied to determination of the bleomycins in human serum, urine and rabbit serum samples. In this work, the spectral properties and the optimum reaction conditions were investigated. The structure of ion-association complexes and the reaction mechanism were discussed.

  5. Glycyrrhizic acid alleviates bleomycin-induced pulmonary fibrosis in rats

    Directory of Open Access Journals (Sweden)

    Lili eGao

    2015-10-01

    Full Text Available Idiopathic pulmonary fibrosis is a progressive and lethal form of interstitial lung disease that lacks effective therapies at present. Glycyrrhizic acid (GA, a natural compound extracted from a traditional Chinese herbal medicine Glycyrrhiza glabra, was recently reported to benefit lung injury and liver fibrosis in animal models, yet whether GA has a therapeutic effect on pulmonary fibrosis is unknown. In this study, we investigated the potential therapeutic effect of GA on pulmonary fibrosis in a rat model with bleomycin (BLM-induced pulmonary fibrosis. The results indicated that GA treatment remarkably ameliorated BLM-induced pulmonary fibrosis and attenuated BLM-induced inflammation, oxidative stress, epithelial-mesenchymal transition and activation of tansforming growth factor-beta signaling pathway in the lungs. Further, we demonstrated that GA treatment inhibited proliferation of 3T6 fibroblast cells, induced cell cycle arrest and promoted apoptosis in vitro, implying that GA-mediated suppression of fibroproliferation may contribute to the anti-fibrotic effect against BLM-induced pulmonary fibrosis. In summary, our study suggests a therapeutic potential of GA in the treatment of pulmonary fibrosis.

  6. Interleukin-22 Inhibits Bleomycin-Induced Pulmonary Fibrosis

    Directory of Open Access Journals (Sweden)

    Minrui Liang

    2013-01-01

    Full Text Available Pulmonary fibrosis is a progressive and fatal fibrotic disease of the lungs with unclear etiology. Recent insight has suggested that early injury/inflammation of alveolar epithelial cells could lead to dysregulation of tissue repair driven by multiple cytokines. Although dysregulation of interleukin- (IL- 22 is involved in various pulmonary pathophysiological processes, the role of IL-22 in fibrotic lung diseases is still unclear and needs to be further addressed. Here we investigated the effect of IL-22 on alveolar epithelial cells in the bleomycin- (BLM- induced pulmonary fibrosis. BLM-treated mice showed significantly decreased level of IL-22 in the lung. IL-22 produced γδT cells were also decreased significantly both in the tissues of lungs and spleens. Administration of recombinant human IL-22 to alveolar epithelial cell line A549 cells ameliorated epithelial to mesenchymal transition (EMT and partially reversed the impaired cell viability induced by BLM. Furthermore, blockage of IL-22 deteriorated pulmonary fibrosis, with elevated EMT marker (α-smooth muscle actin (α-SMA and overactivated Smad2. Our results indicate that IL-22 may play a protective role in the development of BLM-induced pulmonary fibrosis and may suggest IL-22 as a novel immunotherapy tool in treating pulmonary fibrosis.

  7. Variation in bleomycin hydrolase gene is associated with reduced survival after chemotherapy for testicular germ cell cancer

    NARCIS (Netherlands)

    de Haas, Esther C; Zwart, Nynke; Meijer, Coby; Nuver, Janine; Suurmeijer, Albert J H; Hoekstra, Harald J; van der Steege, Gerrit; Sleijfer, Dirk Th; Gietema, Jourik A; Boezen, Hendrika

    2008-01-01

    PURPOSE: Response to chemotherapy may be determined by gene polymorphisms involved in metabolism of cytotoxic drugs. A plausible candidate is the gene for bleomycin hydrolase (BLMH), an enzyme that inactivates bleomycin, an essential component of chemotherapy regimens for disseminated testicular ger

  8. Clinical Evaluation of 57Co-labelled Bleomycin for Tumor Localization

    International Nuclear Information System (INIS)

    Investigation with 57Co-Bleomycin in patients with the various cancers and in tumor bearing animals are described. In the patients, 57Co-Bleomycin appears to be one of the useful tumor- seeking radiopharmaceuticals, and worth applicable to clinical uses. Labelled yield of 57Co-Bleo was about 97% by thin layer chromatography. The pyrogen free tests were performed to meet U.S.P. critical ranges. In clinical studies with 57Co-Bleo, 4 cases out of 5 patients with lung cancer, 2 cases among 3 thyroid cancer patients, and all 3 hepatoma patients showed positive tumor scans. The patients with stomach cancer, and the esophageal cancer showed false negative scintigraphy. A case with pulmonary tuberculosis showed a positive scan while liver abscess showed a negative picture. The merits of 57Co-Bleomycin scintigraphy seems to be its relatively high affinity to tumors and low radiation hazard in spite of long physical half life.

  9. Aerobic Exercise Attenuated Bleomycin-Induced Lung Fibrosis in Th2-Dominant Mice

    Science.gov (United States)

    Oliveira-Junior, Manoel Carneiro; Assumpção-Neto, Erasmo; Brandão-Rangel, Maysa Alves Rodrigues; Damaceno-Rodrigues, Nilsa Regina; Garcia Caldini, Elia; Velosa, Ana Paula Pereira; Teodoro, Walcy Rosolia; Ligeiro de Oliveira, Ana Paula; Dolhnikoff, Marisa; Eickelberg, Oliver; Vieira, Rodolfo Paula

    2016-01-01

    Introduction The aim of this study was to investigate the effect of aerobic exercise (AE) in reducing bleomycin-induced fibrosis in mice of a Th2-dominant immune background (BALB/c). Methods BALB/c mice were distributed into: sedentary, control (CON), Exercise-only (EX), sedentary, bleomycin-treated (BLEO) and bleomycin-treated+exercised (BLEO+EX); (n = 8/group). Following treadmill adaptation, 15 days following a single, oro-tracheal administration of bleomycin (1.5U/kg), AE was performed 5 days/week, 60min/day for 4 weeks at moderate intensity (60% of maximum velocity reached during a physical test) and assessed for pulmonary inflammation and remodeling, and cytokine levels in bronchoalveolar lavage (BAL). Results At 45 days post injury, compared to BLEO, BLEO+EX demonstrated reduced collagen deposition in the airways (p<0.001) and also in the lung parenchyma (p<0.001). In BAL, a decreased number of total leukocytes (p<0.01), eosinophils (p<0.001), lymphocytes (p<0.01), macrophages (p<0.01), and neutrophils (p<0.01), as well as reduced pro-inflammatory cytokines (CXCL-1; p<0.01), (IL-1β; p<0.001), (IL-5; p<0.01), (IL-6; p<0.001), (IL-13; p<0.01) and pro-fibrotic growth factor IGF-1 (p<0.001) were observed. Anti-inflammatory cytokine IL-10 was increased (p<0.001). Conclusion AE attenuated bleomycin-induced collagen deposition, inflammation and cytokines accumulation in the lungs of mice with a predominately Th2-background suggesting that therapeutic AE (15–44 days post injury) attenuates the pro-inflammatory, Th2 immune response and fibrosis in the bleomycin model. PMID:27677175

  10. Protective Role of Andrographolide in Bleomycin-Induced Pulmonary Fibrosis in Mice

    Directory of Open Access Journals (Sweden)

    Tao Zhu

    2013-12-01

    Full Text Available Idiopathic pulmonary fibrosis (IPF is a chronic devastating disease with poor prognosis. Multiple pathological processes, including inflammation, epithelial mesenchymal transition (EMT, apoptosis, and oxidative stress, are involved in the pathogenesis of IPF. Recent findings suggested that nuclear factor-κB (NF-κB is constitutively activated in IPF and acts as a central regulator in the pathogenesis of IPF. The aim of our study was to reveal the value of andrographolide on bleomycin-induced inflammation and fibrosis in mice. The indicated dosages of andrographolide were administered in mice with bleomycin-induced pulmonary fibrosis. On day 21, cell counts of total cells, macrophages, neutrophils and lymphocytes, alone with TNF-α in bronchoalveolar lavage fluid (BALF were measured. HE staining and Masson’s trichrome (MT staining were used to observe the histological alterations of lungs. The Ashcroft score and hydroxyproline content of lungs were also measured. TGF-β1 and α-SMA mRNA and protein were analyzed. Activation of NF-κB was determined by western blotting and electrophoretic mobility shift assay (EMSA. On day 21 after bleomycin stimulation, andrographolide dose-dependently inhibited the inflammatory cells and TNF-α in BALF. Meanwhile, our data demonstrated that the Ashcroft score and hydroxyproline content of the bleomycin-stimulated lung were reduced by andrographolide administration. Furthermore, andrographloide suppressed TGF-β1 and α-SMA mRNA and protein expression in bleomycin-induced pulmonary fibrosis. Meanwhile, andrographolide significantly dose-dependently inhibited the ratio of phospho-NF-κB p65/total NF-κB p65 and NF-κB p65 DNA binding activities. Our findings indicate that andrographolide compromised bleomycin-induced pulmonary inflammation and fibrosis possibly through inactivation of NF-κB. Andrographolide holds promise as a novel drug to treat the devastating disease of pulmonary fibrosis.

  11. Hypoxia-Induced Epithelial-Mesenchymal Transition Is Involved in Bleomycin-Induced Lung Fibrosis

    Directory of Open Access Journals (Sweden)

    Liang Guo

    2015-01-01

    Full Text Available Pulmonary fibrosis is a severe disease that contributes to the morbidity and mortality of a number of lung diseases. However, the molecular and cellular mechanisms leading to lung fibrosis are poorly understood. This study investigated the roles of epithelial-mesenchymal transition (EMT and the associated molecular mechanisms in bleomycin-induced lung fibrosis. The bleomycin-induced fibrosis animal model was established by intratracheal injection of a single dose of bleomycin. Protein expression was measured by Western blot, immunohistochemistry, and immunofluorescence. Typical lesions of lung fibrosis were observed 1 week after bleomycin injection. A progressive increase in MMP-2, S100A4, α-SMA, HIF-1α, ZEB1, CD44, phospho-p44/42 (p-p44/42, and phospho-p38 MAPK (p-p38 protein levels as well as activation of EMT was observed in the lung tissues of bleomycin mice. Hypoxia increased HIF-1α and ZEB1 expression and activated EMT in H358 cells. Also, continuous incubation of cells under mild hypoxic conditions increased CD44, p-p44/42, and p-p38 protein levels in H358 cells, which correlated with the increase in S100A4 expression. In conclusion, bleomycin induces progressive lung fibrosis, which may be associated with activation of EMT. The fibrosis-induced hypoxia may further activate EMT in distal alveoli through a hypoxia-HIF-1α-ZEB1 pathway and promote the differentiation of lung epithelial cells into fibroblasts through phosphorylation of p38 MAPK and Erk1/2 proteins.

  12. Problems in the differentiation of lung infiltrates following bleomycin therapy from metastases

    Energy Technology Data Exchange (ETDEWEB)

    Mayr, B.; Bauer, W.M.; Clemm, C.; Hartenstein, R.

    1984-10-01

    Sixty patients with malignant testicular tumours were treated with bleomycin according to the Einhorn regime. Following treatment, pulmonary infiltrates were seen on the chest X-ray of three patients and the CT of six patients. Altogether 24 infiltrates resembling metastases were seen in five patients. Five round foci were combined with infiltrates in other parts of the lung. Regression of the infiltrates after stopping bleomycin, negative tumour markers, the timing of the development of the infiltrates and the regression of the infiltrates in three patients without treatment make it extremely unlikely that the appearances were due to metastases.

  13. Problems in the differentiation of lung infiltrates following bleomycin therapy from metastases

    International Nuclear Information System (INIS)

    Sixty patients with malignant testicular tumours were treated with bleomycin according to the Einhorn regime. Following treatment, pulmonary infiltrates were seen on the chest X-ray of three patients and the CT of six patients. Altogether 24 infiltrates resembling metastases were seen in five patients. Five round foci were combined with infiltrates in other parts of the lung. Regression of the infiltrates after stopping bleomycin, negative tumour markers, the timing of the development of the infiltrates and the regression of the infiltrates in three patients without treatment make it extremely unlikely that the appearances were due to metastases. (orig.)

  14. Hairpin DNA Sequences Bound Strongly by Bleomycin Exhibit Enhanced Double-Strand Cleavage

    OpenAIRE

    Roy, Basab; Hecht, Sidney M.

    2014-01-01

    Clinically used bleomycin A5 has been employed in a study of double-strand cleavage of a library of 10 hairpin DNAs originally selected on the basis of their strong binding to bleomycin. Each of the DNAs underwent double-strand cleavage at more than one site, and all of the cleavage sites were within, or in close proximity to, an eight-base-pair region of the duplex that had been randomized to create the original library. A total of 31 double-strand cleavage sites were identified on the 10 DN...

  15. Combined local and systemic bleomycin administration in electrochemotherapy to reduce the number of treatment sessions

    Directory of Open Access Journals (Sweden)

    Maglietti Felipe

    2016-03-01

    Full Text Available Electrochemotherapy (ECT, a medical treatment widely used in human patients for tumor treatment, increases bleomycin toxicity by 1000 fold in the treated area with an objective response rate of around 80%. Despite its high response rate, there are still 20% of cases in which the patients are not responding. This could be ascribed to the fact that bleomycin, when administered systemically, is not reaching the whole tumor mass properly because of the characteristics of tumor vascularization, in which case local administration could cover areas that are unreachable by systemic administration.

  16. A designer bleomycin with significantly improved DNA cleavage activity.

    Science.gov (United States)

    Huang, Sheng-Xiong; Feng, Zhiyang; Wang, Liyan; Galm, Ute; Wendt-Pienkowski, Evelyn; Yang, Dong; Tao, Meifeng; Coughlin, Jane M; Duan, Yanwen; Shen, Ben

    2012-08-15

    The bleomycins (BLMs) are used clinically in combination with a number of other agents for the treatment of several types of tumors, and the BLM, etoposide, and cisplatin treatment regimen cures 90-95% of metastatic testicular cancer patients. BLM-induced pneumonitis is the most feared, dose-limiting side effect of BLM in chemotherapy, which can progress into lung fibrosis and affect up to 46% of the total patient population. There have been continued efforts to develop new BLM analogues in the search for anticancer drugs with better clinical efficacy and lower lung toxicity. We have previously cloned and characterized the biosynthetic gene clusters for BLMs from Streptomyces verticillus ATCC15003, tallysomycins from Streptoalloteichus hindustanus E465-94 ATCC31158, and zorbamycin (ZBM) from Streptomyces flavoviridis SB9001. Comparative analysis of the three biosynthetic machineries provided the molecular basis for the formulation of hypotheses to engineer novel analogues. We now report engineered production of three new analogues, 6'-hydroxy-ZBM, BLM Z, and 6'-deoxy-BLM Z and the evaluation of their DNA cleavage activities as a measurement for their potential anticancer activity. Our findings unveiled: (i) the disaccharide moiety plays an important role in the DNA cleavage activity of BLMs and ZBMs, (ii) the ZBM disaccharide significantly enhances the potency of BLM, and (iii) 6'-deoxy-BLM Z represents the most potent BLM analogue known to date. The fact that 6'-deoxy-BLM Z can be produced in reasonable quantities by microbial fermentation should greatly facilitate follow-up mechanistic and preclinical studies to potentially advance this analogue into a clinical drug.

  17. Oral N-acetylcysteine reduces bleomycin-induced lung damage and mucin Muc5ac expression in rats.

    Science.gov (United States)

    Mata, M; Ruíz, A; Cerdá, M; Martinez-Losa, M; Cortijo, J; Santangelo, F; Serrano-Mollar, A; Llombart-Bosch, A; Morcillo, E J

    2003-12-01

    Oxidative stress is involved in the pathogenesis of pulmonary fibrosis, therefore antioxidants may be of therapeutic value. Clinical work indicates that N-acetylcysteine (NAC) may be beneficial in this disease. The activity of this antioxidant was examined on bleomycin-induced lung damage, mucus secretory cells hyperplasia and mucin Muc5ac gene expression in rats. NAC (3 mmol x kg(-1) x day(-1)) or saline was given orally to Sprague-Dawley rats for 1 week prior to a single intratracheal instillation of bleomycin (2.5 U x kg(-1)) and for 14 days postinstillation. NAC decreased collagen deposition in bleomycin-exposed rats (hydroxyproline content was 4,257+/-323 and 3,200+/-192 microg x lung(-1) in vehicle- and NAC-treated rats, respectively) and lessened the fibrotic area assessed by morphometric analysis. The bleomycin-induced increases in lung tumour necrosis factor-alpha and myeloperoxidase activity were reduced by NAC treatment. The numbers of mucus secretory cells in airway epithelium, and the Muc5ac messenger ribonucleic acid and protein expression, were markedly augmented in rats exposed to bleomycin. These changes were significantly reduced in NAC-treated rats. These results indicate that bleomycin increases the number of airway secretory cells and their mucin production, and that oral N-acetylcysteine improved pulmonary lesions and reduced the mucus hypersecretion in the bleomycin rat model.

  18. Oral N-acetylcysteine reduces bleomycin-induced lung damage and mucin Muc5ac expression in rats.

    Science.gov (United States)

    Mata, M; Ruíz, A; Cerdá, M; Martinez-Losa, M; Cortijo, J; Santangelo, F; Serrano-Mollar, A; Llombart-Bosch, A; Morcillo, E J

    2003-12-01

    Oxidative stress is involved in the pathogenesis of pulmonary fibrosis, therefore antioxidants may be of therapeutic value. Clinical work indicates that N-acetylcysteine (NAC) may be beneficial in this disease. The activity of this antioxidant was examined on bleomycin-induced lung damage, mucus secretory cells hyperplasia and mucin Muc5ac gene expression in rats. NAC (3 mmol x kg(-1) x day(-1)) or saline was given orally to Sprague-Dawley rats for 1 week prior to a single intratracheal instillation of bleomycin (2.5 U x kg(-1)) and for 14 days postinstillation. NAC decreased collagen deposition in bleomycin-exposed rats (hydroxyproline content was 4,257+/-323 and 3,200+/-192 microg x lung(-1) in vehicle- and NAC-treated rats, respectively) and lessened the fibrotic area assessed by morphometric analysis. The bleomycin-induced increases in lung tumour necrosis factor-alpha and myeloperoxidase activity were reduced by NAC treatment. The numbers of mucus secretory cells in airway epithelium, and the Muc5ac messenger ribonucleic acid and protein expression, were markedly augmented in rats exposed to bleomycin. These changes were significantly reduced in NAC-treated rats. These results indicate that bleomycin increases the number of airway secretory cells and their mucin production, and that oral N-acetylcysteine improved pulmonary lesions and reduced the mucus hypersecretion in the bleomycin rat model. PMID:14680076

  19. Angiotensin-converting enzyme: an indicator of bleomycin-induced pulmonary toxicity in humans?

    DEFF Research Database (Denmark)

    Sørensen, Peter G; Rømer, F K; Cortes, Dina

    1984-01-01

    In order to evaluate bleomycin-associated lung damage in humans, lung function parameters and serum levels of the endothelial-bound angiotensin-converting enzyme (ACE) were determined by serial measurements in 11 patients who were treated for testicular cancer. None developed clinical or radiolog...

  20. Essential role for the ATG4B protease and autophagy in bleomycin-induced pulmonary fibrosis.

    Science.gov (United States)

    Cabrera, Sandra; Maciel, Mariana; Herrera, Iliana; Nava, Teresa; Vergara, Fabián; Gaxiola, Miguel; López-Otín, Carlos; Selman, Moisés; Pardo, Annie

    2015-04-01

    Autophagy is a critical cellular homeostatic process that controls the turnover of damaged organelles and proteins. Impaired autophagic activity is involved in a number of diseases, including idiopathic pulmonary fibrosis suggesting that altered autophagy may contribute to fibrogenesis. However, the specific role of autophagy in lung fibrosis is still undefined. In this study, we show for the first time, how autophagy disruption contributes to bleomycin-induced lung fibrosis in vivo using an Atg4b-deficient mouse as a model. Atg4b-deficient mice displayed a significantly higher inflammatory response at 7 d after bleomycin treatment associated with increased neutrophilic infiltration and significant alterations in proinflammatory cytokines. Likewise, we found that Atg4b disruption resulted in augmented apoptosis affecting predominantly alveolar and bronchiolar epithelial cells. At 28 d post-bleomycin instillation Atg4b-deficient mice exhibited more extensive and severe fibrosis with increased collagen accumulation and deregulated extracellular matrix-related gene expression. Together, our findings indicate that the ATG4B protease and autophagy play a crucial role protecting epithelial cells against bleomycin-induced stress and apoptosis, and in the regulation of the inflammatory and fibrotic responses.

  1. Studies on bleomycin-induced repair DNA synthesis in permeable mouse ascites sarcoma cells.

    Directory of Open Access Journals (Sweden)

    Mori,Shigeru

    1989-04-01

    Full Text Available To study the mechanism of DNA excision repair, a DNA repair system employing permeable mouse sarcoma (SR-C3H/He cells was established and characterized. SR-C3H/He cells were permeabilized with a 0.0175% Triton X-100 solution. The permeable cells were treated with 1 mM ATP and 0.11 mM bleomycin, and then washed thoroughly to remove ATP and bleomycin. Repair DNA synthesis occurred in the bleomycin-damaged, permeable SR-C3H/He cells when incubated with ATP and four deoxyribonucleoside triphosphates. The repair nature of the DNA synthesis was confirmed by the BrdUMP density shift technique, and by the reduced sensitivity of the newly synthesized DNA to Escherichia coli exonuclease III. The DNA synthesis was optimally enhanced by addition of 0.08 M NaCl. Studies using selective inhibitors of DNA synthesis showed that aphidicolin-sensitive DNA polymerase (DNA polymerase alpha and/or delta and DNA polymerase beta were involved in the repair process. The present DNA repair system is thought to be useful to study nuclear DNA damage by bleomycin, removal of the damaged ends by an exonuclease, repair DNA synthesis by DNA polymerases and repair patch ligation by DNA ligase(s.

  2. The Effect of Chemical Therapy with Bleomycin Sulfate on the Functional Parameters of the Endocrine Pancreas

    Directory of Open Access Journals (Sweden)

    Carlos Alberto da Silva

    2009-05-01

    Full Text Available Objective The objective of the present study was to evaluate the effect of bleomycin sulfate on parameters related to the functionality of pancreatic tissue, with emphasis on the glucose tolerance test, insulin tolerance test, insulinemia and static secretion of insulin as well as the insulin receptor, and PKA, PKC and GLUT2 concentrations in the pancreatic islets. Design Twenty-four male rats were divided into 2 groups: control and treated with bleomycin (2.5 mg/kg, intratracheal mode. After 7 days, the animals were euthanized and the analyses were carried out. Statistics The normality and the homoscedasticity of the data distribution were tested and ANOVA was applied. The Tukey post hoc test followed ANOVA for the comparison of the static insulin secretion test at different glucose concentrations. Results In the glucose tolerance test, the bleomycin group showed a larger area (17,306±539 mg/dLx60min than that of the control group (9,151±517 mg/dLx60min and in the insulin tolerance test, there was a greater percentage fall in glycemia (8.08±0.56% in the bleomycin than in the control group (3.87±1.14%. The bleomycin group also presented a reduction in insulin secretion and an increase in plasmatic insulin concentration in the static insulin secretion test. With respect to the concentrations of the insulin receptor, GLUT2, PKC and PKA in the pancreatic islets of the bleomycin group, there was an increase in GLUT2 (48.4% and PKC (70.8% and a reduction in PKA (38.5%. Conclusion During treatment with bleomycin, innumerable chemical-metabolic alterations were unleashed in the tissues which were not primary targets of the chemical therapy and which could compromise the homeostasis of the systems taking part in the glycemic adjustment, predisposing the organism to the development of a pre-diabetic pattern whose degree of incidence or reversibility is still unknown to the scientific community.

  3. Identification and quantification of bleomycin in serum and tumor tissue by liquid chromatography coupled to high resolution mass spectrometry.

    Science.gov (United States)

    Kosjek, Tina; Krajnc, Anja; Gornik, Tjasa; Zigon, Dusan; Groselj, Ales; Sersa, Gregor; Cemazar, Maja

    2016-11-01

    Bleomycin is a cytotoxic antibiotic available as a compost of structurally strongly related glycopeptides, which is in vivo found chelated with several metals. Its pharmacotherapy has merely been based on experimental dose - response data, whereas its biodistribution and pharmacokinetics remain fundamentally unknown. This is reasoned by an absence of a specific and sensitive mass spectrometry-based analytical method for its determination in biological tissues. We herein reveal the results of our study on the mass spectrometric behavior of two main bleomycin fractions A2 and B2, including their metal complexes, particularly the predominant copper chelates. In the electrospray ion source bleomycin forms double charged species, where for the metal-free fraction A2 and its copper complex m/z 707.76 and m/z 707.21 are seen, respectively. Hence, the second isotopic ion of the chelate (m/z 707.71) nearly coincides with the first isotopic ion of the metal-free fraction. This phenomenon can only be followed by high-resolution mass spectrometry, and is considered the plausible reason, why the attempts to determine bleomycin with mass spectrometry have been so scarce. The presented paper further describes a sensitive and selective liquid chromatography - mass spectrometry analytical method for determination of bleomycin in serum and tumor tissues. This newly developed method was employed for bleomycin pharmacokinetic studies in serum and tumors of laboratory animals. Additionally, the method was employed for determination of bleomycin pharmacokinetic parameters in elderly patients in order to determine the effective therapeutic window of electrochemotherapy with bleomycin. PMID:27591601

  4. Death by bleomycin pulmonary toxicity in ovarian dysgerminoma with pathologic complete response to chemotherapy. A case report

    OpenAIRE

    Calzas Rodríguez, Julia; Carmen Juarez Morales, María del; Casero, Miguel Angel Racionero

    2016-01-01

    With cisplatin-based chemotherapy, most patients with ovarian dysgerminoma will survive long-term. Bleomycin is an important part of ovarian germ cell tumors (OGCT) treatment, and its dose-limiting toxicity is the development of pulmonary toxicity and it is increased in patients older than 40 years. We report the case of an elderly patient with an unresectable ovarian dysgerminoma who received neoadjuvant chemotherapy and who developed fatal bleomycin pulmonary toxicity (BPT) after surgery. A...

  5. FELD better not thinking of metastases only when liver lesions appear after bleomycin-based treatment for non-seminoma testis from metastases

    International Nuclear Information System (INIS)

    Bleomycin has become an integral part of chemotherapy in patients with germ-cell tumors. One of the most feared side effects is bleomycin-induced pneumonitis. In patients with mild or moderate BIP, radiological signs disappear almost completely within nine months after discontinuation of bleomycin treatment. We present a patient with a history of non seminoma of the testis and bleomycin-induced pneumonitis. During follow-up, regression of the hypothesis of eosinophilic migration to the liver after regression of bleomycin-induced pneumonitis is highly suspicious based on transient eosinophilia and focal eosinophilic liver disease. As follow up may consist of CT scanning in germ-line tumor patients, transient eosinophilic liver lesions reported during regressive bleomycin-induced pneumonitis should not be presumed automatically as metastatic tumor relapse and require further sequential imaging and pathological examination

  6. Preparation of [6lCu]Bleomycin Complexes as a Potential PET radiopharmaceutical and it's biological evaluation in normal and tumor-bearing rodents

    International Nuclear Information System (INIS)

    [61Cu]Bleomycin ([61Cu]Bleomycin) was prepared using [61Cu]CuCl2, produced via natZn(p,x)61Cu (180μA proton irradiation, 22 MeV, 3.2 h), purified by ion chromatography method. [61Cu]Bleomycin was prepared at optimized conditions (room temperature, 45 min, 0.1 mg bleomycin for 2-10 mCi 61CuCl2) with radiochemical purity over 98% determined by HPLC and radio-thin layer chromatography. [61Cu]Bleomycin was administered into the normal and tumor bearing rodents up to 210 minutes followed by biodistribution and co incidence imaging studies. A significant tumor/non tumor accumulation was observed either by animal scarification or imaging method. [61Cu] Bleomycin can be a potential PET radiotracer for tumor imaging.

  7. Regulation of alveolar macrophage transforming growth factor-beta secretion by corticosteroids in bleomycin-induced pulmonary inflammation in the rat.

    OpenAIRE

    Khalil, N.; Whitman, C.; Zuo, L; Danielpour, D; Greenberg, A

    1993-01-01

    In a model of pulmonary inflammation and fibrosis induced by the antineoplastic antibiotic, bleomycin, we previously demonstrated that TGF-beta was markedly elevated within 7 d of bleomycin administration. At the time of maximal TGF-beta production, TGF-beta 1 was localized by immunohistochemistry to be present almost exclusively in alveolar macrophages. In this study, we have demonstrated that alveolar macrophages stimulated by bleomycin-induced injury secrete large quantities of biologicall...

  8. Radiogenic male breast cancer with in vitro sensitivity to ionizing radiation and bleomycin

    International Nuclear Information System (INIS)

    A cytogenetically normal man with gynecomastia and a family history of diverse cancers developed adenocarcinoma of the breast 30 years following thymic irradiation. In vitro experiments measuring colony-forming ability of cultured skin fibroblasts from family members implied that the patient had a small but significant increase in sensitivity to ionizing radiation, and a moderate increase in sensitivity to bleomycin, a radiomimetic drug. Enhanced radiosensitivity of fibroblasts from the patient's mother, and bleomycin sensitivity of fibroblasts from the sister suggested, but did not prove, that genetic susceptibility affected the risk of radiogenic cancer in this individual. In vitro studies of cancer-prone kindreds are a useful research strategy in delineating mechanisms of carcinogenesis

  9. Treatment of brain tumours with electroporation and bleomycin in an in vivo rat model

    OpenAIRE

    Ljungvall, Magnus; Salford, Leif; Persson, Bertil R

    2013-01-01

    The purpose of the study was to examine the possibilities of prolonging the life of rats with brain tumours using electroporation only while conducting impedance scans to evaluate the rate of electroporation. During the experiments, the treated rats in the first batch had tumors grow for 14 days and were then given electroporation with 8 + 8 exponential pulses at 800 v/cm, and 15 micro-F. Three of the animals given electroporation and bleomycin and one of the animals given e...

  10. CXC CHEMOKINE RECEPTOR 3 MODULATES BLEOMYCIN-INDUCED PULMONARY INJURY VIA INVOLVING INFLAMMATORY PROCESS

    Institute of Scientific and Technical Information of China (English)

    Jin-ming Gao; Bao Lu; Zi-jian Guo

    2006-01-01

    Objective To investigate the role of CXC chemokine receptor 3(CXCR3 ) in bleomycin-induced lung injury by using CXCR3 gene deficient mice.Methods Sex-, age-, and weight-matched C57BL/6 CXCR3 gene knockout mice and C57BL/6 wide type mice were challenged by injection of bleomycin via trachea. Lung tissue was stained with HE method. Airway resistance was measured. Bronchoalveolar lavage (BAL) was performed using phosphate buffered saline twice, cell number and differentials were counted by Diff-Qnick staining. Interleukin(IL)-4, IL-5, IL-12p40, and interfon-γ in BAL fluid and lung homogenate were measured by enzyme-linked immunosorbent assay. Unpaired t test was explored to compare the difference between two groups.Results On day 7 after bleomycin injection via trachea, CXCR3 knockout mice were protected from bleomycininduced lung injury as evidenced by fewer accumulation of inflammatory cells in the airway and lung interstitium compared with their wild type littermates ( P<0.05 ). Airway resistance was also lower in CXCR3 knockout mice compared with wild type mice (P<0.01 ). Significantly lower level of inflammatory cytokines release, including the altered production of IL-4 and IL-5 both in BAL fluid and lung tissue was seen in CXCR3 knockout mice than in wild type mice (both P<0.05).Conclusion CXCR3 signaling promotes inflammatory cells recruiting and initiates inflammatory cytokines cascade following endotracheal bleomycin administration, indicating that CXCR3 might be a therapeutic target for pulmonary injury.

  11. Endostatin, an angiogenesis inhibitor, ameliorates bleomycin-induced pulmonary fibrosis in rats

    OpenAIRE

    Wan, Yun-Yan; Tian, Guang-Yan; Guo, Hai-Sheng; Kang, Yan-Meng; Yao, Zhou-Hong; Li, Xi-Li; Liu, Qing-Hua; Lin, Dian-Jie

    2013-01-01

    Background Recent evidence has demonstrated the role of angiogenesis in the pathogenesis of pulmonary fibrosis. Endostatin, a proteolytic fragment of collagen XVIII, is a potent inhibitor of angiogenesis. The aim of our study was to assess whether endostatin has beneficial effects on bleomycin (BLM)-induced pulmonary fibrosis in rats. Methods The rats were randomly divided into five experimental groups: (A) saline only, (B) BLM only, (C) BLM plus early endostatin treatment, (D) BLM plus late ...

  12. Scanning electron microscopic study of capillary change in bleomycin-induced pulmonary fibrosis.

    OpenAIRE

    Kwon, K. Y.; Park, K K; Chang, E. S.

    1991-01-01

    The architectural changes which occur in the capillaries are difficult to illustrate without a three-dimensional tool, such as scanning electron microscopy. Therefore, a scanning electron microscopic study was occasionally undertaken to show the capillary changes of lung fibrosis. Fibrosis was induced in twenty rats by an intratracheal injection of bleomycin. After 30 days the rats were sacrificed, and light microscopy and scanning electron microscopy were performed. The vascular trees of bot...

  13. Radiation nephritis following combined abdominal radiation and chemotherapy (bleomycin-vinblastine)

    Energy Technology Data Exchange (ETDEWEB)

    Churchill, D.N.; Hong, K.; Gault, M.H.

    1978-06-01

    A 29-year-old man presented with acute glomerulonephritis five weeks following completion of combined chemotherapy (bleomycin-vinblastine) and abdominal radiation for testicular carcinoma. There was no evidence for a post-infectious cause or a systemic collagen disorder. The renal biopsy showed changes consistent with radiation nephritis. The combined radiation and chemotherapy may have, by additive or synergistic action, caused the early appearance of radiation nephritis.

  14. Relationship between the time of doubling of pulmonary tumours and the uptake of labelled bleomycin

    International Nuclear Information System (INIS)

    The correlations between the uptake of cobalt 57 labelled bleomycin and, firstly, survival and, secondly, the time necessary for a primary bronchial carcinoma to double in volume were studied. Analysis of 22 cases showed significant correlations to p=0,001. The greater the fixation index, the shorter was the doubling time and the survival. One may consider that this finding permits measurement of the cellular proliferation of carcinomas, the clinical interest of which is obvious

  15. Stimulation of alveolar macrophages by BCG vaccine enhances the process of lung fibrosis induced by bleomycin.

    Science.gov (United States)

    Chyczewska, E; Chyczewski, L; Bańkowski, E; Sułkowski, S; Nikliński, J

    1993-01-01

    It was found that the BCG vaccine injected subcutaneously to the rats enhances the process of lung fibrosis induced by bleomycin. Pretreatment of rats with this vaccine results in accumulation of activated macrophages in lung interstitium and in the bronchoalveolar spaces. It may be suggested that the activated macrophages release various cytokines which may stimulate the proliferation of fibroblasts and biosynthesis of extracellular matrix components.

  16. Protective Role of Andrographolide in Bleomycin-Induced Pulmonary Fibrosis in Mice

    OpenAIRE

    Tao Zhu; , Wei Zhang; Min Xiao; Hongying Chen; Hong Jin

    2013-01-01

    Idiopathic pulmonary fibrosis (IPF) is a chronic devastating disease with poor prognosis. Multiple pathological processes, including inflammation, epithelial mesenchymal transition (EMT), apoptosis, and oxidative stress, are involved in the pathogenesis of IPF. Recent findings suggested that nuclear factor-κB (NF-κB) is constitutively activated in IPF and acts as a central regulator in the pathogenesis of IPF. The aim of our study was to reveal the value of andrographolide on bleomycin-induce...

  17. Andrographolide plays an important role in bleomycin-induced pulmonary fibrosis treatment

    OpenAIRE

    Yin, Jia-ning; Li, Ya-Nan; Gao, Yang; Li, Shi-Bo; Li, Jian-Dong

    2015-01-01

    Pulmonary fibrosis (PF) leads to chronic inflammation and accumulation of macrophages, neutrophils, and lymphocytes in the alveoli. The factors involved in the development of PF include reactive oxygen species and tissue remodelling regulators. The present study demonstrates the effect of andrographolide on bleomycin (BLM)-induced PF in Sprague-Dawley rats. We investigated the total bronchoalveolar lavage fluid protein (BALF) and hydroxyproline (HYP) content along with the level of oxidative ...

  18. Local delivery of biodegradable pirfenidone nanoparticles ameliorates bleomycin-induced pulmonary fibrosis in mice

    Science.gov (United States)

    Trivedi, Ruchit; Redente, Elizabeth F.; Thakur, Ashish; Riches, David W. H.; Kompella, Uday B.

    2012-12-01

    Our purpose was to assess sustained delivery and enhanced efficacy of pirfenidone-loaded nanoparticles after intratracheal instillation. Poly(lactide-co-glycolide) nanoparticles containing pirfenidone (NPs) were prepared and characterized. Biodistribution of NPs and solution was assessed using LC-MS after intratracheal administration in C57Bl/6 mice at 3 and 24 h and 1 week post-administration. Efficacy was tested in C57Bl/6 mice in a bleomycin-induced pulmonary fibrosis model. Mice received 10 μg pirfenidone intratracheally in solution or NPs, once a week, for 3 weeks after bleomycin administration. Drug effects were monitored on day 28. Lung hydroxyproline content, total number of cells, and numbers of macrophages, lymphocytes, and neutrophils in bronchoalveolar lavage (BAL) were assessed. Numbers of macrophages, lymphocytes, and neutrophils were assessed in the lung as well. NPs sustained significantly higher levels of pirfenidone in the lungs and BAL at 24 h and 1 week, compared to the solution group. Pirfenidone solution and NPs significantly reduced hydroxyproline levels by 57 and 81%, respectively, compared to bleomycin alone. At the end of 4 weeks, BAL cellularity was reduced by 25.4% and 56% with solution and NP treatment, respectively. The numbers of lymphocytes and neutrophils in the BAL were also reduced by 58.9 and 82.4% for solution and 74.5% and 89.7% for NPs, respectively. The number of inflammatory macrophages in the lung was reduced by 62.8% and the number of neutrophils was reduced by 59.1% in the NP group and by 37.7% and 44.5%, respectively, in the solution group, compared to bleomycin alone. In conclusion, nanoparticles sustain lung pirfenidone delivery and enhance its anti-fibrotic efficacy.

  19. Local delivery of biodegradable pirfenidone nanoparticles ameliorates bleomycin-induced pulmonary fibrosis in mice

    International Nuclear Information System (INIS)

    Our purpose was to assess sustained delivery and enhanced efficacy of pirfenidone-loaded nanoparticles after intratracheal instillation. Poly(lactide-co-glycolide) nanoparticles containing pirfenidone (NPs) were prepared and characterized. Biodistribution of NPs and solution was assessed using LC-MS after intratracheal administration in C57Bl/6 mice at 3 and 24 h and 1 week post-administration. Efficacy was tested in C57Bl/6 mice in a bleomycin-induced pulmonary fibrosis model. Mice received 10 μg pirfenidone intratracheally in solution or NPs, once a week, for 3 weeks after bleomycin administration. Drug effects were monitored on day 28. Lung hydroxyproline content, total number of cells, and numbers of macrophages, lymphocytes, and neutrophils in bronchoalveolar lavage (BAL) were assessed. Numbers of macrophages, lymphocytes, and neutrophils were assessed in the lung as well. NPs sustained significantly higher levels of pirfenidone in the lungs and BAL at 24 h and 1 week, compared to the solution group. Pirfenidone solution and NPs significantly reduced hydroxyproline levels by 57 and 81%, respectively, compared to bleomycin alone. At the end of 4 weeks, BAL cellularity was reduced by 25.4% and 56% with solution and NP treatment, respectively. The numbers of lymphocytes and neutrophils in the BAL were also reduced by 58.9 and 82.4% for solution and 74.5% and 89.7% for NPs, respectively. The number of inflammatory macrophages in the lung was reduced by 62.8% and the number of neutrophils was reduced by 59.1% in the NP group and by 37.7% and 44.5%, respectively, in the solution group, compared to bleomycin alone. In conclusion, nanoparticles sustain lung pirfenidone delivery and enhance its anti-fibrotic efficacy. (paper)

  20. Atomized paclitaxel liposome inhalation treatment of bleomycin-induced pulmonary fibrosis in rats.

    Science.gov (United States)

    Zhou, Y; Zhu, W P; Cai, X J; Chen, M

    2016-01-01

    We sought to determine the efficacy of atomized paclitaxel liposome inhalation treatment of pulmonary fibrosis in a bleomycin-induced rat model. Forty male Sprague-Dawley rats were randomly divided into four groups: healthy control, pulmonary fibrosis without treatment, paclitaxel liposome inhalation-treated, and intravenous paclitaxel liposome-treated. Fibrosis was induced by bleomycin injection. A total of 20 mg/kg paclitaxel liposome was administered by inhalation every other day for a total of 10 doses. The intravenous group received 5 mg/kg paclitaxel liposome on days 1, 7, 14, and 21. We observed the general condition, weight change, survival index, and pathological changes in the lung tissue of the rats. Quantitative analysis of collagen types I and III and transforming growth factor (TGF)-β1 expression in the lungs was also performed. The paclitaxel liposome inhalation and intravenous delivery methods improved survival index and pulmonary fibrosis Ashcroft score, and decreased the thickness of the alveolar interval. No obvious difference was found between the two groups. Compared with the untreated group, paclitaxel liposome inhalation and intravenous injection significantly reduced the levels of collagen types I and III and TGF-β1 expression equally. In conclusion, atomized paclitaxel liposome inhalation protects against severe pulmonary fibrosis in a bleomycin-induced rat model. This delivery method has less systemic side effects and increased safety over intravenous injection. PMID:27173212

  1. Interspecies cytogenetic comparisons: Studies with x-radiation and bleomycin sulfate

    International Nuclear Information System (INIS)

    A series of in vitro experiments were conducted to determine if there are innate differences in the sensitivity of peripheral blood lymphocytes (PBLs) from different mammalian species to clastogens. Mouse, rat, and human whole blood samples were exposed to either 0, 0.38, 0.75, 1.5, or 3.0 Gy x-radiation or 0, 5, 10, 20, 40, or 80 μg/ml bleomycin for 4 hr. Bromodeoxyuridine-containing cultures were initiated and the PBLs stimulated to divide with phytohemagglutinin. All cultures were harvested following a 3-hr colcemid treatment. Slides were made and differentially stained, and first-division metaphases were scored for chromosome aberrations. In the x-radiation studies human PBLs were significantly more sensitive than mouse PBLs which were in turn more sensitive than rat PBLs as measured by either the total percent aberrant cells or the number of dicentrics. Data from all three species could be fitted to a linear-quadratic model. Results with bleomycin suggest that the mouse and human PBLs are equally sensitive to the clastogenic effects of bleomycin. Both appeared to be more sensitive than the rat PBLs, but the variation between experiments was such that the results among species were not significantly different. These results indicate that there may be inherent differences in sensitivity among PBLs of mammalian species; however, more studies are needed to determine if the differences presented here hold for other agents. 39 refs., 2 figs., 4 tabs

  2. Fasudil, a Rho-Kinase Inhibitor, Attenuates Bleomycin-Induced Pulmonary Fibrosis in Mice

    Directory of Open Access Journals (Sweden)

    Zuojun Xu

    2012-07-01

    Full Text Available The mechanisms underlying the pathogenesis of idiopathic pulmonary fibrosis (IPF involve multiple pathways, such as inflammation, epithelial mesenchymal transition, coagulation, oxidative stress, and developmental processes. The small GTPase, RhoA, and its target protein, Rho-kinase (ROCK, may interact with other signaling pathways known to contribute to pulmonary fibrosis. This study aimed to determine the beneficial effects and mechanisms of fasudil, a selective ROCK inhibitor, on bleomycin-induced pulmonary fibrosis in mice. Our results showed that the Aschcroft score and hydroxyproline content of the bleomycin-treated mouse lung decreased in response to fasudil treatment. The number of infiltrated inflammatory cells in the bronchoalveolar lavage fluid (BALF was attenuated by fasudil. In addition, fasudil reduced the production of transforming growth factor-β1 (TGF-β1, connective tissue growth factor (CTGF, alpha-smooth muscle actin (α-SMA, and plasminogen activator inhibitor-1 (PAI-1 mRNA and protein expression in bleomycin-induced pulmonary fibrosis. These findings suggest that fasudil may be a potential therapeutic candidate for the treatment of pulmonary fibrosis.

  3. Biological studies of samarium-153 bleomycin complex in human breast cancer murine xenografts for therapeutic applications

    International Nuclear Information System (INIS)

    In this work, a potential therapeutic DNA targeting agent, 153Sm-bleomycin complex (153Sm-BLM), was developed and the tumor accumulation studies were performed using single photon emission computed tomography (SPECT) and scarification studies. 153Sm-BLM was prepared at optimized conditions (room temperature, 4-8 h, 0.1 mg bleomycin for 740-3700 MBq 153SmCl3, radiochemical purity over 98%, HPLC, specific activity = 55 TBq/mmol). 153Sm-BLM was administered into human breast cancer murine xenografts and the biodistribution and imaging studies were performed up to 48 h. 153Sm-BLM demonstrated superior tumor accumulation properties in contrast with the other radiolabeled bleomycins with tumor:blood ratios of 41, 72 and 182 at 4, 24 and 48 h, respectively, and tumor:muscle ratios of 23, 33 and > 1490 at 4, 24 and 48 h, respectively, while administered intravenously. The SPECT images also demonstrated the obvious tumor uptake at the chest region of the breast-tumor bearing mice. These initial experiments demonstrate significant accumulation of 153Sm-BLM in tumor tissues. (orig.)

  4. Preventive effects of vitamin D treatment on bleomycin-induced pulmonary fibrosis.

    Science.gov (United States)

    Zhang, Zongmei; Yu, Xiaoting; Fang, Xia; Liang, Aibin; Yu, Zhang; Gu, Pan; Zeng, Yu; He, Jian; Zhu, Hailong; Li, Shuai; Fan, Desheng; Han, Fei; Zhang, Lanjing; Yi, Xianghua

    2015-01-01

    Patients with pulmonary fibrosis often have low vitamin D levels, the effects of which are largely unknown. We here report that early vitamin D supplementation significantly reduced the severity of pulmonary fibrosis and inflammatory cell accumulationin in the bleomycin-induced pulmonary fibrosis mouse model on supplementary days 14, 21 and 28 (P rising hydroxyproline level on days 14, 21 and 28, whereas the vitamin D treatment group showed consistently lower hydroxyproline level but still higher than that of the control group (P < 0.001). Our immunohistochemistry and densitometry analyses showed less staining for α-smooth muscle actin, a myofibroblast marker, in the vitamin D group compared to the bleomycin group (P < 0.001). Thus, vitamin D treatment could prevent bleomycin-induced pulmonary fibrosis by delaying or suppressing ultrastructural changes, as well as attenuating hydroxyproline accumulation and inhibiting myofibroblastic proliferation. These data further our understanding of the roles of vitamin D in pulmonary fibrogenesis and in the treatment of pulmonary fibrosis. PMID:26627341

  5. Periostin Deficiency Causes Severe and Lethal Lung Injury in Mice With Bleomycin Administration.

    Science.gov (United States)

    Kondoh, Hirofumi; Nishiyama, Takashi; Kikuchi, Yoshinao; Fukayama, Masashi; Saito, Mitsuru; Kii, Isao; Kudo, Akira

    2016-07-01

    Pulmonary capillary leakage followed by influx of blood fluid into the air space of lung alveoli is a crucial step in the progression of acute lung injury (ALI). This influx is due to increased permeability of the alveolar-capillary barrier. The extracellular matrix (ECM) between the capillary and the epithelium would be expected to be involved in prevention of the influx; however, the role of the ECM remains to be addressed. Here, we show that the ECM architecture organized by periostin, a matricellular protein, plays a pivotal role in the survival of bleomycin-exposed mice. Periostin was localized in the alveolar walls. Although periostin-null mice displayed no significant difference in lung histology and air-blood permeability, they exhibited early lethality in a model of bleomycin-induced lung injury, compared with their wild-type counterparts. This early lethality may have been due to increased pulmonary leakage of blood fluid into the air space in the bleomycin-exposed periostin-null mice. These results suggest that periostin in the ECM architecture prevents pulmonary leakage of blood fluid, thus increasing the survival rate in mice with ALI. Thus, this study provides an evidence for the protective role of the ECM architecture in the lung alveoli. PMID:27270966

  6. B cell activating factor is central to bleomycin- and IL-17-mediated experimental pulmonary fibrosis.

    Science.gov (United States)

    François, Antoine; Gombault, Aurélie; Villeret, Bérengère; Alsaleh, Ghada; Fanny, Manoussa; Gasse, Paméla; Adam, Sylvain Marchand; Crestani, Bruno; Sibilia, Jean; Schneider, Pascal; Bahram, Seiamak; Quesniaux, Valérie; Ryffel, Bernhard; Wachsmann, Dominique; Gottenberg, Jacques-Eric; Couillin, Isabelle

    2015-01-01

    Idiopathic pulmonary fibrosis (IPF) is a progressive devastating, yet untreatable fibrotic disease of unknown origin. We investigated the contribution of the B-cell activating factor (BAFF), a TNF family member recently implicated in the regulation of pathogenic IL-17-producing cells in autoimmune diseases. The contribution of BAFF was assessed in a murine model of lung fibrosis induced by airway administered bleomycin. We show that murine BAFF levels were strongly increased in the bronchoalveolar space and lungs after bleomycin exposure. We identified Gr1(+) neutrophils as an important source of BAFF upon BLM-induced lung inflammation and fibrosis. Genetic ablation of BAFF or BAFF neutralization by a soluble receptor significantly attenuated pulmonary fibrosis and IL-1β levels. We further demonstrate that bleomycin-induced BAFF expression and lung fibrosis were IL-1β and IL-17A dependent. BAFF was required for rIL-17A-induced lung fibrosis and augmented IL-17A production by CD3(+) T cells from murine fibrotic lungs ex vivo. Finally we report elevated levels of BAFF in bronchoalveolar lavages from IPF patients. Our data therefore support a role for BAFF in the establishment of pulmonary fibrosis and a crosstalk between IL-1β, BAFF and IL-17A.

  7. Bleomycin-induced pulmonary fibrosis after tumor lysis syndrome in a case of advanced yolk sac tumor treated with bleomycin, etoposide and cisplatin (BEP) chemotherapy.

    Science.gov (United States)

    Doi, Mihoko; Okamoto, Yohei; Yamauchi, Masami; Naitou, Hiroyuki; Shinozaki, Katsunori

    2012-10-01

    Ovarian yolk sac tumor (YST) is a highly aggressive malignancy arising in young women. Chemotherapy has dramatically improved the prognosis, and bleomycin, etoposide, and cisplatin (BEP) combination chemotherapy appears to be the most effective combination regimen. A 23-year-old woman was admitted to our hospital with worsening abdominal distention and a lower abdominal mass. She was diagnosed with a stage IIIc pure YST of the right ovary, and right salpingo-oophorectomy was performed; there were numerous disseminated peritoneal tumors within the abdominal cavity. A few days postoperatively, massive ascites developed, and right hydronephrosis occurred. Chemotherapy with BEP was started, and after 24 h of administration, oliguria and tumor lysis syndrome (TLS) developed. Continuous hemodiafiltration was started, and hemodialysis was initiated following full-dose standard cisplatin and etoposide on days 2-5 of the 1st cycle. After the electrolyte abnormalities and the elevation of creatinine became normal, the patient received an additional three cycles of BEP and achieved complete remission. However, she also suffered from severe non-hematological toxicities, including grade 3 left ventricular dysfunction and grade 4 pulmonary fibrosis. In the case of rapidly progressing and high-volume YST treated with BEP chemotherapy, special attention should be paid to bleomycin-induced pulmonary toxicity following TLS. Further study is required to optimize drug exposure to ensure efficacy and reduce the risk of side effects in this population. PMID:22127348

  8. A cell-free system for studying a priming factor involved in repair of bleomycin-damaged DNA.

    Directory of Open Access Journals (Sweden)

    Seki,Shuji

    1989-04-01

    Full Text Available A simple cell-free system for studying a priming factor involved in the repair of bleomycin-damaged DNA was established. The template-primer used for the repair DNA synthesis was prepared by treating the closed circular, superhelical form of pUC19 plasmid DNA with 2.2 microM bleomycin and 20 microM ferrous ions. Single-strand breaks were introduced into pUC19 DNA by the bleomycin treatment, and the DNA was consequently converted largely into the open circular form. A system for repair of this bleomycin-damaged DNA was constructed with a priming factor, DNA polymerase (DNA polymerase beta or Klenow fragment of DNA polymerase I, ATP, T4 DNA ligase and four deoxynucleoside triphosphates. After incubation, the conformation of the DNA was analyzed by agarose gel electrophoresis and electron microscopy. The open circular DNA was largely converted to the closed circular DNA, indicating that the single-strand breaks of DNA were repaired. When the priming factor was omitted, DNA repair did not occur. The present system seemed to be applicable to the study of priming factors involved in the repair of DNA with single-strand breaks caused not only by bleomycin but also by ionizing radiation or active oxygen.

  9. Administration of bleomycin via the oropharyngeal aspiration route leads to sustained lung fibrosis in mice and rats as quantified by UTE-MRI and histology.

    Directory of Open Access Journals (Sweden)

    Christine Egger

    Full Text Available Pulmonary fibrosis can be experimentally induced in small rodents by bleomycin. The antibiotic is usually administered via the intratracheal or intranasal routes. In the present study, we investigated the oropharyngeal aspiration of bleomycin as an alternative route for the induction of lung fibrosis in rats and mice. The development of lung injury was followed in vivo by ultrashort echo time magnetic resonance imaging (UTE-MRI and by post-mortem analyses (histology of collagen, hydroxyproline determination, and qRT-PCR. In C57BL/6 mice, oropharyngeal aspiration of bleomycin led to more prominent lung fibrosis as compared to intranasal administration. Consequently, the oropharyngeal aspiration route allowed a dose reduction of bleomycin and, therewith, a model refinement. Moreover, the distribution of collagen after oropharyngeal aspiration of bleomycin was more homogenous than after intranasal administration: for the oropharyngeal aspiration route, fibrotic areas appeared all over the lung lobes, while for the intranasal route fibrotic lesions appeared mainly around the largest superior airways. Thus, oropharyngeal aspiration of bleomycin induced morphological changes that were more comparable to the human disease than the intranasal administration route did. Oropharyngeal aspiration of bleomycin led to a homogeneous fibrotic injury also in rat lungs. The present data suggest oropharyngeal aspiration of bleomycin as a less invasive means to induce homogeneous and sustained fibrosis in the lungs of mice and rats.

  10. Preparation of [66Ga]bleomycin complex as a possible PET radiopharmaceutical

    International Nuclear Information System (INIS)

    Several radiolabeled bleomycin derivatives have been developed for imaging and/or therapy of neoplastic tissues. The most important imaging compounds contain indium-111, cobalt- 57, and rhodium-105. In our previous studies we have prepared radiolabeled bleomycin complexes such as gallium-67 as therapeutic and/or imaging agents. Our recent studies on the preparation and tumour imaging properties of [67Ga]bleomycin in normal and tumour-bearing mice showed a good tumour/blood and tumour/muscle ratio suggesting that it is an appropriate diagnostic agent. Due to the interesting properties and increasing importance of positron emission tomography, we investigated the possibility of incorporating 66Ga as a positron emitter with an antineoplastic compound, bleomycin, for use in tumour imaging. We optimized 66Ga complex formation conditions with bleomycin, to develop [66Ga]BLM. We hereby report the production of 66Ga, preparation, optimization, stability, and formulation studies of [66Ga]-bleomycin complex. Targetry: An electroplated 66Zn target on a copper backing plate was irradiated at an angle of 6 degrees toward the proton beam in order to achieve higher production yield. The target was cooled by a flow of 18 deg. C distilled water with a rate of 50 Lit/min. Chemical Separation: The irradiated target was dissolved by 10 N HCl (15 ml, H2O2 added) and the solution was passed through a cation exchange resin (Dowex 50 Wx8, H+ form) (h:10 cm, diameter:1 cm). The resulting high-purity [66Ga]GaCl3 solution was used directly in the labeling step. Labeling of bleomycin with [66Ga]GaCl3: [66Ga]GaCl3 (0.25-2.5 mCi) dissolved in acidic medium obtained above (0.5-2 ml) was transferred to a 2 ml-vial and pH was adjusted to various pHs (1-7) using 1M HCl and/or 1M NaOH. The mixture was evaporated by slight warming under a nitrogen flow. A mixture of BLM (0.25-2.5 mg) in normal saline (0.1 ml) was then added and was heated at different temperatures (25, 50, 80, and 100 deg. C) and was

  11. Bleomycin-induced DNA synthesis in a cell-free system using a permeable mouse sarcoma cell Extract.

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    Seki,Shuji

    1987-10-01

    Full Text Available To investigate factors involved in excision repair DNA synthesis, a soluble extract was prepared from permeable mouse sarcoma (SR-C3H/He cells by homogenization and ultracentrifugation. DNA synthesis measured by using native calf thymus DNA as the template-primer and the extract as the polymerase source showed low activity. The DNA synthesis was enhanced more than ten-fold by the addition of an appropriate concentration of bleomycin, a radiomimetic DNA-damaging drug. Using selective inhibitors of DNA polymerases, it was shown that the DNA polymerase involved in the bleomycin-induced DNA synthesis was DNA polymerase beta. In addition to DNA polymerase beta, an exonuclease which converts bleomycin-damaged DNA into suitable template-primers for repair DNA synthesis appeared to be present in the permeable cell extract.

  12. Death by bleomycin pulmonary toxicity in ovarian dysgerminoma with pathologic complete response to chemotherapy. A case report.

    Science.gov (United States)

    Calzas Rodríguez, Julia; Carmen Juarez Morales, María Del; Casero, Miguel Angel Racionero

    2016-01-01

    With cisplatin-based chemotherapy, most patients with ovarian dysgerminoma will survive long-term. Bleomycin is an important part of ovarian germ cell tumors (OGCT) treatment, and its dose-limiting toxicity is the development of pulmonary toxicity and it is increased in patients older than 40 years. We report the case of an elderly patient with an unresectable ovarian dysgerminoma who received neoadjuvant chemotherapy and who developed fatal bleomycin pulmonary toxicity (BPT) after surgery. A monitoring of pulmonary function is not routinely recommended for detecting BPT, although together with carefully assessment for symptoms or signs suggestive of pulmonary toxicity is the best way to reduce the risk of BPT. The frequency of pulmonary events in older patients makes us to think about the possibility of either reduce the dose of bleomycin or removing it from the BEP in ovarian GCT. PMID:27330950

  13. Increased Cellular NAD+ Level through NQO1 Enzymatic Action Has Protective Effects on Bleomycin-Induced Lung Fibrosis in Mice

    Science.gov (United States)

    Oh, Gi-Su; Lee, Su-Bin; Karna, Anjani; Kim, Hyung-Jin; Shen, AiHua; Pandit, Arpana; Lee, SeungHoon

    2016-01-01

    Background Idiopathic pulmonary fibrosis is a common interstitial lung disease; it is a chronic, progressive, and fatal lung disease of unknown etiology. Over the last two decades, knowledge about the underlying mechanisms of pulmonary fibrosis has improved markedly and facilitated the identification of potential targets for novel therapies. However, despite the large number of antifibrotic drugs being described in experimental pre-clinical studies, the translation of these findings into clinical practices has not been accomplished yet. NADH:quinone oxidoreductase 1 (NQO1) is a homodimeric enzyme that catalyzes the oxidation of NADH to NAD+ by various quinones and thereby elevates the intracellular NAD+ levels. In this study, we examined the effect of increase in cellular NAD+ levels on bleomycin-induced lung fibrosis in mice. Methods C57BL/6 mice were treated with intratracheal instillation of bleomycin. The mice were orally administered with β-lapachone from 3 days before exposure to bleomycin to 1-3 weeks after exposure to bleomycin. Bronchoalveolar lavage fluid (BALF) was collected for analyzing the infiltration of immune cells. In vitro, A549 cells were treated with transforming growth factor β1 (TGF-β1) and β-lapachone to analyze the extracellular matrix (ECM) and epithelial-mesenchymal transition (EMT). Results β-Lapachone strongly attenuated bleomycin-induced lung inflammation and fibrosis, characterized by histological staining, infiltrated immune cells in BALF, inflammatory cytokines, fibrotic score, and TGF-β1, α-smooth muscle actin accumulation. In addition, β-lapachone showed a protective role in TGF-β1–induced ECM expression and EMT in A549 cells. Conclusion Our results suggest that β-lapachone can protect against bleomycin-induced lung inflammation and fibrosis in mice and TGF-β1–induced EMT in vitro, by elevating the NAD+/NADH ratio through NQO1 activation.

  14. Leukotriene B4 mediates macrophage influx and pulmonary hypertension in bleomycin-induced chronic neonatal lung injury.

    Science.gov (United States)

    Ee, Mong Tieng; Kantores, Crystal; Ivanovska, Julijana; Wong, Mathew J; Jain, Amish; Jankov, Robert P

    2016-08-01

    Systemically-administered bleomycin causes inflammation, arrested lung growth, and pulmonary hypertension (PHT) in the neonatal rat, similar to human infants with severe bronchopulmonary dysplasia (BPD). Leukotrienes (LTs) are inflammatory lipid mediators produced by multiple cell types in the lung. The major LTs, LTB4 and cysteinyl LTs, are suggested to contribute to BPD, but their specific roles remain largely unexplored in experimental models. We hypothesized that LTs are increased in bleomycin-induced BPD-like injury, and that inhibition of LT production would prevent inflammatory cell influx and thereby ameliorate lung injury. Rat pups were exposed to bleomycin (1 mg·kg(-1)·day(-1) ip) or vehicle (control) from postnatal days 1-14 and were treated with either zileuton (5-lipoxygenase inhibitor), montelukast (cysteinyl LT1 receptor antagonist), or SC57461A (LTA4 hydrolase inhibitor) 10 mg·kg(-1)·day(-1) ip. Bleomycin led to increased lung content of LTB4, but not cysteinyl LTs. Bleomycin-induced increases in tissue neutrophils and macrophages and lung contents of LTB4 and tumor necrosis factor-α were all prevented by treatment with zileuton. Treatment with zileuton or SC57461A also prevented the hemodynamic and structural markers of chronic PHT, including raised pulmonary vascular resistance, increased Fulton index, and arterial wall remodeling. However, neither treatment prevented impaired alveolarization or vascular hypoplasia secondary to bleomycin. Treatment with montelukast had no effect on macrophage influx, PHT, or on abnormal lung structure. We conclude that LTB4 plays a crucial role in lung inflammation and PHT in experimental BPD. Agents targeting LTB4 or LTB4-mediated signaling may have utility in infants at risk of developing BPD-associated PHT. PMID:27317685

  15. Disruption of Calcium Signaling in Fibroblasts and Attenuation of Bleomycin-Induced Fibrosis by Nifedipine.

    Science.gov (United States)

    Mukherjee, Subhendu; Ayaub, Ehab A; Murphy, James; Lu, Chao; Kolb, Martin; Ask, Kjetil; Janssen, Luke J

    2015-10-01

    Fibrotic lung disease afflicts millions of people; the central problem is progressive lung destruction and remodeling. We have shown that external growth factors regulate fibroblast function not only through canonical signaling pathways but also through propagation of periodic oscillations in Ca(2+). In this study, we characterized the pharmacological sensitivity of the Ca(2+)oscillations and determined whether a blocker of those oscillations can prevent the progression of fibrosis in vivo. We found Ca(2+) oscillations evoked by exogenously applied transforming growth factor β in normal human fibroblasts were substantially reduced by 1 μM nifedipine or 1 μM verapamil (both L-type blockers), by 2.7 μM mibefradil (a mixed L-/T-type blocker), by 40 μM NiCl2 (selective at this concentration against T-type current), by 30 mM KCl (which partially depolarizes the membrane and thereby fully inactivates T-type current but leaves L-type current intact), or by 1 mM NiCl2 (blocks both L- and T-type currents). In our in vivo study in mice, nifedipine prevented bleomycin-induced fibrotic changes (increased lung stiffness, overexpression of smooth muscle actin, increased extracellular matrix deposition, and increased soluble collagen and hydroxyproline content). Nifedipine had little or no effect on lung inflammation, suggesting its protective effect on lung fibrosis was not due to an antiinflammatory effect but rather was due to altering the profibrotic response to bleomycin. Collectively, these data show that nifedipine disrupts Ca(2+) oscillations in fibroblasts and prevents the impairment of lung function in the bleomycin model of pulmonary fibrosis. Our results provide compelling proof-of-principle that interfering with Ca(2+) signaling may be beneficial against pulmonary fibrosis.

  16. Effects of 1,25( OH)2D3 on bleomycin-induced pulmonary fibrosis in mice

    Institute of Scientific and Technical Information of China (English)

    张宗梅

    2014-01-01

    Objective To observe the effects of 1,25(OH)2D3on bleomycin-induced pulmonary fibrosis in mice and to explore its mechanisms.Methods Ninety male C57BL/6mice,6 to 8 weeks old,were randomly divided into 3groups according to the table of random numbers:a control group,a model group and a treatment group(n=30each).Bleomycin was injected to the mice in the latter 2groups by single intratracheal injection to duplicate the pulmonary fibrosis model,while the control group was injected with

  17. Advanced and rapidly progressing head and neck cancer: good palliation following intralesional bleomycin.

    LENUS (Irish Health Repository)

    Quintyne, Keith Ian

    2011-09-01

    The authors herein report the case of a 61-year-old man undergoing adjuvant therapy for locally advanced laryngeal cancer, who developed parastomal recurrence in his radiation field around his tracheotomy site, while he was undergoing radiation therapy, and compromised the secure placement of his tracheotomy tube and maintenance of his upper airway. MRI restaging and biopsy confirmed recurrence and progressive disease in his mediastinum. He underwent local therapy with intralesional bleomycin with good palliation, and ability to maintain the patency of his upper airway.

  18. Antifibrotic effects of crocetin in scleroderma fibroblasts and in bleomycin-induced sclerotic mice

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    Yinghua Song

    2013-10-01

    Full Text Available OBJECTIVE: To investigate the antifibrotic effects of crocetin in scleroderma fibroblasts and in sclerotic mice. METHODS: Skin fibroblasts that were isolated from three systemic scleroderma (SSc patients and three healthy subjects were treated with crocetin (0.1, 1 or 10 μM. Cell proliferation was measured with an MTT assay. Alpha-smooth muscle actin was detected via an immunohistochemical method. Alpha 1 (I procollagen (COL1A1, alpha 1 (III procollagen (COL3A1, matrix metalloproteinase (MMP-1 and tissue inhibitor of matrix metalloproteinase (TIMP-1 mRNA levels were measured using real-time PCR. SSc mice were established by the subcutaneous injection of bleomycin. Crocetin (50 mg/kg/d was injected intraperitoneally for 14 days. Dermal thickness and lung fibrosis were assessed with Masson's trichrome staining. Plasma ET-1 was detected with an enzyme-linked immunosorbent assay (ELISA. Skin and lung ET-1 and COL1A1 mRNA levels were measured via real-time PCR. RESULTS: Crocetin inhibited the proliferation of SSc and normal fibroblasts, an effect that increased with crocetin concentration and incubation time. Crocetin decreased the expression of α-SMA and the levels of mRNA for COL1A1, COL3A1 and matrix metalloproteinase-1, while crocetin increased TIMP-1 mRNA levels in both SSc and normal fibroblasts. Skin and lung fibrosis was induced, and the levels of ET-1 in the plasma, skin and lungs were elevated in bleomycin-injected mice. Crocetin alleviated the thickening of the dermis and lung fibrosis; decreased COL1A1 mRNA levels in the skin and lung; and simultaneously decreased ET-1 concentrations in the plasma and ET-1 mRNA levels in the skin and lungs of the bleomycin-induced sclerotic mice, especially during the early phase (weeks 1-3. CONCLUSION: Crocetin inhibits cell proliferation, differentiation and collagen production in SSc fibroblasts. Crocetin alleviates skin and lung fibrosis in a bleomycin-induced SSc mouse model, in part due to a

  19. Serum bleomycin-detectable iron in patients with thalassemia major with normal range of serum iron.

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    Han,Khin Ei

    1995-06-01

    Full Text Available "Free" iron, a potentially radical-generating low mass iron, and not found in normal human blood, was increased in the serum of blood-transfused thalassemia major patients seen in the Yangon General Hospital, Yangon, Myanmar (Burma. The low mass iron was detected by the bleomycin assay. Fifty-one blood samples were analyzed (from 28 males and 23 females. High "free" iron was detected in 47 sera samples from thalassemia patients. Serum ferritin, which reflects the body store iron, was higher than the normal range (10-200 ng/ml in 49 patients. On the other hand, serum iron of 39 sera samples fell within the normal range (50-150 micrograms/dl. Four were less than 50 micrograms/dl and eight were more than 150 micrograms/dl. Almost all the patients' sera of normal or higher serum iron level contained "free" iron. Thus, almost all the sera from thalassemic patients from Myanmar contain bleomycin-detectable iron, even when serum iron is within the normal range. In developing countries where undernutrition is prevalent (serum albumin in these patients was 3.6 +/- 0.4 g/dl, P < 0.0001 vs. control value of 4.0 - 4.8 g/dl, normal serum iron does not preclude the presence of free iron in the serum.

  20. Human lung tumors: SPECT quantitation of differences in Co-57 bleomycin uptake

    International Nuclear Information System (INIS)

    A newly developed single photon emission computed tomography (SPECT) method was used to measure noninvasively the concentration of labeled drugs in human lung tumors. The validity of the method was established by the high correlation (r = .92) between in vivo SPECT measurement of the concentration of glucoheptonate labeled with technetium-99m and in vitro measurement of the concentration of the drug in specimens of nine of the same tumors obtained at surgery. The in vivo concentration of intravenously injected bleomycin labeled with cobalt-57 was measured over time in 14 human lung tumors. Significant differences were found in the uptake of bleomycin by the tumors, even those with the same histologic characteristics, when the concentration over time, the tumor/blood ratio at 30 minutes, and the tumor cumulative concentration were measured in vivo. Since the drug concentration in the blood was not related to the concentration in the tumor (r = .54), uptake of chemotherapeutic drugs should be measured in each patient individually

  1. CD4(+)CD25(hi)Foxp3(+) Cells Exacerbate Bleomycin-Induced Pulmonary Fibrosis.

    Science.gov (United States)

    Birjandi, Shirin Z; Palchevskiy, Vyacheslav; Xue, Ying Ying; Nunez, Stefanie; Kern, Rita; Weigt, S Sam; Lynch, Joseph P; Chatila, Talal A; Belperio, John A

    2016-08-01

    Idiopathic pulmonary fibrosis is a fatal lung disease with a median survival of 2 to 5 years. A decade of studies has downplayed inflammation contributing to its pathogenesis. However, these studies preceded the discovery of regulatory T cells (Tregs) and all of their functions. On the basis of human studies demonstrating Tregs can decrease graft-versus-host disease and vasculitides, there is consideration of their use to treat idiopathic pulmonary fibrosis. We hypothesized that Treg therapy would attenuate the fibroplasia involved in a preclinical murine model of pulmonary fibrosis. IL-2 complex was used in vivo to expand CD4(+)CD25(hi)Foxp3(+) cells in the lung during intratracheal bleomycin challenge; however, this unexpectedly led to an increase in lung fibrosis. More important, this increase in fibrosis was a lymphocyte-dependent process. We corroborated these results using a CD4(+)CD25(hi)Foxp3(+) cellular-based therapy. Mechanistically, we demonstrated that CD4(+)CD25(hi)Foxp3(+) cells undergo alterations during bleomycin challenge and the IL-2 complex had no effect on profibrotic (eg, transforming growth factor-β) or type 17 immune response cytokines; however, there was a marked down-regulation of the type 1 and augmentation of the type 2 immune response cytokines from the lungs. Collectively, our animal studies show that a specific lung injury can induce Treg alterations, which can augment pulmonary fibrosis. PMID:27317904

  2. Tetrathiomolybdate therapy protects against bleomycin-induced pulmonary fibrosis in mice.

    Science.gov (United States)

    Brewer, George J; Ullenbruch, Matthew R; Dick, Robert; Olivarez, Leovigildo; Phan, Sem H

    2003-03-01

    Tetrathiomolybdate (TM), a drug developed for the treatment of Wilson's disease, produces an antiangiogenic effect by reducing systemic copper levels. Several angiogenic cytokines appear to depend on normal levels of copper for activity. In both animal tumor models and in cancer patients, TM therapy has proved effective in inhibiting the growth of tumors. We have hypothesized that the activities of fibrotic and inflammatory cytokines are also subject to modulation by the availability of copper in a manner similar to angiogenic cytokines. As a first step in evaluating whether TM plays a therapeutic role in diseases of inflammation and fibrosis, we studied the effects of TM on a murine model of bleomycin-induced pulmonary fibrosis. Oral TM therapy resulted in dose-dependent reduction in serum ceruloplasmin, a surrogate marker of systemic copper levels. Significant decreases in systemic copper levels were associated with marked reduction in lung fibrosis as determined on the basis of histopathologic findings and a biochemical measure of fibrosis. The protection afforded by TM was also reflected in significantly reduced bleomycin-induced body-weight loss. In the next phase of this work, we will seek to determine the mechanisms by which TM brings about this therapeutic benefit.

  3. Intralesional Bleomycin as an Adjunct Therapeutic Modality in Eyelid and Extraocular Malignancies and Tumors.

    Science.gov (United States)

    Meyer, David; Gooding, Caroline

    2015-01-01

    To present our recent experience with intralesional bleomycin (IBI) in nonmelanoma extraocular tumors, and present previous experience on periocular capillary hemangiomas and orbital lymphangiomas in a tertiary referral hospital. This was a retrospective descriptive study of patients with eyelid and extraocular malignancies where conventional therapies failed, or surgery was contraindicated or refused and were offered IBI as an alternate therapy. All patients were recruited from the Oculoplastics Clinic at Tygerberg Academic Hospital, Cape Town, South Africa. A solution containing 1 international unit of bleomycin per milliliter saline was injected intralesionally together with 2% lignocaine in a ratio of 4:1. The injected volume was calculated to be equivalent to the estimated volume of the lesion. A multipuncture technique with a 29-gauge needle was used. Patients requiring retreatment were injected every 4-8 weeks until satisfactory clinical endpoints were achieved. Our previous experience with IBI in extensive capillary hemangiomas and orbital lymphangiomas is reviewed. Cases are presented to illustrate that IBI induced significant regression and reduction in tumor size and marked clinical improvement of the eyelid and orbital basal cell carcinomas, Kaposi sarcoma, and mycosis fungoides. The improvements obviated the need for further surgical intervention in most cases. Based on clinical experience we propose that IBI should be considered a treatment modality in select cases of the malignant eyelid and ophthalmic vascular tumors where the conventional standard of care is not possible. IBI is a reasonable alternative or adjunct to consider in such cases. PMID:26692709

  4. Biphasic pulses enhance bleomycin efficacy in a spontaneous canine genital tumor model of chemoresistance: Sticker sarcoma

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    Citro Gennaro

    2008-11-01

    Full Text Available Abstract Sticker's sarcoma (also known as transmissible venereal tumor is a horizontally transmitted neoplasm of the dog, that is passed with coitus. It is a locally aggressive tumor with a low tendency to metastatic spread. The most common locations are the genitals, the nose, the perianal area. Standard treatment consists with chemotherapy with vincristine, however other therapies such as, cryotherapy, immunotherapy or, in selected cases, radiation therapy, have been reported. In this article we describe the outcome of a small cohort of canine patients, with chemotherapy resistant transmissible venereal tumor (TVT, treated with bleomycin selectively driven by trains of biphasic pulses (electrochemotherapy. Three canine patients, with refractory TVT, entered the study and received two sessions of ECT under sedation. The pets had local injection of bleomycin at the concentration of 1.5 mg/ml and five minutes after the chemotherapy, trains of 8 biphasic electric pulses lasting 50 + 50 μs each, with 1 ms interpulse intervals, were delivered by means of modified caliper or, for difficult districts, through paired needle electrode. All the patients responded to the treatment and are still in remission at different times. Electrochemotherapy appears as a safe and efficacious modality for the treatment of TVT and warrants further investigations.

  5. The LIM-only protein FHL2 attenuates lung inflammation during bleomycin-induced fibrosis.

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    Abdulaleem Alnajar

    Full Text Available Fibrogenesis is usually initiated when regenerative processes have failed and/or chronic inflammation occurs. It is characterised by the activation of tissue fibroblasts and dysregulated synthesis of extracellular matrix proteins. FHL2 (four-and-a-half LIM domain protein 2 is a scaffolding protein that interacts with numerous cellular proteins, regulating signalling cascades and gene transcription. It is involved in tissue remodelling and tumour progression. Recent data suggest that FHL2 might support fibrogenesis by maintaining the transcriptional expression of alpha smooth muscle actin and the excessive synthesis and assembly of matrix proteins in activated fibroblasts. Here, we present evidence that FHL2 does not promote bleomycin-induced lung fibrosis, but rather suppresses this process by attenuating lung inflammation. Loss of FHL2 results in increased expression of the pro-inflammatory matrix protein tenascin C and downregulation of the macrophage activating C-type lectin receptor DC-SIGN. Consequently, FHL2 knockout mice developed a severe and long-lasting lung pathology following bleomycin administration due to enhanced expression of tenascin C and impaired activation of inflammation-resolving macrophages.

  6. Radio-isotope scanning using labelled bleomycin in positive and differential diagnosis of primary and secondary malignant pulmonary lesions

    International Nuclear Information System (INIS)

    A lung scan using bleomycin labelled with cobalt 57 was carried out in 308 patients representing 191 primary malignant tumours, 48 pulmonary metastases and 69 benign lesions. The primary and secondary malignant lesions always gave rise to a hyperactive focus except in 8 cases of primary lung tumour. The negative examination may be explained, either by the small size of the lesion or by radiotherapy in progress. Among the benign lesions, only advanced tuberculosis and very inflammatory lung diseases frequently took up labelled bleomycin (15 hyperactive foci out of 69 benign lesions). Quantitative measurements, i.e. ratio of the lesional activity/activity of healthy lung tissue, were carried out in all patients. The malignant lesions were usually more active than the benign lesions. There was no definite correlation between the uptake of labelled bleomycin and the histological nature of the lesion. However, undifferentiated and anaplastic carcinomas were often more active. One should emphasize that these results show that a hyperactive focus has a 94% chance of being a carcinoma. The absence of bleomycin uptake means that there is a 92% chance of a benign lesion

  7. Chemical activity of anticancer compounds : computational studies on the mechanism of bleomycin and the recognition of flavonoids

    NARCIS (Netherlands)

    Karawajczyk, Anna

    2007-01-01

    The thesis is focused on the DNA-cleaving antibiotic bleomycin that is successfully used in the chemotherapy against several types of cancer like head and neck cancer or certain lymphomas and testicular cancer. Although it has been in use for more than two decades, the mechanism of its action is not

  8. Comparative Analysis of the Biosynthetic Gene Clusters and Pathways for Three Structurally Related Antitumor Antibiotics Bleomycin, Tallysomycin and Zorbamycin†

    OpenAIRE

    Galm, Ute; Wendt-Pienkowski, Evelyn; Wang, Liyan; Huang, Sheng-Xiong; Unsin, Claudia; Tao, Meifeng; Coughlin, Jane M.; Shen, Ben

    2011-01-01

    The biosynthetic gene clusters for the glycopeptide antitumor antibiotics bleomycin (BLM), tallysomycin (TLM), and zorbamycin (ZBM) have been recently cloned and characterized from Streptomyces verticillus ATCC15003, Streptoalloteichus hindustanus E465-94 ATCC31158, and Streptomyces flavoviridis ATCC21892, respectively. The striking similarities and differences among the biosynthetic gene clusters for the three structurally related glycopeptide antitumor antibiotics prompted us to compare and...

  9. Gene expression profiling of human dermal fibroblasts exposed to bleomycin sulphate does not differentiate between radiation sensitive and control patients

    International Nuclear Information System (INIS)

    Gene expression profiling of the transcriptional response of human dermal fibroblasts to in vitro radiation has shown promise as a predictive test of radiosensitivity. This study tested if treatment with the radiomimetic drug bleomycin sulphate could be used to differentiate radiation sensitive patients and controls in patients who had previously received radiotherapy for early breast cancer. Eight patients who developed marked late radiation change assessed by photographic breast appearance and 8 matched patients without any change were selected from women entered in a prospective randomised trial of breast radiotherapy fractionation. Gene expression profiling of primary skin fibroblasts exposed in vitro to bleomycin sulphate and mock treated fibroblast controls was performed. 973 genes were up-regulated and 923 down-reguated in bleomycin sulphate treated compared to mock treated control fibroblasts. Gene ontology analysis revealed enriched groups were cellular localisation, apoptosis, cell cycle and DNA damage response for the deregulated genes. No transcriptional differences were identified between fibroblasts from radiation sensitive cases and control patients; subgroup analysis using cases exhibiting severe radiation sensitivity or with high risk alleles present in TGF β1 also showed no difference. The transcriptional response of human dermal fibroblasts to bleomycin sulphate has been characterised. No differences between clinically radiation sensitive and control patients were detected using this approach

  10. Amniotic fluid stem cells inhibit the progression of bleomycin-induced pulmonary fibrosis via CCL2 modulation in bronchoalveolar lavage.

    Directory of Open Access Journals (Sweden)

    Orquidea Garcia

    Full Text Available The potential for amniotic fluid stem cell (AFSC treatment to inhibit the progression of fibrotic lung injury has not been described. We have previously demonstrated that AFSC can attenuate both acute and chronic-fibrotic kidney injury through modification of the cytokine environment. Fibrotic lung injury, such as in Idiopathic Pulmonary Fibrosis (IPF, is mediated through pro-fibrotic and pro-inflammatory cytokine activity. Thus, we hypothesized that AFSC treatment might inhibit the progression of bleomycin-induced pulmonary fibrosis through cytokine modulation. In particular, we aimed to investigate the effect of AFSC treatment on the modulation of the pro-fibrotic cytokine CCL2, which is increased in human IPF patients and is correlated with poor prognoses, advanced disease states and worse fibrotic outcomes. The impacts of intravenous murine AFSC given at acute (day 0 or chronic (day 14 intervention time-points after bleomycin injury were analyzed at either day 3 or day 28 post-injury. Murine AFSC treatment at either day 0 or day 14 post-bleomycin injury significantly inhibited collagen deposition and preserved pulmonary function. CCL2 expression increased in bleomycin-injured bronchoalveolar lavage (BAL, but significantly decreased following AFSC treatment at either day 0 or at day 14. AFSC were observed to localize within fibrotic lesions in the lung, showing preferential targeting of AFSC to the area of fibrosis. We also observed that MMP-2 was transiently increased in BAL following AFSC treatment. Increased MMP-2 activity was further associated with cleavage of CCL2, rendering it a putative antagonist for CCL2/CCR2 signaling, which we surmise is a potential mechanism for CCL2 reduction in BAL following AFSC treatment. Based on this data, we concluded that AFSC have the potential to inhibit the development or progression of fibrosis in a bleomycin injury model during both acute and chronic remodeling events.

  11. Modulation of bleomycin-induced lung fibrosis by pegylated hyaluronidase and dopamine receptor antagonist in mice.

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    Evgenii Germanovich Skurikhin

    Full Text Available Hyaluronidases are groups of enzymes that degrade hyaluronic acid (HA. To stop enzymatic hydrolysis we modified testicular hyaluronidase (HYAL by activated polyethylene oxide with the help of electron-beam synthesis. As a result we received pegylated hyaluronidase (pegHYAL. Spiperone is a selective D2 dopamine receptor antagonist. It was demonstrated on the model of a single bleomycin damage of alveolar epithelium that during the inflammatory phase monotherapy by pegHYAL or spiperone reduced the populations of hematopoietic stem /progenitor cells in the lung parenchyma. PegHYAL also reduced the levels of transforming growth factor (TGF-β, interleukin (IL-1β, tumor necrosis factor (TNF-α in the serum and lungs, while spiperone reduced the level of the serum IL-1β. Polytherapy by spiperone and pegHYAL caused the increase of the quantity of hematopoietic stem/ progenitor cells in the lungs. Such an influx of blood cell precursors was observed on the background of considerable fall level of TGF-β and the increase level of TNF-α in the serum and lungs. These results show pegHYAL reduced the bleomycin-induced fibrosis reaction (production and accumulation of collagen in the lung parenchyma. This effect was observed at a single and repetitive bleomycin damage of alveolar epithelium, the antifibrotic activity of pegHYAL surpassing the activity of testicular HYAL. The antifibrotic effect of pegHYAL is enhanced by an additional instillation of spiperone. Therapy by pegHYAL causes the flow of CD31‒ CD34‒ CD45‒ CD44+ CD73+ CD90+ CD106+-cells into the fibrous lungs. These cells are incapable of differentiating into fibroblast cells. Spiperone instillation separately or together with pegHYAL reduced the MSC-like cells considerably. These data enable us to assume, that pegHYAL is a new and promising instrument both for preventive and therapy of toxic pneumofibrosis. The blockage of D2 dopamine receptors with the following change of hyaluronan

  12. Bleomycin in octaarginine-modified fusogenic liposomes results in improved tumor growth inhibition.

    Science.gov (United States)

    Koshkaryev, Alexander; Piroyan, Aleksandr; Torchilin, Vladimir P

    2013-07-01

    Bleomycin (BLM) is an example of an anticancer drug that should be delivered into cytosol for its efficient therapeutic action. With this in mind, we developed octaarginine (R8)-modified fusogenic DOPE-liposomes (R8-DOPE-BLM). R8-modification dramatically increased (up to 50-fold) the cell-liposome interaction. R8-DOPE-liposomes were internalized via macropinocytosis and did not end up in the lysosomes. R8-DOPE-BLM led to a significantly stronger cell death and DNA damage in vitro relative to all controls. R8-DOPE-BLM demonstrated a prominent anticancer effect in the BALB/c mice bearing 4T1 tumors. Thus, R8-DOPE-BLM provided efficient intracellular delivery of BLM leading to strong tumor growth inhibition in vivo. PMID:22743614

  13. Labelling of bleomycin with technetium-99m for diagnosis in nuclear medicine

    International Nuclear Information System (INIS)

    A study about the behavior of the labelling yield of an antineoplastic drug (bleomycin) with a short-leved radionuclide (99 sup(m) Tc), using An(II) as a reductor agent, is presented. Parameters like the pH in the labelling, influence of the reaction time and mass of tin on the labelling yield were analysed. To simplify the labelling,, a lyofilized kit of Sn(II)/BLM in evacuated vials was prepared. The quality control involving paper chromatography, sterility and 'in vivo' test was made. The 'in vivo' tests were made both in healthy rats and in those with tumorous tissues, under barbituric action. The biological distribution, the concentration time of the products in tumors, the excretion time and excretion via were studied by means of scintigraphy and scintiphotos. (Author)

  14. Pulmonary Function in Patients With Germ Cell Cancer Treated With Bleomycin, Etoposide, and Cisplatin

    DEFF Research Database (Denmark)

    Lauritsen, Jakob; Kier, Maria Gry Gundgaard; Bandak, Mikkel;

    2016-01-01

    expiratory volume in 1 second and forced vital capacity remained unchanged after BEP but increased significantly to levels above pretreatment during follow-up. International Germ Cell Cancer Collaborative Group (IGCCCG) prognostic group, mediastinal primary, pulmonary metastases, and smoking all......PURPOSE: For patients with germ cell cancer, various pulmonary toxicity risk factors have been hypothesized for treatment with bleomycin, etoposide, and cisplatin (BEP). Because existing studies have shortcomings, we present a large, unselected cohort of patients who have undergone close monitoring...... of lung function before, during, and after treatment with BEP to disclose valid pulmonary toxicity risk factors. PATIENTS AND METHODS: All patients who were treated with BEP at Rigshospitalet, Copenhagen, Denmark, from 1984 to 2007, were included. Pulmonary function tests (PFTs) that measured...

  15. Lung-specific loss of α3 laminin worsens bleomycin-induced pulmonary fibrosis.

    Science.gov (United States)

    Morales-Nebreda, Luisa I; Rogel, Micah R; Eisenberg, Jessica L; Hamill, Kevin J; Soberanes, Saul; Nigdelioglu, Recep; Chi, Monica; Cho, Takugo; Radigan, Kathryn A; Ridge, Karen M; Misharin, Alexander V; Woychek, Alex; Hopkinson, Susan; Perlman, Harris; Mutlu, Gokhan M; Pardo, Annie; Selman, Moises; Jones, Jonathan C R; Budinger, G R Scott

    2015-04-01

    Laminins are heterotrimeric proteins that are secreted by the alveolar epithelium into the basement membrane, and their expression is altered in extracellular matrices from patients with pulmonary fibrosis. In a small number of patients with pulmonary fibrosis, we found that the normal basement membrane distribution of the α3 laminin subunit was lost in fibrotic regions of the lung. To determine if these changes play a causal role in the development of fibrosis, we generated mice lacking the α3 laminin subunit specifically in the lung epithelium by crossing mice expressing Cre recombinase driven by the surfactant protein C promoter (SPC-Cre) with mice expressing floxed alleles encoding the α3 laminin gene (Lama3(fl/fl)). These mice exhibited no developmental abnormalities in the lungs up to 6 months of age, but, compared with control mice, had worsened mortality, increased inflammation, and increased fibrosis after the intratracheal administration of bleomycin. Similarly, the severity of fibrosis induced by an adenovirus encoding an active form of transforming growth factor-β was worse in mice deficient in α3 laminin in the lung. Taken together, our results suggest that the loss of α3 laminin in the lung epithelium does not affect lung development, but plays a causal role in the development of fibrosis in response to bleomycin or adenovirally delivered transforming growth factor-β. Thus, we speculate that the loss of the normal basement membrane organization of α3 laminin that we observe in fibrotic regions from the lungs of patients with pulmonary fibrosis contributes to their disease progression. PMID:25188360

  16. Lung-specific loss of α3 laminin worsens bleomycin-induced pulmonary fibrosis.

    Science.gov (United States)

    Morales-Nebreda, Luisa I; Rogel, Micah R; Eisenberg, Jessica L; Hamill, Kevin J; Soberanes, Saul; Nigdelioglu, Recep; Chi, Monica; Cho, Takugo; Radigan, Kathryn A; Ridge, Karen M; Misharin, Alexander V; Woychek, Alex; Hopkinson, Susan; Perlman, Harris; Mutlu, Gokhan M; Pardo, Annie; Selman, Moises; Jones, Jonathan C R; Budinger, G R Scott

    2015-04-01

    Laminins are heterotrimeric proteins that are secreted by the alveolar epithelium into the basement membrane, and their expression is altered in extracellular matrices from patients with pulmonary fibrosis. In a small number of patients with pulmonary fibrosis, we found that the normal basement membrane distribution of the α3 laminin subunit was lost in fibrotic regions of the lung. To determine if these changes play a causal role in the development of fibrosis, we generated mice lacking the α3 laminin subunit specifically in the lung epithelium by crossing mice expressing Cre recombinase driven by the surfactant protein C promoter (SPC-Cre) with mice expressing floxed alleles encoding the α3 laminin gene (Lama3(fl/fl)). These mice exhibited no developmental abnormalities in the lungs up to 6 months of age, but, compared with control mice, had worsened mortality, increased inflammation, and increased fibrosis after the intratracheal administration of bleomycin. Similarly, the severity of fibrosis induced by an adenovirus encoding an active form of transforming growth factor-β was worse in mice deficient in α3 laminin in the lung. Taken together, our results suggest that the loss of α3 laminin in the lung epithelium does not affect lung development, but plays a causal role in the development of fibrosis in response to bleomycin or adenovirally delivered transforming growth factor-β. Thus, we speculate that the loss of the normal basement membrane organization of α3 laminin that we observe in fibrotic regions from the lungs of patients with pulmonary fibrosis contributes to their disease progression.

  17. Minimally Invasive Treatment of Giant Haemangiomas of the Liver: Embolisation With Bleomycin

    Energy Technology Data Exchange (ETDEWEB)

    Bozkaya, Halil, E-mail: halilbozkaya@yahoo.com; Cinar, Celal, E-mail: celalcinar@hotmail.com [Ege University, Division of Interventional Radiology, Department of Radiology, School of Medicine (Turkey); Besir, Fahri Halit, E-mail: drfhbesir@gmail.com [Duzce University, Department of Radiology, School of Medicine (Turkey); Parıldar, Mustafa, E-mail: mparildar@yahoo.com; Oran, Ismail, E-mail: ismailoran@gmail.com [Ege University, Division of Interventional Radiology, Department of Radiology, School of Medicine (Turkey)

    2013-04-12

    PurposeThe management of patients with giant haemangioma of the liver remains controversial. Although the usual treatment method for symptomatic giant haemangioma is surgery, the classical paradigm of operative resection remains. In this study, we evaluated the symptomatic improvement and size-reduction effect of embolisation with bleomycin mixed with lipiodol for the treatment of symptomatic giant hepatic haemangioma.MethodsThis study included 26 patients [21 female, five male; age 41–65 years (mean 49.83 ± 1.53)] with symptomatic giant haemangioma unfit for surgery and treated with selective embolisation by bleomycin mixed with lipiodol. The patients were followed-up (mean 7.4 ± 0.81 months) clinically and using imaging methods. Statistical analysis was performed using SPSS version 16.0, and p < 0.05 was considered to indicate statistical significance.ResultsEmbolisation of 32 lesions in 26 patients was performed. The mean volume of the haemangiomas was 446.28 ± 88 cm{sup 3} (range 3.39–1559 cm{sup 3}) before intervention and 244.43 ± 54.38 cm{sup 3} (range 94–967 cm{sup 3}) after intervention. No mortality or morbidity related to the treatment was identified. Symptomatic improvement was observed in all patients, and significant volume reduction was achieved (p = 0.001).ConclusionThe morbidity of surgical treatment in patients with giant liver hemangioma were similar to those obtained in patients followed-up without treatment. Therefore, follow-up without treatment is preferred in most patients. Thus, minimally invasive embolisation is an alternative and effective treatment for giant symptomatic haemangioma of the liver.

  18. Secretory leukocyte protease inhibitor gene deletion alters bleomycin-induced lung injury, but not development of pulmonary fibrosis.

    Science.gov (United States)

    Habgood, Anthony N; Tatler, Amanda L; Porte, Joanne; Wahl, Sharon M; Laurent, Geoffrey J; John, Alison E; Johnson, Simon R; Jenkins, Gisli

    2016-06-01

    Idiopathic pulmonary fibrosis is a progressive, fatal disease with limited treatment options. Protease-mediated transforming growth factor-β (TGF-β) activation has been proposed as a pathogenic mechanism of lung fibrosis. Protease activity in the lung is tightly regulated by protease inhibitors, particularly secretory leukocyte protease inhibitor (SLPI). The bleomycin model of lung fibrosis was used to determine the effect of increased protease activity in the lungs of Slpi(-/-) mice following injury. Slpi(-/-), and wild-type, mice received oropharyngeal administration of bleomycin (30 IU) and the development of pulmonary fibrosis was assessed. Pro and active forms of matrix metalloproteinase (MMP)-2 and MMP-9 were measured. Lung fibrosis was determined by collagen subtype-specific gene expression, hydroxyproline concentration, and histological assessment. Alveolar TGF-β activation was measured using bronchoalveolar lavage cell pSmad2 levels and global TGF-β activity was assessed by pSmad2 immunohistochemistry. The active-MMP-9 to pro-MMP-9 ratio was significantly increased in Slpi(-/-) animals compared with wild-type animals, demonstrating enhanced metalloproteinase activity. Wild-type animals showed an increase in TGF-β activation following bleomycin, with a progressive and sustained increase in collagen type I, alpha 1 (Col1α1), III, alpha 1(Col3α1), IV, alpha 1(Col4α1) mRNA expression, and a significant increase in total lung collagen 28 days post bleomycin. In contrast Slpi(-/-) mice showed no significant increase of alveolar TGF-β activity following bleomycin, above their already elevated levels, although global TGF-β activity did increase. Slpi(-/-) mice had impaired collagen gene expression but animals demonstrated minimal reduction in lung fibrosis compared with wild-type animals. These data suggest that enhanced proteolysis does not further enhance TGF-β activation, and inhibits sustained Col1α1, Col3α1, and Col4α1 gene expression

  19. Secretory leukocyte protease inhibitor gene deletion alters bleomycin-induced lung injury, but not development of pulmonary fibrosis.

    Science.gov (United States)

    Habgood, Anthony N; Tatler, Amanda L; Porte, Joanne; Wahl, Sharon M; Laurent, Geoffrey J; John, Alison E; Johnson, Simon R; Jenkins, Gisli

    2016-06-01

    Idiopathic pulmonary fibrosis is a progressive, fatal disease with limited treatment options. Protease-mediated transforming growth factor-β (TGF-β) activation has been proposed as a pathogenic mechanism of lung fibrosis. Protease activity in the lung is tightly regulated by protease inhibitors, particularly secretory leukocyte protease inhibitor (SLPI). The bleomycin model of lung fibrosis was used to determine the effect of increased protease activity in the lungs of Slpi(-/-) mice following injury. Slpi(-/-), and wild-type, mice received oropharyngeal administration of bleomycin (30 IU) and the development of pulmonary fibrosis was assessed. Pro and active forms of matrix metalloproteinase (MMP)-2 and MMP-9 were measured. Lung fibrosis was determined by collagen subtype-specific gene expression, hydroxyproline concentration, and histological assessment. Alveolar TGF-β activation was measured using bronchoalveolar lavage cell pSmad2 levels and global TGF-β activity was assessed by pSmad2 immunohistochemistry. The active-MMP-9 to pro-MMP-9 ratio was significantly increased in Slpi(-/-) animals compared with wild-type animals, demonstrating enhanced metalloproteinase activity. Wild-type animals showed an increase in TGF-β activation following bleomycin, with a progressive and sustained increase in collagen type I, alpha 1 (Col1α1), III, alpha 1(Col3α1), IV, alpha 1(Col4α1) mRNA expression, and a significant increase in total lung collagen 28 days post bleomycin. In contrast Slpi(-/-) mice showed no significant increase of alveolar TGF-β activity following bleomycin, above their already elevated levels, although global TGF-β activity did increase. Slpi(-/-) mice had impaired collagen gene expression but animals demonstrated minimal reduction in lung fibrosis compared with wild-type animals. These data suggest that enhanced proteolysis does not further enhance TGF-β activation, and inhibits sustained Col1α1, Col3α1, and Col4α1 gene expression

  20. BlmB and TlmB provide resistance to the bleomycin family of antitumor antibiotics by N-acetylating metal-free bleomycin, tallysomycin, phleomycin, and zorbamycin.

    Science.gov (United States)

    Coughlin, Jane M; Rudolf, Jeffrey D; Wendt-Pienkowski, Evelyn; Wang, Liyan; Unsin, Claudia; Galm, Ute; Yang, Dong; Tao, Meifeng; Shen, Ben

    2014-11-11

    The bleomycin (BLM) family of glycopeptide-derived antitumor antibiotics consists of BLMs, tallysomycins (TLMs), phleomycins (PLMs), and zorbamycin (ZBM). The self-resistant elements BlmB and TlmB, discovered from the BLM- and TLM-producing organisms Streptomyces verticillus ATCC15003 and Streptoalloteichus hindustanus E465-94 ATCC31158, respectively, are N-acetyltransferases that provide resistance to the producers by disrupting the metal-binding domain of the antibiotics required for activity. Although each member of the BLM family of antibiotics possesses a conserved metal-binding domain, the structural differences between each member, namely, the bithiazole moiety and C-terminal amine of BLMs, have been suggested to instill substrate specificity within BlmB. Here we report that BlmB and TlmB readily accept and acetylate BLMs, TLMs, PLMs, and ZBM in vitro but only in the metal-free forms. Kinetic analysis of BlmB and TlmB reveals there is no strong preference or rate enhancement for specific substrates, indicating that the structural differences between each member of the BLM family play a negligible role in substrate recognition, binding, or catalysis. Intriguingly, the zbm gene cluster from Streptomyces flavoviridis ATCC21892 does not contain an N-acetyltransferase, yet ZBM is readily acetylated by BlmB and TlmB. We subsequently established that S. flavoviridis lacks the homologue of BlmB and TlmB, and ZbmA, the ZBM-binding protein, alone is sufficient to provide ZBM resistance. We further confirmed that BlmB can indeed confer resistance to ZBM in vivo in S. flavoviridis, introduction of which into wild-type S. flavoviridis further increases the level of resistance.

  1. Assessment of the tumourigenic and metastatic properties of SK-MEL28 melanoma cells surviving electrochemotherapy with bleomycin

    International Nuclear Information System (INIS)

    Electrochemotherapy is a local treatment combining chemotherapy and electroporation and is highly effective treatment approach for subcutaneous tumours of various histologies. Contrary to surgery and radiation, the effect of electrochemotherapy on metastatic potential of tumour cells has not been extensively studied. The aim of the study was to evaluate the effect of electrochemotherapy with bleomycin on the metastatic potential of human melanoma cells in vitro. Viable cells 48 hours after electrochemotherapy were tested for their ability to migrate and invade through Matrigel coated porous membrane. In addition, microarray analysis and quantitative Real-Time PCR were used to detect changes in gene expression after electrochemotherapy. Cell migration and invasion were not changed in melanoma cells surviving electrochemotherapy. Interestingly, only a low number of tumourigenesis related genes was differentially expressed after electrochemotherapy. Our data suggest that metastatic potential of human melanoma cells is not affected by electrochemotherapy with bleomycin, confirming safe role of electrochemotherapy in the clinics

  2. Calcium electroporation in three cell lines; a comparison of bleomycin and calcium, calcium compounds, and pulsing conditions

    DEFF Research Database (Denmark)

    Frandsen, Stine Krog; Gissel, Hanne; Hojman, Pernille;

    2013-01-01

    BACKGROUND: Electroporation with calcium (calcium electroporation) can induce ATP depletion-associated cellular death. In the clinical setting, the cytotoxic drug bleomycin is currently used with electroporation (electrochemotherapy) for palliative treatment of tumors. Calcium electroporation...... offers several advantages over standard treatment options: calcium is inexpensive and may readily be applied without special precautions, as is the case with cytostatic drugs. Therefore, details on the use of calcium electroporation are essential for carrying out clinical trials comparing calcium...... electroporation and electrochemotherapy. METHODS: The effects of calcium electroporation and bleomycin electroporation (alone or in combination) were compared in three different cell lines (DC-3F, transformed Chinese hamster lung fibroblast; K-562, human leukemia; and murine Lewis Lung Carcinoma). Furthermore...

  3. Therapeutic use of fisetin, curcumin, and mesoporous carbaon nanoparticle loaded fisetin in bleomycin-induced idiopathic pulmonary fibrosis

    OpenAIRE

    Srabani Kar; Surajlata Konsam; Garima Hore; Shinjini Mitra; Silpak Biswas; Aryabaran Sinha; Nikhil Ranjan Jana; Ena Ray Banerjee

    2015-01-01

    Idiopathic pulmonary fibrosis (IPF) is a devastating disease of unknown etiology, for which there is no curative pharmacological therapy. Bleomycin, an anti-neoplastic agent that causes lung fibrosis in human patients has been used extensively in rodent models to mimic IPF. The conventional therapy has been steroids and immunosuppressive agents. But only a minority of patients responds to such a therapy. IPF is a progressive, ultimately fatal disorder for which substantive medical therapy is ...

  4. Inhibition of bleomycin-induced pulmonary fibrosis by nordihydroguaiaretic acid. The role of alveolar macrophage activation and mediator production.

    OpenAIRE

    Phan, S. H.; Kunkel, S L

    1986-01-01

    The role of alveolar macrophage activation and release of mediators remains unclear. In this study, this role is examined with respect to the effects of relatively selective inhibitors of arachidonate metabolism on the pathogenesis of pulmonary fibrosis. CBA/J mice were administered bleomycin (0.037 units) endotracheally to induce pulmonary fibrosis. Daily intraperitoneal injections of a lipoxygenase inhibitor, nordihydroguaiaretic acid (NDGA) inhibited pulmonary fibrosis in a dose-dependent ...

  5. Effects of turmeric and its active principle, curcumin, on bleomycin-induced chromosome aberrations in Chinese hamster ovary cells

    OpenAIRE

    Araújo Maria Cristina P.; Dias Francisca da Luz; Kronka Sergio N.; Takahashi Catarina S.

    1999-01-01

    Naturally occurring antioxidants have been extensively studied for their capacity to protect organisms and cells from oxidative damage. Many plant constituents including turmeric and curcumin appear to be potent antimutagens and antioxidants. The effects of turmeric and curcumin on chromosomal aberration frequencies induced by the radiomimetic agent bleomycin (BLM) were investigated in Chinese hamster ovary (CHO) cells. Three concentrations of each drug, turmeric (100, 250 and 500 mg/ml) and ...

  6. Effect of polyunsaturated fatty acids and their metabolites on bleomycin-induced cytotoxic action on human neuroblastoma cells in vitro.

    Directory of Open Access Journals (Sweden)

    Sailaja Polavarapu

    Full Text Available In the present study, we noted that bleomycin induced growth inhibitory action was augmented by all the polyunsaturated fatty acids (PUFAs tested on human neuroblastoma IMR-32 (0.5 × 10(4 cells/100 µl of IMR cells (EPA > DHA > ALA = GLA = AA > DGLA = LA: ∼ 60, 40, 30, 10-20% respectively at the maximum doses used. Of all the prostaglandins (PGE1, PGE2, PGF2α, and PGI2 and leukotrienes (LTD4 and LTE4 tested; PGE1, PGE2 and LTD4 inhibited the growth of IMR-32 cells to a significant degree at the highest doses used. Lipoxin A4 (LXA4, 19,20-dihydroxydocosapentaenoate (19, 20 DiHDPA and 10(S,17(S-dihydroxy-4Z,7Z,11E,13Z,15E,19Z-docosahexaenoic acid (protectin: 10(S,17(SDiHDoHE, metabolites of DHA, significantly inhibited the growth of IMR-32 cells. Pre-treatment with AA, GLA, DGLA and EPA and simultaneous treatment with all PUFAs used in the study augmented growth inhibitory action of bleomycin. Surprisingly, both indomethacin and nordihydroguaiaretic acid (NDGA at 60 and 20 µg/ml respectively enhanced the growth of IMR-32 cells even in the presence of bleomycin. AA enhanced oxidant stress in IMR-32 cells as evidenced by an increase in lipid peroxides, superoxide dismutase levels and glutathione peroxidase activity. These results suggest that PUFAs suppress growth of human neuroblastoma cells, augment growth inhibitory action of bleomycin by enhancing formation of lipid peroxides and altering the status of anti-oxidants and, in all probability, increase the formation of lipoxins, resolvins and protectins from their respective precursors that possess growth inhibitory actions.

  7. Spironolactone attenuates bleomycin-induced pulmonary injury partially via modulating mononuclear phagocyte phenotype switching in circulating and alveolar compartments.

    Directory of Open Access Journals (Sweden)

    Wen-Jie Ji

    Full Text Available BACKGROUND: Recent experimental studies provide evidence indicating that manipulation of the mononuclear phagocyte phenotype could be a feasible approach to alter the severity and persistence of pulmonary injury and fibrosis. Mineralocorticoid receptor (MR has been reported as a target to regulate macrophage polarization. The present work was designed to investigate the therapeutic potential of MR antagonism in bleomycin-induced acute lung injury and fibrosis. METHODOLOGY/PRINCIPAL FINDINGS: We first demonstrated the expression of MR in magnetic bead-purified Ly6G-/CD11b+ circulating monocytes and in alveolar macrophages harvested in bronchoalveolar lavage fluid (BALF from C57BL/6 mice. Then, a pharmacological intervention study using spironolactone (20 mg/kg/day by oral gavage revealed that MR antagonism led to decreased inflammatory cell infiltration, cytokine production (downregulated monocyte chemoattractant protein-1, transforming growth factor β1, and interleukin-1β at mRNA and protein levels and collagen deposition (decreased lung total hydroxyproline content and collagen positive area by Masson' trichrome staining in bleomycin treated (2.5 mg/kg, via oropharyngeal instillation male C57BL/6 mice. Moreover, serial flow cytometry analysis in blood, BALF and enzymatically digested lung tissue, revealed that spironolactone could partially inhibit bleomycin-induced circulating Ly6C(hi monocyte expansion, and reduce alternative activation (F4/80+CD11c+CD206+ of mononuclear phagocyte in alveoli, whereas the phenotype of interstitial macrophage (F4/80+CD11c- remained unaffected by spironolactone during investigation. CONCLUSIONS/SIGNIFICANCE: The present work provides the experimental evidence that spironolactone could attenuate bleomycin-induced acute pulmonary injury and fibrosis, partially via inhibition of MR-mediated circulating monocyte and alveolar macrophage phenotype switching.

  8. Effects of Spaceflight on Molecular and Cellular Responses to Bleomycin-Induced DNA Damages in Confluent Human Fibroblasts

    Science.gov (United States)

    Lu, Tao; Zhang, Ye; Wong, Michael; Stodieck, Louis; Karouia, Fathi; Wu, Honglu

    2016-01-01

    Spaceflights expose human beings to various risk factors. Among them are microgravity related physiological stresses in immune, cytoskeletal, and cardiovascular systems, and space radiation related elevation of cancer risk. Cosmic radiation consists of energetic protons and other heavier charged particles that induce DNA damages. Effective DNA damage response and repair mechanism is important to maintain genomic integrity and reduce cancer risk. There were studies on effects of spaceflight and microgravity on DNA damage response in cell and animal models, but the published results were mostly conflicting and inconsistent. To investigate effects of spaceflight on molecular and cellular responses to DNA damages, bleomycin, an anti-cancer drug and radiomimetic reagent, was used to induce DNA damages in confluent human fibroblasts flown to the International Space Station (ISS) and on ground. After exposure to 1.0 µg/ml bleomycin for 3 hours, cells were fixed for immunofluorescence assays and for RNA preparation. Extents of DNA damages were quantified by foci and pattern counting of phosphorylated histone protein H2AX (?-H2AX). The cells on the ISS showed modestly increased average foci counts per nucleus while the distribution of patterns was similar to that on the ground. PCR array analysis showed that expressions of several genes, including CDKN1A and PCNA, were significantly changed in response to DNA damages induced by bleomycin in both flight and ground control cells. However, there were no significant differences in the overall expression profile of DNA damage response genes between the flight and ground samples. Analysis of cellular proliferation status with Ki-67 staining showed a slightly higher proliferating population in cells on the ISS than those on ground. Our results suggested that the difference in ?-H2AX focus counts between flight and ground was due to the higher percentage of proliferating cells in space, but spaceflight did not significantly affect

  9. Effectiveness of rosiglitazone on bleomycin-induced lung fibrosis: Assessed by micro-computed tomography and pathologic scores

    Energy Technology Data Exchange (ETDEWEB)

    Jin, Gong Yong; Bok, Se Mi; Han, Young Min [Department of Radiology, Chonbuk National University Medical School, Jeonju (Korea, Republic of); Chung, Myung Ja [Department of Pathology, Chonbuk National University Medical School, Jeonju (Korea, Republic of); Yoon, Kwon-Ha [Department of Radiology, Iksan Hospital, Iksan (Korea, Republic of); Kim, So Ri [Department of Internal Medicine and Research Center for Pulmonary Disorders, Chonbuk National University Medical School, Jeonju (Korea, Republic of); Lee, Yong Chul, E-mail: leeyc@jbnu.ac.kr [Department of Internal Medicine and Research Center for Pulmonary Disorders, Chonbuk National University Medical School, Jeonju (Korea, Republic of)

    2012-08-15

    Peroxisome proliferator-activated receptor-{gamma} (PPAR{gamma}) agonists exhibit potent anti-fibrotic effects in the lung and other tissues. Recently, micro-computed tomography (CT) has been a useful tool for the investigation of lung diseases in small animals and is now increasingly applied to visualize and quantify the pulmonary structures. However, there is little information on the assessment for therapeutic effects of PPAR{gamma} agonists on the pulmonary fibrosis in mice using micro-CT. This study was aimed to determine the capability of micro-CT in examining the effects of rosiglitazone on pulmonary fibrosis. We used a murine model of bleomycin-induced lung fibrosis to evaluate the feasibility of micro-CT in evaluating the therapeutic potential of rosiglitazone on pulmonary fibrosis, comparing with pathologic scores. On micro-CT findings, ground glass opacity (80%) and consolidation (20%) were observed predominantly at 3 weeks after the instillation of bleomycin, and the radiologic features became more complex at 6 weeks. In bleomycin-instilled mice treated with rosiglitazone, the majority (80%) showed normal lung features on micro-CT. Radiological-pathologic correlation analyses revealed that ground glass opacity and consolidation were correlated closely with acute inflammation, while reticular opacity was well correlated with histological honeycomb appearance. These results demonstrate that rosiglitazone displays a protective effect on pulmonary fibrosis in mice and that the visualization of bleomycin-induced pulmonary fibrosis using micro-CT is satisfactory to assess the effects of rosiglitazone. It implies that micro-CT can be applied to evaluate therapeutic efficacies of a variety of candidate drugs for lung diseases.

  10. Comparison of therapeutic response of keloids and hypertrophic scars to cryotherapy plus intralesional steroid and bleomycin tattoo

    Directory of Open Access Journals (Sweden)

    Farahnaz Fatemi

    2005-01-01

    Full Text Available Keloids and hypertrophic scars are abnormal responses of body to skin injuries. Overproduction of compacted fibrous tissue is the basic cause of these lesions. In this study the result of treatment of these skin conditions with bleomycin tattoo are compared with cryotherapy and triamcinolone injection. This study involved 45 patients with hypertrophic scar or keloid. Patients were divided into two groups consecutively. Group A (23 patients was treated with bleomycin tattoo and the group B with cryotherapy and triamcinolone injection. There were four therapeutic sessions one month apart. All patients were followedup for three month after the end of treatment .The therapeutic response was determined as reduction of lesion size or flattening relative to initial size. Therapeutic response was 88.3±14% in group A and 67.4 ±22.5% in group B (p<0.001. In group A 69%, but in group B only 49% of patients were asymptomatic after the end of treatment. In group A there was no relation between therapeutic response and lesion size (p=0.58 but in group B lesions those were smaller (<100mm2 had better therapeutic response than larger ones (p=0.007. It was concluded that bleomycin tattoo is more effective in treatment of hypertrophic scar and keloid than traditional treatment, cryotherapy plus triamcinolone injection especially in larger ones.

  11. The triterpenoid CDDO-Me inhibits bleomycin-induced lung inflammation and fibrosis.

    Directory of Open Access Journals (Sweden)

    Ajit A Kulkarni

    Full Text Available Pulmonary Fibrosis (PF is a devastating progressive disease in which normal lung structure and function is compromised by scarring. Lung fibrosis can be caused by thoracic radiation, injury from chemotherapy and systemic diseases such as rheumatoid arthritis that involve inflammatory responses. CDDO-Me (Methyl 2-cyano-3,12-dioxooleana-1,9(11dien-28-oate, Bardoxolone methyl is a novel triterpenoid with anti-fibrotic and anti-inflammatory properties as shown by our in vitro studies. Based on this evidence, we hypothesized that CDDO-Me would reduce lung inflammation, fibrosis and lung function impairment in a bleomycin model of lung injury and fibrosis. To test this hypothesis, mice received bleomycin via oropharyngeal aspiration (OA on day zero and CDDO-Me during the inflammatory phase from days -1 to 9 every other day. Bronchoalveolar lavage fluid (BALF and lung tissue were harvested on day 7 to evaluate inflammation, while fibrosis and lung function were evaluated on day 21. On day 7, CDDO-Me reduced total BALF protein by 50%, alveolar macrophage infiltration by 40%, neutrophil infiltration by 90% (p≤0.01, inhibited production of the inflammatory cytokines KC and IL-6 by over 90% (p≤0.001, and excess production of the pro-fibrotic cytokine TGFβ by 50%. CDDO-Me also inhibited α-smooth muscle actin and fibronectin mRNA by 50% (p≤0.05. On day 21, CDDO-Me treatment reduced histological fibrosis, collagen deposition and αSMA production. Lung function was significantly improved at day 21 by treatment with CDDO-Me, as demonstrated by respiratory rate and dynamic compliance. These new findings reveal that CDDO-Me exhibits potent anti-fibrotic and anti-inflammatory properties in vivo. CDDO-Me is a potential new class of drugs to arrest inflammation and ameliorate fibrosis in patients who are predisposed to lung injury and fibrosis incited by cancer treatments (e.g. chemotherapy and radiation and by systemic autoimmune diseases.

  12. The experimental study of intra-bronchus embolization of bleomycin-lipiodol emulsion in dogs

    International Nuclear Information System (INIS)

    Objective: To investigate the possibility of using bleomycin-lipiodol emulsion (BLE) as an agent for functional pulmonary lobectomy. Methods: The bilateral lungs of sixteen healthy mongrel dogs were randomly divided into the Control group and the FPLT group. In FPLT group the target pulmonary, lobes were filled with BLE and then the target bronchi were occluded. In Control group the pulmonary lobes were done with nothing. The dogs were took X-ray films pre-procedure and post-procedure and then on 1st, 7th, 14th, 21st, and 28th day, respectively, some of them were sacrificed after procedure for histopathologieal examination. Results: Histopathologically in the early time the target pulmonary lobes were mainly inflammatory effusion. After seven days the alveoli collapsed, pulmonary interstitium widened and fibrous connective tissue proliferated. After twenty-eight days the target pulmonary lobes were atelectasis and entirely fibrosis. The fibrosis grade based on Ashcroft's semiquantitative grading system. The grade of pulmonary fibrosis was 0.66±0.06, 2.76±0.24, 4.70±0.22, 6.74±0.25 and 7.69±0.23 in FPLT group and 0.62±0.05, 0.63±0.10, 0.63±0.07, 0.62±011 and 0.63±0.10 in control group separately at 1st, 7th, 14th, 2lst and 28th day after procedure. There was significant difference in the corresponding period between the FPLT group and the control group (P<0.01) and between first day (0.66±0.06) and fourteenth day(4.70 ± 0.22) (P<0.01) and fourteenth day and twenty-eighth day (7.69±0.23) (P<0.01). Conclusion: Intra-bronchus embolization of bleomycin-lipiodol emulsion can result in atelectasis and fibrosis of the target pulmonary, lobes can achieve FPLT. (authors)

  13. Inhibitory effects of amines from Citrus reticulata on bleomycin-induced pulmonary fibrosis in rats.

    Science.gov (United States)

    Zhou, Xian-Mei; Cao, Zhen-Dong; Xiao, Na; Shen, Qi; Li, Jian-Xin

    2016-02-01

    Idiopathic pulmonary fibrosis (IPF) is a progressive, fatal lung disease for which, thus far, there are no effective treatments. The pericarp of Citrus reticulata, as a traditional herbal drug, has been used for the clinical treatment of lung-related diseases in China for many years. In the present study, the amines from the pericarp of Citrus reticulata were isolated, and their hydrochlorides were prepared. The results of screening using cultured human embryonic lung fibroblasts (hELFs) revealed that, of the amines, 4-methoxyphenethylamine hydrochloride (designated as amine hydrochloride 1) possessed the most potent inhibitory effect. Further in vivo experiments using a rat model of bleomycin-induced pulmonary fibrosis demonstrated that the oral administration of amine hydrochloride 1 significantly lowered the hydroxyproline content in both serum and lung tissue, and alleviated pulmonary alveolitis and fibrosis. Immunohistochemical analysis revealed that amine hydrochloride 1 exerted its inhibitory effect against IPF through the downregulation of lung transforming growth factor (TGF)-β1 protein expression. Our results demonstrated that amine hydrochloride 1 prevented the development of bleomycin‑induced lung fibrosis in rats. Thus, our data suggest that the amines from the pericarp of Citrus reticulata have therapeutic potential for use in the treatment of IPF. PMID:26675886

  14. Protective Effect of Onion Extract on Bleomycin-Induced Cytotoxicity and Genotoxicity in Human Lymphocytes.

    Science.gov (United States)

    Cho, Yoon Hee; Lee, Joong Won; Woo, Hae Dong; Lee, Sunyeong; Kim, Yang Jee; Lee, Younghyun; Shin, Sangah; Joung, Hyojee; Chung, Hai Won

    2016-02-01

    Following one of the world's largest nuclear accidents, occured at Fukushima, Japan in 2011, a significant scientific effort has focused on minimizing the potential adverse health effects due to radiation exposure. The use of natural dietary antioxidants to reduce the risk of radiation-induced oxidative DNA damage is a simple strategy for minimizing radiation-related cancer rates and improving overall health. The onion is among the richest sources of dietary flavonoids and is an important food for increasing their overall intake. Therefore, we examined the effect of an onion extract on cyto- and geno-toxicity in human lymphocytes treated with bleomycin (BLM), a radiomimetic agent. In addition, we measured the frequency of micronuclei (MN) and DNA damage following treatment with BLM using a cytokinesis-blocked micronucleus assay and a single cell gel electrophoresis assay. We observed a significant increase in cell viability in lymphocytes treated with onion extract then exposed to BLM compared to cells treated with BLM alone. The frequency of BLM induced MN and DNA damage increased in a dose-dependent manner; however, when lymphocytes were pretreated with onion extract (10 and 20 μL/mL), the frequency of BLM-induced MN was decreased at all doses of BLM and DNA damage was decreased at 3 μg/mL of BLM. These results suggest that onion extract may have protective effects against BLM-induced cyto- and genotoxicity in human lymphocytes. PMID:26907305

  15. Combined bleomycin and irradiation in preoperative treatment of advanced squamous cell carcinoma of the vulva

    Energy Technology Data Exchange (ETDEWEB)

    Scheistroeen, M. (Norwegian Radium Hospital, Oslo (Norway)); Trope, C. (Norwegian Radium Hospital, Oslo (Norway))

    1993-01-01

    Forty-two patients with advanced squamous cell carcinoma of the vulva were treated with a combination regimen of bleomycin 180 mg and external irradiation 30-45 Gy. Twenty patients had primary lesions, and 22 patients had recurrent disease. Fifteen (75%) of the patients with primary disease showed objective response (five complete and ten partial response). Four underwent surgery. Of these, one is alive after 60 months with no evidence of disease. Two have died of unrelated causes without signs of recurrence. Seventeen relapsed and died of carcinoma of the vulva. Median survival for patients treated for primary disease was 8.0 months. Thirteen (59%) of 22 patients treated for recurrence showed objective response (two complete and eleven partial responses). None underwent surgery. All these patients died of carcinoma of the vulva. Median survival was 6.4 months. Toxicity was acceptable, and there were no treatment-related deaths. Even taking into account that our patients had very advanced disease, the results are disappointing. An increase of the radiation dose beyond the maximum of 45 Gy given, and more aggressive surgery, might have improved the results. (orig.).

  16. Hirsutella sinensis mycelium attenuates bleomycin-induced pulmonary inflammation and fibrosis in vivo.

    Science.gov (United States)

    Huang, Tsung-Teng; Lai, Hsin-Chih; Ko, Yun-Fei; Ojcius, David M; Lan, Ying-Wei; Martel, Jan; Young, John D; Chong, Kowit-Yu

    2015-01-01

    Hirsutella sinensis mycelium (HSM), the anamorph of Cordyceps sinensis, is a traditional Chinese medicine that has been shown to possess various pharmacological properties. We previously reported that this fungus suppresses interleukin-1β and IL-18 secretion by inhibiting both canonical and non-canonical inflammasomes in human macrophages. However, whether HSM may be used to prevent lung fibrosis and the mechanism underlying this activity remain unclear. Our results show that pretreatment with HSM inhibits TGF-β1-induced expression of fibronectin and α-SMA in lung fibroblasts. HSM also restores superoxide dismutase expression in TGF-β1-treated lung fibroblasts and inhibits reactive oxygen species production in lung epithelial cells. Furthermore, HSM pretreatment markedly reduces bleomycin-induced lung injury and fibrosis in mice. Accordingly, HSM reduces inflammatory cell accumulation in bronchoalveolar lavage fluid and proinflammatory cytokines levels in lung tissues. The HSM extract also significantly reduces TGF-β1 in lung tissues, and this effect is accompanied by decreased collagen 3α1 and α-SMA levels. Moreover, HSM reduces expression of the NLRP3 inflammasome and P2X7R in lung tissues, whereas it enhances expression of superoxide dismutase. These findings suggest that HSM may be used for the treatment of pulmonary inflammation and fibrosis. PMID:26497260

  17. Combined bleomycin and irradiation in preoperative treatment of advanced squamous cell carcinoma of the vulva

    International Nuclear Information System (INIS)

    Forty-two patients with advanced squamous cell carcinoma of the vulva were treated with a combination regimen of bleomycin 180 mg and external irradiation 30-45 Gy. Twenty patients had primary lesions, and 22 patients had recurrent disease. Fifteen (75%) of the patients with primary disease showed objective response (five complete and ten partial response). Four underwent surgery. Of these, one is alive after 60 months with no evidence of disease. Two have died of unrelated causes without signs of recurrence. Seventeen relapsed and died of carcinoma of the vulva. Median survival for patients treated for primary disease was 8.0 months. Thirteen (59%) of 22 patients treated for recurrence showed objective response (two complete and eleven partial responses). None underwent surgery. All these patients died of carcinoma of the vulva. Median survival was 6.4 months. Toxicity was acceptable, and there were no treatment-related deaths. Even taking into account that our patients had very advanced disease, the results are disappointing. An increase of the radiation dose beyond the maximum of 45 Gy given, and more aggressive surgery, might have improved the results. (orig.)

  18. Autoradiographic and histological findings in vulva carcinomas with local bleomycin therapy

    International Nuclear Information System (INIS)

    Bleomycin was administered to 25 female patients with vulva carcinoma with problematic location of high operation risk. Macroscopically, in 75% of the cases, there was a tumour reduction of more than 50%. In addition to an immediate effect, at a later date (tau- = 21 days) the tumour was observed to have diminished. Histologically, in the well-reacting tumours a higher differentiation, foreign body granulomas, tumour decomposition, tumour-giant cells, and proliferation of the connective tissue. The histological changes were accompanied by a significant restriction of the proliferation which could be proven autoradiographically. The reaction of the carcinomas depended on the stage of the tumour, the degree of differentiation of the tumours, on the initial proliferation activity, and the age of the patients, however not on the sort of pre-treatment and the extent of the carcinoma. The local application of BLM should be reserved exclusively for cases with problematic location and high operation risk. The application of BLM in connection with a radiotherapy or poly-chemotherapy is discussed for these cases. (orig.) 891 MG/orig. 892 RDG

  19. Combined Cytogenotoxic Effects of Bee Venom and Bleomycin on Rat Lymphocytes: An In Vitro Study

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    Yasmina M. Abd-Elhakim

    2014-01-01

    Full Text Available This study was carried out to determine the cytotoxic and genotoxic effects of bee venom (BV and/or the chemotherapeutic agent bleomycin (BLM on healthy isolated rat lymphocytes utilizing morphometric and molecular techniques. Using the Ficoll-Histopaque density gradient centrifugation technique, lymphocytes were isolated, divided into groups, and subjected to BV and/or BLM at incubation medium concentrations of 10 or 20 μg/mL respectively for 24 and 72 hrs. An MTT assay and fluorescent microscopy examinations were used to assess the cytotoxic effects. To determine the predominant type of BV and/or BLM-induced cell death, LDH release assay was employed beside quantitative expression analyses of the apoptosis-related genes (Caspase-3 and Bcl-2. The genotoxic effects of the tested compounds were evaluated via DNA fragmentation assay. The results of these assays demonstrated that BV potentiates BLM-induced cytotoxicity through increased LDH release and diminished cell viability. Nevertheless, BV significantly inhibited the BLM-induced DNA damage. The results verify that BV significantly attenuates the genotoxic effects of BLM on noncancerous isolated rat lymphocytes but does not diminish BLM cytotoxicity.

  20. Protective Effect of Onion Extract on Bleomycin-Induced Cytotoxicity and Genotoxicity in Human Lymphocytes

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    Yoon Hee Cho

    2016-02-01

    Full Text Available Following one of the world’s largest nuclear accidents, occured at Fukushima, Japan in 2011, a significant scientific effort has focused on minimizing the potential adverse health effects due to radiation exposure. The use of natural dietary antioxidants to reduce the risk of radiation-induced oxidative DNA damage is a simple strategy for minimizing radiation-related cancer rates and improving overall health. The onion is among the richest sources of dietary flavonoids and is an important food for increasing their overall intake. Therefore, we examined the effect of an onion extract on cyto- and geno-toxicity in human lymphocytes treated with bleomycin (BLM, a radiomimetic agent. In addition, we measured the frequency of micronuclei (MN and DNA damage following treatment with BLM using a cytokinesis-blocked micronucleus assay and a single cell gel electrophoresis assay. We observed a significant increase in cell viability in lymphocytes treated with onion extract then exposed to BLM compared to cells treated with BLM alone. The frequency of BLM induced MN and DNA damage increased in a dose-dependent manner; however, when lymphocytes were pretreated with onion extract (10 and 20 μL/mL, the frequency of BLM-induced MN was decreased at all doses of BLM and DNA damage was decreased at 3 μg/mL of BLM. These results suggest that onion extract may have protective effects against BLM-induced cyto- and genotoxicity in human lymphocytes.

  1. Internal parameters monitored during intraarterial cytostatic therapy with methotrexate and bleomycin combined with radiotherapy

    International Nuclear Information System (INIS)

    Over a period of ten years, i.e., 1973 to 1983, the Vienna Clinic of Mandibular and Facial Surgery treated 109 patients with primary inoperable malignant tumors using regional chemotherapy, i.e., a combination of methotrexate and bleomycin. 95 patients in the groups were also irradiated. The aim of the internal examinations was to assess whether from the beginning of cytostatic therapy it would be possible to deduct from laboratory chemical examinations some prognostic factors, or whether changes in internal parameters during therapy correspond to the further development of the growth. The examination of chemical parameters showed that the permanently reduced levels of Fe and anemia are demonstrably adverse factors for prognosis. The drop in leukocyte and thrombocyte counts and the toxic damage of bone marrow also proved to be such an adverse factor. On the other hand the rise in serum levels of LDH, AST and ALT in the process of therapy may be assessed as favourable factors for the prognosis of the disease. (author). 1 fig., 12 refs

  2. Paracetamol Supplementation Does Not Alter The Antitumor Activity and Lung Toxicity of Bleomycin

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    Ghada M. Suddek

    2014-01-01

    Full Text Available Bleomycin (BLM is well known by its antitumor activity both in vitro and in vivo. However, pulmonary fibrosis has been considered the dose limiting toxicity of the drug. Hyperpyrexia following injection of BLM was reported thus, paracetamol is sometimes administered with BLM as antipyretic drug. Actually, paracetamol was found to interfere with cytotoxicity of some drugs. This study was conducted to investigate the effect of paracetamol administration on the antitumor and lung toxicity of BLM. The antitumor activity was evaluated both in vitro and in vivo using Ehrlich ascites carcinoma (EAC cells. Paracetamol did not alter the antitumor effect of BLM in vitro or in vivo. The lung toxicity of BLM was evidenced by decrease in the body weight, increase in the lung/body weight ratio, decrease in the response of pulmonary arterial rings to 5-hydroxytryptamine (5-HT and increase in the contractility of tracheal smooth muscles induced by acetylcholine (ACh. The toxicity was also confirmed biochemically by marked increases in hydroxyproline and lipid peroxidation in rat lung and the decrease in reduced glutathione (GSH level. Pretreatment with paracetamol did not significantly change lipid peroxidation, GSH level, percent survival of rats or the response of pulmonary arterial rings and tracheal smooth muscles to 5-HT and ACh respectively. The results of the present study indicated that paracetamol neither modified the antitumor effect of BLM nor changed drug-induced lung toxicity.

  3. Bleomycin Loaded Magnetite Nanoparticles Functionalized by Polyacrylic Acid as a New Antitumoral Drug Delivery System

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    Yue Xu

    2013-01-01

    Full Text Available Objective. To prepare, characterize, and analyze the release behavior of bleomycin-loaded magnetite nanoparticles (BLM-MNPs coated with polyacrylic acid (PAA as a new drug delivery system that can be specifically distributed in the tumor site. Methods. BLM-MNPs coated with PAA were prepared using a solvothermal approach. The particles were characterized using scanning electron microscope (SEM, vibrating sample magnetometer (VSM, and Fourier transform infrared spectroscopy (FTIR. The loading and release behaviors of BLM-MNPs were examined by a mathematical formula and in vitro release profile at pH 7.5. Results. The sphere Fe3O4 nanoparticles with the size of approximately 30 nm exhibit a saturation magnetization of 87 emu/g. The noncoordinated carboxylate groups of PAA confer on the good dispersibility in the aqueous solution and lead to a good loading efficiency of BLM reaching 50% or higher. Approximately 98% of immobilized BLM could be released within 24 h, of which 22.4% was released in the first hour and then the remaining was released slowly and quantitatively in the next 23 hours. Conclusion. BLM-MNPs were prepared and characterized successfully. The particles show high saturation magnetization, high drug loading capacity, and favorable release property, which could contribute to the specific delivery and controllable release of BLM, and the BLM-MNPs could be a potential candidate for the development of treating solid tumors.

  4. Role of thioredoxin nitration in bleomycin-induced pulmonary fibrosis in rats.

    Science.gov (United States)

    Wang, Lei; Song, Yimin; Li, Xiankui; Guo, Haizhou; Zhang, Guojun

    2016-01-01

    Oxidant stimulation has been suggested to play an important role in the pathogenesis of idiopathic pulmonary fibrosis (IPF). Our study aimed to investigate the role and mechanisms of thioredoxin (Trx) nitration during the development of IPF. A rat model of IPF was established by intratracheal instillation of bleomycin (BLM). Male Wistar rats were randomly distributed among the control group and BLM-treated group, in which rats were intratracheally instilled with a single dose of BLM (5.0 mg/kg body mass in 1.0 mL phosphate-buffered saline). At 7 or 28 days after instillation the rats were euthanized. Histopathological and biochemical examinations were performed. The activity and protein level of thioredoxin were assessed. The thioredoxin nitration level was determined using immunoprecipitation and immunoblotting techniques. Our results demonstrated that protein tyrosine nitration increased in the BLM-treated group compared with the control group. Trx activity decreased in the BLM group compared with control group, whereas Trx expression and nitration level increased dramatically in the BLM group compared with the control group. Our results indicated that Trx nitration might be involved in the pathogenesis of IPF.

  5. Induction of complete and incomplete chromosome aberrations by bleomycin in human lymphocytes

    Energy Technology Data Exchange (ETDEWEB)

    Benkhaled, L.; Xuncla, M.; Caballin, M.R. [Universitat Autonoma de Barcelona, Unitat d' Antropologia Biologica, Departament de Biologia Animal, Biologia Vegetal i Ecologia, E-08193 Bellaterra (Spain); Barrios, L. [Universitat Autonoma de Barcelona, Unitat de Biologia Cel.lular, Departament de Biologia Cel.lular, Fisiologia i Immunologia (Spain); Barquinero, J.F. [Universitat Autonoma de Barcelona, Unitat d' Antropologia Biologica, Departament de Biologia Animal, Biologia Vegetal i Ecologia, E-08193 Bellaterra (Spain)], E-mail: Francesc.Barquinero@uab.es

    2008-01-01

    Bleomycin (BLM) is a clastogenic compound, which due to the overdispersion in the cell distribution of induced dicentrics has been compared to the effect of high-LET radiation. Recently, it has been described that in fibroblast derived cell lines BLM induces incomplete chromosome elements more efficiently than any type of ionizing radiation. The objective of the present study was to evaluate in human lymphocytes the induction of dicentrics and incomplete chromosome elements by BLM. Peripheral blood samples have been treated with different concentrations of BLM. Two cytogenetic techniques were applied, fluorescence plus Giemsa (FPG) and FISH using pan-centromeric and pan-telomeric probes. The observed frequency of dicentric equivalents increases linearly with the BLM concentration, and for all BLM concentrations the distribution of dicentric equivalents was overdispersed. In the FISH study the ratio between total incomplete elements and multicentrics was 0.27. The overdispersion in the dicentric cell distribution, and the linear BLM-concentration dependence of dicentrics can be compared to the effect of high-LET radiation, on the contrary the ratio of incomplete elements and multicentrics is similar to the one induced by low-LET radiation ({approx}0.40). The elevated proportion of interstitial deletions in relation to total acentric fragments, higher than any type of ionizing radiation could be a characteristic signature of the clastogenic effect of BLM.

  6. Expression of PEPT2 mRNA in the lung of rat with bleomycin-induced pulmonary fibrosis

    Institute of Scientific and Technical Information of China (English)

    Li Li; Dianhua Wang; Xuan Zhang; Xing Song

    2013-01-01

    Objective:Pulmonary fibrosis is a common pathological phenomena in lung cancer patients after chemotherapy or radiotherapy, which is a key factor hindering to transport ion of high concentrated drug to the lung tissue, peptide trans-porter has become targets of the rational design of peptides and peptide drug. The purpose of the study is to investigate the expression of PEPT2 mRNA in the lung of rats with bleomycin (BLM)-induced pulmonary fibrosis. Methods:Fifty healthy adult Spragne-Dawley rats were randomized into five groups, the rats in BLM 7d, 14d and 28d groups were treated with a single instil ation of 5 mg/kg of BLM, to induced pulmonary fibrosis models. On days 7, 14 and 28, the animals were kil ed by exsan-guination respectively. Normal saline (NS) group were treated by NS, on days 14, the animals were kil ed by exsanguinations. Control group were untreated. The lung samples were processed for light microscopy and determined the hydroxyproline (HYP) concentration. The expression of PEPT2 mRNA were measured by RT-PCR. PEPT2 cDNA fragments were tested by dideoxy chain termination. Results:Compared with control and NS group, HYP levels increased on day 7 of BLM group, but there was no statistical significant dif erence (P>0.05). HYP levels markedly increased on days 14 and 28 of BLM group, there was statistical significant dif erence (P0.05). Conclusion:The pulmonary fibrosis models of SD rats can be induced by a single instil ation of 5 mg/kg of bleomycin on 28d. There were no significant changes of PEPT2 mRNA expression in the lung of rats with bleomycin-induced pulmonary fibrosis.

  7. Comparative study of fixation of Co57 labelled bleomycin, labelled gallium citrate and Hg197 labelled mercury chloride, benign or malignant pulmonary lesions

    International Nuclear Information System (INIS)

    Over the last ten years, numerous labelled molecules have been used in lung diseases, in order to attempt definite localisation of primary or secondary carcinoma. Three of these substances are now used: cobalt 57-labelled bleomycin, Hg197Cl2 and Ga67 citrate. A study of 34 patient with malignant or tuberculous lung disease with definite diagnosis, permitted demonstration of the fact that the highest uptake, or the best images, were obtained with labelled bleomycin. However, the long period of Co57 limits its indications in young subjects and, in these cases, HgCl2 is indicated

  8. Effects of Spaceflight on Molecular and Cellular Responses to Bleomycin-induced DNA Damages in Confluent Human Fibroblasts

    Science.gov (United States)

    Lu, Tao; Wu, Honglu; Karouia, Fathi; Stodieck, Louis; Zhang, Ye; Wong, Michael

    2016-07-01

    Spaceflights expose human beings to various risk factors. Among them are microgravity related physiological stresses in immune, cytoskeletal, and cardiovascular systems, and space radiation related elevation of cancer risk. Cosmic radiation consists of energetic protons and other heavier charged particles that induce DNA damages. Effective DNA damage response and repair mechanism is important to maintain genomic integrity and reduce cancer risk. There were studies on effects of spaceflight and microgravity on DNA damage response in cell and animal models, but the published results were mostly conflicting and inconsistent. To investigate effects of spaceflight on molecular and cellular responses to DNA damages, bleomycin, an anti-cancer drug and radiomimetic reagent, was used to induce DNA damages in confluent human fibroblasts flown to the International Space Station (ISS) and on ground. After exposure to 1.0 mg/ml bleomycin for 3 hours, cells were fixed for immunofluorescence assays and for RNA preparation. Extents of DNA damages were quantified by focus pattern and focus number counting of phosphorylated histone protein H2AX (γg-H2AX). The cells on the ISS showed modestly increased average focus counts per nucleus while the distribution of patterns was similar to that on the ground. PCR array analysis showed that expressions of several genes, including CDKN1A and PCNA, were significantly changed in response to DNA damages induced by bleomycin in both flight and ground control cells. However, there were no significant differences in the overall expression profiles of DNA damage response genes between the flight and ground samples. Analysis of cellular proliferation status with Ki-67 staining showed a slightly higher proliferating population in cells on the ISS than those on ground. Our results suggested that the difference in γg-H2AX focus counts between flight and ground was due to the higher percentage of proliferating cells in space, but spaceflight did not

  9. Effect of intramuscular injection of hepatocyte growth factor plasmid DNA with electroporation on bleomycin-induced lung fibrosis in rats

    Institute of Scientific and Technical Information of China (English)

    LONG Xiang; XIONG Sheng-dao; XIONG Wei-ning; XU Yong-jian

    2007-01-01

    Background So far, there is no efficient treatment for pulmonary fibrosis. The objective of this study was to determine whether intramuscular injection of the hepatocyte growth factor (HGF) plasmid DNA by in vivo electroporation could prevent bleomycin-induced pulmonary fibrosis in rats, and to investigate the possible mechanisms.Methods Twenty male Wistar rats were randomly divided into four groups: control group(group C), model group (group M), early intervention group (group Ⅰ ) and late intervention group (groupⅡ). Groups M, Ⅰ and Ⅱ were intratracheally infused with bleomycin, then injected the plasmid pcDNA3.1-hHGF to group Ⅰ on day 7, 14 and 21. Group Ⅱ received the same treatment like Group Ⅰ on day 14 and 21. All the rats were killed on day 28 after bleomycin injection. We detected Homo HGF expression in the rats with ELISA method and estimated the pathological fibrosis score of lung tissue using hematoxylin eosin (HE) and Massion staining. The mRNA expression of transforming growth factor-β1 (TGF-β1),cycloxygenase-2 (COX-2), and rat HGF in rat pulmonary parenchyma were evaluated by RT-PCR.Immunohistochemistry and Western blotting were performed to determine the protein expression of transforming TGF-β1 and COX-2 in lung parenchyma.Results The plasmid pcDNA3.1-hHGF could express hHGF in NIH3T3 cells and the hHGF protein is secreted into the culture medium. The expression of hHGF protein could be monitored in quadriceps muscle, plasma and lung in Groups Ⅰ and Ⅱ. Pulmonary fibrosis levels of Groups Ⅰ and Ⅱ were obviously lower than that of group M (P<0.05).Expression of TGF-β1 protein and mRNA in lung tissue was markedly decreased in Groups Ⅰ and Ⅱ compared with Group M (P<0.05). The level of expression of HGF and COX-2 mRNA was higher in Groups Ⅰ and Ⅱ than in Group M (P<0.05).Conclusions Injection of the plasmid pcDNA3.1-hHGF into skeletal muscle with electroporation has a potential role in the treatment of bleomycin

  10. Niche nanoparticle-based FRET assay for bleomycin detection via DNA scission.

    Science.gov (United States)

    Pei, Haimeng; Zheng, Yiqun; Kong, Rongmei; Xia, Lian; Qu, Fengli

    2016-11-15

    We describe a highly sensitive nanoparticle-based fluorescence resonance energy transfer (FRET) probe developed without using molecular fluorophores as donors and acceptors. The success of this work relies on the strategy that DNA scission was designed to occur to the probe when target presented, which enabled the fluorescence signal "turn-on" of graphene quantum dots (GQDs) and thus quantitative analysis. In particular, amino-modified SiO2 NPs were initially coated by GQDs to form highly emitting SiO2/GQDs, followed by conjunction with DNA functionalized gold nanoparticles (Au NPs-DNA) to form SiO2/GQDs-DNA-Au NPs composite. Owing to the FRET interactions between the GQDs and Au NPs, the fluorescence of GQDs was effectively quenched by Au NPs. When bleomycin (BLM), a model analyte, was mixed with the probe, the fluorescence signal of GQDs would be restored due to the removal of Au NPs from the SiO2/GQDs surface by DNA scission treatment with BLM in the presence of Fe (II). The current FRET probe shows a good linear relationship between the fluorescence intensity and the concentration of BLM in the range from 0.5nM to 1μM with a detection limit of 0.2nM. The probe also shows satisfactory results for the analysis of clinical serum samples. This method provides versatility to the application of GQDs in FRET biosensing and could be potentially extended to other similar systems by replacing the linker between the GQDs and Au NPs. PMID:27155119

  11. Endogenous annexin A1 counter-regulates bleomycin-induced lung fibrosis

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    Flower Roderick J

    2011-10-01

    Full Text Available Abstract Background The balancing functions of pro/anti-inflammatory mediators of the complex innate responses have been investigated in a variety of experimental inflammatory settings. Annexin-A1 (AnxA1 is one mediator of endogenous anti-inflammation, affording regulation of leukocyte trafficking and activation in many contexts, yet its role in lung pathologies has been scarcely investigated, despite being highly expressed in lung cells. Here we have applied the bleomycin lung fibrosis model to AnxA1 null mice over a 21-day time-course, to monitor potential impact of this mediator on the control of the inflammatory and fibrotic phases. Results Analyses in wild-type mice revealed strict spatial and temporal regulation of the Anxa1 gene, e.g. up-regulation in epithelial cells and infiltrated granulocytes at day 7, followed by augmented protein levels in alveolar macrophages by day 21. Absence of AnxA1 caused increases in: i the degree of inflammation at day 7; and ii indexes of fibrosis (assessed by deposition of hydroxyproline in the lung at day 7 and 21. These alterations in AnxA1 null mice were paralleled by augmented TGF-β1, IFN-γ and TNF-α generation compared to wild-type mice. Finally, treatment of wild type animals with an AnxA1 peptido-mimetic, given prophylactically (from day 0 to 21 or therapeutically (from day 14 onward, ameliorated both signs of inflammation and fibrosis. Conclusion Collectively these data reveal a pathophysiological relevance for endogenous AnxA1 in lung inflammation and, more importantly, fibrosis, and may open new insights for the pharmacological treatment of lung fibrosis.

  12. Effect of early treatment with transcutaneous electrical diaphragmatic stimulation (TEDS on pulmonary inflammation induced by bleomycin

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    Laisa A. Santos

    2013-12-01

    Full Text Available BACKGROUND : Bleomycin (B is an antineoplastic drug that has pulmonary fibrosis as a side effect. There are few experimental studies about the effects of physical therapy treatment in this case. OBJECTIVE: The objective was to study rat lungs treated with B and precocious intervention by transcutaneous electrical diaphragmatic stimulation (TEDS. METHOD : Wistar rats were divided into 4 groups (n=5: a control group (C; a stimulated group (TEDS; a group treated with a single dose of B (intratracheally, 2.5 mg/kg (B; and a group treated with B and electric stimulation (B + TEDS. After the B instillation, the electrical stimulation was applied for 7 days, for a duration of 20 minutes. Lung fragments were histologically processed with hematoxylin and eosin (HE and 8-isoprostane-PGF2α (8-iso-PGF2α. The density of the alveolar area was determined by planimetry, the inflammatory profile was defined by the number of cells, and the level of oxidative stress in the pulmonary tissue was evaluated by 8-iso-PGF2α. For statistical analysis of the data, the Shapiro-Wilk test was used, followed by a one-way ANOVA with the post-hoc Bonferroni test (p≤0.05. RESULTS : The B group exhibited a significant reduction in the area density, and the acute treatment with B + TEDS prevented this reduction. There were increased numbers of fibroblasts, leukocytes, and macrophages in the B group, as well as increased lipid peroxidation, which was observed only in this group. CONCLUSION : B promoted a reduction in the alveolar density area, thereby inducing the inflammatory process and increasing the production of free radicals. These effects were minimized by the application of TEDS at the initial treatment stage.

  13. Degradation of DNA by iron-bleomycin: mechanistic implications of product 18O incorporation

    International Nuclear Information System (INIS)

    Interaction of d(CGCGCG) with Bleomycin (BLM), activated either with Fe(III) and H2O2 or Fe(II), O2 and one electron, results in production of cytosine and a modified oligonucleotide strand (1). Reduction of 1 with NaBD4 followed by enzymatic digestion, derivatization, and GC-MS permits the identification of 2-deoxypentitols-1,4-d2 as their tetra-trimethylsilyl (TMS) derivatives. Similar products have also been isolated from calf thymus DNA and poly(dG-dC). These results provide unequivocal evidence for the intermediacy of a 4' ketone, 1' aldehyde modified carbohydrate. An alternate mode of DNA degradation requires additional O2 and leads to formation of 3' phosphoglycolate termini and base propenals. Glycolate (GA), released from calf thymus DNA, poly(dA-dT) or d(CGCGCG) by enzymatic digestion, can be isolated by chromatography on DEAE Sephadex, silylated and analyzed by GC-MS. This analysis, after incubation with Fe(II) x 18O2 x BLM or Fe(III) x H216O2 x BLM plus 18O2, reveals the incorporation of a single atom of 18O at the C-1 position. Pulse-chase experiments demonstrate that it is the excess molecular oxygen and not the O2 required for drug activation that is incorporated into the carboxylate group of 3' phosphoglycolate and provide evidence for the proposed addition of O2 to a C4' carbon radical. Isotopic enrichments of the other products of DNA oxidation, formed in the presence of 18O2 are also being determined

  14. SPECT quantitation of cobalt-57 bleomycin delivery to human brain tumors

    International Nuclear Information System (INIS)

    A newly developed and validated noninvasive quantitative SPECT method was used to measure the in vivo uptake of [57Co]bleomycin (Co-bleo) in 13 human brain tumors and the uptake of [/sup 99m/Tc]glucoheptonate (GH) in 23 brain tumors. Significant differences in tumor uptake were found. The tumor concentration over time, the tumor to blood radioactivity at 30 min and the tumor cumulative concentration of radioactivity showed marked differences even between tumors with the same histology. Only a weak correlation was found between tumor concentration of Co-bleo and of GH. Therefore, a simple imaging agent such as GH cannot, at the present time, serve as an indicator of individual tumor uptake and further experience with other agents is still necessary. Contrary to the generally held view, no correlation was found between the concentration of drug in the blood and its tumor concentration. It is suggested, therefore, that the level of a drug in the blood cannot be used as a criterion of the amount that will penetrate the tumor. Direct SPECT measurement of the concentration of the drug in the tumor itself should be performed. The bioavailability of a drug is critical in order for it to exert it tumoricidal effect. The results, showing marked differences in uptake between brain tumors, suggest that before chemotherapy is administered, uptake of the chemotherapeutic drug in the individual tumor to be treated should be assessed and comparisons should be made between the uptake of a series of drugs to determine which drug would be most efficacious on the basis of its uptake as well as its tumor cell killing potential

  15. Neotuberostemonine attenuates bleomycin-induced pulmonary fibrosis by suppressing the recruitment and activation of macrophages.

    Science.gov (United States)

    Xiang, Juan; Cheng, Si; Feng, Tianlong; Wu, Yan; Xie, Weina; Zhang, Mian; Xu, Xianghong; Zhang, Chaofeng

    2016-07-01

    Neotuberostemonine (NTS) is one of the main antitussive alkaloids in the root of Stemona tuberosa Lour. This study aimed to investigate the effects of NTS on bleomycin (BLM)-induced pulmonary fibrosis in mice and the underlying mechanism. After BLM administration, NTS were orally administered to mice at 20 and 40mg/kg per day from days 8 to 21, with nintedanib as a positive control. The effect of NTS on BLM-induced mice was assessed via histopathological examination by HE and Masson's trichrome staining, TGF-β1 level and macrophage recruitment by immunohistochemical staining, expression of profibrotic media and M1/M2 polarization by western blot. RAW 264.7 cells were used to evaluate whether NTS (1, 10, 100μM) directly affected macrophages. The results revealed that NTS treatment significantly ameliorated lung histopathological changes and decreased inflammatory cell counts in the bronchoalveolar lavage fluid. The over-expression of collagen, α-SMA and TGF-β1 was reduced by NTS. Furthermore, NTS markedly lowered the expression of MMP-2 and TIMP-1 while raised the expression of MMP-9. A further analysis showed that NTS was able to decrease the recruitment of macrophages and to inhibit the M2 polarization in mice lung tissues. The experiment in vitro showed that NTS significantly reduced the arginase-1 (marker for M2) expression in a dose-dependent manner but down-regulated the iNOS (marker for M1) expression only at 100μM. In conclusion, our study demonstrated for the first time that NTS has a significant protective effect on BLM-induced pulmonary fibrosis through suppressing the recruitment and M2 polarization of macrophages. PMID:27144994

  16. Neotuberostemonine attenuates bleomycin-induced pulmonary fibrosis by suppressing the recruitment and activation of macrophages.

    Science.gov (United States)

    Xiang, Juan; Cheng, Si; Feng, Tianlong; Wu, Yan; Xie, Weina; Zhang, Mian; Xu, Xianghong; Zhang, Chaofeng

    2016-07-01

    Neotuberostemonine (NTS) is one of the main antitussive alkaloids in the root of Stemona tuberosa Lour. This study aimed to investigate the effects of NTS on bleomycin (BLM)-induced pulmonary fibrosis in mice and the underlying mechanism. After BLM administration, NTS were orally administered to mice at 20 and 40mg/kg per day from days 8 to 21, with nintedanib as a positive control. The effect of NTS on BLM-induced mice was assessed via histopathological examination by HE and Masson's trichrome staining, TGF-β1 level and macrophage recruitment by immunohistochemical staining, expression of profibrotic media and M1/M2 polarization by western blot. RAW 264.7 cells were used to evaluate whether NTS (1, 10, 100μM) directly affected macrophages. The results revealed that NTS treatment significantly ameliorated lung histopathological changes and decreased inflammatory cell counts in the bronchoalveolar lavage fluid. The over-expression of collagen, α-SMA and TGF-β1 was reduced by NTS. Furthermore, NTS markedly lowered the expression of MMP-2 and TIMP-1 while raised the expression of MMP-9. A further analysis showed that NTS was able to decrease the recruitment of macrophages and to inhibit the M2 polarization in mice lung tissues. The experiment in vitro showed that NTS significantly reduced the arginase-1 (marker for M2) expression in a dose-dependent manner but down-regulated the iNOS (marker for M1) expression only at 100μM. In conclusion, our study demonstrated for the first time that NTS has a significant protective effect on BLM-induced pulmonary fibrosis through suppressing the recruitment and M2 polarization of macrophages.

  17. Host predisposition by endogenous Transforming Growth Factor-β1 overexpression promotes pulmonary fibrosis following bleomycin injury

    Directory of Open Access Journals (Sweden)

    Ferguson Mark WJ

    2007-09-01

    Full Text Available Abstract Background Idiopathic Pulmonary Fibrosis (IPF is a progressive diffuse disease involving the lung parenchyma. Despite recent advances, the molecular mechanisms of the initiation and progression of this disease remain elusive. Previous studies have demonstrated TGFβ1 as a key effector cytokine in the development of lung fibrosis. Methods In this study we have used a transgenic mouse based strategy to identify the effect of overexpression of this key effector mediator on the development of pulmonary fibrosis in response to exogenous injury. We bred two lines (line 25 and 18 of transgenic mice (Tr+ that overexpressed active TGFβ1. Three-month old transgenic and wild type mice were subsequently wounded with intraperitoneal bleomycin. Mice were sacrificed at 6 weeks post-bleomycin and their lungs analysed histologically and biochemically. Results The severity of lung fibrosis was significantly greater in the Tr+ mice compared to the wild type mice. Using an oligonucleotide microarray based strategy we identified discrete patterns of gene expression contributing to TGFβ1 associated pulmonary fibrosis. Conclusion This data emphasises the importance of a host predisposition in the form of endogenous TGFβ1, in the development of pulmonary fibrosis in response to an exogenous injury.

  18. The resonance Rayleigh scattering of the interaction of copper(Ⅱ)-bleomycinA2 with DNA and its analytical application

    Institute of Scientific and Technical Information of China (English)

    2010-01-01

    The forming of bleomycinA2-Cu(Ⅱ) cationic chelate and the interaction of the chelate with DNA have been investigated by using resonance Rayleigh scattering(RRS),molecular absorption and fluorescence spectra.The result shows that in aqueous solution,bleomycinA2(BLMA2) can react with Cu(Ⅱ) to form 1:1 cationic chelate which contributes to the changes of the absorption spectra and the quenched fluorescence of BLMA2.When the cationic chelate further bound with DNA to form ternary ion-association complexes,the remarkable enhancement of the RRS intensity was observed.In this work,the optimum conditions for the coordination reaction of BLMA2 with Cu(Ⅱ) and some influencing factors have been investigated.The reaction mechanism of BLMA2-Cu(Ⅱ) binding with DNA was suggested and a binding model was proposed.In addition,the fluorescence quenching type of BLMA2 was investigated.A highly sensitive,simple and rapid new method for the determination of DNA by using BLMA2-Cu(Ⅱ) as RRS probe has been developed.The detection limits(3σ) are 7.2 ng/mL for ctDNA,7.1 ng/mL for sDNA and 18 ng/mL for hsDNA.The method can be applied to the determination of trace amounts of DNA.

  19. Interaction of the antiemetics ondansetron and granisetron with the cytotoxicity induced by irradiation, epirubicin, bleomycin, estramustine, and cisplatin in vitro

    Energy Technology Data Exchange (ETDEWEB)

    Behnam Motlagh, P. [Dept. of Oncology, Umeaa Univ. Hospital (Sweden); Henriksson, R. [Dept. of Oncology, Umeaa Univ. Hospital (Sweden); Grankvist, K. [Dept. of Clinical Chemistry, Umeaa Univ. Hospital (Sweden)

    1995-12-31

    At cancer treatment, the use of antiemetics are often needed due to induction of nausea and vomiting. Some antiemetics have been shown to interact with the direct cytotoxic effects. The newly developed antiemetics have, so far as we know, not been studied in this respect. In the present study, the effects of the 5-HT{sub 3} receptor antagonists ondansetron and granisetron were evaluated on the cytotoxicity, induced by irradiation, bleomycin, epirubicin, estramustine, and cisplatin using fibroblasts (V79) and lung cancer cells (P31) in vitro. Ondansetron or granisetron (10{sup -5} mol/l) had no effect on the survival of irradiated cells. Granisetron (10{sup -5} mol/l) significantly potentiated cytoxocity of 2.5 mg/l epirubicin on fibroblasts whereas the effect of granisetron (10{sup -7} mol/l) on the cytotoxic effect of 25 mg/l bleomycin, and estramustine (80 mg/l) seemed additive to lung cancer cells. Ondansetron was non-interactive with the cytotoxicity induced by any of the anti-cancer drugs. Although the encountered observation with an enhancing effect of granisetron on the epirubicin-induced cytotoxicity is seen in a specific experimental situation in vitro, the fact that 5-HT{sub 3} receptor antagonists are routinely used during cancer treatment indicate that attention should be given to a possible interaction with the antineoplastic action of cancer treatment. (orig.).

  20. The response of normal and ataxia-telangiectasia cells to bleomycin: relationships between chromosome damage, cell cycle delay and cell killing.

    Science.gov (United States)

    Zampetti-Bosseler, F; Scott, D

    1985-08-01

    In agreement with our earlier observation (Scott and Zampetti-Bosseler, 1982) on X-irradiated normal and ataxia-telangiectasia (A-T) fibroblasts, we now report that after bleomycin or neocarzinostatin treatment also, A-T cells exhibit less G2 delay than normal cells. We confirm that A-T cells sustain more chromosome damage and lethality than normal cells after bleomycin. These observations support the hypothesis (Painter and Young, 1980) that A-T cells are defective in the recognition of certain lesions which normally lead to delays in progression through the cell cycle, during which they are repaired, and which, if unrepaired, lead to cell-lethal chromosome damage. However, we find that after bleomycin, as opposed to X-rays, the contribution of this type of lesion to cell death is minimal. The predominant lesions leading to cell death after bleomycin are not manifested at chromosome aberrations and do not lead to G2 delay or DNA-synthesis inhibition. A-T cells are defective in the recognition and/or repair of both types of lesion.

  1. The valence state of technetium-99 in its complexes with bleomycin, 1-hydroxy-ethylidene-1,1-diphosphonate and human serum albumin

    NARCIS (Netherlands)

    Korteland, J.; Dekker, B.G.; Ligny, C.L. de

    1980-01-01

    The valence state of technetium-99 in its complexes with bleomycin, 1-hydroxy-ethylidene-1,1-diphosphonate and human serum albumin was determined by titration of 99TcO4− with Sn(II) in the presence of these complexing agents. Both direct titration, and addition of an excess of Sn(II) and back-titrat

  2. Integrative analyses of miRNA and proteomics identify potential biological pathways associated with onset of pulmonary fibrosis in the bleomycin rat model

    International Nuclear Information System (INIS)

    To determine miRNAs and their predicted target proteins regulatory networks which are potentially involved in onset of pulmonary fibrosis in the bleomycin rat model, we conducted integrative miRNA microarray and iTRAQ-coupled LC-MS/MS proteomic analyses, and evaluated the significance of altered biological functions and pathways. We observed that alterations of miRNAs and proteins are associated with the early phase of bleomycin-induced pulmonary fibrosis, and identified potential target pairs by using ingenuity pathway analysis. Using the data set of these alterations, it was demonstrated that those miRNAs, in association with their predicted target proteins, are potentially involved in canonical pathways reflective of initial epithelial injury and fibrogenic processes, and biofunctions related to induction of cellular development, movement, growth, and proliferation. Prediction of activated functions suggested that lung cells acquire proliferative, migratory, and invasive capabilities, and resistance to cell death especially in the very early phase of bleomycin-induced pulmonary fibrosis. The present study will provide new insights for understanding the molecular pathogenesis of idiopathic pulmonary fibrosis. - Highlights: • We analyzed bleomycin-induced pulmonary fibrosis in the rat. • Integrative analyses of miRNA microarray and proteomics were conducted. • We determined the alterations of miRNAs and their potential target proteins. • The alterations may control biological functions and pathways in pulmonary fibrosis. • Our result may provide new insights of pulmonary fibrosis

  3. Integrative analyses of miRNA and proteomics identify potential biological pathways associated with onset of pulmonary fibrosis in the bleomycin rat model

    Energy Technology Data Exchange (ETDEWEB)

    Fukunaga, Satoki [Department of Molecular Pathology, Osaka City University Graduate School of Medicine, 1-4-3 Asahi-machi, Abeno-ku, Osaka 545-8585 (Japan); Environmental Health Science Laboratory, Sumitomo Chemical Co., Ltd., 3-1-98 Kasugade-Naka, Konohana-ku, Osaka 554-8558 (Japan); Kakehashi, Anna [Department of Molecular Pathology, Osaka City University Graduate School of Medicine, 1-4-3 Asahi-machi, Abeno-ku, Osaka 545-8585 (Japan); Sumida, Kayo; Kushida, Masahiko; Asano, Hiroyuki [Environmental Health Science Laboratory, Sumitomo Chemical Co., Ltd., 3-1-98 Kasugade-Naka, Konohana-ku, Osaka 554-8558 (Japan); Gi, Min [Department of Molecular Pathology, Osaka City University Graduate School of Medicine, 1-4-3 Asahi-machi, Abeno-ku, Osaka 545-8585 (Japan); Wanibuchi, Hideki, E-mail: wani@med.osaka-cu.ac.jp [Department of Molecular Pathology, Osaka City University Graduate School of Medicine, 1-4-3 Asahi-machi, Abeno-ku, Osaka 545-8585 (Japan)

    2015-08-01

    To determine miRNAs and their predicted target proteins regulatory networks which are potentially involved in onset of pulmonary fibrosis in the bleomycin rat model, we conducted integrative miRNA microarray and iTRAQ-coupled LC-MS/MS proteomic analyses, and evaluated the significance of altered biological functions and pathways. We observed that alterations of miRNAs and proteins are associated with the early phase of bleomycin-induced pulmonary fibrosis, and identified potential target pairs by using ingenuity pathway analysis. Using the data set of these alterations, it was demonstrated that those miRNAs, in association with their predicted target proteins, are potentially involved in canonical pathways reflective of initial epithelial injury and fibrogenic processes, and biofunctions related to induction of cellular development, movement, growth, and proliferation. Prediction of activated functions suggested that lung cells acquire proliferative, migratory, and invasive capabilities, and resistance to cell death especially in the very early phase of bleomycin-induced pulmonary fibrosis. The present study will provide new insights for understanding the molecular pathogenesis of idiopathic pulmonary fibrosis. - Highlights: • We analyzed bleomycin-induced pulmonary fibrosis in the rat. • Integrative analyses of miRNA microarray and proteomics were conducted. • We determined the alterations of miRNAs and their potential target proteins. • The alterations may control biological functions and pathways in pulmonary fibrosis. • Our result may provide new insights of pulmonary fibrosis.

  4. LOW DOSE PIRFENIDONE SUPPRESSES TRANSFORMING GROWTH FACTOR BETA-1 AND TISSUE INHIBITOR OF METALLOPROTEINASE-1,AND PROTECTS RATS FROM LUNG FIBROSIS INDUCED BY BLEOMYCIN

    Institute of Scientific and Technical Information of China (English)

    Xin-lun Tian; Wei Yao; Zi-jian Guo; Li Gu; Yuan-jue Zhu

    2006-01-01

    Objective To investigate the optimal dosage of pirfenidone for the treatment of pulmonary fibrosis induced by bleomycin in Wistar rats, and the alteration of expressions of transforming growth factor beta-1 (TGF-β1), tissue inhibitor of metalloproteinase-1 (TIMP-1), and matrix metalloproteinase-13 (MMP-13) in lung tissue.Methods Male Wistar rats were endotracheally instilled with bleomycin or normal saline. Pirfenidone (25-800 mg·kg-1·d-1), dexamethasone (3 mg/kg), or 1% carboxymethylcellulose sodium were given daily by feed 2 days before instillation of bleomycin. Groups T7 and T14 were fed pirfenidone 50 mg·kg -1·d-1 at 7 days or 14 days after bleomycin instillation. Lungs were harvested at 28 days after bleomycin instillation. Patholological changes in lung tissues were evaluated with HE staining. Lung collagen was stained by sirius red and measured by content of hydroxyproline. Expression of proteins of TGF-β, TIMP-1, and MMP-13 were detected by Western blotting.Results At doses of 25, 50, and 100 mg·kg-1·d-1, pirfenidone had significant anti-fibrofic effects for bleomycin-induced rat pulmonary fibrosis, and these effects were most significantly attenuated at the dosage of 50mg·kg-1 1d-1 (HE: P<0.01, P<0.01, and P =0.064; sirius red: P<0.05, P<0.01, and P<0. 05; hydroxyproline: P=0.595, P<0.01, and P=0.976). Pirfenidone at a dosage of 50 mg·kg -1·d-1 inhibited protein expression of TGF-β1 and TIMP-1 in lung tissue in the early phase (0.79 and 0.75 times of control group), but had no effect on expression of MMP-13.Conclusion Low dose pirfenidone, especially at dosage of 50 mg·kg-1·d-1, has significant anti-fibrotic effects on bleomycin-induced rat pulmonary fibrosis. Pirfenidone partially inhibits the enhancement of the expression of TGF-β1 and TIMP-1 in lung tissue.

  5. Prostaglandin Transporter (PGT/SLCO2A1 Protects the Lung from Bleomycin-Induced Fibrosis.

    Directory of Open Access Journals (Sweden)

    Takeo Nakanishi

    Full Text Available Prostaglandin (PG E2 exhibits an anti-fibrotic effect in the lung in response to inflammatory reactions and is a high-affinity substrate of PG transporter (SLCO2A1. The present study aimed to evaluate the pathophysiological relevance of SLCO2A1 to bleomycin (BLM-induced pulmonary fibrosis in mice. Immunohistochemical analysis indicated that Slco2a1 protein was expressed in airway and alveolar type I (ATI and II (ATII epithelial cells, and electron-microscopic immunohistochemistry further demonstrated cell surface expression of Slco2a1 in ATI cells in wild type (WT C57BL/6 mice. PGE2 uptake activity was abrogated in ATI-like cells from Slco2a1-deficient (Slco2a1-/- mice, which was clearly observed in the cells from WT mice. Furthermore, the PGE2 concentrations in lung tissues were lower in Slco2a1-/- than in WT mice. The pathological relevance of SLCO2A1 was further studied in mouse BLM-induced pulmonary fibrosis models. BLM (1 mg/kg or vehicle (phosphate buffered saline was intratracheally injected into WT and Slco2a1-/- mice, and BLM-induced fibrosis was evaluated on day 14. BLM induced more severe fibrosis in Slco2a1-/- than in WT mice, as indicated by thickened interstitial connective tissue and enhanced collagen deposition. PGE2 levels were higher in bronchoalveolar lavage fluid, but lower in lung tissues of Slco2a1-/- mice. Transcriptional upregulation of TGF-β1 was associated with enhanced gene transcriptions of downstream targets including plasminogen activator inhitor-1. Furthermore, Western blot analysis demonstrated a significant activation of protein kinase C (PKC δ along with a modest activation of Smad3 in lung from Slco2a1-/- mice, suggesting a role of PKCδ associated with TGF-β signaling in aggravated fibrosis in BLM-treated Slco2a1-/- mice. In conclusion, pulmonary PGE2 disposition is largely regulated by SLCO2A1, demonstrating that SLCO2A1 plays a critical role in protecting the lung from BLM-induced fibrosis.

  6. Preventive Effects of Rhodiola rosea L. on Bleomycin-Induced Pulmonary Fibrosis in Rats

    Science.gov (United States)

    Zhang, Ke; Si, Xiao-Ping; Huang, Jian; Han, Jian; Liang, Xu; Xu, Xiao-Bo; Wang, Yi-Ting; Li, Guo-Yu; Wang, Hang-Yu; Wang, Jin-Hui

    2016-01-01

    Rhodiola rosea L. (RRL) possesses a wide range of pharmacological properties, including lung-protective activity, and has been utilized in folk medicine for several 100 years. However, the lung-protective mechanism remains unclear. This study investigated the possible lung-protective activity mechanism of RRL in a pulmonary fibrosis (PF) rat model. Lung fibrotic injury was induced in Sprague–Dawley rats by single intratracheal instillation of saline containing bleomycin (BLM; 5 mg/kg). The rats were administered 125, 250, or 500 mg/kg of a 95% ethanol extract of RRL for 28 days. The animals were killed to detect changes in body weight, serum levels of glutathione (GSH) and total superoxide dismutase (T-SOD), as well as lung tissue hydroxyproline (HYP) content. Tumor necrosis factor-α (TNF-α), transforming growth factor-β1 (TGF-β1), and interleukin 6 (IL-6) levels were measured in bronchoalveolar lavage fluid (BALF) by enzyme-linked immunosorbent assay. Hematoxylin and eosin, Masson’s trichrome, and immunohistochemical staining were performed to observe the histopathological changes in lung tissues. Additionally, target-related proteins were measured by Western blotting. RRL alleviated the loss of body weight induced by instilling BLM in PF rats, particularly at the 500 mg/kg per day dose. RRL reduced HYP (p < 0.01) and increased GSH and T-SOD contents. BALF levels of TNF-α, TGF-β1, and IL-6 decreased significantly in the RRL-treated groups. Expression levels of matrix metalloproteinase-9 (MMP-9) and α-smooth muscle actin decreased significantly in a dose-dependent manner in response to RRL. Moreover, the levels of TGF-β1 and tissue inhibitor of metalloproteinase-1 in lung tissues also decreased in the RRL-treated groups. RRL alleviated BLM-induced PF in rats. Our results reveal that the protective effects of RRL against fibrotic lung injury in rats are correlated with its anti-inflammatory, antioxidative, and anti-fibrotic properties. MMP-9 may play

  7. Dysregulated macrophages are present in bleomycin-induced murine laryngotracheal stenosis

    Science.gov (United States)

    Hillel, Alexander T.; Samad, Idris; Ma, Garret; Ding, Dacheng; Sadler, Kaitlyn; Powell, Jonathan D.; Lane, Andrew P.; Horton, Maureen R.

    2015-01-01

    Objective To define the inflammatory cell infiltrate preceding fibrosis in a laryngotracheal stenosis (LTS) murine model. Study Design Prospective controlled murine study. Setting Tertiary care hospital in a research university. Subjects and Methods Chemomechanical injury mice (n=44) sustained bleomycin-coated wire-brush injury to the laryngotracheal complex while mechanical injury controls (n=42) underwent PBS-coated wire-brush injury. Mock surgery controls (n=34) underwent anterior transcervical tracheal exposure only. Inflammatory and fibrosis protein and gene expression was assessed in each condition. Immunohistochemistry served as a secondary outcome. Results In chemomechanical injury mice, there was an up-regulation of: Collagen I (p<0.0001, p<0.0001), Tgf-β (p=0.0023, p=0.0008), and elastin (p<0.0001, p<0.0001) on Day 7, acute inflammatory gene: Il1β (p=0.0027, p=0.0008) on Day 1, and macrophage gene: CD11b (p=0.0026, p=0.0033) on Day 1 versus mechanical and mock controls respectively. M1 marker iNOS expression decreased (p=0.0014) while M2 marker arg1 (p=0.0002) increased on Day 7 compared to mechanical controls. Flow cytometry demonstrated increased macrophages (p=0.0058, day 4) and M1 macrophages (p=0.0148, day 4, p=0.0343, day 7, p=0.0229, day 10) compared to mock controls. There were similarities between chemomechanical and mechanical injury mice with an increase in M2 macrophages at day 10 (p=0.0196). Conclusions The mouse model demonstrated increased macrophages involved with the development of LTS. Macrophage immunophenotype suggested that dysregulated M2 macrophages have a role in abnormal laryngotracheal wound healing in both species. These results support this animal model as a representation for human disease. Furthermore, this data delineates inflammatory cells and signaling pathways in LTS that may potentially be modulated to lessen fibroblast proliferation and collagen deposition. PMID:26084828

  8. Biosynthesis of collagen crosslinks. III. In vivo labeling and stability of lung collagen in rats with bleomycin-induced pulmonary fibrosis

    Energy Technology Data Exchange (ETDEWEB)

    Last, J.A.; Reiser, K.M. (Univ. of California, Davis (USA))

    1989-08-01

    Rats were injected intraperitoneally with 1 mCi (each) of (3H)lysine at Day 11 of neonatal life to label their lung collagen. Five weeks later, half of the animals were given an intratracheal injection of 1.5 U of bleomycin sulfate via a tracheostomy; control animals received saline intratracheally by the same technique. Age-matched groups of control and bleomycin-treated rats were killed, and their lung collagen was analyzed at zero (control animals only), 1, 2, 4, 6, and 10 wk after bleomycin administration, a time course appropriate for development of pulmonary fibrosis in this animal model. We measured radioactivity in hydroxylysine and in the difunctional collagen crosslinks hydroxylysinonorleucine and dihydroxylysinonorleucine at each time point. No evidence of breakdown of this pool of mature, preformed collagen was observed in lungs of either the control or the bleomycin-treated rats. We also measured the total lung content of hydroxypyridinium, a trifunctional collagen crosslink, by its intrinsic fluorescence. There was no evidence of collagen degradation in lungs of either group of rats by this criterion either. We conclude that there is no biochemically detectable turnover of mature lung collagen, defined as that pool of lung collagen that is obligatorily extracellular (i.e., crosslinked and containing labeled hydroxylysine from an injection of precursor 5 to 15 wk earlier), in either normal rat lungs or lungs of rats made fibrotic with bleomycin. Statistical analysis of the data suggests that our methodology was sensitive and precise enough to have detected turnover of less than 0.5% of lung collagen per day, some 20-fold less than estimates of lung collagen turnover that have been suggested to be occurring in vivo by others using different techniques and presumably studying different pools of lung collagen.

  9. Gene Expression Profile Changes and Cellular Responses to Bleomycin-Induced DNA Damage in Human Fibroblast Cells in Space

    Science.gov (United States)

    Lu, Tao; Zhang, Ye; Kidane, Yared; Feiveson, Alan; Stodieck, Louis; Karouia, Fathi; Rohde, Larry; Wu, Honglu

    2016-01-01

    Living organisms are constantly exposed to space radiation that consists of energetic protons and other heavier charged particles. In addition, DNA in space can be damaged by toxic chemicals or reactive oxygen species generated due to increased levels of environmental and psychological stresses. Understanding the impact of spaceflight factors, microgravity in particular, on cellular responses to DNA damage affects the accuracy of the radiation risk assessment for astronauts and the mutation rate in microorganisms. Although possible synergistic effects of space radiation and microgravity have been investigated since the early days of the human space program, the published results were mostly conflicting and inconsistent. To investigate the effects of spaceflight on cellular responses to DNA damage, confluent human fibroblast cells (AG1522) flown on the International Space Station (ISS) were treated with bleomycin for three hours in the true microgravity environment, which induced DNA damages including double-strand breaks (DSB). Damages in the DNA were quantified by immunofluorescence staining for ?-H2AX, which showed similar percentages of different types of stained cells between flight and ground. However, there was a slight shift in the distribution of the ?-H2AX foci number in the flown cells with countable foci. Comparison of the cells in confluent and in exponential growth conditions indicated that the proliferation rate between flight and the ground may be responsible for such a shift. A microarray analysis of gene expressions in response to bleomycin treatment was also performed. Comparison of the responsive pathways between the flown and ground cells showed similar responses with the p53 network being the top upstream regulator. Similar responses at the RNA level between different gravity conditions were also observed with a PCR array analysis containing a set of genes involved in DNA damage signaling; with BBC3, CDKN1A, PCNA and PPM1D being significantly

  10. Effects and possible anti-tumor immunity of electrochemotherapy with bleomycin on human colon cancer xenografts in nude mice

    Institute of Scientific and Technical Information of China (English)

    Min-Hua Zheng; Bao-Ming Yu; Bo Feng; Jian-Wen Li; Ai-Guo Lu; Ming-Liang Wang; Wei-Guo Hu; Ji-Yuan Sun; Yan-Yan Hu; Jun-Jun Ma

    2005-01-01

    AIM: To evaluate the anti-tumor effects and possible involvement of anti-tumor immunity of electrochemotherapy (ECT) employing electroporation and bleomycin in human colon cancer xenografts in nude mice, and to establish the experimental basis for clinical application of ECT.METHODS: Forty nude mice, inoculated subcutaneously human colon cancer cell line LoVo for 3 wk, were allocated randomly into four groups: B+E+ (ECT), B+E- (administration of bleomycin alone), B-E+ (administration of electric pulses alone), and B-E- (no treatment). Tumor volumes were measured daily. The animals were killed on the 7th d, the weights of xenografts were measured, and histologies of tumors were evaluated. Cytotoxicity of spleen natural killer (NK) and lymphokine-activated killer (LAK) cells was then assessed by lactic dehydrogenase release assay.RESULTS: The mean tumor volume of group B+E+ was statistically different from the other three groups after the treatment (F= 36.80, P<0.01). There was one case of complete response, seven cases of partial response (PR) in group B+E+, one case of PR in group B+E- and group B-E+ respectively, and no response was observed in group B-E-. The difference of response between group B+E+ and the other three groups was statistically significant (χ2 = 25.67, P<0.01). Histologically, extensive necrosis of tumor cells with considerable vascular damage and inflammatory cells infiltration were observed in group B+E+. There was no statistical difference between the cytotoxicity of NK and LAK cells in the four treatment groups.CONCLUSION: ECT significantly enhances the chemosensitivity and effects of chemotherapy in human colon cancer xenografts in nude mice, and could be a kind of novel treatment modality for human colon cancer.The generation of T-cell-dependent, tumor-specific immunity might be involved in the process of ECT.

  11. Determination of hidden chromosome instability in persons suffered from the action of factors of the Chernobyl accident by the modified 'G2 bleomycin sensitivity assay'

    International Nuclear Information System (INIS)

    With the help of the modified 'G2-bleomycin sensitivity assay' the voluntary investigation of hidden chromosome instability in 53 persons with different radiation exposures had been fulfilled. In all examined groups, the individual levels of chromosome injuries under identical bleomycin exposure varied in a wide range and didn't depend on their initial values in intact cultures. Among control donors and individuals with low radiation exposure, ∼ 33 % hypertensive persons had been identified that can be considered as a genetically caused phenomenon. In patients recovered from acute radiation, 57.9 % persons expressed the hidden chromosome instability. The data obtained allow us to assume that high doses of ionizing radiation can modify the inherited susceptibility of human chromosomes to a mutagen exposure.

  12. Diallylsulfide attenuates excessive collagen production and apoptosis in a rat model of bleomycin induced pulmonary fibrosis through the involvement of protease activated receptor-2

    International Nuclear Information System (INIS)

    Pulmonary fibrosis (PF) can be a devastating lung disease. It is primarily caused by inflammation leading to severe damage of the alveolar epithelial cells. The pathophysiology of PF is not yet been clearly defined, but studying lung parenchymal injury by involving reactive oxygen species (ROS) through the activation of protease activated receptor-2 (PAR-2) may provide promising results. PAR-2 is a G-protein coupled receptor is known to play an important role in the development of PF. In this study, we investigated the inhibitory role of diallylsulfide (DAS) against ROS mediated activation of PAR-2 and collagen production accompanied by epithelial cell apoptosis. Bleomycin induced ROS levels may prompt to induce the expression of PAR-2 as well as extracellular matrix proteins (ECM), such as MMP 2 and 9, collagen specific proteins HSP-47, α-SMA, and cytokines IL-6, and IL-8RA. Importantly DAS treatment effectively decreased the expression of all these proteins. The inhibitory effect of DAS on profibrotic molecules is mediated by blocking the ROS level. To identify apoptotic signaling as a mediator of PF induction, we performed apoptotic protein expression, DNA fragmentation analysis and ultrastructural details of the lung tissue were performed. DAS treatment restored all these changes to near normalcy. In conclusion, treatment of PF bearing rats with DAS results in amelioration of the ROS production, PAR-2 activation, ECM production, collagen synthesis and alveolar epithelial cell apoptosis during bleomycin induction. We attained the first evidence that treatment of DAS decreases the ROS levels and may provide a potential therapeutic effect attenuating bleomycin induced PF. - Highlights: • DAS inhibits PAR-2 activity; bleomycin stimulates PAR-2 activity. • Increase in PAR-2 activity is correlated with pulmonary fibrosis • DAS reduces pro-inflammatory activity linked to facilitating pulmonary fibrosis. • DAS inhibits apoptosis of alveolar epithelial cells

  13. Treatment Outcomes of AIDS-Associated Kaposi's Sarcoma under a Routine Antiretroviral Therapy Program in Lilongwe, Malawi: Bleomycin/Vincristine Compared to Vincristine Monotherapy

    OpenAIRE

    Mwafongo, Albert A.; ROSENBERG, Nora E.; Wingston Ng'ambi; Werner, Alexandra B.; Garneau, William M.; Joe Gumulira; Sam Phiri; Mina C Hosseinipour

    2014-01-01

    Purpose Despite Kaposi's sarcoma (KS) being the most prevalent AIDS-associated cancer in resource limited settings, optimal treatment options remain unknown. We assessed whether bleomycin/vincristine compared to vincristine monotherapy was associated with improved treatment outcomes for AIDS-associated KS among patients initiating combination antiretroviral therapy (cART) in Malawi. Methods All patients initiating cART and chemotherapy for AIDS-related KS were identified from an electronic da...

  14. Diallylsulfide attenuates excessive collagen production and apoptosis in a rat model of bleomycin induced pulmonary fibrosis through the involvement of protease activated receptor-2

    Energy Technology Data Exchange (ETDEWEB)

    Kalayarasan, Srinivasan, E-mail: kalaivasanbio@gmail.com; Sriram, Narayanan; Soumyakrishnan, Syamala; Sudhandiran, Ganapasam, E-mail: sudhandiran@yahoo.com

    2013-09-01

    Pulmonary fibrosis (PF) can be a devastating lung disease. It is primarily caused by inflammation leading to severe damage of the alveolar epithelial cells. The pathophysiology of PF is not yet been clearly defined, but studying lung parenchymal injury by involving reactive oxygen species (ROS) through the activation of protease activated receptor-2 (PAR-2) may provide promising results. PAR-2 is a G-protein coupled receptor is known to play an important role in the development of PF. In this study, we investigated the inhibitory role of diallylsulfide (DAS) against ROS mediated activation of PAR-2 and collagen production accompanied by epithelial cell apoptosis. Bleomycin induced ROS levels may prompt to induce the expression of PAR-2 as well as extracellular matrix proteins (ECM), such as MMP 2 and 9, collagen specific proteins HSP-47, α-SMA, and cytokines IL-6, and IL-8RA. Importantly DAS treatment effectively decreased the expression of all these proteins. The inhibitory effect of DAS on profibrotic molecules is mediated by blocking the ROS level. To identify apoptotic signaling as a mediator of PF induction, we performed apoptotic protein expression, DNA fragmentation analysis and ultrastructural details of the lung tissue were performed. DAS treatment restored all these changes to near normalcy. In conclusion, treatment of PF bearing rats with DAS results in amelioration of the ROS production, PAR-2 activation, ECM production, collagen synthesis and alveolar epithelial cell apoptosis during bleomycin induction. We attained the first evidence that treatment of DAS decreases the ROS levels and may provide a potential therapeutic effect attenuating bleomycin induced PF. - Highlights: • DAS inhibits PAR-2 activity; bleomycin stimulates PAR-2 activity. • Increase in PAR-2 activity is correlated with pulmonary fibrosis • DAS reduces pro-inflammatory activity linked to facilitating pulmonary fibrosis. • DAS inhibits apoptosis of alveolar epithelial cells.

  15. Resistance to bleomycin in cancer cell lines is characterized by prolonged doubling time, reduced DNA damage and evasion of G2/M arrest and apoptosis.

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    Qi Wang

    Full Text Available BACKGROUND: To establish, characterize and elucidate potential mechanisms of acquired bleomycin (BLM resistance using human cancer cell lines. Seven BLM-resistant cell lines were established by exposure to escalating BLM concentrations over a period of 16-24 months. IC50 values and cell doubling times were quantified using a real time cytotoxicity assay. COMET and γ-H2AX assays, cell cycle analysis, and apoptosis assessment further investigated the mechanisms of BLM resistance in these cell lines. RESULTS: Compared with parental cell lines, real time cytotoxicity assays revealed 7 to 49 fold increases in IC50 and a mean doubling time increase of 147 % (range 64 %-352% in BLM-resistant sub-clones (p<0.05 for both. Higher maintenance BLM concentrations were associated with higher IC50 and increased doubling times (p<0.05. Significantly reduced DNA damage (COMET and γ-H2AX assays, G2/M arrest, and apoptosis (p<0.05 for each set of comparison following high-dose acute BLM exposure was observed in resistant sub-clones, compared with their BLM-sensitive parental counterparts. Three weeks of BLM-free culturing resulted in a partial return to BLM sensitivity in 3/7 BLM-resistant sub-clones (p<0.05. CONCLUSION: Bleomycin resistance may be associated with reduced DNA damage after bleomycin exposure, resulting in reduced G2/M arrest, and reduced apoptosis.

  16. Bleomycin-Treated Chimeric Thy1-Deficient Mice with Thy1-Deficient Myofibroblasts and Thy-Positive Lymphocytes Resolve Inflammation without Affecting the Fibrotic Response

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    Pazit Y. Cohen

    2015-01-01

    Full Text Available Lung fibrosis is characterized by abnormal accumulation of fibroblasts in the interstitium of the alveolar space. Two populations of myofibroblasts, distinguished by Thy1 expression, are detected in human and murine lungs. Accumulation of Thy1-negative (Thy1− myofibroblasts was shown in the lungs of humans with idiopathic pulmonary fibrosis (IPF and of bleomycin-treated mice. We aimed to identify genetic changes in lung myofibroblasts following Thy1 crosslinking and assess the impact of specific lung myofibroblast Thy1-deficiency, in vivo, in bleomycin-injured mouse lungs. Thy1 increased in mouse lung lymphocytes following bleomycin injury but decreased in myofibroblasts when fibrosis was at the highest point (14 days, as assessed by immunohistochemistry. Using gene chip analysis, we detected that myofibroblast Thy1 crosslinking mediates downregulation of genes promoting cell proliferation, survival, and differentiation, and reduces production of extracellular matrix (ECM components, while concurrently mediating the upregulation of genes known to foster inflammation and immunological functions. Chimeric Thy1-deficient mice with Thy1+ lymphocytes and Thy1− myofibroblasts showed fibrosis similar to wild-type mice and an increased number of CD4/CD25 regulatory T cells, with a concomitant decrease in inflammation. Lung myofibroblasts downregulate Thy1 expression to increase their proliferation but to diminish the in vivo inflammatory milieu. Inflammation is not essential for evolution of fibrosis as was previously stated.

  17. Rapamycin attenuates bleomycin-induced pulmonary fibrosis in rats and the expression of metalloproteinase-9 and tissue inhibitors of metalloproteinase-1 in lung tissue

    Institute of Scientific and Technical Information of China (English)

    Jin Xiaoguang; Dai Huaping; Ding Ke; Xu Xuefeng; Pang Baosen; Wang Chen

    2014-01-01

    Background Idiopathic pulmonary fibrosis (IPF) is the most common and devastating form of interstitial lung disease (ILD) in the clinic.There is no effective therapy except for lung transplantation.Rapamycin is an immunosuppressive drug with potent antifibrotic activity.The purpose of this study was to examine the effects of rapamycin on bleomycininduced pulmonary fibrosis in rats and the relation to the expression of metalloproteinase-9 (MMP-9) and tissue inhibitor of metalloproteinase-1 (TIMP-1).Methods Sprague-Dawley rats were treated with intratracheal injection of 0.3 ml of bleomycin (5 mg/kg) in sterile 0.9% saline to make the pulmonary fibrosis model.Rapamycin was given at a dose of 0.5 mg/kg per gavage,beginning one day before bleomycin instillation and once daily until animal sacrifice.Ten rats in each group were sacrificed at 3,7,14,28 and 56 days after bleomycin administration.Alveolitis and pulmonary fibrosis were semi-quantitatively assessed after HE staining and Masson staining under an Olympus BX40 microscope with an IDA-2000 Image Analysis System.Type Ⅰ and Ⅲ collagen fibers were identified by Picro-sirius-polarization.Hydroxyproline content in lung tissue was quantified by a colorimetric-based spectrophotometric assay,MMP-9 and TIMP-1 were detected by immunohistochemistry and by realtime quantitative reverse transcriptase polymerase chain reaction (RT-PCR).Results Bleomycin induced alveolitis and pulmonary fibrosis of rats was inhibited by rapamycin.Significant inhibition of alveolitis and hydroxyproline product were demonstrated when daily administration of rapamycin lasted for at least 14 days.The inhibitory efficacy on pulmonary fibrosis was unremarkable until rapamycin treatment lasted for at least 28 days (P <0.05).It was also demonstrated that rapamycin treatment reduced the expression of MMP-9 and TIMP-1 in lung tissue that was increased by bleomycin.Conclusion These results highlight the significance of rapamycin in alleviating

  18. STAT1 Antisense Oligonucleotides Attenuate the Proinflammatory Cytokine Release of Alveolar Macrophages in Bleomycin-Induced Fibrosis

    Institute of Scientific and Technical Information of China (English)

    Xianming Fan; Zengli Wang

    2005-01-01

    To investigate the effect of signal transducers and activators of transcription 1 (STAT1) antisense oligonucleotides (ASON) on concentrations of TNF-α, IL-8, NO secreted by alveolar macrophages (AMs) in bleomycin-induced rat pulmonary fibrosis, five adult female Wistar rats were intratracheally instilled with bleomycin. After 7 days, the rats were killed by right ventricle of heart exsanguinations under ketamine anaesthesia and bronchoalveolar lavage (BAL) was performed to obtain AMs. AMs were divided into four groups, treated with STAT1 ASON, STAT1 sense oligonucleotides (SON), dexamethasone (DEX) and medium alone (control), respectively. AMs and media were collected after culture for 36 h. The mRNA and protein expressions of STAT1 and ICAM-1 in AMs were detected by RT-PCR and ELISA, respectively. The concentrations of TNF-α, IL-8, NO in cultured medium were detected.The STAT1 mRNA expression by AMs in the STAT1 ASON group was lower than those of AMs in the STAT1 SON group, the DEX group and the control group (p < 0.05). Moreover, the STAT1 mRNA expression by AMs in the DEX group was also lower than those of AMs in the STAT1 SON group and the control group (p < 0.05), but the STAT1 mRNA expression by AMs in the STAT1 SON group was not different from that of the control group (p >0.05). The protein expressions of STAT1 and ICAM-1 and the mRNA expression of ICAM-1 showed similar changes to the STAT1 mRNA expression by AMs. The concentrations of TNF-α, IL-8, NO in cultured medium from STAT1 ASON group were lower than those from STAT1 SON, DEX and the control groups (p < 0.05). Moreover,the concentrations of TNF-α, IL-8, NO in cultured medium from DEX group were also lower than those from the control and STAT1 SON group (p < 0.05), but no difference between STAT1 SON group and the control (p > 0.05).The results suggest that STAT1 ASON could inhibit the secretion of TNF-α, IL-8, NO in AMs, and STAT1 could become a target of treating pulmonary fibrosis.

  19. Antifibrotic effects of curcumin are associated with overexpression of cathepsins K and L in bleomycin treated mice and human fibroblasts

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    Zhang Dongwei

    2011-11-01

    Full Text Available Abstract Background Lung fibrosis is characterized by fibroblast proliferation and the deposition of collagens. Curcumin, a polyphenol antioxidant from the spice tumeric, has been shown to effectively counteract fibroblast proliferation and reducing inflammation and fibrotic progression in animal models of bleomycin-induced lung injury. However, there is little mechanistic insight in the biological activity of curcumin. Here, we study the effects of curcumin on the expression and activity of cathepsins which have been implicated in the development of fibrotic lung diseases. Methods We investigated the effects of curcumin administration to bleomycin stimulated C57BL/6 mice and human fetal lung fibroblasts (HFL-1 on the expression of cathepsins K and L which have been implicated in matrix degradation, TGF-β1 modulation, and apoptosis. Lung tissues were evaluated for their contents of cathepsins K and L, collagen, and TGF-β1. HFL-1 cells were used to investigate the effects of curcumin and cathepsin inhibition on cell proliferation, migration, apoptosis, and the expression of cathepsins K and L and TGF-β1. Results Collagen deposition in lungs was decreased by 17-28% after curcumin treatment which was accompanied by increased expression levels of cathepsins L (25%-39% and K (41%-76% and a 30% decrease in TGF-β1 expression. Moreover, Tunel staining of lung tissue revealed a 33-41% increase in apoptotic cells after curcumin treatment. These in vivo data correlated well with data obtained from the human fibroblast line, HFL-1. Here, cathepsin K and L expression increased 190% and 240%, respectively, in the presence of curcumin and the expression of TGF-β1 decreased by 34%. Furthermore, curcumin significantly decreased cell proliferation and migration and increased the expression of surrogate markers of apoptosis. In contrast, these curcumin effects were partly reversed by a potent cathepsin inhibitor. Conclusion This study demonstrates that

  20. Biochemical evaluation of a 108-member deglycobleomycin library: viability of a selection strategy for identifying bleomycin analogues with altered properties.

    Science.gov (United States)

    Ma, Qian; Xu, Zhidong; Schroeder, Benjamin R; Sun, Wenyue; Wei, Fang; Hashimoto, Shigeki; Konishi, Kazuhide; Leitheiser, Christopher J; Hecht, Sidney M

    2007-10-17

    The bleomycins (BLMs) are clinically used glycopeptide antitumor antibiotics that have been shown to mediate the sequence-selective oxidative damage of both DNA and RNA. Previously, we described the solid-phase synthesis of a library of 108 unique analogues of deglycoBLM A6, a congener that cleaves DNA analogously to BLM itself. Each member of the library was assayed for its ability to effect single- and double-strand nicking of duplex DNA, sequence-selective DNA cleavage, and RNA cleavage in the presence and absence of a metal ion cofactor. All of the analogues tested were found to mediate concentration-dependent plasmid DNA relaxation to some extent, and a number exhibited double-strand cleavage with an efficiency comparable to or greater than deglycoBLM A6. Further, some analogues having altered linker and metal-binding domains mediated altered sequence-selective cleavage, and a few were found to cleave a tRNA3Lys transcript both in the presence and in the absence of a metal cofactor. The results provide insights into structural elements within BLM that control DNA and RNA cleavage. The present study also permits inferences to be drawn regarding the practicality of a selection strategy for the solid-phase construction and evaluation of large libraries of BLM analogues having altered properties.

  1. Enhanced anti-tumor activity and reduced toxicity by combination andrographolide and bleomycin in ascitic tumor-bearing mice.

    Science.gov (United States)

    Guo, Huizhen; Zhang, Zhenbiao; Su, Zuqing; Sun, Chaoyue; Zhang, Xie; Zhao, Xiaoning; Lai, Xiaoping; Su, Ziren; Li, Yucui; Zhan, Janis Yaxian

    2016-04-01

    Bleomycin (BLM) is an effective anti-carcinogen. With the main detrimental effects of inducing pulmonary fibrosis on patients, its clinical use is limited. Developing agents that enhance the efficacy and attenuate the side effects of cancer chemotherapy are critical. Andrographolide (Andro), an active diterpenoid labdane component extracted from Andrographis panicula, is generally prescribed for treatment of inflammatory associated diseases. The study showed that BLM combined with Andro was significantly more effective than BLM alone on inhibiting the tumor growth, arresting the cell cycle at G0/G1 phase, promoting the capase-3 and capase-8 activity to induce cancer cell apoptosis. The underlying mechanisms may be related to the transcriptional regulation of P53/P21/Cyclin pathways. Moreover, BLM induced pulmonary fibrosis in tumor-bearing mice, but BLM combined with Andro dramatically alleviated the lesion in pulmonary fibrosis by activating the SOD, suppressing MDA and HYP production, in the meanwhile attenuating the IL-1β, TNF- α, IL-6 and TGF-β1 level. These mechanisms were associated with its effect on inhibition of protein expression of TGF-β, α-SMA, p-Smad2/3, enhanced expression of Smad7. Thus, it demonstrated that Andro might be a potential adjuvant therapeutic agent for BLM. PMID:26874212

  2. Combined Lung Transfer of NO and CO in Patients Receiving Methotrexate or Bleomycin Therapy Compared to Normal Subjects

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    Chantal Viart-Ferber

    2013-01-01

    Full Text Available The first aim of the study is to determine whether combined lung diffusing capacities of nitric oxide (TLNO and of carbon monoxide (TLCO are accurate in the followup of patients receiving either methotrexate (MTX or bleomycin (BLM. The second objective is to determine whether TLCO, TLNO, KCO, and TLCO/VI% (inspiratory volume expressed as percentage of predicted value correlate better with the diffusing capacity of the membrane (Dm and/or capillary lung volume (Vc. TLNO and TLCO were measured in three groups: 22 “normal” subjects (N group, 17 patients receiving MTX, and 12 patients treated with BLM. TLCO, TLNO, Dm, and Vc were much lower in the MTX and BLM groups compared to those of the N one. The ratio TLNO/TLCO was higher in the BLM group compared to that of the N group and compared to that of the MTX group. KCO correlated neither with Dc nor with Vc, whereas TLCO/VI% correlated significantly with both Dm and Vc. Combined measurement of TLCO and TLNO seems to be useful in the followup of patients receiving agents inducing lung toxicity and gives a good idea of the alveolar membrane and the capillary volume.

  3. Topics in free radical-mediated DNA damage: purines and damage amplification - superoxic reactions - bleomycin, the incomplete radiomimetic

    International Nuclear Information System (INIS)

    Only a small percentage of the DNA damage set by ionizing radiation in the living cell manifests itself as lethal. It is now increasingly accepted that clustered lesions may constitute the kind of damage that the repair enzymes cannot adequately deal with. The question is raised as to whether damage amplification reactions (radical transfer reactions) may contribute to these clustered lesions, and examples of such damage amplification reactions are given. In one example a purine is involved. With 2'-deoxy adenosine and 2'-deoxy guanosine it is shown that these purine nucleosides undergo unexpected radical reactions. Evidence for the radical transfer from the purine to the sugar moiety is provided by the formation of the 5'-aldehydes. These products have been assayed with 2-thiobarbituric acid (TBA), a reagent commonly applied to the detection of malonaldehyde. TBA-reactive material has also been assayed in γ-irradiated DNA, about one-third of this is free malonaldehyde, while the major part of the TBA-reactive material remains bound to the DNA. In contrast, bleomycin-treated DNA yields practically no free malonaldehyde, and the major TBA-reactive products are identified as the thymine and adenine base propenals. (Author)

  4. Anti-genotoxic effect of naringin against bleomycin-induced genomic damage in human lymphocytes in vitro.

    Science.gov (United States)

    Yilmaz, Dilek; Teksoy, Ozgun; Bilaloglu, Rahmi; Çinkilic, Nilufer

    2016-01-01

    Naringin is a flavonoid found in grapefruit and other citrus fruits that shows antioxidant activity. The aim of the present study was to determine the anti-genotoxic and protective effects of naringin on the chemotherapeutic/radiomimetic agent bleomycin (BLM) in human blood lymphocyte cultures in vitro using micronucleus test and chromosomal aberrations (CA) assay. We tested the three doses of naringin (1, 2, 3 µg/mL) and a single dose of BLM (20 µg/mL). BLM significantly increased the total CAs and micronucleus frequency at a concentration of 20 µg/mL. Naringin did not show any toxicity in doses of 1, 2, and 3 µg/mL. Combined treatments of BLM and naringin (2 and 3 µg/mL) significantly reduced micronucleus formation. Naringin dose-dependently decreased the total chromosome aberrations frequency induced by BLM. These results indicate that naringin could prevent BLM (20 µg/mL)-induced genotoxicity. PMID:25941869

  5. Preventive and therapeutic effects of thymosin β4 N-terminal fragment Ac-SDKP in the bleomycin model of pulmonary fibrosis.

    Science.gov (United States)

    Conte, Enrico; Fagone, Evelina; Gili, Elisa; Fruciano, Mary; Iemmolo, Maria; Pistorio, Maria Provvidenza; Impellizzeri, Daniela; Cordaro, Marika; Cuzzocrea, Salvatore; Vancheri, Carlo

    2016-06-01

    In this study, the bleomycin model of pulmonary fibrosis was utilized to investigate putative anti-fibrotic activity of Ac-SDKP in vivo. Male CD-1 mice received intra-tracheal bleomycin (BLEO, 1 mg/kg) instillation in the absence or presence of Ac-SDKP (a dose of 0.6 mg/kg delivered intra-peritoneally on the day of BLEO treatment, d0, followed by bi-weekly additional doses). To evaluate therapeutic effects in a subset of mice, Ac-SDKP was administered one week after BLEO instillation (d7). Animals were sacrificed at one, two, or three weeks later. Measurement of fluid and collagen content in the lung, Broncho Alveolar Lavage Fluid (BALF) analysis, lung histology, immunohistochemistry (IHC), and molecular analysis were performed. Compared to BLEO-treated mice, animals that received also Ac-SDKP (at both d0 and d7) had significantly decreased mortality, weight loss, inflammation (edema, and leukocyte lung infiltration), lung damage (histological evidence of lung injury), and fibrosis (collagen histological staining and soluble collagen content in the lung) at up to 21 days. Moreover, IHC and quantitative RT-PCR results demonstrated a significant decrease in BLEO-induced IL-17 and TGF-β expression in lung tissue. Importantly, α-SMA expression, the hallmark of myofibroblast differentiation, was also decreased. This is the first report showing not only a preventive protective role of Ac-SDKP but also its significant therapeutic effects in the bleomycin model of pulmonary fibrosis, thus supporting further preclinical and clinical studies.

  6. Chromatin condensation and differential sensitivity of mammalian and insect cells to DNA strand breaks induced by bleomycin

    Energy Technology Data Exchange (ETDEWEB)

    Lopez-Larraza, Daniel M. [IMBICE, C.C. 403, 1900 La Plata (Argentina)]. E-mail: danielop@imbice.org.ar; Padron, Juan [IMBICE, C.C. 403, 1900 La Plata (Argentina); Ronci, Natalia E. [IMBICE, C.C. 403, 1900 La Plata (Argentina); Vidal Rioja, Lidia A. [IMBICE, C.C. 403, 1900 La Plata (Argentina)

    2006-08-30

    Bleomycin (BLM) induces DNA damage in living cells. In this report we analyzed the role of chromatin compactness in the differential response of mosquito (ATC-15) and mammalian (CHO) cells to DNA strand breaks induced by BLM. We used cells unexposed and exposed to sodium butyrate (NaB), which induces chromatin decondensation. By nucleoid sedimentation assay and digestions of nuclei with DNAse I, untreated mosquito cells (no BLM; no NaB) were shown to have more chromatin condensation than untreated CHO cells. By alkaline unwinding ATC-15 cells treated with NaB showed more BLM-induced DNA strand breaks than NaB-untreated CHO cells. The time-course of BLM-induced DNA damage to nuclear DNA was similar for NaB-untreated mammalian and insect cells, but with mosquito cells showing less DNA strand breaks, both at physiological temperatures and at 4 {sup o}C. However, when DNA repair was inhibited by low temperatures and chromatin was decondensed by NaB treatments, differences in BLM-induced DNA damage between these cells lines were no longer observed. In both cell lines, NaB did not affect BLM action on cell growth and viability. On the other hand, the low sensitivity of ATC-15 cells to BLM was reflected in their better growth efficiency. These cells exhibited a satisfactory growth at BLM doses that produced a permanent arrest of growth in CHO cells. The data suggest that mosquito cells might have linker DNAs shorter than those of mammalian cells, which would result in the observed both greater chromatin condensation and greater resistance to DNA damage induced by BLM as compared to CHO cells.

  7. VEGFmRNA and eNOSmRNA expression in immature rabbits with bleomycin-induced pulmonary hypertension

    Institute of Scientific and Technical Information of China (English)

    龚方戚; 林幼敏; 汤宏峰; 顾伟忠; 汪伟; 康曼丽

    2004-01-01

    Objective: To investigate the evolution of pulmonary hypertension, the pathological changes of pulmonary arteries, and the expression of VEGFmRNA and eNOSmRNA of pulmonary arterial endothelial cells in immature rabbits treated with intratracheal bleomycin (BLM). Methods: Immature rabbits were divided into control and BLM group. Two and four weeks after intratracheal normal saline or BLM injection, the systolic, diastolic and mean pulmonary artery pressure (PASP, PADP, MPAP) were measured by micro-catheter; the pathological changes and the expression of VEGFmRNA and eNOSmRNA of endothelial cells in pulmonary arteries were evaluated by HE and in situ hybridization.Results: Two and four weeks after intratracheal injection of BLM, the PASP, PADP and MPAP increased 53%, 49%, 52%in 2 weeks, and 43%, 89%, 56% in 4 weeks; the wall thickness increased and the cavity in middle and small pulmonary arteries became narrow; the Thickness Index (TI) and Area Index (AI) increased 25%, 14% in 2 weeks, and 22%, 24% in 4 weeks; the level of VEGFmRNA and eNOSmRNA expression decreased 46%, 43% in 2 weeks, and 43%, 51% in 4 weeks.There was no significant difference between 2 weeks and 4 weeks BLM groups. Conclusion: The pulmonary artery pressure was elevated, the thickness of wall increased and the cavity became narrow in middle and small pulmonary arteries, and the level of VEGFmRNA and eNOSmRNA expression in pulmonary arterial endothelial cells decreased in immature rabbits after 2 weeks and 4 weeks of intratracheal 4 U/kg BLM injection.

  8. Heat Shock Protein 27 Plays a Pivotal Role in Myofibroblast Differentiation and in the Development of Bleomycin-Induced Pulmonary Fibrosis

    Science.gov (United States)

    Park, Ah-Mee; Kanai, Kyosuke; Itoh, Tatsuki; Sato, Takao; Tsukui, Tatsuya; Inagaki, Yutaka; Selman, Moises; Matsushima, Kouji; Yoshie, Osamu

    2016-01-01

    Heat shock protein 27 (HSP27) is a member of the small molecular weight HSP family. Upon treatment with transforming growth factor β1 (TGF-β1), we observed upregulation of HSP27 along with that of α-smooth muscle actin (α-SMA), a marker of myofibroblast differentiation, in cultured human and mouse lung fibroblasts. Furthermore, by using siRNA knockdown, we demonstrated that HSP27 was involved in cell survival and upregulation of fibronectin, osteopontin (OPN) and type 1 collagen, all functional markers of myofibroblast differentiation, in TGF-β1-treated MRC-5 cells. In lung tissues of bleomycin-treated mice, HSP27 was strongly upregulated and substantially co-localized with α-SMA, OPN and type I collagen but not with proSP-C (a marker of type II alveolar epithelial cells), E-cadherin (a marker of epithelial cells) or F4/80 (a marker of macrophages). A similar co-localization of HSP27 and α-SMA was observed in lung tissues of patients with idiopathic pulmonary fibrosis. Furthermore, airway delivery of HSP27 siRNA effectively suppressed bleomycin-induced pulmonary fibrosis in mice. Collectively, our findings indicate that HSP27 is critically involved in myofibroblast differentiation of lung fibroblasts and may be a promising therapeutic target for lung fibrotic diseases. PMID:26859835

  9. Effects of turmeric and its active principle, curcumin, on bleomycin-induced chromosome aberrations in Chinese hamster ovary cells

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    Maria Cristina P. Araújo

    1999-09-01

    Full Text Available Naturally occurring antioxidants have been extensively studied for their capacity to protect organisms and cells from oxidative damage. Many plant constituents including turmeric and curcumin appear to be potent antimutagens and antioxidants. The effects of turmeric and curcumin on chromosomal aberration frequencies induced by the radiomimetic agent bleomycin (BLM were investigated in Chinese hamster ovary (CHO cells. Three concentrations of each drug, turmeric (100, 250 and 500 mg/ml and curcumin (2.5, 5 and 10 mg/ml, were combined with BLM (10 mg/ml in CHO cells treated during the G1/S, S or G2/S phases of the cell cycle. Neither turmeric nor curcumin prevented BLM-induced chromosomal damage in any phases of the cell cycle. Conversely, a potentiation of the clastogenicity of BLM by curcumin was clearly observed in cells treated during the S and G2/S phases. Curcumin was also clastogenic by itself at 10 µg/ml in two protocols used. However, the exact mechanism by which curcumin produced clastogenic and potentiating effects remains unknown.Antioxidantes de ocorrência natural têm sido exaustivamente estudados quanto a sua capacidade de proteger organimos e células contra danos oxidativos. Muitos constituintes das plantas, incluindo cúrcuma e curcumina, parecem ser potentes antimutágenos e antioxidantes. Os efeitos de cúrcuma e curcumina na freqüência de aberrações cromossômicas induzidas pelo agente radiomimético bleomicina (BLM foram investigados em células do ovário de hamster chinês (CHO. Três concentrações de cada droga, cúrcuma (100, 250 e 500 mg/ml e curcumina (2,5, 5,0 e 10 mg/ml, foram combinadas com BLM (10 mg/ml em células CHO tratadas durante as fases G1/S, S ou G2/S do ciclo celular. Nem cúrcuma nem curcumina evitaram o dano cromossômico induzido pela BLM em fase alguma do ciclo celular. Ao contrário, a potenciação da clastogenicidade da BLM pelo curcumina foi nitidamente observada em células tratadas

  10. Bleomycin-induced epithelial–mesenchymal transition in sclerotic skin of mice: Possible role of oxidative stress in the pathogenesis

    International Nuclear Information System (INIS)

    Epithelial–mesenchymal transition (EMT) derived myofibroblasts are partly responsible for the increased collagen synthesis and deposition that occur in tissue fibrosis; however EMT occurrence in skin fibrosis and its mechanism remain unknown. The aim of this study was to investigate whether epithelial cells undergo EMT and determine the role of oxidative stress in this process. BALB/c mice were subcutaneously injected with bleomycin (BLM) or phosphate buffer saline (PBS) into the shaved back daily for 2, 3, and 4 weeks. Skin collagen deposition was evaluated by histopathology and Western blotting. EMT characteristics in the skin were determined by histopathology and immunofluorescent staining for E-cadherin and vimentin, which were further evaluated by Western blotting and reverse transcriptase polymerase chain reaction (RT-PCR). To investigate the role of oxidative stress in EMT, the antioxidant N-acetylcysteine (NAC) was intraperitoneally (100 mg/kg body weight/day) injected daily for 3 weeks. The epithelial suprabasal cells were detached from the basement membrane zone (BMZ) in the sclerotic skin treated with BLM. Immunofluorescent staining indicated vimentin-positive epithelial cells frequently occurring in the thickened epidermis of BLM-treated mice. Western blotting and RT-PCR showed that the expression of E-cadherin was significantly decreased but that of vimentin significantly increased in the skin treated with BLM. NAC attenuated BLM induced oxidative damage, changes in E-cadherin and vimentin expressions and collagen deposition in the sclerotic skin of mice. This study provides the first evidence that BLM induces the EMT of the epithelial cells superficial to the basement membrane zone in the skin fibrosis. Oxidative stress may contribute, at least in part, to BLM induced EMT and skin fibrosis in mice. - Highlights: • We provided the first evidence that EMT occurred in BLM-induced skin fibrosis. • Epithelial cells superficial to the BMZ underwent

  11. Secretoglobin 3A2 Exhibits Anti-Fibrotic Activity in Bleomycin-Induced Pulmonary Fibrosis Model Mice.

    Directory of Open Access Journals (Sweden)

    Yan Cai

    Full Text Available Secretoglobin (SCGB 3A2 is a novel lung-enriched cytokine, previously shown to exhibit anti-inflammatory, growth factor, and anti-fibrotic activities. The latter activity was demonstrated using exogenously-administered recombinant SCGB3A2 in the bleomycin (BLM-induced pulmonary fibrosis model. Whether SCGB3A2 exhibits anti-fibrotic activity in vivo is not known.Mice null for the Scgb3a2 gene were subjected to the BLM-induced pulmonary fibrosis model, and the severity of pulmonary fibrosis determined using histological and biochemical methods.BLM treatment caused weight loss of both Scgb3a2-null and wild-type mice, however, the loss was far more pronounced in BLM-treated Scgb3a2-null than wild-type mice, and the weight of day 21 of BLM-treated Scgb3a2-null mice was about half of that of BLM-treated wild-type mice. Hematoxylin & Eosin, Masson Trichrome, and Sirius Red staining of lung sections, Ashcroft fibrosis scores, hydroxyproline contents, and the levels of mRNAs encoding various collagens demonstrated that BLM-treated Scgb3a2-null mouse lungs had more severe fibrosis than those of wild-type mouse lungs. Total and differential inflammatory cell numbers in bronchoalveolar lavage fluids, and levels of lung mRNAs including those encoding Th2 cytokines such as IL-4 and profibrotic cytokines such as TGFβ were higher in BLM-treated Scgb3a2-null mouse lungs as compared to those of wild-type mouse lungs. In contrast, mRNAs encoding surfactant proteins A, B, C, and D, and SCGB1A1 did not differ between BLM-treated Scgb3a2-null and wild-type mouse lungs.The role of SCGB3A2 in fibrosis was revisited using Scgb3a2-null mice and littermate controls in the BLM-induced pulmonary fibrosis model. The pulmonary fibrosis in the Scgb3a2-null mice was more severe than the wild-type controls, thus establishing that SCGB3A2 has anti-fibrotic activity in vivo. Importantly, surfactant proteins and SCGB1A1 appear not to be involved in the susceptibility of Scgb3a2

  12. Bleomycin-induced epithelial–mesenchymal transition in sclerotic skin of mice: Possible role of oxidative stress in the pathogenesis

    Energy Technology Data Exchange (ETDEWEB)

    Zhou, Cheng-Fan, E-mail: zhouchengfan@sohu.com [Institute of Dermatology, the First Affiliated Hospital, Anhui Medical University, Hefei, Anhui 230022 (China); Department of Occupational Health and Environmental Health, School of Public Health, Anhui Medical University, Hefei, Anhui 230032 (China); Zhou, Deng-Chuan [Department of Emergency Medicine and Critical Care Medicine, the First Affiliated Hospital, Anhui Medical University, Hefei, Anhui 230022 (China); Zhang, Jia-Xiang; Wang, Feng; Cha, Wan-Sheng [Department of Occupational Health and Environmental Health, School of Public Health, Anhui Medical University, Hefei, Anhui 230032 (China); Wu, Chang-Hao [Department of Biochemistry and Physiology, Faculty of Health and Medical Sciences, University of Surrey (United Kingdom); Zhu, Qi-Xing, E-mail: zqxing@yeah.net [Institute of Dermatology, the First Affiliated Hospital, Anhui Medical University, Hefei, Anhui 230022 (China); Department of Occupational Health and Environmental Health, School of Public Health, Anhui Medical University, Hefei, Anhui 230032 (China)

    2014-06-15

    Epithelial–mesenchymal transition (EMT) derived myofibroblasts are partly responsible for the increased collagen synthesis and deposition that occur in tissue fibrosis; however EMT occurrence in skin fibrosis and its mechanism remain unknown. The aim of this study was to investigate whether epithelial cells undergo EMT and determine the role of oxidative stress in this process. BALB/c mice were subcutaneously injected with bleomycin (BLM) or phosphate buffer saline (PBS) into the shaved back daily for 2, 3, and 4 weeks. Skin collagen deposition was evaluated by histopathology and Western blotting. EMT characteristics in the skin were determined by histopathology and immunofluorescent staining for E-cadherin and vimentin, which were further evaluated by Western blotting and reverse transcriptase polymerase chain reaction (RT-PCR). To investigate the role of oxidative stress in EMT, the antioxidant N-acetylcysteine (NAC) was intraperitoneally (100 mg/kg body weight/day) injected daily for 3 weeks. The epithelial suprabasal cells were detached from the basement membrane zone (BMZ) in the sclerotic skin treated with BLM. Immunofluorescent staining indicated vimentin-positive epithelial cells frequently occurring in the thickened epidermis of BLM-treated mice. Western blotting and RT-PCR showed that the expression of E-cadherin was significantly decreased but that of vimentin significantly increased in the skin treated with BLM. NAC attenuated BLM induced oxidative damage, changes in E-cadherin and vimentin expressions and collagen deposition in the sclerotic skin of mice. This study provides the first evidence that BLM induces the EMT of the epithelial cells superficial to the basement membrane zone in the skin fibrosis. Oxidative stress may contribute, at least in part, to BLM induced EMT and skin fibrosis in mice. - Highlights: • We provided the first evidence that EMT occurred in BLM-induced skin fibrosis. • Epithelial cells superficial to the BMZ underwent

  13. Meiotic and Mitotic Phenotypes Conferred by the blm1-1 Mutation in Saccharomyces cerevisiae and MSH4 Suppression of the Bleomycin Hypersusceptibility

    Directory of Open Access Journals (Sweden)

    Carol Wood Moore

    2003-01-01

    Full Text Available Abstract: Oxidative damage can lead to a number of diseases, and can be fatal. The blm1-1 mutation of Saccharomyces cerevisiae confers hypersusceptibility to lethal effects of the oxidative, anticancer and antifungal agent, bleomycin. For the current report, additional defects conferred by the mutation in meiosis and mitosis were investigated. The viability of spores produced during meiosis by homozygous normal BLM1/BLM1, heterozygous BLM1/blm1-1, and homozygous mutant blm1-1/blm1-1 diploid strains was studied and compared. Approximately 88% of the tetrads derived from homozygous blm1-1/blm1-1 mutant diploid cells only produced one or two viable spores. In contrast, just one tetrad among all BLM1/BLM1 and BLM1/blm1-1 tetrads only produced one or two viable spores. Rather, 94% of BLM1/BLM1 tetrads and 100% of BLM1/blm1-1 tetrads produced asci with four or three viable spores. Thus, at least one copy of the BLM1 gene is essential for the production of four viable spores after meiosis. During mitotic growth, mutant blm1-1 strains grew at reduced rates and produced cells with high frequencies of unusual morphologies compared to wild-type strains. These results indicated BLM1 is also essential for normal mitotic growth. We also investigated the suppression by the MSH4 gene, a meiosis-specific MutS homolog, of the bleomycin hypersusceptibility of blm1-1 mutant cells, and the relationship of MSH4 to BLM1. We screened a genomic library, and isolated the MSH4 gene on the basis of its ability to suppress lethal effects of bleomycin in blm1-1 cells. However, genetic mapping studies indicated that BLM1 and MSH4 are not the same gene. The possibility that chromosomal nondisjunction could be the basis for the inability of blm1-1/blm1-1 mutant cells to produce four viable spores after meiosis is discussed.

  14. Combined chemotherapy and radiotherapy in diffuse large cell immunoblastic lymphoma: a phase II study of CHOP/bleomycin/methotrexate alternating with ifosfamide/methotrexate/etoposide

    International Nuclear Information System (INIS)

    The clinical outcome of 23 patients with high grade diffuse large cell immunoblastic lymphoma (Working Formulation, category H) treated by an intensive shortened schedule regimen of chemotherapy is described. Alternating cycles of cyclophosphamide, doxorubicin, vincristine, bleomycin and prednisolone, and ifosfamide, etoposide and methotrexate were given over an 18-week (range 16.0-20.8) period. External beam radiotherapy was administered as consolation therapy to sites of original bulky disease in 17 patients. Treatment was well tolerated, though there were two toxic deaths. A 90% response rate was obtained. Sixteen of 18 patients followed for a minimum of 36 months are alive and in complete remission, representing a disease free survival of 69.5%; two further patients are alive following autologous bone marrow transplant. The 3-year disease free survival was 73% (±9%) and the overall 3-year survival 78% (±9%). (author)

  15. MAP3K19 Is a Novel Regulator of TGF-β Signaling That Impacts Bleomycin-Induced Lung Injury and Pulmonary Fibrosis.

    Directory of Open Access Journals (Sweden)

    Stefen A Boehme

    Full Text Available Idiopathic pulmonary fibrosis (IPF is a progressive, debilitating disease for which two medications, pirfenidone and nintedanib, have only recently been approved for treatment. The cytokine TGF-β has been shown to be a central mediator in the disease process. We investigated the role of a novel kinase, MAP3K19, upregulated in IPF tissue, in TGF-β-induced signal transduction and in bleomycin-induced pulmonary fibrosis. MAP3K19 has a very limited tissue expression, restricted primarily to the lungs and trachea. In pulmonary tissue, expression was predominantly localized to alveolar and interstitial macrophages, bronchial epithelial cells and type II pneumocytes of the epithelium. MAP3K19 was also found to be overexpressed in bronchoalveolar lavage macrophages from IPF patients compared to normal patients. Treatment of A549 or THP-1 cells with either MAP3K19 siRNA or a highly potent and specific inhibitor reduced phospho-Smad2 & 3 nuclear translocation following TGF-β stimulation. TGF-β-induced gene transcription was also strongly inhibited by both the MAP3K19 inhibitor and nintedanib, whereas pirfenidone had a much less pronounced effect. In combination, the MAP3K19 inhibitor appeared to act synergistically with either pirfenidone or nintedanib, at the level of target gene transcription or protein production. Finally, in an animal model of IPF, inhibition of MAP3K19 strongly attenuated bleomycin-induced pulmonary fibrosis when administered either prophylactically ortherapeutically. In summary, these results strongly suggest that inhibition of MAP3K19 may have a beneficial therapeutic effect in the treatment of IPF and represents a novel strategy to target this disease.

  16. Knock out of S1P3 receptor signaling attenuates inflammation and fibrosis in bleomycin-induced lung injury mice model.

    Directory of Open Access Journals (Sweden)

    Ken Murakami

    Full Text Available Sphingosine-1-phosphate (S1P is a bioactive sphingolipid metabolite involved in many critical cellular processes, including proliferation, migration, and angiogenesis, through interaction with a family of five G protein-coupled receptors (S1P1-5. Some reports have implicated S1P as an important inflammatory mediator of the pathogenesis of airway inflammation, but the role of S1P3 in the pathogenesis of lung diseases is not completely understood. We used S1P3-deficient (knockout (KO mice to clarify the role of S1P3 receptor signaling in the pathogenesis of pulmonary inflammation and fibrosis using a bleomycin-induced model of lung injury. On the seventh day after bleomycin administration, S1P3 KO mice exhibited significantly less body weight loss and pulmonary inflammation than wild-type (WT mice. On the 28th day, there was less pulmonary fibrosis in S1P3 KO mice than in WT mice. S1P3 KO mice demonstrated a 56% reduction in total cell count in bronchoalveolar lavage fluid (BALF collected on the seventh day compared with WT mice; however, the differential white blood cell profiles were similar. BALF analysis on the seventh day showed that connective tissue growth factor (CTGF levels were significantly decreased in S1P3 KO mice compared with WT mice, although no differences were observed in monocyte chemotactic protein-1 (MCP-1 or transforming growth factor β1 (TGF-β1 levels. Finally, S1P levels in BALF collected on the 7th day after treatment were not significantly different between WT and S1P3 KO mice. Our results indicate that S1P3 receptor signaling plays an important role in pulmonary inflammation and fibrosis and that this signaling occurs via CTGF expression. This suggests that this pathway might be a therapeutic target for pulmonary fibrosis.

  17. Persistent improved results after adding vincristine and bleomycin to a cyclophosphamide/hydroxorubicin/Vm-26/prednisone combination (CHVmP) in stage III-IV intermediate- and high-grade non-Hodgkin's lymphoma. The EORTC Lymphoma Cooperative Group.

    Science.gov (United States)

    Meerwaldt, J H; Carde, P; Somers, R; Thomas, J; Kluin-Nelemans, J C; Bron, D; Noordijk, E M; Cosset, J M; Bijnens, L; Teodorovic, I; Hagenbeek, A

    1997-01-01

    CHOP has been and still is regarded by many as the 'standard' treatment of advanced non-Hodgkin's lymphoma. In 1980 the EORTC Lymphoma Cooperative Group started a study to evaluate the addition of vincristine and bleomycin to its standard four-drug combination chemotherapy, CHVmP (cyclophosphamide, hydroxorubicin, Vm-26, prednisone). Eligible patients were stage III or IV, intermediate- to high-grade non-Hodgkin's lymphoma (Working Formulation E-I). One-hundred-eighty-nine patients were entered, of whom 140 were eligible and evaluable. A previous report showed an improved response rate and failure-free survival (FFS) and overall survival for the combination CHVmP-VB. At ten years, the outcome still favors the addition of vincristine and bleomycin. The FFS was 34% vs. 23% and the overall survival 34% vs 22%. This difference was mainly due to a difference in CR rate (74% vs. 49%), Relapse-free survival for patients reaching a CR was the same in both arms. When the patients were grouped according to the International Prognostic Factor Index, no statistically significant difference could be observed in favor of one treatment within either group. This trial clearly demonstrates the benefit gained by the addition of vincristine and bleomycin to 'standard' chemotherapy for intermediate and high-grade non-Hodgkin's lymphoma.

  18. 博莱霉素涂层支架对胆管良性狭窄的影响%Effects of bleomycin eluting stent on benign biliary stricture

    Institute of Scientific and Technical Information of China (English)

    张庆普; 张晓; 黄涛; 赵付生; 贾廷印; 延学军

    2014-01-01

    Objective To investigate the effects of bleomycin eluting stent on benign biliary stricture.Methods Twenty-four New Zeal white rabbits with bile duct injury were randomly assigned into group A (n =12) and group B (n =12),subject to the implantation of the extrahepatic bile duct bleomycin-coated stents and ordinary stents.After 0 d and 4 weeks,the ear vein blood was taken for determination of total bilirubin,then the rabbits were sacrifaced,the papaffin-embedded sections were prepared by the implanted stents,and stained with hematoxylin and eosin (HE).The computer image detection system was used to examine the changes of gallbladder lumen areas in two groups.Fas,transforming growth factor-β1 (TGF-β1),and α-smooth muscle actin (α-SMA) antibodies were employed for immunostaining in two groups.Results Fas gene expression level in bile duct tissue of group A was significantly higher than in group B (P < 0.05).TGF-β1 and α-SMA expression levels in group A were significantly lower than in group B (P < 0.05).The extrahepatic bile duct stenosis was significantly alleviated,and liver function improved significantly in group A as compared with group B (P < 0.05).Conclusion Bleomycin enhances the expression of Fas gene in rabbit smooth muscle cells,promotes apoptosis,inhibits fibroblast activity,and decreases the deposit of collagen,resulting in the suppression of bile duct stricture,and the recovery of liver function.%目的 观察博莱霉素涂层支架对兔胆管良性狭窄的影响.方法 24只新西兰白兔行胆管损伤后平均分入A、B组,分别将博莱霉素涂层支架和普通支架植入两组兔的肝外胆管内.0d、4周后,取耳缘静脉血,检测总胆红素变化,随后处死兔,取植入支架行石蜡切片,行苏木素-伊红(HE)染色,并采用计算机图像检测系统检测两组胆管腔面积变化,同时各组切片行Fas、转化生长因子-β1(TGF-β1)、α-平滑肌肌动蛋白(α-SMA)抗体进行免疫

  19. Characterization of Quin-C1 for its anti-inflammatory property in a mouse model of bleomycin-induced lung injury

    Institute of Scientific and Technical Information of China (English)

    Min HE; Ni CHENG; Wei-wei GAO; Meng ZHANG; Yue-yun ZHANG; Richard D YE; Ming-wei WANG

    2011-01-01

    Aim: To study the in vivo effects of Quin-C1, a highly specific agonist for formyl peptide receptor 2 (FPR2/ALX), in a mouse model of bleomycin (BLM)-induced lung injury.Methods: Male ICR mice were injected intratracheally with BLM (d O), and intraperitoneally with Quin-C1 (0.2 mg/d) or vehicle between d 1 and d 28, during which pulmonary inflammation was monitored. A similar regimen was carried out between d 5 and d 28 to dif-ferentiate anti-inflammatory from anti-fibrotic effects. During the treatment, leukocyte numbers in bronchoalveolar lavage fluid (BALF)were counted, and FPR2/ALX transcripts, tumor necrosis factor а (TNF-а), interleukin-1β (IL-1β), the mouse keratinocyte-derived chemokine (KC), transforming growth factor 1β (TGF-1β) and C-X-C motif chemokine 10 (CXCL10) expression levels in the lung tissue were also measured. Both hydroxyprollne content and histological changes were examined on d 28 to assess the severity of lung fibro-sis.Results: BLM caused a significant increase in expression levels of all the selected cytokines and chemokines, as well as a thickening of the alveolar wall. Treatment with Quin-C1 significantly reduced the neutrophil and lymphocyte counts in BALF, diminished expres-sion of TNF-а, IL-1β, KC, and TGF-1β, and decreased collagen deposition in lung tissue. The treatment also lowered the content of lung hydroxyproline. Quin-C1 did not ameliorate lung fibrosis when the treatment was started 5 d after the BLM challenge, suggesting that the protection may be attributed to its anti-inflammatory effects. Exposure to BLM or BLM plus Quin-C1 did not change the level of FPR2/ALX transcripts (mFprl, mFpr2, and Lxa4r) in the lung tissue.Conclusion: The results demonstrate an anti-inflammatory role for Quin-C1 in bleomycin-induced lung injury, which may be further explored for therapeutic applications.

  20. Alteration in Intrapulmonary Pharmacokinetics of Aerosolized Model Compounds Due to Disruption of the Alveolar Epithelial Barriers Following Bleomycin-Induced Pulmonary Fibrosis in Rats.

    Science.gov (United States)

    Togami, Kohei; Chono, Sumio; Tada, Hitoshi

    2016-03-01

    Idiopathic pulmonary fibrosis is a lethal lung disease that is characterized by the accumulation of extracellular matrix and a change in lung structure. In this study, intrapulmonary pharmacokinetics of aerosolized model compounds were evaluated using rats with bleomycin-induced pulmonary fibrosis. Aerosol formulations of indocyanine green, 6-carboxyfluorescein (6-CF), and fluorescein isothiocyanate dextrans (FD; 4.4, 10, 70, and 250 kDa) were administered to rat lungs using a MicroSprayer. Indocyanine green fluorescence signals were significantly weaker in fibrotic lungs than in control lungs and 6-CF and FD concentrations in the plasma of pulmonary fibrotic animals were markedly higher than in the plasma of control animals. Moreover, disrupted epithelial tight junctions, including claudins-1, -3, and -5, were observed in pulmonary fibrotic lesions using immunofluorescence microscopy. In addition, destruction of tight junctions on model alveolar epithelial cells (NCI-H441) by transforming growth factor-β1 treatment enhanced the permeability of 6-CF and FDs through NCI-H441 cell monolayers. These results indicate that aerosolized drugs are easily distributed into the plasma after leakage through damaged tight junctions of alveolar epithelium. Therefore, the development of delivery systems for anti-fibrotic agents to improve intrapulmonary pharmacokinetics may be necessary for effective idiopathic pulmonary fibrosis therapy.

  1. Alteration in Intrapulmonary Pharmacokinetics of Aerosolized Model Compounds Due to Disruption of the Alveolar Epithelial Barriers Following Bleomycin-Induced Pulmonary Fibrosis in Rats.

    Science.gov (United States)

    Togami, Kohei; Chono, Sumio; Tada, Hitoshi

    2016-03-01

    Idiopathic pulmonary fibrosis is a lethal lung disease that is characterized by the accumulation of extracellular matrix and a change in lung structure. In this study, intrapulmonary pharmacokinetics of aerosolized model compounds were evaluated using rats with bleomycin-induced pulmonary fibrosis. Aerosol formulations of indocyanine green, 6-carboxyfluorescein (6-CF), and fluorescein isothiocyanate dextrans (FD; 4.4, 10, 70, and 250 kDa) were administered to rat lungs using a MicroSprayer. Indocyanine green fluorescence signals were significantly weaker in fibrotic lungs than in control lungs and 6-CF and FD concentrations in the plasma of pulmonary fibrotic animals were markedly higher than in the plasma of control animals. Moreover, disrupted epithelial tight junctions, including claudins-1, -3, and -5, were observed in pulmonary fibrotic lesions using immunofluorescence microscopy. In addition, destruction of tight junctions on model alveolar epithelial cells (NCI-H441) by transforming growth factor-β1 treatment enhanced the permeability of 6-CF and FDs through NCI-H441 cell monolayers. These results indicate that aerosolized drugs are easily distributed into the plasma after leakage through damaged tight junctions of alveolar epithelium. Therefore, the development of delivery systems for anti-fibrotic agents to improve intrapulmonary pharmacokinetics may be necessary for effective idiopathic pulmonary fibrosis therapy. PMID:26886341

  2. Bleomycin, adiamycin, cyclophosphamide, vincristine, deacadron, etoposide (BACOD-E) chemotherapy for the treatment of non-Hodgkin`s lymphoma. Long-term survival rate and complications

    Energy Technology Data Exchange (ETDEWEB)

    Isobe, Kouichi; Yasuda, Shigeo; Itami, Jun [Chiba Univ. (Japan). School of Medicine] [and others

    1998-06-01

    This study was performed to analyze the effect of Bleomycin, Adriamycin, Cyclophosphamide, Vincristine, Deacadron, Etoposide (BACOD-E) chemotherapy for patients with non-Hodgkin`s lymphoma. Seventy patients with non-Hodgkin`s lymphoma (stage I: 15, stage II: 23, stage III: 20, and stage IV: 12) were treated at the Department of Radiology, Chiba University Hospital, between 1987 and 1995. The response rates for treatment were CR: 63%, PR: 35%, and PD: 2%. The overall disease-free 5-year survival rate was 54%, and those for each stage were as follows: stage I: 78%, stage II: 55%, stage III: 51%, and stage IV: 28%. There were no significant differences between patients with and without B symptoms, or those with and without elevated LDH levels. Treatment associated deaths occurred in six patients. Two patients died due to side effects of chemotherapy during treatment, and one patient due to leukemia 2 years and 5 months after treatment. One patient died due to radiation pneumonitis, one patient due to heart failure, and one patient due to an unknown reason one month after treatment. This chemotherapy may be useful for patients with advanced disease or unfavorable prognostic factors such as B symptoms or elevated LDH. Moreover, the addition of radiation therapy may prolong survival. (author)

  3. Dose evaluation of therapeutic radiolabeled bleomycin complexes based on biodistribution data in wild-type rats:Effect of radionuclides in absorbed dose of different organs

    Institute of Scientific and Technical Information of China (English)

    Hassan Yousefnia; Samaneh Zolghadri; Amir Reza Jalilian; Mohammad Ghannadi-Maragheh

    2015-01-01

    Bleomycins (BLMs), as tumor-seeking antibiotics, have been used for over 20 years in treatment of several types of cancers. Several radioisotopes are used in radiolabeling of BLMs for therapeutic and diagnostic purpos-es. An important points in developing new radiopharmaceuticals, especially therapeutic agents, is the absorbed dose delivered in critical organs. In this work, absorbed dose to organs after injection of 153Sm-, 177Lu-and 166Ho-labeled BLM was investigated by radiation dose assessment resource (RADAR) method based on biodis-tribution data in wild-type rats. The absorbed dose effect of the radionuclides was evaluated. The maximum absorbed dose for the complexes was observed in the kidneys, liver and lungs. For all the radiolabeled BLMs, bone and red marrow received considerable absorbed dose. Due to the high energy beta particles emitted by 166Ho, higher absorbed dose is observed for 166Ho-BLM in the most organs. The reported data can be useful for the determination of the maximum permissible injected activity of the radiolabeled BLMs in the treatment planning programs.

  4. Regeneration of alveolar type I and II cells from Scgb1a1-expressing cells following severe pulmonary damage induced by bleomycin and influenza.

    Directory of Open Access Journals (Sweden)

    Dahai Zheng

    Full Text Available The lung comprises an extensive surface of epithelia constantly exposed to environmental insults. Maintaining the integrity of the alveolar epithelia is critical for lung function and gaseous exchange. However, following severe pulmonary damage, what progenitor cells give rise to alveolar type I and II cells during the regeneration of alveolar epithelia has not been fully determined. In this study, we have investigated this issue by using transgenic mice in which Scgb1a1-expressing cells and their progeny can be genetically labeled with EGFP. We show that following severe alveolar damage induced either by bleomycin or by infection with influenza virus, the majority of the newly generated alveolar type II cells in the damaged parenchyma were labeled with EGFP. A large proportion of EGFP-expressing type I cells were also observed among the type II cells. These findings strongly suggest that Scgb1a1-expressing cells, most likely Clara cells, are a major cell type that gives rise to alveolar type I and II cells during the regeneration of alveolar epithelia in response to severe pulmonary damage in mice.

  5. Bleomycin, adiamycin, cyclophosphamide, vincristine, deacadron, etoposide (BACOD-E) chemotherapy for the treatment of non-Hodgkin's lymphoma. Long-term survival rate and complications

    International Nuclear Information System (INIS)

    This study was performed to analyze the effect of Bleomycin, Adriamycin, Cyclophosphamide, Vincristine, Deacadron, Etoposide (BACOD-E) chemotherapy for patients with non-Hodgkin's lymphoma. Seventy patients with non-Hodgkin's lymphoma (stage I: 15, stage II: 23, stage III: 20, and stage IV: 12) were treated at the Department of Radiology, Chiba University Hospital, between 1987 and 1995. The response rates for treatment were CR: 63%, PR: 35%, and PD: 2%. The overall disease-free 5-year survival rate was 54%, and those for each stage were as follows: stage I: 78%, stage II: 55%, stage III: 51%, and stage IV: 28%. There were no significant differences between patients with and without B symptoms, or those with and without elevated LDH levels. Treatment associated deaths occurred in six patients. Two patients died due to side effects of chemotherapy during treatment, and one patient due to leukemia 2 years and 5 months after treatment. One patient died due to radiation pneumonitis, one patient due to heart failure, and one patient due to an unknown reason one month after treatment. This chemotherapy may be useful for patients with advanced disease or unfavorable prognostic factors such as B symptoms or elevated LDH. Moreover, the addition of radiation therapy may prolong survival. (author)

  6. Pretreatment with UV light renders the chromatin in human fibroblasts more susceptible to the DNA-damaging agents bleomycin, gamma radiation and 8-methoxypsoralen

    International Nuclear Information System (INIS)

    Confluent human fibroblast cultures were pretreated with either 254 nm UV light (UV) or methyl methanesulphonate (MMS), incubated at 370C and subsequently challenged on ice with bleomycin (BLM), gamma-radiation or 8-methoxy-psoralen (MOP). The resulting number of challenge-induced DNA damages (measured as DNA strand breaks or cross-links) were compared with the numbers induced in similarly challenged but non-pretreated control cells. It was found that the timing of the subsequent challenge of cells pretreated with UV did significantly affect the amount of induced DNA damage. When the challenging agents were administered after a 10-20 min incubation period following UV pretreatment, the amount of induced DNA damage was increased 50% over control cells. In contrast, the timing of the subsequent challenge of cells pretreated with MMS has no influence on the level of challenge-induced damage. It is hypothesized that UV-irradiated chromatin undergoes a time-dependent decondensation that renders it more susceptible to the induction of strand breaks and cross-links by BLM, gamma-radiation and MOP. A possible role for chromatin decondensation in UV-induced excision repair is discussed. (author)

  7. Toxicity of aggressive multimodality therapy including cisplatinum, bleomycin and methotrexate with radiation and/or surgery for advanced head and neck cancer

    International Nuclear Information System (INIS)

    A combined modality regimen employing induction chemotherapy with cisplatinum, bleomycin and methotrexate followed by surgery and/or radiation therapy was initiated in patients with advanced squamous cell carcinoma of the head and neck. In the first 23 patients treated with this program there was a 90% response rate to induction chemotherapy (9% CR and 81% PR). Toxicity associated with radiotherapy, but not surgery, was increased with 11 of 23 patients (48%) who experienced some toxicity during or immediately after radiotherapy. Mucositis was worse than expected and severe delayed mucositis was seen in 2 patients, one of whom required hospitalization. Late complications, possibly related to therapy included one myocardial infarction and one episode of hypoglycemia, both of which were fatal. One other patient voluntarily failed to take prescribed oral leucovorin, dying of unrescued methotrexate toxicity during adjuvant therapy, a questionable suicide. Further follow-up analysis of failure will be necessary to determine if the value of a combined modality regimen in producing an increased cure rate and long term survival will out weigh increased toxicity

  8. Aerosolized STAT1 Antisense Oligodeoxynucleotides Decrease the Concentrations of Inflammatory Mediators in Bronchoalveolar Lavage Fluid in Bleomycin-Induced Rat Pulmonary Fibrosis

    Institute of Scientific and Technical Information of China (English)

    Ming Zeng; Bin Liao; Chen Zhu; Wenjun Wang; Xiaoqin Zhan; Xianming Fan

    2008-01-01

    It has been demonstrated that alveolar macrophages (AMs) play a key role in the pathogenesis of pulmonary fibrosis by releasing a variety of cytokines and inflammatory mediators. In addition, abnormal signal transducer and activator of transcription-1 (STAT1) activation in AMs may play a pivotal role in the process of alveolitis and pulmonary fibrosis. In this study, we transfected STAT1 antisense oligodeoxynucleotide (ASON) into rats by aerosolization, and then investigated the effect of STAT1 ASON on inflammatory mediators such as TGF-β, PDGF and TNF-α in bronchoalveolar lavage fluid (BALF) from rats with bleomycin (BLM)-induced rat pulmonary fibrosis. Our results showed that STAT1 ASON by aerosolization could enter into lung tissues and AMs. STAT1 ASON could inhibit mRNA and protein expressions of STATI and ICAM-1 in AMs of rat with pulmonary fibrosis, and had no toxic side effect on liver and kidney. Aerosolized STAT1 ASON could ameliorate the alveolitis through inhibiting the secretion of inflammatory mediators in BLM-induced rat pulmonary fibrosis. These results suggest that aerosolized STAT1 ASON might be considered as a promising new strategy in the treatment of pulmonary fibrosis. Cellular & Molecular Immunology. 2008;5(3):219-224.

  9. High-dose-rate brachytherapy with local injection of bleomycin for N0 oral tongue cancer. Possibilities of the control of tumor implant by inserting applicators and the decrease in tumor dose

    International Nuclear Information System (INIS)

    Twenty-eight patients with N0 oral tongue cancer were treated with high-dose-rate (HDR) interstitial brachytherapy combined with local injection of bleomycin between December 1997 and June 2001 at the Department of Radiology, National Kyushu Medical Center Hospital. A median dose of 5 mg of bleomycin was injected locally, and 16-20 Gy was delivered to the area surrounding applicators for control of the tumor implant during the initial two days. The two-year local recurrence-free survival rate was 96% [T1, 2: 100% (8/8, 15/15), T3: 80% (4/5)]. The two-year secondary neck node metastasis rate was 7.1% [T1: 12.5% (1/8), T2: 6.7% (1/15), T3: 0% (0/5)]. There were no tumor implants in any patients. We tried to decrease the minimal tumor dose step by step. The groups with median minimal tumor doses of 60 Gy, 50 Gy, and 40 Gy had local recurrence rates of 12.5% (1/8), 0% (0/14), and 0% (0/6), respectively. Local recurrence rates were not increased by decreasing the minimal tumor dose. Two patients (7%) had secondary neck node metastasis. Late adverse effects were tongue ulcer: 11% (3/28), oral floor ulcer: 4% (1/28), and osteonecrosis: 4% (1/28). These results suggest that control of the tumor implant and the decrease in minimal tumor dose below 60 Gy may be possible with the local injection of bleomycin and delivery of doses to the area surrounding the applicators when N0 tongue cancer is treated using 192Ir-HDR brachytherapy. (author)

  10. Celastrol enhances Nrf2 mediated antioxidant enzymes and exhibits anti-fibrotic effect through regulation of collagen production against bleomycin-induced pulmonary fibrosis.

    Science.gov (United States)

    Divya, Thomas; Dineshbabu, Vadivel; Soumyakrishnan, Syamala; Sureshkumar, Anandasadagopan; Sudhandiran, Ganapasam

    2016-02-25

    Pulmonary fibrosis (PF) is characterized by excessive accumulation of extracellular matrix components in the alveolar region which distorts the normal lung architecture and impairs the respiratory function. The aim of this study is to evaluate the anti-fibrotic effect of celastrol, a quinine-methide tri-terpenoid mainly found in Thunder God Vine root extracts against bleomycin (BLM)-induced PF through the enhancement of antioxidant defense system. A single intratracheal instillation of BLM (3 U/kg.bw) was administered in rats to induce PF. Celastrol (5 mg/kg) was given intraperitoneally, twice a week for a period of 28 days. BLM-induced rats exhibits declined activities of enzymatic and non-enzymatic antioxidants which were restored upon treatment with celastrol. BLM-induced rats show increased total and differential cell counts as compared to control and celastrol treated rats. Histopathological analysis shows increased inflammation and alveolar damage; while assay of hydroxyproline and Masson's trichrome staining shows an increased collagen deposition in BLM-challenged rats that were decreased upon celastrol treatment. Celastrol also reduces inflammation in BLM-induced rats as evidenced by decrease in the expressions of mast cells, Tumor necrosis factor-alpha (TNF- α) and matrix metalloproteinases (MMPs) 2 and 9. Further, Western blot analysis shows that celastrol is a potent inducer of NF-E2-related factor 2 (Nrf2) and it restores the activities of Phase II enzymes such as hemoxygenase-1 (HO-1), glutathione-S-transferase (GSTs) and NADP(H): quinine oxidoreductase (NQO1) which were declined upon BLM administration. The results of this study show evidence on the protective effect of celastrol against BLM-induced PF through its antioxidant and anti-fibrotic effects. PMID:26768587

  11. Atomic resolution structure of EhpR: phenazine resistance in Enterobacter agglomerans Eh1087 follows principles of bleomycin/mitomycin C resistance in other bacteria

    Directory of Open Access Journals (Sweden)

    Itzen Aymelt

    2011-08-01

    Full Text Available Abstract Background The phenazines are redox-active secondary metabolites that a large number of bacterial strains produce and excrete into the environment. They possess antibiotic activity owing to the fact that they can reduce molecular oxygen to toxic reactive oxygen species. In order to take advantage of this activity, phenazine producers need to protect themselves against phenazine toxicity. Whereas it is believed that phenazine-producing pseudomonads possess highly active superoxide dismutases and catalases, it has recently been found that the plant-colonizing bacterium Enterobacter agglomerans expresses a small gene ehpR to render itself resistant towards D-alanyl-griseoluteic acid, the phenazine antibiotic produced by this strain. Results To understand the resistance mechanism installed by EhpR we have determined its crystal structure in the apo form at 2.15 Å resolution and in complex with griseoluteic acid at 1.01 Å, respectively. While EhpR shares a common fold with glyoxalase-I/bleomycin resistance proteins, the ligand binding site does not contain residues that some related proteins employ to chemically alter their substrates. Binding of the antibiotic is mediated by π-stacking interactions of the aromatic moiety with the side chains of aromatic amino acids and by a few polar interactions. The dissociation constant KD between EhpR and griseoluteic acid was quantified as 244 ± 45 μM by microscale thermophoresis measurements. Conclusions The data accumulated here suggest that EhpR confers resistance by binding D-alanyl-griseoluteic acid and acting as a chaperone involved in exporting the antibiotic rather than by altering it chemically. It is tempting to speculate that EhpR acts in concert with EhpJ, a transport protein of the major facilitator superfamily that is also encoded in the phenazine biosynthesis operon of E. agglomerans. The low affinity of EhpR for griseoluteic acid may be required for its physiological function.

  12. Aliskiren attenuates bleomycin-induced pulmonary fibrosis in rats: focus on oxidative stress, advanced glycation end products, and matrix metalloproteinase-9.

    Science.gov (United States)

    Abuelezz, Sally A; Hendawy, Nevien; Osman, Wesam M

    2016-08-01

    Pulmonary fibrosis is a progressive lung disorder with high mortality rate and limited successful treatment. This study was designed to assess the potential anti-oxidant and anti-fibrotic effects of aliskiren (Alsk) during bleomycin (BLM)-induced pulmonary fibrosis. Male Wistar rats were used as control untreated or treated with the following: a single dose of 2.5 mg/kg of BLM endotracheally and BLM and Alsk (either low dose 30 mg/kg/day or high dose 60 mg/kg/day), and another group was given Alsk 60 mg/kg/day alone. Alsk was given by gavage. Alsk anti-oxidant and anti-fibrotic effects were assessed. BLM significantly increased relative lung weight and the levels of lactate dehydrogenase and total and differential leucocytic count in bronchoalveolar lavage that was significantly ameliorated by high-dose Alsk treatment. As markers of oxidative stress, BLM caused a significant increase in the levels of lipid peroxides and nitric oxide accompanied with a significant decrease of superoxide dismutase and glutathione transferase enzymes. High-dose Alsk treatment restored these markers toward normal values. Alsk counteracted the overexpression of advanced glycation end products, matrix metalloproteinase-9 (MMP-9), and tissue inhibitor of metalloproteinases-1 in lung tissue induced by BLM. Fibrosis assessed by measuring hydroxyproline content, which markedly increased in the BLM group, was also significantly reduced by Alsk. These were confirmed by histopathological and immunohistochemical examination which revealed that Alsk attenuates signs of pulmonary fibrosis and decreased the overexpressed MMP-9 and transforming growth factor β1. Collectively, these findings indicate that Alsk has a potential anti-fibrotic effect beside its anti-oxidant activity. PMID:27154762

  13. Use of senescence-accelerated mouse model in bleomycin-induced lung injury suggests that bone marrow-derived cells can alter the outcome of lung injury in aged mice.

    Science.gov (United States)

    Xu, Jianguo; Gonzalez, Edilson T; Iyer, Smita S; Mac, Valerie; Mora, Ana L; Sutliff, Roy L; Reed, Alana; Brigham, Kenneth L; Kelly, Patricia; Rojas, Mauricio

    2009-07-01

    The incidence of pulmonary fibrosis increases with age. Studies from our group have implicated circulating progenitor cells, termed fibrocytes, in lung fibrosis. In this study, we investigate whether the preceding determinants of inflammation and fibrosis were augmented with aging. We compared responses to intratracheal bleomycin in senescence-accelerated prone mice (SAMP), with responses in age-matched control senescence-accelerated resistant mice (SAMR). SAMP mice demonstrated an exaggerated inflammatory response as evidenced by lung histology. Bleomycin-induced fibrosis was significantly higher in SAMP mice compared with SAMR controls. Consistent with fibrotic changes in the lung, SAMP mice expressed higher levels of transforming growth factor-beta1 in the lung. Furthermore, SAMP mice showed higher numbers of fibrocytes and higher levels of stromal cell-derived factor-1 in the peripheral blood. This study provides the novel observation that apart from increases in inflammatory and fibrotic factors in response to injury, the increased mobilization of fibrocytes may be involved in age-related susceptibility to lung fibrosis. PMID:19359440

  14. Multidrug chemotherapy (vincristine-bleomycin-methotrexate) followed by radiotherapy in inoperable carcinomas of the head and neck: preliminary report of a pilot study of the Radiation Therapy Oncology Group

    International Nuclear Information System (INIS)

    This is a preliminary report on the Radiation Therapy Oncology Group (RTOG) pilot study 77-08, of a combination of chemotherapy with vincristine-bleomycin-methotrexate, followed by radiotherapy, for inoperable carcinomas of the head and neck. The main objectives of the study were to determine toxicity and tumor control. Patients who were included had untreated carcinomas, with no distant metastases, and with adequate pulmonary, renal, and liver function. Forty patients were registered for the study. Chemotherapy started with vincristine--1.5 mgs/m2 (maximum of 2 mgs) by I.V. injection, followed by bleomycin drip for 48 hours (15 units/day), and then methotrexate (200 mgs/m2 divided in equal doses 6 hours apart) with folinic acid rescue. Eleven patients received one course of the stated chemotherapy; 28 were given two courses with one week rest period between them. Radical curative radiotherapy was started usually two weeks after chemotherapy. A surgical procedure was considered if the patient was found operable after receiving a dose of 5000 rad with continuous therapy or at 3000 rad with split-course therapy. The level of toxicity that resulted from this combined therapy was considered acceptable. The percentage of complete response of the primary tumor was 6% with chemotherapy; this increased to 46% after irradiation, and to 65% when surgery was added

  15. Second-line chemotherapy with bleomycin, methotrexate, and vinorelbine (BMV) for patients with squamous cell carcinoma of the head, neck and esophagus (SCC-HN&E) pretreated with a cisplatin-containing regimen: a phase II study.

    Science.gov (United States)

    Moroni, M; Giannetta, L; Gelosa, G; Secondino, S; Chillura, G; Colombo, E; Siena, S

    2003-08-01

    We evaluated the toxicity and activity of bleomycin, methotrexate and vinorelbine (BMV) combination chemotherapy in cisplatin-pretreated patients with squamous cell carcinoma of the head, neck and esophagus (SCC-HN&E) with the aim of identifying a second-line therapy combination and schedule that might offer an improved therapeutic index. BMV (bleomycin 15 I.U., total dose, methotrexate 30 mg/m2, and vinorelbine 30 mg/m2) was administered intravenously every 2 weeks until disease progression, to 26 consecutive patients. Clinical and CT-scan evaluations revealed 7 partial responses (PR) 127%, 95% confidence interval: 9.6%-44.4%], and 13 patients with stable disease (SD) [50%]. The mean progression-free survival for patients who achieved a PR or SD was 6.47 months (range 4-13 months), with 75% of these patients experiencing partial relief of symptoms, mainly pain and dysphagia. BMV, administered second-line in an outpatient setting, has activity similar to that of the taxanes, but with a more acceptable toxicity profile including an absence of alopecia.

  16. 抗KL-6抗体减弱博莱霉素诱导的肺纤维化%Bleomycin-induced pulmonary fibrosis is attenuated by anti-KL-6 antibody

    Institute of Scientific and Technical Information of China (English)

    徐凌; 杨丹榕; 朱松雷; 顾杰; 丁凤鸣; 边巍; 容朝晖; 沈策

    2013-01-01

    目的 探讨抗KL-6抗体对博莱霉素诱导的肺纤维化的预防作用及可能机制.方法 用气管内滴注博莱霉素的方法制作小鼠肺纤维化模型,于滴注博莱霉素前2天开始雾化抗KL-6抗体,至滴注博莱霉素后第21天.通过支气管肺泡灌洗液细胞计数及分类评价肺部炎症情况,通过肺组织病理评分、羟脯氨酸含量评价肺纤维化情况.通过肺组织中KL-6、转化生长因子p1(TGF-β1)、肝细胞生长因子(HGF)水平、Ⅰ型和Ⅲ型胶原的表达及上皮细胞凋亡情况探讨其可能机制.结果 预防性应用抗KL6抗体可显著降低第21天支气管肺泡灌洗液中的细胞总数及巨噬细胞、淋巴细胞数(P<0.05);降低第14、21天时的肺组织病理评分、羟脯氨酸含量及Ⅰ型、Ⅲ型胶原的表达(P<0.05);降低各时间点上肺组织中KL-6、TGF-β1水平(P<0.05);升高第14、21天时HGF水平(P<0.05);减少各个时间点上的上皮细胞凋亡数(P<0.05).结论 预防性应用抗KL-6抗体可减弱博莱霉素诱导的炎症和纤维化反应,其治疗效应可能是通过降低Ⅰ型和Ⅲ型胶原的表达、增加HGF的产生、减少KL 6和TGF-β1的产生、降低肺上皮细胞的凋亡而发挥作用.%Objective To assess the effect and mechanisms of anti-KL-6 antibody on bleomycininduced pulmonary fibrosis in mice.Methods Pulmonary fibrosis was induced in C57BL/6 mice by intratracheal instillation of bleomycin.Anti-KL-6 antibody was given from two days before bleomycin instillation to the 21st day after bleomycin instillation.Lung inflammation was assessed by bronchoalveolar lavage fluid (BALF) differential cell count.Changes in tissue remodeling were evaluated by quantified pathological examination,measurement of hydroxyproline content.Collagen type Ⅰ and type Ⅲ were detected by qRT-PCR,KL-6,transforming growth factor-β1 (TGF-β1),and hepatocyte growth factor (HGF) in lung tissues were detected by ELISA,and epithelial

  17. 博莱霉素联合局部热疗治疗恶性胸腔积液的临床观察%Clinical observation of bleomycin combined with local thermotherapy in the treatment of malignant pleural effusion

    Institute of Scientific and Technical Information of China (English)

    周洋; 黄河; 张家洪; 龚建化

    2014-01-01

    Objective To observe the clinical effect of bleomycin combined with local thermotherapy in the treatment of NSCLC patients with malignant pleural effusion. Methods 50 NSCLC patients with malignant pleural effusion were randomly divided into two groups. All patients were treated with thoracentesis and inserted central ve-nous catheter to drainage pleural effusion. After exhaustion of pleural effusion, the control group was treated with ble-omycin by pleural perfusion, and the experiment group was treated with local thermotherapy on the base of the control group. The treatment, side effect and quality of life were compared. Results After the treatment, the KPS scores of living quality and the total effective rate of controlling pleural effusion were better in the experiment group than in the control group (P<0. 05), and the side effect was significant lower in the experiment group than in the control group (P<0. 05). Conclusion Bleomycin combined with local thermotherapy has a synergistic effect in the treatment of NSCLC with malignant pleural effusion.%目的:观察博莱霉素联合局部热疗治疗非小细胞肺癌( NSCLC)恶性胸腔积液的临床疗效。方法将50例NSCLC恶性胸腔积液的患者随机分为两组,采用胸腔穿刺术置入中心静脉导管引流胸腔积液,待排尽胸腔积液后,对照组给予胸腔灌注博莱霉素,实验组在对照组的基础上给予患者局部热疗,比较两组治疗情况、毒副反应及生活质量改善情况。结果两组患者治疗后,实验组患者的生活质量KPS评分及控制胸水的总有效率均明显高于对照组(P<0.05),且不良反应明显少于对照组(P<0.05)。结论博莱霉素联合局部热疗治疗NSCLC恶性胸腔积液具有协同作用,值得临床推广。

  18. Experimental Study on Effect of Compound Biejia Ruangan Prescription(复方鳖甲软肝方) on High-Resolution Computerized Tomographic Images in Bleomycin Induced Pulmonary Fibrosis Rats

    Institute of Scientific and Technical Information of China (English)

    张东伟; 王继峰; 牛建昭; 高宝华; 李贡宇

    2003-01-01

    Objective: To study the therapeutic effect of Compound Biejia Ruangan prescription (CBRP) on rat model with pulmonary fibrosis induced by bleomycin. Methods: Fifty-four male Sprague-Dawley rats were randomly divided into 6 groups (9 rats in each group). From the first day to the 28th day of the experiment, except to those in the sham-model control group that were treated with normal saline, the same amount of bleomycin injection as the normal saline given to the control group was given through endotracheal instillation to all the rats in all the other groups. From the 29th day of the modeling, CBRP solution of different dosages was respectively injected into the rats in the high, moderate and low CBRP dose group, while equal volume of normal saline was given to those in the sham-model control group and the model control group, and an equal volume of prednisone solution was given to rats in the prednisone group. On the 80th day, the high-resolution computerized tomographic (HRCT) images were observed on an equal footing, and HRCT-pathology was correlatively studied. Results: Different HRCT pathological changes were shown in the rats with pulmonary fibrosis, such as lung consolidation, thickening of interlobular septum and interlobular mesenchyma as well as lobular deformation, nodule shadow, abnormal brochiovascular tract, thickened pleura with irregular junction and polished glass-like dense shadows. Honeycomb lung was observed in some cases. Pathological sections showed fibrotic proliferation of lung tissues and noticeable pulmonary interstitial fibrosis. CBRP could improve HRCT images of rats with pulmonary fibrosis, and lower fibrotic proliferation of the lung tissue.Conclusion: CBRP plays its therapeutic role possibly through its effect on the structure of the lung in rats with pulmonary fibrosis.

  19. The cannabinoid quinol VCE-004.8 alleviates bleomycin-induced scleroderma and exerts potent antifibrotic effects through peroxisome proliferator-activated receptor-γ and CB2 pathways.

    Science.gov (United States)

    del Río, Carmen; Navarrete, Carmen; Collado, Juan A; Bellido, M Luz; Gómez-Cañas, María; Pazos, M Ruth; Fernández-Ruiz, Javier; Pollastro, Federica; Appendino, Giovanni; Calzado, Marco A; Cantarero, Irene; Muñoz, Eduardo

    2016-02-18

    Scleroderma is a group of rare diseases associated with early and transient inflammation and vascular injury, followed by fibrosis affecting the skin and multiple internal organs. Fibroblast activation is the hallmark of scleroderma, and disrupting the intracellular TGFβ signaling may provide a novel approach to controlling fibrosis. Because of its potential role in modulating inflammatory and fibrotic responses, both PPARγ and CB2 receptors represent attractive targets for the development of cannabinoid-based therapies. We have developed a non-thiophilic and chemically stable derivative of the CBD quinol (VCE-004.8) that behaves as a dual agonist of PPARγ and CB2 receptors, VCE-004.8 inhibited TGFβ-induced Col1A2 gene transcription and collagen synthesis. Moreover, VCE-004.8 inhibited TGFβ-mediated myofibroblast differentiation and impaired wound-healing activity. The anti-fibrotic efficacy in vivo was investigated in a murine model of dermal fibrosis induced by bleomycin. VCE-004.8 reduced dermal thickness, blood vessels collagen accumulation and prevented mast cell degranulation and macrophage infiltration in the skin. These effects were impaired by the PPARγ antagonist T0070907 and the CB2 antagonist AM630. In addition, VCE-004.8 downregulated the expression of several key genes associated with fibrosis, qualifying this semi-synthetic cannabinoid as a novel compound for the management of scleroderma and, potentially, other fibrotic diseases.

  20. Salidroside protects against bleomycin-induced pulmonary fibrosis: activation of Nrf2-antioxidant signaling, and inhibition of NF-κB and TGF-β1/Smad-2/-3 pathways.

    Science.gov (United States)

    Tang, Haiying; Gao, Lili; Mao, Jingwei; He, Huanyu; Liu, Jia; Cai, Xin; Lin, Hongli; Wu, Taihua

    2016-03-01

    Pulmonary fibrosis (PF) can severely disrupt lung function, leading to fatal consequences. Salidroside is a principal active ingredient of Rhodiola rosea and has recently been reported to protect against lung injures. The present study was aimed at exploring its therapeutic effects on PF. Lung fibrotic injuries were induced in SD rats by a single intratracheal instillation of 5 mg/kg bleomycin (BLM). Then, these rats were administrated with 50, 100, or 200 mg/kg salidroside for 28 days. BLM-triggered structure distortion, collagen overproduction, excessive inflammatory infiltration, and pro-inflammatory cytokine release, and oxidative stress damages in lung tissues were attenuated by salidroside in a dose-dependent manner. Furthermore, salidroside was noted to inhibit IκBα phosphorylation and nuclear factor kappa B (NF-κB) p65 nuclear accumulation while activating Nrf2-antioxidant signaling in BLM-treated lungs. Downregulation of E-cadherin and upregulation of vimentin, fibronectin, and α-smooth muscle actin (α-SMA) indicated an epithelial-mesenchymal transition (EMT)-like shift in BLM-treated lungs. These changes were suppressed by salidroside. The expression of TGF-β1 and the phosphorylation of its downstream targets, Smad-2/-3, were enhanced by BLM, but weakened by salidroside. Additionally, salidroside was capable of reversing the recombinant TGF-β1-induced EMT-like changes in alveolar epithelial cells in vitro. Our study reveals that salidroside's protective effects against fibrotic lung injuries are correlated to its anti-inflammatory, antioxidative, and antifibrotic properties. PMID:26577463

  1. 3种材质输液容器对盐酸博来霉素A2和B2的吸附性考察%Study on Adsorbability of Bleomycin Hydrochloride A2 and B2 in 3 Different Kinds of Intravenous Solution Containers

    Institute of Scientific and Technical Information of China (English)

    潘文; 黄天文; 雷宇; 梁宁生; 涂文升

    2012-01-01

    目的:考察非聚氯乙烯(PVC)多层共挤膜输液袋、聚丙烯(PP)输液瓶和玻璃瓶3种材质输液容器对盐酸博来霉素的吸附性.方法:取相同量的盐酸博来霉素加入3种包装材质的2种输液(5%葡萄糖注射液和5%葡萄糖氯化钠注射液)中,混合均匀后分别于0、6、24、48 h时取样,采用高效液相色谱法测定药物浓度,与0h时浓度相比计算相对百分含量.结果:48h时,溶媒分别为5%葡萄糖注射液和5%葡萄糖氯化钠注射液时,在PP输液瓶中,盐酸博来霉素A2、B2相对百分含量分别为90.81%、89.56%和55.65%、82.4%;而在另2种材质包装的2种溶媒中,盐酸博来霉素A2、B2相对百分含量均大于95%.结论:3种材质中,以PP输液瓶对盐酸博来霉素吸附性最强,尤其是在以5%葡萄糖氯化钠注射液为溶媒时;临床使用该药时应避免选用该材质输液瓶.%OBJECTIVE: To investigate the adsorbability of non-polyvinly chloride (NPVC) infusion bags, polypropylene (PP) infusion bags and glass bottles to bleomycin hydrochloride, respectively. METHODS: Bleomycin hydrochloride was separately added into above infusion bags or bottles containing 5% Glucose injection (GS) or 5% Glucose sodium chloride injection (GNS). Samples of drug solutions were collected at 0, 6, 24, 48 hours and analyzed by HPLC methods. Relevant percentage content was calculated, compared with concentration at 0 h. RESULTS: At 48 h, solvent were 5% GS and 5% GNS, and relevant percentage contents of bleomycin hydrochloride A2 and B2 in PP bottles were 90.81% , 89.56% and 55.65% , 82.4%. Relevant percentage contents of bleomycin hydrochloride A2 and B2 in other 2 kinds of container were all more than 95%. CONCLUSION: Among 3 kinds of materials, PP infusion bottle shows the strongest adsorbability, especially for 5% GNS as solvent. PP should not be used for bleomycin hydrochloride.

  2. Results of a combination of bleomycin and triamcinolone acetonide in the treatment of keloids and hypertrophic scars Resultados de uma combinação de bleomicina e triamcinolone acetonide no tratamento de quelóides e cicatrizes hipertróficas

    Directory of Open Access Journals (Sweden)

    Francisco Miguel Camacho-Martínez

    2013-06-01

    Full Text Available While treatment of keloids and hypertrophic scars normally shows modest results, we found that treatment with bleomycin was more promising. The present study was divided into two parts. In the first part the aim was to show the results using a combination of bleomycin and triamcinolone acetonide per cm2 (BTA. In the second part the objective was to determine the response to both drugs in large keloids that were divided into 1 cm2 squares, treating each square with the dose previously used. In the first part of the study, the clinical response of 37 keloids ranging from 0.3 to 1.8 cm2 treated with BTA were followed up over a period of 1- 2 years. 0.375 IU bleomycin and 4 mg triamcinolone acetonide were injected every 3 months. In the second part of the study we reviewed the clinical response in six patients with large keloids. The monthly dose administered never exceeded 3 IU of bleomycin. The first study showed 36 keloids (97.29% softening after the first dose. In the second study, 5 showed different responses (the response was complete in the four smaller keloids. The largest keloid needed 9 doses to achieve an improvement of 70%. In conclusion, combined treatment with 0.375 IU of bleomycin and 4mg of triamcinolone acetonide to 1 cm2 was considered to be an acceptable procedure for the treatment of keloids. The best results were obtained in keloids over 1 cm2 or when divided into 1 cm2 square areas. Larger series need to be performed in order to confirm these results..Enquanto normalmente o tratamento de queloides e cicatrizes hipertróficas mostra resultados moderados, o tratamento com bleomicina revelou resultados mais promissores. Este estudo foi dividido em duas partes. Na primeira parte, o objetivo foi mostrar os resultados da utilização de uma combinação de bleomicina e acetonido de triancinolona por cm2 (BAT. Na segunda parte, o objetivo foi determinar a resposta aos dois medicamentos em queloides grandes, que foram divididos em

  3. Quantitative treatment of intratumoral injection of bleomycin based on MRI volume measurements of pharynx and larynx hemangioma%根据MRI体积测量咽喉部血管瘤平阳霉素瘤内定量介入治疗

    Institute of Scientific and Technical Information of China (English)

    陈国郝; 张榕; 程金妹; 方哲明

    2012-01-01

    目的 探讨在电子喉镜及内窥镜专用注射小针双重辅助下,根据瘤体体积(MRI测量),精确定位定量瘤内注射平阳霉素混合液治疗咽喉部血管瘤的方法及疗效.方法 收集5年来咽喉部血管瘤25例,MRI增强扫描,测量瘤体体积,电子喉镜明确定位后,利用内镜专用注射小针头(奥林帕斯WF-1816PN),根据瘤体体积,按比例瘤内精确定量注射平阳霉素混合液.结果 治愈的20例,显效5例.经2年以上的随访,未见复发.结论 根据瘤体MRI体积测量,定量控制平阳霉素瘤内介入治疗,方法安全可靠,简单有效.%[ Objective ] The article is intended to have a discussion on the approaches and curative effects of the treatment of pharynx and larynx hemangioma by injecting exact amount of the mixture of bleomycin into the exact tumor position, which was operated under electronic laryngoscope based on tumor size. [ Methods ] 25 cases, in recent 5 years, of pharynx and larynx hemangioma were recruited; Tumor size was measured under MRI enhanced scan; After the exact positioning by electronic laryngoscope based on the tumor size, injected into tumor the mixture of bleomycin in exact amount and position with the small needles specially used in electronic laryngoscope. [Results] 20 cases proved cured and 5 cases proved effective with no recurrence after 2 years' follow-up. [Conclusion] It is simple, effective and safety-guaranteed to treat pharynx and larynx hemangioman by injecting into tumor the mixture of bleomycin in exact amount and position based on the MRI measurement of tumor size.

  4. 不同剂量吉非替尼对博莱霉素所致大鼠肺纤维化影响的比较%Comparison of the influence of different doses of gefitinib on the rat pulmonary fibrosis induced by bleomycin

    Institute of Scientific and Technical Information of China (English)

    黄文亭; 林采余; 韩睿; 王玉波; 陈恒屹; 卢从华; 李力; 何勇

    2014-01-01

    Objective To compare the effect of different doses of gefitinib on the extent of fibrosis in rat models of pulmonary fi‐brosis induced by bleomycin (BLM) .Methods Seventy five female rats were randomly assigned to five groups and treated as fol‐lows :the rats in control group were given water orally with administration of saline intratracheally ;the rats in BLM group were giv‐en water orally with a single intratracheal injection of BLM (5 mg/kg body weight in 0 .2 mL phosphate buffered saline);the rats in BLM+Ge20 group was given gefitinib at dose of 20 mg・ kg -1 ・ d-1 orally with administration of bleomycin intratracheally ;the rats in BLM+Ge90 group were given gefitinib at dose of 90 mg・kg -1 ・d-1 orally with administration of BLM intratracheally ;the rats in BLM+Ge200 group were given gefitinib at dose of 200 mg・kg -1 ・d-1 orally with administration of BLM intratracheally . Twenty one days later ,all rats were sacrificed .Left pulmonary lobes from all animals were removed and stained with hematoxylin , eosin and Masson′s trichrome respectively for pathological examination ,and the right pulmonary lobe tissues were used for the hydroxyproline contents measurement (by ELISA ) .Results Gefitinib augumeted rat pulmonary fibrosis induced by bleomycinin with significantly increasing Ashcroft score ,lung collagen accumulation and the level of hydroxyproline (HYP) in BLM + Ge200 group (P0 .05) .Conclusion Gefitinib augumets rat pulmonary fibrosis induced by bleomycin .The bigger the gefitinib dosage is ,the more severe pulmonary fibrosis would be .%目的:对比观察不同剂量吉非替尼对博莱霉素所致大鼠肺纤维化的影响。方法将75只雄性SD大鼠分为5组:对照组、博莱霉素组、低剂量吉非替尼联用组、中剂量吉非替尼联用组、高剂量吉非替尼联用组,每组15只。观察大鼠存活情况,第21天时杀鼠取左肺石蜡切片行HE染色及Masson染色,右肺ELISA方法检测羟脯氨

  5. 布洛芬抑制博莱霉素诱导的肺纤维化小鼠一氧化氮生成的机制研究%Effect of Ibuprofen on Nitric Oxide Generation in Bleomycin-pulmonary Fibrosis Mice

    Institute of Scientific and Technical Information of China (English)

    王春雷; 张烨; 蔡开霞; 王斯琪

    2013-01-01

    目的 研究布洛芬对博莱霉素诱导的肺纤维化小鼠一氧化氮(NO)生成的影响及可能机制.方法 通过气管内滴注博莱霉素复制小鼠肺纤维化模型,治疗组经腹腔注射给予不同剂量的布洛芬.用NO化学法试剂盒测定血清NO水平;用免疫组织化学法检测肺组织核因子κB(NF-κB);用Western blot法检测各组肺组织诱导性NO合成酶(iNOS)蛋白表达水平.结果 与正常对照组比较,模型组血清NO水平、NF-κB含量和iNOS的表达显著增加(P<0.01),布洛芬5 mg/kg治疗组未见明显变化,而布洛芬10 mg/kg和20 mg/kg治疗组则明显降低(P<0.05,P< 0.01).布洛芬20 mg/kg治疗组血清NO含量、肺组织NF-κB含量和iNOS的表达明显低于布洛芬5 mg/kg和10 mg/kg治疗组.结论 布洛芬可抑制由博莱霉素引起的iNOS和NF-κB的上调,降低肺纤维化小鼠NO水平,可能是降低肺纤维化机制之一.%Objective To study the effect of ibuprofen on nitric oxide generation and explore possible mechanism in bleomycin-induced pulmonary fibrosis mice. Methods Pulmonary fibrosis mouse model was established by intratracheal instillation of bleomycin, and the treatment group received different doses of ibuprofen through intraperitoneal injection. Serum nitric oxide was analyzed using nitric oxide chemical method kit. Lung tissue nuclear factor-κB was detected by immunohistochemical method and inducible nitric oxide synthase in lung tissue was determined by Western blot. Results Compared with normal control group,serum nitric oxide,nuclear factor-ΚB and inducible nitric oxide synthase of lung tissue were significantly increased in model group (P < 0.01). There was no significant difference in serum nitric oxide, nuclear factor-κB and inducible nitric oxide synthase of lung tissue between ibuprofen group (5 mg/kg) and normal control group. The increased serum nitric oxide,nuclear factor-κB and inducible nitric oxide synthase of lung tissue were

  6. Preventive effects of Citrus reticulata essential oil on bleomycin-induced pulmonary fibrosis in rats and the mechanism%陈皮挥发油对大鼠肺纤维化的干预作用

    Institute of Scientific and Technical Information of China (English)

    周贤梅; 赵阳; 何翠翠; 李建新

    2012-01-01

    化具有干预作用,其作用机制可能是通过调节氧化和抗氧化失衡,降低CTGF蛋白及其mRNA表达,减少胶原沉积以减轻纤维化程度.%OBJECTIVE: To investigate the effects of essential oil of Citrus reticulata (EOCR) on proliferation of human embryonic lung fibroblasts (HELFs),and to explore its protective effects on bleomycin (BLM)-induced lung fibrosis in rats.METHODS: Routinely cultured HELFs during the logarithmic phase of growth were divided into control and treated groups,and applied for evaluation of inhibitory activity using methylthiazol tetrazolium (MTT) assay.A rat model of BLM-induced pulmonary fibrosis was used for the evaluation of antifibrotic effect of EOCR.Forty-two Sprague-Dawley rats were randomly divided into normal group,model group,prednisone group and different doses of EOCR groups.BLM was intratracheally instilled into all the rats except those in the normal group,and EOCR was orally given to BLM-treated rats at doses of 25,50,100 and 200 mg/kg once per day for four weeks.The rats in the normal group were intratracheally administered the same volume of saline.On the 28th day,rats were sacrificed under anesthesia,and the serum and lung tissues were collected.Superoxide dismutase (SOD) activities and malondialdehyde (MDA) contents in serum and lung tissues were analyzed with corresponding kits; type Ⅰ collagen (Col Ⅰ ) content in lung tissues was evaluated with enzyme-linked immunosorbent assay; pulmonary fibrosis was assessed by lung histology; protein and mRNA expressions of connective tissue growth factor (CTGF) in lung tissues were measured with immunohistochemical and in situ hybridization semiquantitative image analyses,respectively.RESULTS: The EOCR at different concentrations displayed inhibitory activity on proliferation of HELFs.In in vivo experiment,the weight gain of the rats in groups treated with EOCR at doses of 50,100 and 200 mg/kg per day was significantly higher than those in the model group at

  7. 平阳霉素联合32P不同治疗方式对儿童血管瘤的疗效对照%Comparative effect on different treatment methods of Bleomycin and 32P in children with hemangiomas

    Institute of Scientific and Technical Information of China (English)

    杨蕾华

    2012-01-01

    Objective To explore the clinical effect of Bleomycin combined with 32P in the treatment of children with he-mangiomas, and to provide the effective reference for the clinical treatment of hemangiomas. Methods From May 2008 to May 2010 in our hospital, 82 cases of children with hemangiomas were selected as the object of clinical observation. The children were divided into two groups, with 42 cases of the observation group and 40 cases of the control group. The observation group was treated by Bleomycin combined with 32P Injection, the control group was treated by 32P for local injection and external application. The different ages, different types of hemangioma, gender and number of lesions and the incidence of adverse reactions of two groups were compared. Results The observation group had a significant curative effect on cavernous hemangioma and mixed hemangioma, the control group had a significant curative effect on capillary hemangioma and port wine stains; the age factor had significant influence for treatment approaches of children with hemangioma in two groups, the younger, the better application therapy's effect of 32P local injection and external application, Bleomycin combined with 32P has a better effect on children over the age of 2; the gender and number of lesions had no significant effect on the efficacy of two treatment methods; there was no significant difference in the incidence of adverse reactions of two groups, but there was a significant difference in the kinds of adverse reactions of two groups. Conclusion Bleomycin combined with 32P is a good way of treating elder children with hemangioma, which is worthy of promotion.%目的 探讨联用平阳霉素和32P治疗儿童血管瘤的临床效果,为临床血管瘤的治疗提供有效的借鉴.方法 选择2008年5月~2010年5月到我院接受治疗的82例血管瘤患儿作为临床观察对象.将患儿分为观察组和对照组,其中观察组42例,对照组40例.

  8. Modulation of the mutagenic effect of benzo[a]pyrene and bleomycin by isoflavone extracts in a rat hepatoma cell line Modulação do efeito mutagênico do benzo[a]pireno e bleomicina por extratos de isoflavonas em células de hepatoma de roedor

    Directory of Open Access Journals (Sweden)

    Mário Sérgio Mantovani

    2012-06-01

    Full Text Available Epidemiologic studies show that the intake of foods rich in isoflavones (phytoestrogens, such as soybeans, confers protection against various types of cancer, what increases the scientific and popular interest on these compounds. In the present study, phytoestrogens extracts from soybeans were tested for genotoxic potential and modulatory effects on benzo[a]pyrene and bleomycin. Two phytoestrogens were evaluated in vitro, phytoestrogen “A” was supplied by EMBRAPA-Soja, Londrina – PR, and phytoestrogen “B” was purchased in a local drug store. The methods used were the comet assay (genotoxicity and antigenotoxicity and micronucleus test with cytokinesis block (mutagenicity in rat hepatoma cells (HTC cell. The isoflavones were tested at three concentrations pre-established by the MTT cytotoxicity assay. Both isoflavone extracts showed no genotoxic effects in the comet assay, but showed induction of micronucleus. In the evaluation of the phytoestrogens for a modulatory effect, both phytoestrogens extracts showed antigenotoxicity in the comet assay.Estudos epidemiológicos mostram que a ingestão de alimentos ricos em isoflavonas (fitoestrógenos, como a soja, confere proteção contra vários tipos de câncer, o que aumenta o interesse científico e popular sobre esses compostos. No presente estudo, os fitoestrógenos de extrato de soja foram testados quanto aos efeitos genotóxicos e modulador de benzo [a] pireno e bleomicina. Dois fitoestrogênios foram avaliados in vitro, o fitoestrógenos “A” foi fornecido pela Embrapa-Soja, Londrina - PR, e o fitoestrógenos “B” foi comprado em uma farmácia de manipulação local. Os métodos utilizados foram o teste do Cometa (genotoxicidade e antigenotoxicidade e teste do Micronúcleo com Bloqueio Citocinese (mutagenicidade em células de hepatoma de rato (HTC celulares. As isoflavonas foram testadas em três concentrações pré-estabelecidas pelo ensaio de citotoxidade MTT. Ambos os

  9. Interleukin-22 Inhibits Bleomycin-Induced Pulmonary Fibrosis

    OpenAIRE

    Minrui Liang; Jiucun Wang; Haiyan Chu; Xiaoxia Zhu; Hang He; Qiong Liu; Jianhua Qiu; Xiaodong Zhou; Ming Guan; Yu Xue; Xiangjun Chen; Hejian Zou

    2013-01-01

    Pulmonary fibrosis is a progressive and fatal fibrotic disease of the lungs with unclear etiology. Recent insight has suggested that early injury/inflammation of alveolar epithelial cells could lead to dysregulation of tissue repair driven by multiple cytokines. Although dysregulation of interleukin- (IL-) 22 is involved in various pulmonary pathophysiological processes, the role of IL-22 in fibrotic lung diseases is still unclear and needs to be further addressed. Here we investigated the ef...

  10. Capillary remodeling in bleomycin-induced pulmonary fibrosis.

    OpenAIRE

    Schraufnagel, D. E.; Mehta, D.; Harshbarger, R.; Treviranus, K.; Wang, N. S.

    1986-01-01

    Lung fibrosis is a process in which collagen is laid down and the delicate capillary-alveolar relationship is disturbed. The architectural changes which occur in the capillaries, a main element of the oxygen transferring unit, are difficult to illustrate without a three-dimensional tool, such as scanning electron microscopy. Therefore, a scanning electron microscopic study was undertaken to show the capillary changes of lung fibrosis. Fibrosis was induced in rats by intratracheal instillation...

  11. Experiences with 57Co-labelled bleomycin in tumour diagnosis

    International Nuclear Information System (INIS)

    57Co-BLM is a tumour-affine substance which has been tested in clinical experiments in more than 100 patients. The main indication for 57Co-BLM tumour scintiscanning is in the diagnosis of liver metastases where the detection limit can be considerably improved, in particular by the subtraction method proposed by Haubold. So far, no other tumour-affine substance has yielded satisfactory results. In contrast to gallium, 57Co is excreted mostly renally; The BLM content of the liver 24 h p.i. is less than 1% of the dose applied. The low background activity thus provides a good chance of locating small liver metastases with the aid of radioactively labelled BLM. (orig./AJ)

  12. Th17及Tc17细胞在博来霉素致系统性硬化病小鼠模型外周血、皮肤和肺组织中的表达%Expression of Th17 and Tc17 cells in the peripheral blood, skin and lung in a murine model of bleomycin-induced systemic sclerosis

    Institute of Scientific and Technical Information of China (English)

    雷玲; 钟小宁; 赵铖; 米存东; 李佳荃; 曾晶晶; 孙雪皎

    2012-01-01

    肤、肺组织的比例增高,且以Th17细胞为主,其表达与皮肤、肺部炎症和纤维化病变密切相关,并可通过分泌IL-17参与SSc的发病.%Objective To study the expression and significance of Th17 and Tc17 cells in the peripheral blood,skin and lung in a murine model of bleomycin (BLM)-induced systemic sclerosis (SSc).Methods Thirty female BALB/c mouse were randomly divided into 3 groups,including a control group ( A group),a injected with BLM 4 week without pulmonary fibrosis(PF) group( B group) and with obviously PF group(C group).Pathological changes of skin and lung were detected.The proportion of CD4+,CD8+,CD4+IL-17+(Th17),CD8+IL-17+(Tc17) cells in the peripheral blood,skin and lung of mouse was determined by flow cytometry.The mRNA expressions of RORγt,IL-17A in skin and lung of mouse were evaluated by real-time PCR.Enzyme linked immunosorbent assay(ELISA) was used to measure the levels of IL-17 in serum.Results Dermal hydroxyproline(HYP) contents and the score of PF were significantly increased in C group [ (3.07±1.26) μg/mg,4.0±1.41 ]and B group [ (2.43±0.61) μμg/mg,1.50±0.76]as compared with A group [ (1.45±0.40) μg/mg,0.60±0.70 ],and pulmonary HYP contents was obviously increased in C group than in A and B groups,all P<0.05.Compared with the A group,the percentage of CD4+ and Th17 cells in the peripheral blood,skin and lung of B and C groups,Tc17 cells of C group was significantly increased,and CD8+ cells was significantly decreased(all P<0.05).The ratio of Th17/CD4+CD8+ in the peripheral blood,skin and lung of B and C groups [ ( 1.41 ±0.36)%,( 1.79±0.77)% ],[ (2.58±1.07)%,(5.23±2.34)% ]and [ (3.50±1.20)%,(4.02±1.32) % ]was significantly increased compared with A group (0.71±0.25)%,(1.15±0.59)%,(0.99±0.46)%.The ratio of Tc17/CD4+CD8+ in the lung of C groups( 1.62±0.53) % and in the skin of B and C groups [ (1.70±0.70) %,( 1.63±0.63 ) % ]was significantly increased compared with A

  13. Intratracheal transplantation of alveolar type II cells reverses bleomycin-induced lung fibrosis

    OpenAIRE

    Serrano-Mollar, Anna; Nácher, María; Gay-Jordi, Gemma; Closa, Daniel; Xaubet, Antoni; Bulbena, Oriol

    2007-01-01

    [Rationale]: Transplantation of stem cells has been proposed as a strategy for repair of lung fibrosis. Nevertheless, many studies have yielded controversial results that currently limit the potential use of these cells as an efficient treatment. Alveolar type II cells are the progenitor cells of the pulmonary epithelium and usually proliferate after epithelial cell injury. During lung fibrosis, however, the altered regeneration process leads to uncontrolled fibroblast proliferation. [Objecti...

  14. Rat alveolar myofibroblasts acquire alpha-smooth muscle actin expression during bleomycin-induced pulmonary fibrosis.

    OpenAIRE

    Vyalov, S. L.; Gabbiani, G.; Kapanci, Y.

    1993-01-01

    The majority of fibroblasts in alveolar septa are characterized by the presence of cytoplasmic bundles of microfilaments that contain cytoplasmic actin isoforms; these cells have been named contractile interstitial cells or V-type myofibroblasts. In the rat, they express desmin as intermediate filament protein. In this study, we explored the possibility that modulation and replication of such septal fibroblasts result in the appearance of alpha-smooth muscle (alpha-SM) actin-positive myofibro...

  15. Rapamycin Regulates Bleomycin-Induced Lung Damage in SP-C-Deficient Mice

    OpenAIRE

    Madala, Satish K.; Melissa D. Maxfield; Davidson, Cynthia R; Schmidt, Stephanie M.; Daniel Garry; Machiko Ikegami; Hardie, William D.; Glasser, Stephan W.

    2011-01-01

    Injury to the distal respiratory epithelium has been implicated as an underlying cause of idiopathic lung diseases. Mutations that result in SP-C deficiencies are linked to a small subset of spontaneous and familial cases of interstitial lung disease (ILD) and interstitial pulmonary fibrosis (IPF). Gene-targeted mice that lack SP-C ( − / − ) develop an irregular ILD-like disease with age and are a model of the human SP-C related disease. In the current study, we investigated whether...

  16. Pharmacological targeting of protease-activated receptor 2 affords protection from bleomycin-induced pulmonary fibrosis

    NARCIS (Netherlands)

    C. Lin (Cong); J. von der Thusen (Jan); J. Daalhuisen (Joost); M. Ten Brink (Marieke); B. Crestani (Bruno); T. van der Poll (Tom); K. Borensztajn (Keren); C. Arnold Spek (C.)

    2015-01-01

    textabstractIdiopathic pulmonary fibrosis is the most devastating diffuse fibrosing lung disease that remains refractory to therapy. Despite increasing evidence that protease-activated receptor 2 (PAR-2) contributes to fibrosis, its importance in pulmonary fibrosis is under debate. We addressed whet

  17. Prevention of bleomycin induced pulmonary fibrosis by a novel anti-fibrotic peptide with relaxin like activity.

    OpenAIRE

    A. Pini; R. Shemesh; CS Samuel; RA Bathgate; Zauberman, A; C. Hermesh; A. Wool; Bani, D.; Rotman, G

    2010-01-01

    Pulmonary fibrosis is a progressive and lethal lung disease characterized by accumulation of extracellular matrix and loss of pulmonary function. No cure exists for this pathologic condition, and current treatments often fail to slow its progression or relieve its symptoms. Relaxin was previously shown to induce a matrix-degrading phenotype in human lung fibroblasts in vitro and to inhibit pulmonary fibrosis in vivo. A novel peptide that targets the relaxin RXFP1/LGR7 receptor was recently id...

  18. Effect of radiation on the growth of normal and malignant human oesophageal explant cultures pre-treated with bleomycin

    Energy Technology Data Exchange (ETDEWEB)

    Seymour, C.B.; Cusack, A.; Mothersill, C.; Hennessy, T.P.

    1988-05-01

    A method has been developed for testing the response of oesophageal explants from tumour and surrounding normal tissue in the same patient to chemotherapy and ..gamma..-radiation, singly and in combination. The test allows treatment combinations, time and order of administration of agents to the tissue to be accurately controlled. Cytotoxicity, determined by measuring the area of outgrowth from an explant 2 weeks after plating, is the most useful short-term end-point, although many other are possible. Results showing differential cytotoxicity of belomycin with and without radiation in squamous and adenocarcinoma of the oesophagus and surrounding normal tissue from the same patient indicate tumour cells are relatively resistant to radiation alone, low levels of belomycin with or without radiation preferentially spare tumour cells and high levels, in combination with any radiation dose tested, but not without radiation, spare normal cells and give a significantly high amount of relative tumour cell kill. Belomycin must be added to the cells just before or just after irradiation to obtain the normal-tissue sparing effect.

  19. Distinct Roles for the A2B Adenosine Receptor in Acute and Chronic Stages of Bleomycin-Induced Lung Injury

    OpenAIRE

    Yang ZHOU; Schneider, Daniel J.; Morschl, Eva; Song, Ling; Pedroza, Mesias; Karmouty-Quintana, Harry; Le, Thuy.; Sun, Chun-Xiao; Blackburn, Michael R.

    2010-01-01

    Adenosine is an extracellular signaling molecule that is generated in response to cell injury where it orchestrates tissue protection and repair. Whereas adenosine is best known for promoting anti-inflammatory activities during acute injury responses, prolonged elevations can enhance destructive tissue remodeling processes associated with chronic disease states. The generation of adenosine and the subsequent activation of the adenosine 2B receptor (A2BR) is an important processes in the regul...

  20. Paclitaxel and Carboplatin or Bleomycin Sulfate, Etoposide Phosphate, and Cisplatin in Treating Patients With Advanced or Recurrent Sex Cord-Ovarian Stromal Tumors

    Science.gov (United States)

    2016-03-16

    Ovarian Granulosa Cell Tumor; Ovarian Gynandroblastoma; Ovarian Sertoli-Leydig Cell Tumor; Ovarian Sex Cord Tumor With Annular Tubules; Ovarian Sex Cord-Stromal Tumor; Ovarian Sex Cord-Stromal Tumor of Mixed or Unclassified Cell Types; Ovarian Steroid Cell Tumor

  1. Protease-Activated Receptor-2 Induces Myofibroblast Differentiation and Tissue Factor Up-Regulation during Bleomycin-Induced Lung Injury Potential Role in Pulmonary Fibrosis

    NARCIS (Netherlands)

    K. Borensztajn; P. Bresser; C. van der Loos; I. Bot; B. van den Blink; M.A. den Bakker; J. Daalhuisen; A.P. Groot; M.P. Peppelenbosch; J.H. von der Thüsen; C.A. Spek

    2010-01-01

    Idiopathic pulmonary fibrosis constitutes the most devastating form of fibrotic lung disorders and re mains refractory to current therapies The coagula non cascade is frequently activated during pulmonary fibrosis but this observation has so far resisted a mechanistic explanation Recent data suggest

  2. Protease-activated receptor-2 induces myofibroblast differentiation and tissue factor up-regulation during bleomycin-induced lung injury: Potential role in pulmonary fibrosis

    NARCIS (Netherlands)

    K. Borensztajn (Keren); P. Bresser (Paul); C.M. van der Loos; I. Bot (Ilze); B. van den Blink (Bernt); M.A. den Bakker (Michael); J. Daalhuisen (Joost); A.P. Groot (Angelique); M.P. Peppelenbosch (Maikel); J. von der Thusen (Jan); C.A. Spek (Arnold)

    2010-01-01

    textabstractIdiopathic pulmonary fibrosis constitutes the most devastating form of fibrotic lung disorders and remains refractory to current therapies. The coagulation cascade is frequently activated during pulmonary fibrosis, but this observation has so far resisted a mechanistic explanation. Recen

  3. Effect of expression of TGF-beta and TNF-alpha with Qidan granule treatment in rats by bleomycin-induced pulmonary fibrosis

    Institute of Scientific and Technical Information of China (English)

    辛洪涛; 宋秀杰; 靳长俊; 王静; 黄琛; 张欣; 王建平; 姜淑娟

    2003-01-01

    Objective: To evaluate the therapeutic effects and mechanisms of Qidan granule in blemycinA5-induced pulmonary interstitial fibrosis (PIF)in rats. Methods: PIF models were established by blemycinA5-induced in rats. They were treated by Qidan granule and Hydrocortisone respectively. The pathological changes and collagen protein disposition were observed, and the expression of TGF-β, TNF-α proteins were measured by immunohistochemical technique. Results: The pulmonary alveolitis and fibrosis were alleviated remarkably in Qidan granule group compared with those in the model control group and hydrocortisone group (P<0.01). The expression of TGF-β and TNF-α protein were higher in Qidan granule group than those in normal group ,and were significantly less than those in the model control group and in hydrocortisone group (P<0.01). Conclusion: Qidan granule would ameliorate the pulmonary alveolitis and fibrosis. TGF-β and TNF-α might play an important role in the development of alveolitis and fibrosis in rats.

  4. About PF

    Science.gov (United States)

    ... nitrofurantoin, sulfasalazine) Heart disease (amiodarone, propranolol) Seizures (phenytoin) Cancer (methotrexate, bleomycin, oxaliplatin, radiation therapy) Genetic/Inherited diseases Approximately ...

  5. Redox activation of Fe(III)-thiosemicarbazones and Fe(III)-bleomycin by thioredoxin reductase: specificity of enzymatic redox centers and analysis of reactive species formation by ESR spin trapping

    OpenAIRE

    Myers, Judith M.; Cheng, Qing; Antholine, William E.; Kalyanaraman, Balaraman; Filipovska, Aleksandra; Arnér, ArnerElias S.J.; Myers, Charles R.

    2013-01-01

    Thiosemicarbazones such as triapine (Tp) and Dp44mT are tridentate iron (Fe) chelators that have well-documented anti-neoplastic activity. While Fe-thiosemicarbazones can undergo redox-cycling to generate reactive species that may have important roles in their cytotoxicity, there is only limited insight into specific cellular agents that can rapidly reduce Fe(III)-thiosemicarbazones and thereby promote their redox activity. Here we report that thioredoxin reductase-1 (TrxR1) and glutathione r...

  6. Serine/threonine kinase-protein kinase B and extracellular signal-regulated kinase regulate ventilator-induced pulmonary fibrosis after bleomycin-induced acute lung injury: a prospective, controlled animal experiment

    OpenAIRE

    Li, Li-Fu; Liao, Shuen-Kuei; Huang, Chung-Chi; Hung, Ming-Jui; Quinn, Deborah A

    2008-01-01

    Introduction Lung fibrosis, reduced lung compliance, and severe hypoxemia found in patients with acute lung injury often result in a need for the support of mechanical ventilation. High-tidal-volume mechanical ventilation can increase lung damage and fibrogeneic activity but the mechanisms regulating the interaction between high tidal volume and lung fibrosis are unclear. We hypothesized that high-tidal-volume ventilation increased pulmonary fibrosis in acute lung injury via the serine/threon...

  7. Effect and mechanism of hydrogen water inhibits pulmonary fibrosis-induced by Bleomycin in mice%含氢水对实验性小鼠肺纤维化的抑制作用及机制

    Institute of Scientific and Technical Information of China (English)

    田华; 姚树桐; 高凤美

    2012-01-01

    目的 研究含氢水对博来霉素(BLM)诱发的小鼠肺纤维化的抑制作用及其机制.方法 54只C57BL/6小鼠随机分为对照(C)组、模型(M)组和氢水干预(H)组,经气管内注射BLM(5 mg/kg)复制肺纤维化模型,分别在建模后7、14和28 d结束实验.分别采用HE和Masson染色检测肺组织炎症反应及肺纤维化程度,肺组织匀浆进行丙二醛(MDA)含量和超氧化物歧化酶(SOD)活性检测;免疫组织化学法检测肺组织核因子-κB p65(NF-κB p65)和肿瘤坏死因子-α(TNF-α)的表达情况.结果 含氢水明显减轻BLM所致的肺组织炎症反应和肺纤维化程度;与相同时间点的M组比较,H组的MDA含量降低而SOD活性增高(P<0.05或P <0.01),且肺组织NF-κB p65和TNF-α表达均受到抑制(P<0.05).结论 含氢水可减轻BLM所诱导的小鼠肺纤维化,其机制可能与抑制炎症反应和氧化应激有关.

  8. Application Of Cisplatin Combined With Bleomycin In Interventional Chemotherapy For Cervical Cancer%PB方案在宫颈癌介入化疗中的疗效观察及对Wee1表达的影响

    Institute of Scientific and Technical Information of China (English)

    张金敏; 王翔宇; 李南; 江金潇; 王蓁

    2014-01-01

    目的:研究PB方案(顺铂DDP、博莱霉素BLM),并了解其对Wee1蛋白表达的影响.方法:1、用PB方案对64例Ⅰ B~ⅡB期宫颈癌病人进行介入化疗,观察化疗前后宫颈肿瘤体积变化及化疗后反应,评价介入化疗的效果.2、比较介入化疗后手术患者(观察组)与直接手术患者(对照组)术中情况及术后病理情况,评价介入化疗的近期疗效.3、测定介入前后Wee1表达的变化,及与临床病理的关系,了解PB方案对Wee1的影响.结果:PB方案介入化疗的有效率(CR+ PR)为87.5%,缓解率为96.9%,34.4%出现了发热反应,未见其他明显不良反应.试验组和对照组手术时间分别为(2.92±0.3)h和(3.28±0.55)h,术中出血量分别为(453.1±131.9)mL和(542.8±5.6)mL,两组在手术时间和术中出血量方面差异有统计学意义(P<0.05),两组术后在盆腔淋巴结转移、脉管浸润、宫旁浸润及阴道切缘受累方面差异均有统计学意义(P<0.05).PB方案介入化疗后,Wee1的表达较介入化疗前显著降低,差异有统计学意义(P<0.05),和临床分期、病理类型、淋巴结转移及病理分级无关,差异无统计学意义(P>0.05).结论:PB介入化疗方案有效、低毒,对Ⅰ B~ⅡB期宫颈癌治疗具有较好的疗效,PB方案是值得推广的介入化疗方案,Wee1蛋白有望成为监测PB方案介入化疗疗效的指标.

  9. Flagellate erythema

    OpenAIRE

    Eungdamrong, John; McLellan, Beth

    2013-01-01

    A 21-year-old woman presented with a pruritic eruption on her trunk and extremities after receiving bleomycin for treatment of stage III ovarian germ-cell tumor. Physical examination was consistent with bleomycin-induced flagellate erythema. We discuss the pathophysiologic mechanism that produces this dermatitis.

  10. Acute fibrinous and organising pneumonia: a rare histopathological variant of chemotherapy-induced lung injury.

    Science.gov (United States)

    Gupta, Arjun; Sen, Shiraj; Naina, Harris

    2016-01-01

    Bleomycin-induced lung injury is the most common chemotherapy-associated lung disease, and is linked with several histopathological patterns. Acute fibrinous and organising pneumonia (AFOP) is a relatively new and rare histological pattern of diffuse lung injury. We report the first known case of bleomycin-induced AFOP. A 36-year-old man with metastatic testicular cancer received three cycles of bleomycin, etoposide and cisplatin, before being transitioned to paclitaxel, ifosfamide and cisplatin. He subsequently presented with exertional dyspnoea, cough and pleuritic chest pain. CT of the chest demonstrated bilateral ground glass opacities with peribronchovascular distribution and pulmonary function tests demonstrated a restrictive pattern of lung disease with impaired diffusion. Transbronchial biopsy revealed intra-alveolar fibrin deposits with organising pneumonia, consisting of intraluminal loose connective tissue consistent with AFOP. The patient received high-dose corticosteroids with symptomatic and radiographic improvement. AFOP should be recognised as a histopathological variant of bleomycin-induced lung injury. PMID:27053543

  11. Acute fibrinous and organising pneumonia: a rare histopathological variant of chemotherapy-induced lung injury.

    Science.gov (United States)

    Gupta, Arjun; Sen, Shiraj; Naina, Harris

    2016-04-06

    Bleomycin-induced lung injury is the most common chemotherapy-associated lung disease, and is linked with several histopathological patterns. Acute fibrinous and organising pneumonia (AFOP) is a relatively new and rare histological pattern of diffuse lung injury. We report the first known case of bleomycin-induced AFOP. A 36-year-old man with metastatic testicular cancer received three cycles of bleomycin, etoposide and cisplatin, before being transitioned to paclitaxel, ifosfamide and cisplatin. He subsequently presented with exertional dyspnoea, cough and pleuritic chest pain. CT of the chest demonstrated bilateral ground glass opacities with peribronchovascular distribution and pulmonary function tests demonstrated a restrictive pattern of lung disease with impaired diffusion. Transbronchial biopsy revealed intra-alveolar fibrin deposits with organising pneumonia, consisting of intraluminal loose connective tissue consistent with AFOP. The patient received high-dose corticosteroids with symptomatic and radiographic improvement. AFOP should be recognised as a histopathological variant of bleomycin-induced lung injury.

  12. Pep2Path: automated mass spectrometry-guided genome mining of peptidic natural products

    NARCIS (Netherlands)

    Medema, Marnix; Paalvast, Yared; Nguyen, D.D.; Melnik, A.; Dorrestein, P.C.; Takano, Eriko; Breitling, Rainer

    2014-01-01

    Nonribosomally and ribosomally synthesized bioactive peptides constitute a source of molecules of great biomedical importance, including antibiotics such as penicillin, immunosuppressants such as cyclosporine, and cytostatics such as bleomycin. Recently, an innovative mass-spectrometry-based strateg

  13. Effect of Pingyangmycin on human venous malformation endothelial cells

    Institute of Scientific and Technical Information of China (English)

    Yi Fang Zhao; Zhi Jun Sun; Yu Lin Jia; Jun Jia; Ya Meng Si; Ji Hong Zhao; Wen Feng Zhang

    2008-01-01

    @@ Purpose: Venous malformations are common vascular anomalies with a propensity of the head and neck. Intralesional injection of Pingyangmycin (PYM, bleomycin A5 hydrochloride) is a widely used sclerotherapy method for the treatment of venous malformation.

  14. Immune ambivalence

    OpenAIRE

    Mignot, Grégoire; Bugaut, Hélène; Ghiringhelli, François

    2013-01-01

    In addition to cytotoxic effects, anticancer agents can exert multiple immunomodulatory functions. We have recently described the molecular mechanisms whereby bleomycin can 1) promote endoplasmic reticulum stress, causing the immunogenic death of cancer cells and hence strengthening antitumor CD8+ T cell responses; and 2) induce the secretion of transforming growth factor β (TGFβ), which stimulates regulatory T cells. This suggests that bleomycin may be favorably combined with TGFβ-targeting ...

  15. Raynaud′s phenomenon in a child with medulloblastoma as a late effect of chemotherapy

    OpenAIRE

    Erman Atas; Nadir Korkmazer; Hatice A Artik; Oguzhan Babacan; Vural Kesik

    2015-01-01

    There are a lot of early or late side effects of chemotherapies. One of them is Raynaud′s phenomenon (RP). Vascular toxicity associated with antineoplastic agents is notified in bleomycin alone therapy or in combination with cisplatin, vinblastine, and vincristine. The mechanism of RP associated with antineoplastic agents is unknown. All children receiving vinblastine, vincristine, bleomycin and cisplatin therapy, are followed and questioned about their complaint on RP. Long-term follow-up of...

  16. Interstitial lung disease

    Institute of Scientific and Technical Information of China (English)

    2005-01-01

    2005206 The pivotal role of CXCR3 in the patho-genesis of bleomycin-induced pulmonary fibrosis. GAO Jin-ming(高金明), Dept Respir Med, PUMC Hosp, PUMC & CAMS, Beijing 100730. Chin J Tu-berc Respir Dis, 2005; 28 (1): 28-32. Objective: To investigate the contribution of chemokine receptor-CXCR3 to the fibrotic disease process induced by bleomycin in CXCR3 gene defi-

  17. Effect of ambroxol on the concentration of cefotaxime in the bronchoalveolar lavage fluid of rats with pulmonary fibrosis

    OpenAIRE

    Chen, Feng; ZHANG, YUAN-XIA; ZHANG, CAI-QING

    2014-01-01

    This study aimed to investigate the effect of ambroxol on the concentration of cefotaxime in the bronchioalveolar lavage fluid of rats with bleomycin-induced pulmonary fibrosis. A total of 54 Wistar male rats were randomly divided into three groups, namely the normal control group, model group and ambroxol group. On experimental day 0, the rats were intratracheally instilled with bleomycin (5 mg/kg body weight) or sterile saline. The rats in the ambroxol group were then treated with ambroxol ...

  18. Proapoptotic Bid is required for pulmonary fibrosis

    OpenAIRE

    Budinger, G.R. Scott; Mutlu, Gökhan M.; Eisenbart, James; Fuller, Alyson C.; Bellmeyer, Amy A.; Baker, Christina M.; Wilson, Mindy; Ridge, Karen; Terrence A. Barrett; Lee, Vivian Y.; Chandel, Navdeep S.

    2006-01-01

    The molecular mechanisms of pulmonary fibrosis are poorly understood. Previous reports indicate that activation of TGF-β1 is essential for the development of pulmonary fibrosis. Here, we report that the proapoptotic Bcl-2 family member Bid is required for the development of pulmonary fibrosis after the intratracheal instillation of bleomycin. Mice lacking Bid exhibited significantly less pulmonary fibrosis in response to bleomycin compared with WT mice. The attenuation in pulmonary fibrosis w...

  19. Isolation of cDNA clones encoding an enzyme from bovine cells that repairs oxidative DNA damage in vitro: homology with bacterial repair enzymes.

    OpenAIRE

    Robson, C.N.; Milne, A M; Pappin, D J; Hickson, I. D.

    1991-01-01

    Ionizing radiation and radiomimetic compounds, such as hydrogen peroxide and bleomycin, generate DNA strand breaks with fragmented deoxyribose 3' termini via the formation of oxygen-derived free radicals. These fragmented sugars require removal by enzymes with 3' phosphodiesterase activity before DNA synthesis can proceed. An enzyme that reactivates bleomycin-damaged DNA to a substrate for Klenow polymerase has been purified from calf thymus. The enzyme, which has a Mr of 38,000 on SDS-PAGE, ...

  20. Inhibition of basal and TGF beta-induced fibroblast collagen synthesis by antineoplastic agents. Implications for wound healing.

    OpenAIRE

    Hendricks, T.; Martens, M F; Huyben, C M; Wobbes, T.

    1993-01-01

    Antineoplastic drugs, given in the perioperative period, are thought to be a hazard to wound repair. Since fibroblast collagen synthesis is crucial to healing, we examined the effects of bleomycin, cisplatin and 5-fluorouracil on collagen synthesis in confluent cultures of fibroblasts from human colon and skin. The drugs were added in final concentrations between 0.1 and 50 microM. Bleomycin did not affect collagen synthesis in colon fibroblasts but inhibited synthesis in skin fibroblasts. Co...

  1. ABVE-PC and modified BEACOPP regimen in Indian children with Hodgkin lymphoma: Feasibility and efficacy

    OpenAIRE

    Somasundaram Jayabose; Kasi Viswanathan; Vignesh Kumar; Annapoorani Annamalai; Arathi Srinivasan; Julius Xavier Scott; Krishnakumar Rathnam

    2016-01-01

    Aims: To study the toxicity of ABVE-PC (doxorubicin, bleomycin, vincristine, etoposide, prednisone and cyclophosphamide) and modified-BEACOPP (bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, prednisone) in intermediate-risk and high-risk Hodgkin lymphoma patients. Methods: High-risk patients received 4 cycles of modified-BEACOPP (m-BEACOPP) plus 4 cycles of ABVD. Intermediate-risk patients received 4 cycles of ABVE-PC plus 2 cycles of ABVD. Results: From 2010 t...

  2. 博来霉素致肺纤维化大鼠不同时间点吸人STAT1反义寡核苷酸的疗效比较%Therapeutic effects of aerosolized signal transducer and activator of transcription 1 antisense oligonucleotide administered at different time points on bleomycin-induced pulmonary fibrosis: experiment with rats

    Institute of Scientific and Technical Information of China (English)

    李晶; 曾鸣; 朱晨; 王文军; 湛晓勤; 范贤明

    2009-01-01

    目的 探讨雾化吸入信号转导和转录活化因子1(STAT1)反义寡核苷酸(ASON)干预肺纤维化的最佳给药时机.方法 Wistar雌性大鼠25只随机均分为博来霉素(BLM)组、ASON 0 d组、ASON 7 d组、ASON 14 d组和生理盐水(NS)组,前4组气管内灌注BLM建立肺纤维化模型,NS组气管内灌注NS.ASON 0、7、14 d组分别于气管内灌注BLM后立即、第7和14天开始雾化吸入STATI ASON;NS组和BLM组雾化吸入NS.气管内灌注BLM后第28天处死各组大鼠,取肺组织分别行HE和Masson染色,观察肺泡炎和纤维化情况并评分;酶联免疫吸附试验(ELISA)测定支气管肺泡灌洗液(BALF)中转化生长因子β(TGF-β)和肿瘤坏死因子α(TNF-α)浓度.结果 肺组织病理学观察显示ASON 0 d组大鼠肺泡炎和肺纤维化程度明显轻于BLM组和ASON 14 d组,肺泡炎评分(1.80±0.84)和肺纤维化评分(2.60±0.55)均明显低于BLM组(2.40±0.55、4.40±0.55)、ASON 7 d组(2.20±0.45、3.00 ±0.71)和ASON 14 d组(2.20±0.84、4.00±1.00)(均P<0.05);ASON 7 d组肺纤维化评分也明显低于BLM组和ASON 14 d组(均P<0.05).ASON 0 d组BALF中TGF-β与TNF-α浓度[(48.11±3.46)pg/ml、(1.93±0.14)ng/ml]均明显低于BLM组[(57.67±2.46)pg/ml、(2.45±0.25)ng/ml,均P<0.05],TGF-β浓度明显低于ASON 7 d组[(51.42±3.57)pg/ml]和ASON 14 d组[(55.83±1.79)pg/ml](均P<0.05);ASON 7 d组BALF中TGF-β浓度也明显低于BLM组和ASON 14d组(均P<0.05).结论 早期雾化吸入STAT1 ASON对BLM致肺纤维化大鼠的肺纤维化形成有明显阻抑作用,用药越早效果越好,提示雾化吸入STAT1 ASON有可能成为肺纤维化的早期干预手段.%Objective To investigate the curative effects of inhaling signal transducer and activator of transcription 1 (STAT1) antisense oligonucleotide (ASON) on alveolitis and pulmonary fibrosis and the best administration time. Methods Twenty-five adult female Wistar rats were randomly divided into 5 equal groups: BLM group, undergoing intra-tracheal perfusion of BLM so as to establish animal models of alveolitis and pulmonary fibrosis and then inhaling aerosolized normal saline (NS); NS group undergoing intra-tracheal perfusion of NS and then inhaling aerosolized NS; ASON 0 d group, undergoing intra-tracheal perfusion of BLM and then inhaling aerosolized STAT1 ASON 3 ml immediately; ASON 7 d group, undergoing intra-tracheal perfusion of BLM and then inhaling STAT1 ASON 3 ml 7 days later; and ASON 14 d group undergoing intra-tracheal perfusion of BLM and then inhaling aerosolized STAT1 ASON 3 ml 14 days later. Aerosolized inhalation was repeated once every other day for 4 times. Twenty-eight days after intra-tracheal perfusion the rats were sacrificed with their lungs taken out to undergo pathological examination. NS was infused into the right lungs to get bronchoalveolar lavage fluid (BALF). ELISA was used to examine the concentrations of transforming growth factor-β (TGF-β) and tumor necrosis factor-α (TNF-α) in the BALF. Results The pathology result of the lung tissues showed that compared with the BLM and ASON 14 d groups, the alveolitis and pulmonary fibrosis of the ASON 0 d group were obviously milder. The scores of alveolitis and pulmonary fibrosis of the ASON 0 d group were (1.80 ± 0. 84) and (2. 60 ± 0. 55) respectively, both significantly lower than those of the BLM group [(2.40 ± 0. 55) and (4. 40 ± 0. 55) respectively] and those of the ASON 7 d group [(2. 20 ±0. 45) and (3.00 ±0. 71) respectively] (all P < 0. 05). The scores of pulmonary fibrosis of the ASON 7 d group was significantly lower than those of the BLM and ASON 14 d groups (both P < 0. 05). The concentrations of TGF-β and TNF-α in BALF of the ASON 0 d group were (48. 11 ±3.46) pg/ml and (1.93 ± 0. 14) ng/ml respectively, both significantly lower than those of the BLM group [(57. 67 ± 2. 46) pg/ml and (2. 45 ± 0. 25) ng/ml respectively, both P < 0. 05]. The concentration of TGF-β in BALF of the ASON 0 d group was significantly lower than those of the ASON 7 d and ASON 14 d groups [(51.42 ±3. 57) pg/ml and (55.8

  3. The effectiveness of chemotherapy and electrochemotherapy on ovarian cell lines in vitro.

    Science.gov (United States)

    Saczko, J; Pilat, J; Choromanska, A; Rembialkowska, N; Bar, J; Kaminska, I; Zalewski, J; Kulbacka, J

    2016-01-01

    The presented study aimed to evaluate in vitro the effectiveness of improvement standard chemotherapy with bleomycin by electroporation in two various ovarian cancer cell lines. Two human ovarian cell lines OvBH-1 and SKOV-3 were used. The lines were selected because of their resistance to several therapeutic methods. As anticancer drug we use range of concentrations of bleomycin. In EP and ECT experiments different voltage values: from 0 to 1200 V/cm, 8 pulses with duration of 100μs and intervals between pulses 1s long were used. The cells viability after applied treatments was evaluated by MTT assay. The expression of heat shock proteins - HSP27 was examined by immunocytochemical ABC method.The cytotoxicity with different concentrations of bleomycin alone was not significantly decrease in both cell lines. It confirms resistance of these cells to conventional chemotherapy. The highest decrease of cell proliferation was observed after EP with bleomycin after 48h of incubation for 1000 V/cm. The intensity of expression of small heat shock proteins HSP27 slightly increased after ECT in both treated cell lines, in particular in OvBH-1. The presented study indicated that application of electroporation may effectively enhance chemotherapy with bleomycin, particularly in the case of treating ovarian cancer resistant to standard therapy. PMID:26925792

  4. Tumor blood flow modifying effects of electrochemotherapy. A potential vascular targeted mechanism

    International Nuclear Information System (INIS)

    Background. The aim of this study was to determine the tumor blood flow modifying, and potential vascular targeted effect of electrochemotherapy with bleomycin or cisplatin. Materials and methods. Electrochemotherapy was performed by application of short intense electric pulses to the tumors after systemic administration of bleomycin or cisplatin. Evaluated were antitumor effectiveness of electrochemotherapy by tumor measurement, tumor blood flow modifying effect by Patent blue staining technique, and sensitivity of endothelial and tumor cells to the drugs and electrochemotherapy by clonogenicity assay. Results. Electrochemotherapy was effective in treatment of SA-1 tumors in A/J mice resulting in substantial tumor growth delay and also tumor cures. Tumor blood flow reduction following electrochemotherapy correlated well with its antitumor effectiveness. Virtually complete shut down of the tumor blood flow was observed already at 24 h after electrochemotherapy with bleomycin whereas only 50% reduction was observed after electrochemotherapy with cisplatin. Sensitivity of human endothelial HMEC-1 cells to electrochemotherapy suggests a vascular targeted effect for electrochemotherapy in vivo with bleomycin as well as with cisplatin. Conclusion. These results show that, in addition to direct electroporation of tumor cells, other vascular targeted mechanisms are involved in electrochemotherapy with bleomycin or cisplatin, potentially mediated by tumor blood flow reduction, and enhanced tumor cell death as a result of endothelial damage by electrochemotherapy. (author)

  5. The Role of Catalase in Pulmonary Fibrosis

    Directory of Open Access Journals (Sweden)

    Takigawa Tomoko

    2010-12-01

    Full Text Available Abstract Background Catalase is preferentially expressed in bronchiolar and alveolar epithelial cells, and acts as an endogenous antioxidant enzyme in normal lungs. We thus postulated epithelial damage would be associated with a functional deficiency of catalase during the development of lung fibrosis. Methods The present study evaluates the expression of catalase mRNA and protein in human interstitial pneumonias and in mouse bleomycin-induced lung injury. We examined the degree of bleomycin-induced inflammation and fibrosis in the mice with lowered catalase activity. Results In humans, catalase was decreased at the levels of activity, protein content and mRNA expression in fibrotic lungs (n = 12 compared to control lungs (n = 10. Immunohistochemistry revealed a decrease in catalase in bronchiolar epithelium and abnormal re-epithelialization in fibrotic areas. In C57BL/6J mice, catalase activity was suppressed along with downregulation of catalase mRNA in whole lung homogenates after bleomycin administration. In acatalasemic mice, neutrophilic inflammation was prolonged until 14 days, and there was a higher degree of lung fibrosis in association with a higher level of transforming growth factor-β expression and total collagen content following bleomycin treatment compared to wild-type mice. Conclusions Taken together, these findings demonstrate diminished catalase expression and activity in human pulmonary fibrosis and suggest the protective role of catalase against bleomycin-induced inflammation and subsequent fibrosis.

  6. Peculiarities of induction and persistence of hidden chromosome instability in peripheral blood lymphocytes of persons occupationally exposed to ionizing radiation.

    Science.gov (United States)

    Pilinska, M A; Dybsky, S S; Dybska, O B; Shvayko, L I; Sushko, V O

    2014-09-01

    Objective - to investigate the induction of hidden chromosome instability in persons occupationally exposed to ionizing radiation and its persistence in vitro in successive mitoses. Materials and methods. Using two tests ("G2-bleomycin sensitivity assay" and two-term cultivation of human peripheral blood lymphocytes) voluntary cytogenetic examination of 15 individuals participated in the conversion of the "Shelter" ("Chornobyl NPP") into ecologically safe system had been carried out. Total 24 034 metaphase had been analyzed, of which 12 243 - without additional mutagenic exposure, 11 791 - exposed to bleomycin in vitro at concentration of 0.05 μg/ml. Results. The magnitude and dynamics of background as well as bleomycin-induced cytogenetic effects in both terms of lymphocytes' cultivation in occupational group differed significantly from the group of comparison towards increasing of chromosome instability indices with significant interindividual fluctuations. Conclusion. Interindividual differences in persistence of radiation-induced hidden chromosome instability in successive generations of human somatic cells had been found.

  7. Raynaud′s phenomenon in a child with medulloblastoma as a late effect of chemotherapy

    Directory of Open Access Journals (Sweden)

    Erman Atas

    2015-01-01

    Full Text Available There are a lot of early or late side effects of chemotherapies. One of them is Raynaud′s phenomenon (RP. Vascular toxicity associated with antineoplastic agents is notified in bleomycin alone therapy or in combination with cisplatin, vinblastine, and vincristine. The mechanism of RP associated with antineoplastic agents is unknown. All children receiving vinblastine, vincristine, bleomycin and cisplatin therapy, are followed and questioned about their complaint on RP. Long-term follow-up of surviving patients is recommended. Oncologists should be aware of the potential late toxic effects of antineoplastic drugs.

  8. Angiotensin-converting enzyme

    DEFF Research Database (Denmark)

    Sørensen, P G; Rømer, F K; Cortes, D

    1984-01-01

    In order to evaluate bleomycin-associated lung damage in humans, lung function parameters and serum levels of the endothelial-bound angiotensin-converting enzyme (ACE) were determined by serial measurements in 11 patients who were treated for testicular cancer. None developed clinical or radiolog......In order to evaluate bleomycin-associated lung damage in humans, lung function parameters and serum levels of the endothelial-bound angiotensin-converting enzyme (ACE) were determined by serial measurements in 11 patients who were treated for testicular cancer. None developed clinical...

  9. Interstitial lung disease

    Institute of Scientific and Technical Information of China (English)

    2009-01-01

    2009189 Therapeutic effects of aerosolized signal transducer and activator of transcription 1 antisense oligonucleotide administered at different time points on bleomycin-induced pulmonary fibrosis:experiment with rats. LJ Jing(李晶),et al.Dept Respir Med,Affili Hosp,Luzhou Med Coll,Luzhou 646000.Natl Med J China,2009;89(12):831-835.

  10. Ototoxicity following Vinblastine chemotherapy in a patient of Hodgkin′s Lymphoma

    Directory of Open Access Journals (Sweden)

    Raj Kumar Nirban

    2015-01-01

    Full Text Available Sudden hearing loss is a well-known complication of certain chemotherapeutic agents. However, vinblastine has seldom been implicated causing ototoxicity. We report a case of sudden bilateral hearing loss in a 36-year-old male patient of Mixed cellularity Hodgkin′s lymphoma following standard adriamycin, bleomycin, vinblastine, and dacarbazine chemotherapy.

  11. Elektrokemoterapi til behandling af kutane metastaser

    DEFF Research Database (Denmark)

    Falk, Hanne; Matthiessen, Louise Wichmann; Dahlstrøm, Karin;

    2015-01-01

    Cutaneous metastases occur in up to 9% of all patients with cancer and may cause discomfort and stigmatization. Electrochemotherapy is a local treatment using electric pulses to permeabilize cell membranes, enabling chemotherapy, such as bleomycin, to enter the cells and increase the cytotoxic...

  12. Resistance Training Does Not Protect Against Increases in Plasma Cytokine Levels Among Germ Cell Cancer Patients During and After Chemotherapy

    DEFF Research Database (Denmark)

    Christensen, Jesper Frank; Tolver, Anders; Andersen, J.L.;

    2014-01-01

    Abstract Context: Testicular germ cell cancer (GCC) patients treated with cisplatin-etoposide-bleomycin chemotherapy (BEP) have excellent prognosis but have an increased risk of late-occurring morbidities, which may be associated with changes in the inflammatory profile. Objective: The objective ...

  13. Electrochemotherapy for the treatment of recurring aponeurotic fibromatosis in a dog

    OpenAIRE

    Spugnini, Enrico P; Di Tosto, Giovanni; Salemme, Scirin; Pecchia, Luca; Fanciulli, Maurizio; Baldi, Alfonso

    2013-01-01

    This paper reports the clinical findings, histopathology, and clinical outcome of a rare case of aponeurotic fibromatosis in a dog. The dog was treated with 4 courses of electrochemotherapy using the drugs cisplatin and bleomycin. There was complete remission and the dog was still disease-free after 18 months.

  14. Electrochemotherapy for the treatment of recurring aponeurotic fibromatosis in a dog.

    Science.gov (United States)

    Spugnini, Enrico P; Di Tosto, Giovanni; Salemme, Scirin; Pecchia, Luca; Fanciulli, Maurizio; Baldi, Alfonso

    2013-06-01

    This paper reports the clinical findings, histopathology, and clinical outcome of a rare case of aponeurotic fibromatosis in a dog. The dog was treated with 4 courses of electrochemotherapy using the drugs cisplatin and bleomycin. There was complete remission and the dog was still disease-free after 18 months. PMID:24155455

  15. The in vivo fibrotic role of FIZZ1 in pulmonary fibrosis.

    Directory of Open Access Journals (Sweden)

    Tianju Liu

    Full Text Available FIZZ (found in inflammatory zone 1, a member of a cysteine-rich secreted protein family, is highly induced in lung allergic inflammation and bleomycin induced lung fibrosis, and primarily expressed by airway and type II alveolar epithelial cells. This novel mediator is known to stimulate α-smooth muscle actin and collagen expression in lung fibroblasts. The objective of this study was to investigate the in vivo effects of FIZZ1 on the development of lung fibrosis by evaluating bleomycin-induced pulmonary fibrosis in FIZZ1 deficient mice. FIZZ1 knockout mice exhibited no detectable abnormality. When these mice were treated with bleomycin they exhibited significantly impaired pulmonary fibrosis relative to wild type mice, along with impaired proinflammatory cytokine/chemokine expression. Deficient lung fibroblast activation was also noted in the FIZZ1 knockout mice. Moreover, recruitment of bone marrow-derived cells to injured lung was deficient in FIZZ1 knockout mice. Interestingly in vitro FIZZ1 was shown to have chemoattractant activity for bone marrow cells, including bone marrow-derived dendritic cells. Finally, overexpression of FIZZ1 exacerbated fibrosis. These findings suggested that FIZZ1 exhibited profibrogenic properties essential for bleomycin induced pulmonary fibrosis, as reflected by its ability to induce myofibroblast differentiation and recruit bone marrow-derived cells.

  16. Vascular fingerprint and vascular damage markers associated with vascular events in testicular cancer patients during and after chemotherapy

    NARCIS (Netherlands)

    Lubberts, S; Boer, H; Altena, R; Meijer, C; van Roon, A M; Zwart, N; Oosting, S F; Kamphuisen, P W; Nuver, J; Smit, A J; Mulder, A B; Lefrandt, J D; Gietema, J A

    2016-01-01

    BACKGROUND: Metastatic testicular cancer (TC) can be cured with bleomycin, etoposide and cisplatin (BEP) chemotherapy. This comes at the price of an increased cardiovascular disease risk, not only years afterwards, but also during and shortly after chemotherapy. To prevent cardiovascular events, hig

  17. Vascular fingerprint and vascular damage markers associated with vascular events in testicular cancer patients during and after chemotherapy

    NARCIS (Netherlands)

    Lubberts, S.; Boer, H.; Altena, R.; Meijer, C.; van Roon, A. M.; Zwart, N.; Oosting, S. F.; Kamphuisen, P. W.; Nuver, J.; Smit, A. J.; Mulder, A. B.; Lefrandt, J. D.; Gietema, J. A.

    2016-01-01

    Background: Metastatic testicular cancer (TC) can be cured with bleomycin, etoposide and cisplatin (BEP) chemotherapy. This comes at the price of an increased cardiovascular disease risk, not only years afterwards, but also during and shortly after chemotherapy. To prevent cardiovascular events, hig

  18. 5. MUTAGEN SENSITIVITY AND DNA REPAIR CAPACITY (DRC) AS RISK FACTORS FOR NON-SMALL CELL LUNG CANCER

    Institute of Scientific and Technical Information of China (English)

    2001-01-01

    @@An alkaline single cell gel electrophoresis assay has been standardised by which mutagen sensitivity and DNA repair capacity (DRC) can be measured in cryopreserved peripheral blood lymphocytes following induction and repair of DNA damage induced by bleomycin. In an ongoing case-control study, we have applied this assay to Caucasian

  19. Chemotherapy-related vascular toxicity : studies in germ cell tumour patients

    NARCIS (Netherlands)

    Nuver, Janine

    2005-01-01

    Testicular cancer is a highly curable disease that mainly affects men between 20 and 40 years of age. Nowadays, over 80% of patients become long-term survivors following treatment with chemotherapy that consists of a combination of bleomycin, etoposide, and cisplatin (BEP-regimen). Unfortunately, va

  20. MFAP4

    DEFF Research Database (Denmark)

    Mölleken, Christian; Poschmann, Gereon; Bonella, Francesco;

    2016-01-01

    affects the formation of pulmonary fibrosis in the bleomycin model of lung fibrosis. Methods 91 patients with idiopathic pulmonary fibrosis (IPF), 23 with hypersensitivity pneumonitis (HP) and 31 healthy subjects were studied. In the mouse model, C57BL/6 Mfap4+/+ and Mfap4-/- mice between 6-8 weeks of age...

  1. Acute chemotherapy-induced cardiovascular changes in patients with testicular cancer

    NARCIS (Netherlands)

    Nuver, J; Smit, AJ; van der Meer, J; van den Berg, MP; van der Graaf, WTA; Meinardi, MT; Sleijfer, DT; Hoekstra, HJ; van Gessel, AI; van Roon, AM; Gietema, JA

    2005-01-01

    Purpose; After cisplatin- and bleomycin-containing chemotherapy for testicular cancer, part of the patient population will develop acute or long-term cardiovascular toxicity. It is largely unknown whether standard tests can be used to assess chemotherapy-induced cardiovascular changes. Patients and

  2. Salvage therapy of progressive and recurrent Hodgkin's disease: results from a multicenter study of the pediatric DAL/GPOH-HD study group.

    NARCIS (Netherlands)

    Schellong, G.; Dorffel, W.; Claviez, A.; Korholz, D.; Mann, G.; Scheel-Walter, H.G.; Bökkerink, J.P.M.; Riepenhausen, M.; Luders, H.; Potter, R.; Ruhl, U.

    2005-01-01

    PURPOSE: To evaluate a salvage therapy (ST-HD-86) for patients with progressive and relapsed Hodgkin's disease after primary treatment in the pediatric DAL/GPOH studies. The essential chemotherapeutic regimens were ifosfamide, etoposide, and prednisone (IEP) and doxorubicin, bleomycin, vinblastine,

  3. Latent cytomegalovirus infection exacerbates experimental pulmonary fibrosis by activating TGF-β1.

    Science.gov (United States)

    Li, Yonghuai; Gao, Jian; Wang, Guoliang; Fei, Guanghe

    2016-08-01

    The aim of the present study was to investigate the hypotheses that cytomegalovirus (CMV) may trigger idiopathic pulmonary fibrosis (IPF) in a susceptible host and/or that the presence of CMV may alter IPF in response to a well-defined trigger of pulmonary fibrosis. A mouse model of murine CMV (MCMV) infection was established, and the mice were divided into a control group, bleomycin group and an MCMV+bleomycin group. Changes in the weights of the mice were determined in the three groups. Pulmonary fibrosis was detected using a histopathological method. The activity of transforming growth factor (TGF)‑β1 was measured, and the levels of E‑cadherin, Vimentin and phosphorylated (phospho)‑small mothers against decapentaplegic (SMAD)2 were determined using western blot analysis. MCMV was found to invade the lungs, however, it did not cause pulmonary fibrosis. The progression of fibrosis in the mice treated with MCMV+bleomycin was more rapid, compared with that in the control mice. The protein levels of Vimentin and phospho-SMAD2 were upregulated, whereas the level of E‑cadherin was downregulated in the MCMV+bleomycin group,. The results suggested that latent MCMV infection aggravated pulmonary fibrosis in the mouse model, possibly through the activation of TGF-β1. PMID:27279470

  4. Chromosome instability and oxidative stress markers in patients with ataxia telangiectasia and their parents.

    Science.gov (United States)

    Ludwig, Luciane Bitelo; Valiati, Victor Hugo; Palazzo, Roberta Passos; Jardim, Laura Bannach; da Rosa, Darlan Pase; Bona, Silvia; Rodrigues, Graziela; Marroni, Norma Possa; Prá, Daniel; Maluf, Sharbel Weidner

    2013-01-01

    Ataxia telangiectasia (AT) is a rare neurodegenerative disorder, inherited in an autosomal recessive manner. Total blood samples were collected from 20 patients with AT, 13 parents of patients, and 17 healthy volunteers. This study aimed at evaluating the frequency of chromosomal breaks in spontaneous cultures, induced by bleomycin and ionizing radiation, and further evaluated the rates of oxidative stress in AT patients and in their parents, compared to a control group. Three cell cultures were performed to each individual: the first culture did not receive induction to chromosomal instability, the second was exposed to bleomycin, and the last culture was exposed to ionizing radiation. To evaluate the rates of oxidative stress, the markers superoxide dismutase (SOD), catalase (CAT), and thiobarbituric acid (TBARS) were utilized. Significant differences were observed between the three kinds of culture treatments (spontaneous, bleomycin, and radiation induced) and the breaks and chromosomal aberrations in the different groups. The oxidative stress showed no significant differences between the markers. This study showed that techniques of chromosomal instability after the induction of ionizing radiation and bleomycin are efficient in the identification of syndrome patients, with the ionizing radiation being the most effective.

  5. Catalytic Oxidation with a Non-Heme Iron Complex That Generates a Low-Spin FeIIIOOH Intermediate

    NARCIS (Netherlands)

    Roelfes, Gerard; Lubben, Marcel; Hage, Ronald; Que, Jr.; Feringa, Bernard

    2000-01-01

    The antitumor drug bleomycin (BLM) is proposed to act via a low-spin iron(III) hydroperoxide intermediate called “activated bleomycin”. To gain more insight into the mechanistic aspects of catalytic oxidation by these intermediates we have studied the reactivity of [(N4Py)Fe(CH3CN)](ClO4)2 (1) (N4Py

  6. Effects of diterpene phenol extract of Rosmarinus Officinalis on TGFβ1 and mRNA expressions of its signaling pathway molecules in the lung tissue of pulmonary fibrosis rats

    Institute of Scientific and Technical Information of China (English)

    杨礼腾

    2013-01-01

    Objective To investigate the regulative mechanism of the diterpene phenol extract of Rosmarinus Officinalis (DERO) on the imbalance of collagen metabolism of the lung tissue in pulmonary fibrosis rats.Methods Fifty healthy Sprague-Dawley rats were randomly divided into normal saline group (NS) ,bleomycin-induced lung

  7. Phase III study of ACVBP versus ACVBP plus rituximab for patients with localized low-risk diffuse large B-cell lymphoma (LNH03-1b)

    OpenAIRE

    Ketterer, N; Coiffier, B.; Thieblemont, C.; Fermé, C.; Brière, J; Casasnovas, O.; Bologna, S.; Christian, B.; Connerotte, T.; Récher, C; Bordessoule, D; Fruchart, C.; Delarue, R.; Bonnet, Christophe; Morschhauser, F.

    2013-01-01

    Background The superiority of a chemotherapy with doxorubicin, cyclophosphamide, vindesine, bleomycin and prednisone (ACVBP) in comparaison with cyclophosphamide, doxorubicin, vincristin and prednisone plus radiotherapy for Young patients with localized diffuse large B-cell lymphoma (DLBCL) was previously demonstrated. We report the results of a trial which évaluâtes the role of rituximab combined with ACVBP (R- ACVBP) in these patients. ...

  8. A randomized phase III study comparing standard dose BEP with sequential high-dose cisplatin, etoposide, and ifosfamide (VIP) plus stem-cell support in males with poor-prognosis germ-cell cancer. An intergroup study of EORTC, GTCSG, and Grupo Germinal (EORTC 30974)

    DEFF Research Database (Denmark)

    Daugaard, G; Skoneczna, I; Aass, N;

    2011-01-01

    To compare the efficacy of one cycle of standard dose cisplatin, etoposide, and ifosfamide (VIP) plus three cycles of high-dose VIP followed by stem-cell infusion [high-dose chemotherapy (HD-CT arm)] to four cycles of standard cisplatin, etoposide, and bleomycin (BEP) in patients with poor-progno...

  9. Efficacy of adjusted BACOD regimen on the treatment of relapsed refractory diffuse large B cell lymphoma

    Institute of Scientific and Technical Information of China (English)

    龚格格

    2014-01-01

    Objective To compare the efficacy and adverse events of adjusted BACOD(bleomycin,doxorubicin,cyclophosphamide,vincristine,dexamethasone)regimen(continuous intravenous infusion)and conventional BACOD regimen(conventional intravenous drip)in the treatment of relapsed and refractory diffuse large B cell lymphoma(DLBCL).Methods Retrospective analysis of63 cases of relapsed or refractory DLBCL patients was performed,32 patients received conventional BACOD

  10. Taurine attenuates radiation-induced lung fibrosis in C57/Bl6 fibrosis prone mice.

    LENUS (Irish Health Repository)

    Robb, W B

    2010-03-01

    The amino acid taurine has an established role in attenuating lung fibrosis secondary to bleomycin-induced injury. This study evaluates taurine\\'s effect on TGF-beta1 expression and the development of lung fibrosis after single-dose thoracic radiotherapy.

  11. The effect of marrow mesenchymal stem cell transplantation on pulmonary fibrosis in rats

    Institute of Scientific and Technical Information of China (English)

    黄坤

    2012-01-01

    Objective To study the possible mechanisms of marrow mesenchymal stem cells(MSC) in therapy of bleomycin(BLM)-induced pulmonary fibrosis in rats. Methods Fifty-four female Wistar rats were randomly divided into a control group,a BLM group and a MSC group. The control group receivel intratracheal normal

  12. An experimental study on the radiosensitivity and chemosensitivity of MG-63 cell line

    International Nuclear Information System (INIS)

    The purpose of this study was to aid in the prediction of tumor cell tolerance to radiotherapy and/or chemotherapy. For this study, cell surviving curves were obtained for human osteosarcoma MG-63 cell line using semiautomated MTT ass ay. 2, 4, 6, 8, 10 Gy were irradiated at a dose rate of 210 cGy/min using 60Co Irradiator ALDORADO 8. After irradiation, MG- 63 cell lines (3X104 cells/ml) were exposed to bleomycin and cisplatin at concentration of 0.2, 2, 20 μg/ml for 1 hour respectively. The viable cells were determined for each radiation dose and/or each concentration of drug. And they were compared to control values. The obtained results were as follows: 1. There was significant difference of surviving fraction at 4, 6, 8, 10 Gy on MG-63 cell line (p<0.05). 2. There was significant difference of cytotoxicity of bleomycin or cisplatin at all concentration of 0.2, 2, 20 μg/ml (p<0.05) on mg-63 cell line. The cytotoxicity of cisplatin was more effective than bleomycin at concentration after irradiation of 2 Gy on MG-63 cell line. 3. there was significant difference of cytotoxicity of bleomycin or cisplatin at all concentration after irradiation of Gy on MG-63 cell line. 4. There was significant difference of cytotoxicity of bloeomycin or cisplatin at concentration of 20 μg/ml after irradiation than that of irradiation alone (p<0.01). but there was no significant difference of cytotoxicity of bleomycin at concentration of 20 μg/ml after irradiation of 10 Gy than that of irradiation alone.

  13. Autotaxin activity increases locally following lung injury, but is not required for pulmonary lysophosphatidic acid production or fibrosis.

    Science.gov (United States)

    Black, Katharine E; Berdyshev, Evgeny; Bain, Gretchen; Castelino, Flavia V; Shea, Barry S; Probst, Clemens K; Fontaine, Benjamin A; Bronova, Irina; Goulet, Lance; Lagares, David; Ahluwalia, Neil; Knipe, Rachel S; Natarajan, Viswanathan; Tager, Andrew M

    2016-06-01

    Lysophosphatidic acid (LPA) is an important mediator of pulmonary fibrosis. In blood and multiple tumor types, autotaxin produces LPA from lysophosphatidylcholine (LPC) via lysophospholipase D activity, but alternative enzymatic pathways also exist for LPA production. We examined the role of autotaxin (ATX) in pulmonary LPA production during fibrogenesis in a bleomycin mouse model. We found that bleomycin injury increases the bronchoalveolar lavage (BAL) fluid levels of ATX protein 17-fold. However, the LPA and LPC species that increase in BAL of bleomycin-injured mice were discordant, inconsistent with a substrate-product relationship between LPC and LPA in pulmonary fibrosis. LPA species with longer chain polyunsaturated acyl groups predominated in BAL fluid after bleomycin injury, with 22:5 and 22:6 species accounting for 55 and 16% of the total, whereas the predominant BAL LPC species contained shorter chain, saturated acyl groups, with 16:0 and 18:0 species accounting for 56 and 14% of the total. Further, administration of the potent ATX inhibitor PAT-048 to bleomycin-challenged mice markedly decreased ATX activity systemically and in the lung, without effect on pulmonary LPA or fibrosis. Therefore, alternative ATX-independent pathways are likely responsible for local generation of LPA in the injured lung. These pathways will require identification to therapeutically target LPA production in pulmonary fibrosis.-Black, K. E., Berdyshev, E., Bain, G., Castelino, F. V., Shea, B. S., Probst, C. K., Fontaine, B. A., Bronova, I., Goulet, L., Lagares, D., Ahluwalia, N., Knipe, R. S., Natarajan, V., Tager, A. M. Autotaxin activity increases locally following lung injury, but is not required for pulmonary lysophosphatidic acid production or fibrosis.

  14. Fractional ventilation mapping using inert fluorinated gas MRI in rat models of inflammation and fibrosis.

    Science.gov (United States)

    Couch, Marcus J; Fox, Matthew S; Viel, Chris; Gajawada, Gowtham; Li, Tao; Ouriadov, Alexei V; Albert, Mitchell S

    2016-05-01

    The purpose of this study was to extend established methods for fractional ventilation mapping using (19) F MRI of inert fluorinated gases to rat models of pulmonary inflammation and fibrosis. In this study, five rats were instilled with lipopolysaccharide (LPS) in the lungs two days prior to imaging, six rats were instilled with bleomycin in the lungs two weeks prior to imaging and an additional four rats were used as controls. (19) F MR lung imaging was performed at 3 T with rats continuously breathing a mixture of sulfur hexafluoride and O2 . Fractional ventilation maps were obtained using a wash-out approach, by switching the breathing mixture to pure O2 , and acquiring images following each successive wash-out breath. The mean fractional ventilation (r) was 0.29 ± 0.05 for control rats, 0.23 ± 0.10 for LPS-instilled rats and 0.19 ± 0.03 for bleomycin-instilled rats. Bleomycin-instilled rats had a significantly decreased mean r value compared with controls (P = 0.010). Although LPS-instilled rats had a slightly reduced mean r value, this trend was not statistically significant (P = 0.556). Fractional ventilation gradients were calculated in the anterior/posterior (A/P) direction, and the mean A/P gradient was -0.005 ± 0.008 cm(-1) for control rats, 0.013 ± 0.005 cm(-1) for LPS-instilled rats and 0.009 ± 0.018 cm(-1) for bleomycin-instilled rats. Fractional ventilation gradients were significantly different for control rats compared with LPS-instilled rats only (P = 0.016). The ventilation gradients calculated from control rats showed the expected gravitational relationship, while ventilation gradients calculated from LPS- and bleomycin-instilled rats showed the opposite trend. Histology confirmed that LPS-instilled rats had a significantly elevated alveolar wall thickness, while bleomycin-instilled rats showed signs of substantial fibrosis. Overall, (19) F MRI may be able to detect the effects of pulmonary

  15. Electroporation Therapy in Soft Tissue Sarcoma: A Potentially Effective Novel Treatment

    Directory of Open Access Journals (Sweden)

    Remco de Bree

    2006-01-01

    Full Text Available Purpose. Examination of the potential of electroporation therapy (EPT in a patient with metastatic soft tissue sarcoma. Patient. A 24-year-old male who underwent extensive resection and postoperative radiotherapy for a malignant peripheral nerve sheath tumor in the right infratemporal fossa with intracranial extension and invasion of the maxillary sinus and mandible had a recurrence in the scar of his craniotomy for which he was initially treated with doxorubicin. After discontinuation of doxorubicin he developed a metastatic mass at the same site for which he was treated with electroporation therapy. Method. The subcutaneous metastasis was infiltrated with bleomycin and electroporated. Results. Gradually the tumor became increasingly necrotic and demarcated from surrounding tissue. After 10 weeks no tumor was seen anymore. The wound healed secondarily. Discussion. Intralesional bleomycin followed by EPT is potentially effective, well tolerated, and easy to perform in well accessible soft tissue sarcoma sites.

  16. Preclinical validation of electrochemotherapy as an effective treatment for brain tumors

    DEFF Research Database (Denmark)

    Agerholm-Larsen, Birgit; Iversen, Helle K; Ibsen, Per;

    2011-01-01

    eliminated by electrochemotherapy with a novel electrode device developed for use in the brain. By using this method, the cytotoxicity of bleomycin can be augmented more than 300-fold because of increased permeabilization and more direct passage of drug to the cytosol, enabling highly efficient local tumor...... treatment. Bleomycin was injected intracranially into male rats inoculated with rat glia-derived tumor cells 2 weeks before the application of the electrical field (32 pulses, 100 V, 0.1 ms, and 1 Hz). In this model, where presence of tumor was confirmed by magnetic resonance imaging (MRI) before treatment...... treated area, which MRI and histology showed to contain a fluid-filled cavity. In a long-range survival study, treatment side effects seemed to be minimal, with normal rat behavior observed after electrochemotherapy. Our findings suggest that electrochemotherapy may offer a safe and effective new tool to...

  17. Adjuvant chemotherapy in the treatment of intra-oral squamous cell carcinoma

    International Nuclear Information System (INIS)

    Forty five patients with intra-oral squamous cell carcinoma were treated with bleomycin (150 mg) and external irradiation (50 Gy/5 weeks). The response to treatment was observed in 82.2 per cent patients. Another group of 47 patients was irradiated with radical doses of radiotherapy (65 Gy/6 weeks). The response rate was 68.1 per cent. In the former group twenty six patients (57.8 per cent) survived, free from recurrence at five years. The survival rate in the control group was 40.4 per cent (19 out of 47). The toxicity was slightly more pronounced in the patients treated by the combination regime. However, most of them were able to complete the treatment uninterrupted. The literature has been reviewed to evaluate the efficacy of various dosage and fractionation schedules of the bleomycin and radiation, combination. (author). 4 tabs., 12 refs

  18. Coordination chemistry and solution structure of Fe(II)-peplomycin. Two possible coordination geometries.

    Science.gov (United States)

    Li, Yang; Lehmann, Teresa

    2012-06-01

    The solution structure of Fe(II)-peplomycin was determined from NMR data collected for this molecule. As found previously for Fe(II)- and Co(II)-bound bleomycin; the coordination sphere of the metal is composed of the primary and secondary amines in β-aminoalanine, the pyrimidine and imidazole rings in the pyrimidinylpropionamide, and β-hydroxyhistidine moieties, respectively, the amine nitrogen in β-hydroxyhistidine, and either the carbamoyl group in mannose or a solvent molecule. The two most discussed coordination geometries for the aforementioned ligands in metallo-bleomycins have been tested against the NMR data generated for Fe(II)-peplomycin. The interpretation of the experimental evidence obtained through molecular dynamics indicates that both geometries are equally likely in solution for this compound in the absence of DNA, but arguments are offered to explain why one of these geometries is preferred in the presence of DNA.

  19. Hypersensitivity to ionizing radiation, in vitro, in a new chromosomal breakage disorder, the Nijmegen Breakage Syndrome

    International Nuclear Information System (INIS)

    The Nijmegen Breakage Syndrome (NBS) is a new chromosomal instability disorder different from ataxia telangiectasia (AT) and other chromosome-breakage syndromes. Cells from an NBS patient appeared hypersensitive to X-irradiation. X-rays induced significantly more chromosomal damage in NBS lymphocytes and fibroblasts than in normal cells. The difference was most pronounced after irradiation in G2. Further, NBS fibroblasts were more readily by X-rays than normal fibroblasts. In addition, the DNA synthesis in NBS cells was more resistant to X-rays and bleomycin than that in normal cells. The reaction of NBS cells to X-rays and bleomycin was similar to that of cells from patients with ataxia telangiectasia. Our results indicate that NBS and AT, which also have similar chromosomal characteristics, must be closely related. (orig.)

  20. [Mechanisms that protect against homocysteine toxicity].

    Science.gov (United States)

    Zimny, Jarosław

    2008-01-01

    Elevated concentrations of homocysteine (Hcy) in human tissues have been correlated with some diseases, such as cardio-vascular, neurodegenerative, and kidney disorders. Hcy occurs in human blood in several forms. The most reactive is homocysteine thiolactone (HcyTl). It spontaneously homocysteinylates proteins impairing their functions. As has been evidenced recently, organisms developed protective mechanisms against the HcyTl toxicity. The first mechanism discovered was the calcium-dependent enzyme occurring in mammalian sera, known till then as paraoxonase, which hydrolyzes HcyTl to Hcy. Chronologically second mechanism discovered was urinary excretion of HcyTl. The third protective mechanism is the HcyTl hydrolysis catalyzed by intracellular enzyme known as bleomycin hydrolase. This review outlines current knowledge of the Hcy toxicity and of the three aforementioned protective mechanisms, emphasizing the role of bleomycin hydrolase/ homocysteine-thiolactonase. PMID:18610586

  1. Global analysis of gene expression in pulmonary fibrosis reveals distinct programs regulating lung inflammation and fibrosis

    Science.gov (United States)

    Kaminski, Naftali; Allard, John D.; Pittet, Jean F.; Zuo, Fengrong; Griffiths, Mark J. D.; Morris, David; Huang, Xiaozhu; Sheppard, Dean; Heller, Renu A.

    2000-02-01

    The molecular mechanisms of pulmonary fibrosis are poorly understood. We have used oligonucleotide arrays to analyze the gene expression programs that underlie pulmonary fibrosis in response to bleomycin, a drug that causes lung inflammation and fibrosis, in two strains of susceptible mice (129 and C57BL/6). We then compared the gene expression patterns in these mice with 129 mice carrying a null mutation in the epithelial-restricted integrin 6 subunit (6/-), which develop inflammation but are protected from pulmonary fibrosis. Cluster analysis identified two distinct groups of genes involved in the inflammatory and fibrotic responses. Analysis of gene expression at multiple time points after bleomycin administration revealed sequential induction of subsets of genes that characterize each response. The availability of this comprehensive data set should accelerate the development of more effective strategies for intervention at the various stages in the development of fibrotic diseases of the lungs and other organs.

  2. Hypersensitivity to ionizing radiation, in vitro, in a new chromosomal breakage disorder, the Nijmegen Breakage Syndrome

    Energy Technology Data Exchange (ETDEWEB)

    Taalman, R.D.F.M.; Scheres, J.M.J.C.; Hustinx, T.W.J. (Katholieke Univ. Nijmegen (Netherlands). Dept. of Human Genetics); Jaspers, N.G.J.; de Wit, J. (Erasmus Universiteit, Rotterdam (Netherlands). Lab. of Cell Biology and Genetics)

    1983-02-01

    The Nijmegen Breakage Syndrome (NBS) is a new chromosomal instability disorder different from ataxia telangiectasia (AT) and other chromosome-breakage syndromes. Cells from an NBS patient appeared hypersensitive to X-irradiation. X-rays induced significantly more chromosomal damage in NBS lymphocytes and fibroblasts than in normal cells. The difference was most pronounced after irradiation in G/sub 2/. Further, NBS fibroblasts were more readily by X-rays than normal fibroblasts. In addition, the DNA synthesis in NBS cells was more resistant to X-rays and bleomycin than that in normal cells. The reaction of NBS cells to X-rays and bleomycin was similar to that of cells from patients with ataxia telangiectasia. Our results indicate that NBS and AT, which also have similar chromosomal characteristics, must be closely related.

  3. Antitumorale in-vivo-Wirksamkeit von Epigallokatechingallat bei topischer Applikation in Kombination mit der Elektroporation am oralen Plattenepithelkarzinom im Nacktmausmodell

    OpenAIRE

    Opri, Alexander

    2011-01-01

    Introduction: Traditional chemotherapy is often limited by a poor intracellular drug uptake combined with relevant side effects. Electrochemotherapy allows a high intracellular uptake at low local dosage. On our search for a new cytotoxic electroporation agent we examined the efficiancy of the green tea ingredient epigallocatechingallat (EGCG). Methods: 48 nude mice with implanted oral scquamous cell cancer. Treatment in 6 groups (8 animals) with EGCG, Bleomycin, Buffer solution or in com...

  4. Calcium Electroporation: Evidence for Differential Effects in Normal and Malignant Cell Lines, Evaluated in a 3D Spheroid Model

    OpenAIRE

    Frandsen, Stine Krog; Gibot, Laure; Madi, Moinecha; Gehl, Julie; Rols, Marie-Pierre

    2015-01-01

    Background Calcium electroporation describes the use of high voltage electric pulses to introduce supraphysiological calcium concentrations into cells. This promising method is currently in clinical trial as an anti-cancer treatment. One very important issue is the relation between tumor cell kill efficacy–and normal cell sensitivity. Methods Using a 3D spheroid cell culture model we have tested the effect of calcium electroporation and electrochemotherapy using bleomycin on three different h...

  5. Ultrawideband electrochemotherapy

    Science.gov (United States)

    Jordan, David Walter

    2005-11-01

    Ultrawideband electric field pulses have been shown to be effective for electroporation of mammalian cells at electric field strengths accessible to current pulsed-power technology. Dramatic cell killing (up to a factor of 103) was achieved by loading Jurkat cells with bleomycin via UWB electroporation. UWB pulses were as effective as conventional electroporation pulse treatments for enhancement of bleomycin effectiveness. Such treatments permitted increased killing of cells at reduced concentrations of antibiotic agent. The clinical implications of this advance include faster tumor growth reduction with reduced drug side effects to the patient. Cells were exposed to UWB pulses with ˜100 kV/cm peak electric field and ˜100 ns pulse width. These pulses were of interest because, unlike conventional electroporation waveforms, they contained a large high-frequency energy content that could be coupled to tissue by methods not involving direct contact electrodes. Electroporation by UWB pulses was shown to be consistent with classical theoretical models and conventional electroporation with long pulses and lower electric field strengths. At the shortest pulse lengths and highest applied electric field strengths, UWB pulses were effective in permeabilizing mammalian cell membranes to small molecular species (and, by default, ions) by the creation of small pores, despite the inability of such pulses to create sufficiently large pores for transmembrane transport of genes and proteins. The exact mechanism of cell death was not determined. However, all cell observations were consistent with a high intracellular concentration of bleomycin following application of UWB pulses, leading to massive DNA damage and cell death. This result was achieved using a very low extracellular concentration of bleomycin. Measurements of caspase activation and externalization of membrane phosphatidylserine in treated cells demonstrated that caspase-mediated apoptosis was not the dominant

  6. Biomedical application of electroporation: electrochemotherapy and electrogene therapy

    OpenAIRE

    Čemažar, Maja; Todorović, Vesna; Meulenberg, Cecil W.; Tešić, Nataša; Cor, Andrej

    2014-01-01

    Electroporation refers to exposure of cells to external electric field thatresults in transiently or permanently increased permeability of cell membranes. Cancer treatment, where local application of electroporation to tumor nodules is combined with chemotherapeutic drugs bleomycin or cisplatin is called electrochemotherapy. The antitumor effectiveness of electrochemotherapy is primarily based on direct killing of tumor cells due to the increased chemotherapeutic drug uptake, but other mechan...

  7. Electroporation of human microvascular endothelial cells: evidence for an anti-vascular mechanism of electrochemotherapy

    OpenAIRE

    Cemazar, M; Parkins, C. S.; Holder, A L; Chaplin, D. J.; Tozer, G. M.; Sersa, G

    2001-01-01

    Recent studies have indicated that the antitumour effectiveness of electrochemotherapy, a combination of chemotherapeutic drugs with application of high voltage electric pulses applied to the tumour nodule (electroporation), result in a significant reduction in tumour blood flow and may therefore be mediated by an anti-vascular mechanism. The aim of this study was to evaluate the cytotoxicity of electroporation with bleomycin or cisplatin on cultured human microvascular endothelial cells (HME...

  8. The Enhanced Inhibitory Effect of Different Antitumor Agents in Self-Microemulsifying Drug Delivery Systems on Human Cervical Cancer HeLa Cells

    Directory of Open Access Journals (Sweden)

    Zoltán Ujhelyi

    2015-07-01

    Full Text Available The aim of this study was to develop topical self-microemulsifying drug delivery systems (SMEDDS containing antitumor agents (bleomycin, cisplatin and ifosfamide and to investigate their inhibitory potential in SMEDDS on human cervical cancer HeLa cells. The physicochemical properties of cytostatic drug loaded SMEDDS were characterized. The cytotoxicity of main components of SMEDDS was also investigated. Their IC50 values were determined. HeLa cells were treated by different concentrations of cisplatin, bleomycin and ifosfamide alone and in various SMEDDS. The inhibitory effect on cell growth was analyzed by MTT cell viability assay. Inflammation is a driving force that accelerates cancer development. The inhibitory effect of these antitumor agents has also been tested on HeLa cells in the presence of inflammatory mediators (IL-1-β, TNF-α as an in vitro model of inflamed human cervix. Significant differences in the cytotoxicity of cytostatic drugs alone and in SMEDDS have been found in a concentration-dependent manner. The self-micro emulsifying system may potentiate the effectiveness of bleomycin, cisplatin and ifosfamide topically. The effect of SMEDDS containing antitumor agents was decreased significantly in the presence of inflammatory mediators. According to our experiments, the optimal SMEDDS formulation is 1:1:2:6:2 ratios of Isopropyl myristate, Capryol 90, Kolliphor RH 40, Cremophor RH40, Transcutol HP and Labrasol. It can be concluded that SMEDDS may increase the inhibitory effect of bleomycin, ifosfamide and cisplatin on human cervical cancer HeLa cells. Inflammation on HeLa cells hinders the effectiveness of SMEDDS containing antitumor agents. Our results might ensure useful data for development of optimal antitumor formulations.

  9. The Enhanced Inhibitory Effect of Different Antitumor Agents in Self-Microemulsifying Drug Delivery Systems on Human Cervical Cancer HeLa Cells

    OpenAIRE

    Zoltán Ujhelyi; Azin Kalantari; Miklós Vecsernyés; Eszter Róka; Ferenc Fenyvesi; Róbert Póka; Bence Kozma; Ildikó Bácskay

    2015-01-01

    The aim of this study was to develop topical self-microemulsifying drug delivery systems (SMEDDS) containing antitumor agents (bleomycin, cisplatin and ifosfamide) and to investigate their inhibitory potential in SMEDDS on human cervical cancer HeLa cells. The physicochemical properties of cytostatic drug loaded SMEDDS were characterized. The cytotoxicity of main components of SMEDDS was also investigated. Their IC50 values were determined. HeLa cells were treated by different concentrations ...

  10. The enhanced inhibitory effect of different antitumor agents in self-microemulsifying drug delivery systems on human cervical cancer HeLa cells.

    Science.gov (United States)

    Ujhelyi, Zoltán; Kalantari, Azin; Vecsernyés, Miklós; Róka, Eszter; Fenyvesi, Ferenc; Póka, Róbert; Kozma, Bence; Bácskay, Ildikó

    2015-01-01

    The aim of this study was to develop topical self-microemulsifying drug delivery systems (SMEDDS) containing antitumor agents (bleomycin, cisplatin and ifosfamide) and to investigate their inhibitory potential in SMEDDS on human cervical cancer HeLa cells. The physicochemical properties of cytostatic drug loaded SMEDDS were characterized. The cytotoxicity of main components of SMEDDS was also investigated. Their IC50 values were determined. HeLa cells were treated by different concentrations of cisplatin, bleomycin and ifosfamide alone and in various SMEDDS. The inhibitory effect on cell growth was analyzed by MTT cell viability assay. Inflammation is a driving force that accelerates cancer development. The inhibitory effect of these antitumor agents has also been tested on HeLa cells in the presence of inflammatory mediators (IL-1-β, TNF-α) as an in vitro model of inflamed human cervix. Significant differences in the cytotoxicity of cytostatic drugs alone and in SMEDDS have been found in a concentration-dependent manner. The self-micro emulsifying system may potentiate the effectiveness of bleomycin, cisplatin and ifosfamide topically. The effect of SMEDDS containing antitumor agents was decreased significantly in the presence of inflammatory mediators. According to our experiments, the optimal SMEDDS formulation is 1:1:2:6:2 ratios of Isopropyl myristate, Capryol 90, Kolliphor RH 40, Cremophor RH40, Transcutol HP and Labrasol. It can be concluded that SMEDDS may increase the inhibitory effect of bleomycin, ifosfamide and cisplatin on human cervical cancer HeLa cells. Inflammation on HeLa cells hinders the effectiveness of SMEDDS containing antitumor agents. Our results might ensure useful data for development of optimal antitumor formulations. PMID:26197311

  11. The Effects of Aerosolized STAT1 Antisense Oligodeoxynucleotides on Rat Pulmonary Fibrosis

    OpenAIRE

    Wang, Wenjun; Liao, Bin; Zeng, Ming; Zhu, Chen; Fan, Xianming

    2009-01-01

    Previous study showed that aerosolized signal transducer and activator of transcription-1 (STAT1) antisense oligodeoxynucleotide (ASON) inhibited the expression of STAT1 and ICAM-1 mRNA and protein in alveolar macrophages (AMs) and decreased the concentrations of TGF-β, PDGF and TNF-α in bronchioalveolar lavage fluid (BALF) in bleomycin (BLM)-induced rat pulmonary fibrosis. Administration of STAT1 ASON ameliorated alveolitis in rat pulmonary fibrosis. However, further investigations are neede...

  12. Alveolar Type II cell transplantation restores pulmonary surfactant protein levels in lung fibrosis

    OpenAIRE

    Guillamat-Prats, Raquel; Gay-Jordi, Gemma; Xaubet, Antoni; Peinado, Victor; Serrano-Mollar, Anna

    2014-01-01

    Background Alveolar Type II cell transplantation has been proposed as a cell therapy for the treatment of idiopathic pulmonary fibrosis. Its long-term benefits include repair of lung fibrosis, but its success partly depends on the restoration of lung homeostasis. Our aim was to evaluate surfactant protein restoration after alveolar Type II cell transplantation in an experimental model of bleomycin-induced lung fibrosis in rats. Methods Lung fibrosis was induced by intratracheal instillation o...

  13. Targeting of the pulmonary capillary vascular niche promotes lung alveolar repair and ameliorates fibrosis

    OpenAIRE

    Cao, Zhongwei; Lis, Raphael; Ginsberg, Michael; Chavez, Deebly; Shido, Koji; Rabbany, Sina Y.; Fong, Guo-Hua; Sakmar, Thomas P.; Rafii, Shahin; Ding, Bi-Sen

    2016-01-01

    Although the lung can undergo self-repair after injury, fibrosis in chronically injured or diseased lungs can occur at the expense of regeneration. Here we study how a hematopoietic-vascular niche regulates alveolar repair and lung fibrosis. Using intratracheal injection of bleomycin or hydrochloric acid in mice, we show that repetitive lung injury activates pulmonary capillary endothelial cells (PCECs) and perivascular macrophages, impeding alveolar repair and promoting fibrosis. Whereas the...

  14. Cadherin-11 contributes to pulmonary fibrosis: potential role in TGF-β production and epithelial to mesenchymal transition

    OpenAIRE

    Daniel J. Schneider; Wu, Minghua; Thuy T Le; Cho, Seo-Hee; Brenner, Michael B.; Blackburn, Michael R.; Agarwal, Sandeep K

    2012-01-01

    Pulmonary fibrosis, characterized by excess deposition of extracellular matrix by myofibroblasts, is a serious component of chronic lung diseases. Cadherin-11 (CDH11) is increased in wound healing and fibrotic skin. We hypothesized that CDH11 is increased in pulmonary fibrosis and contributes its development. CDH11 expression was assessed in lung tissue from idiopathic pulmonary fibrosis patients. The role of CDH11 in lung fibrosis was determined using the bleomycin model of pulmonary fibrosi...

  15. Estimates of DNA damage by the comet assay in the direct-developing frog Eleutherodactylus johnstonei (Anura, Eleutherodactylidae)

    OpenAIRE

    Laura Carolina Valencia; Adriana García; Martha Patricia Ramírez-Pinilla; Jorge Luis Fuentes

    2011-01-01

    The aim of this study was to use the Comet assay to assess genetic damage in the direct-developing frog Eleutherodactylus johnstonei. A DNA diffusion assay was used to evaluate the effectiveness of alkaline, enzymatic and alkaline/enzymatic treatments for lysing E. johnstonei blood cells and to determine the amount of DNA strand breakage associated with apoptosis and necrosis. Cell sensitivity to the mutagens bleomycin (BLM) and 4-nitro-quinoline-1-oxide (4NQO) was also assessed using the Com...

  16. The effects of DNA double-strand breaks on mouse oocyte meiotic maturation

    OpenAIRE

    Ma, Jun-Yu; Ou Yang, Ying-Chun; Wang, Zhong-Wei; Wang, Zhen-Bo; Jiang, Zong-Zhe; Luo, Shi-Ming; Hou, Yi; Liu, Zhonghua; Schatten, Heide; Sun, Qing-Yuan

    2013-01-01

    Both endogenous and exogenous factors can induce DNA double-strand breaks (DSBs) in oocytes, which is a potential risk for human-assisted reproductive technology as well as animal nuclear transfer. Here we used bleomycin (BLM) and laser micro-beam dissection (LMD) to induce DNA DSBs in germinal vesicle (GV) stage oocytes and compared the germinal vesicle breakdown (GVBD) rates and first polar body extrusion (PBE) rates between DNA DSB oocytes and untreated oocytes. Employing live cell imaging...

  17. ESR of copper and iron complexes with antitumor and cytotoxic properties.

    OpenAIRE

    Antholine, W E; Kalyanaraman, B.; Petering, D H

    1985-01-01

    The relatively few iron and copper metal complexes which have been examined in cells and tissues for their redox properties, radical generation properties, and antitumor activity are discussed for studies which utilized electron spin resonance spectroscopy (ESR). A common property of a number of metal complexes, which include bleomycin, adriamycin, and thiosemicarbazones described in this review, is that they are readily reduced by thiol compounds and oxidized by oxygen or reduced species of ...

  18. Cell Stress Induces Upregulation of Osteopontin via the ERK Pathway in Type II Alveolar Epithelial Cells

    OpenAIRE

    Aki Kato; Takafumi Okura; Chizuru Hamada; Seigo Miyoshi; Hitoshi Katayama; Jitsuo Higaki; Ryoji Ito

    2014-01-01

    Osteopontin (OPN) is a multifunctional protein that plays important roles in cell growth, differentiation, migration and tissue fibrosis. In human idiopathic pulmonary fibrosis and murine bleomycin-induced lung fibrosis, OPN is upregulated in type II alveolar epithelial cells (AEC II). However, the mechanism of OPN induction in AEC II is not fully understood. In this study, we demonstrate the molecular mechanism of OPN induction in AEC II and elucidate the functions of OPN in AEC II and lung ...

  19. A Study on the radiosensitivity and chemosensitivity of YAC-1 Cell Line in Vitroand Maxillofacial

    International Nuclear Information System (INIS)

    The purpose of this study was to aid in the prediction of tumor cell tolerance to radiotherapy and/or chemotherapy. For this study, cell surviving curves were obtained for mouse lymphoma YAC-1 cell line using semiautomated MTT assay. 2, 4, 6, 8, 10 Gy were irradiated at a dose rate of 210 cGy/min using 60Co Irradiator ALDORADO 8. After irradiation, YAC-1 cell lines (3 X 104 cells/ml) were exposed to bleomycin or cisplatin for 1 hour. The viable cells were determined for each radiation dose and/or each concentration of drug at the 4th day. And they were compared to control values. The obtained results were as follows : 1. The surviving curve with gentle slope was obtained after irradiation of 2, 4, 6, 8, 10 Gy on YAC-1 cell line. 2. The cytotoxicity of bleomycin or cisplatin was increased significantly at all concentration of 0.2 μg/ml, 2 μg/ml and 20 μg/ml on YAC-1 cell line (P<0.01). 3. There were no significant differences of surviving fractions among 4 Gy, 6 Gy, and 8 Gy after irradiation of each radiation dose with 2 μg/ml of bleomycin compared with irradiation only on YAC-1 cell line (P<0.05). 5. There were significant differences of surviving fractions between the groups of irradiation only and the groups of irradiation with 2 μg/ml of bleomycin or cisplatin at all doses of 2, 4, 6, 8 and 10 Gy on YAC-1 cell line (P<0.05).

  20. Curing metastatic testicular cancer

    OpenAIRE

    Einhorn, Lawrence H.

    2002-01-01

    Our initial studies with cisplatin + vinblastine + bleomycin began 27 years ago in 1974, changing the cure rate for disseminated disease from 5 to 60%. Subsequently, through random prospective clinical trials, we have modified the treatment regimen to reduce both the duration and dosages of the chemotherapy drugs. Cisplatin + etoposide was first used at Indiana University as salvage chemotherapy in 1978, representing the first time that a solid tumor had been cured with second-line chemothera...

  1. Management of cutaneous metastases using electrochemotherapy

    DEFF Research Database (Denmark)

    Matthiessen, Louise Wichmann; Chalmers, Richard Ling; Sainsbury, David Christopher George;

    2011-01-01

    Cutaneous metastases may cause considerable discomfort as a consequence of ulceration, oozing, bleeding and pain. Electrochemotherapy has proven to be highly effective in the treatment of cutaneous metastases. Electrochemotherapy utilises pulses of electricity to increase the permeability of the ...... cell membrane and thereby augment the effect of chemotherapy. For the drug bleomycin, the effect is enhanced several hundred-fold, enabling once-only treatment. The primary endpoint of this study is to evaluate the efficacy of electrochemotherapy as a palliative treatment....

  2. PROSPECTIVE RANDOMIZED TRIAL OF EFFICACY AND SAFETY OF IODOPOVIDONE VS OXYTETRACYCLINE FOR PLEURODESIS IN SPONTANEOUS PNEUMOTHORAX AND RECURRENT PLEURAL EFFUSIONS

    OpenAIRE

    Uday C; Sanjivani J; Mujeeb Rehman

    2016-01-01

    BACKGROUND Recurrent malignant pleural effusion and spontaneous pneumothorax can be treated by a procedure called pleurodesis by which the pleural space is obliterated. This can be done by surgical means using mechanical force or by introducing any one of the recommended agents into the pleural space via tube thoracostomy or during thoracoscopy. Examples of agents used are talc as powder or as slurry, tetracycline derivatives, antineoplastic agents (Bleomycin, mitoxantrone), q...

  3. Pulmonary function impairment measured by pulmonary function tests in long-term survivors of childhood cancer

    OpenAIRE

    Mulder, R.L.; Thönissen, N.M.; Pal, van der, H.J.H.; Bresser, P.; Hanselaar, W.; Koning, C.C.E.; Oldenburger, F.; Heij, H A; Caron, H.N.; Kremer, L.C.M.

    2011-01-01

    Childhood cancer survivors (CCSs) have an increased risk of morbidity and mortality. The prevalence and risk factors of pulmonary function impairment were investigated in a large cohort of CCSs treated with potentially pulmotoxic therapy with a minimal follow-up of 5 years after diagnosis. The study cohort consisted of all adult 5-year CCSs who were treated with bleomycin, pulmonary radiotherapy and/or pulmonary surgery in the Emma Children's Hospital/Academic Medical Center between 1966 and ...

  4. Long-term Disease Free and Successful Pregnancy in a Woman with Gonadal Dysgenesis and Malignant Germ Cell Tumor

    OpenAIRE

    Azamsadat Mousavi; Mitra Gilani; Shirin Goodarzi; Ensieh Tehraninejad; Hayedeh Haeri

    2012-01-01

    Objective: To report a case of long-term disease free and successful pregnancy after fertility sparing staging surgery with adjuvant chemotherapy in a 46,Xy gonadal dysgenetic with malignant germ cell tumor.Materials and methods: A case report from a university hospital about a 19-year-old female with 46,XY karyotype ( Swyer syndrome). The patient underwent bilateral gonadectomy and staging with uterus preservation. Six course adjuvant chemotherapy with VBP (Vinblastin, Bleomycin, Cisplatin) ...

  5. Enhanced cytotoxicity of antineoplastic agents following prolonged exposure to misonidazole.

    OpenAIRE

    Roizin-Towle, L. A.; Hall, E. J.

    1981-01-01

    Chinese hamster V79 cells cultured in vitro were used to investigated the cytotoxicity of various anti-cancer drugs subsequent to a prolonged treatment of the cells with Misonidazole (MISO). The sensitivity of the cells to Bleomycin (BLM), Melphalan or cis-Platinum (cis-DDP) was significantly increased by prior incubation with MISO under hypoxic conditions. When cysteamine, a radical scavenger, was present during the pretreatment with MISO, this enhancement of cytotoxicity was greatly reduced...

  6. Effects of baicalin on collagen Ι and collagen ΙΙΙ expression in pulmonary arteries of rats with hypoxic pulmonary hypertension

    OpenAIRE

    Liu, Panpan; YAN, SHUANGQUAN; Chen, Mayun; CHEN, ALI; Yao, Dan; Xu, Xiaomei; Cai, Xueding; Wang, Liangxing; Huang, Xiaoying

    2015-01-01

    The synthesis and accumulation of collagen play an important role in the formation and progression of hypoxic pulmonary hypertension. Baicalin has been reported to prevent bleomycin-induced pulmonary fibrosis. However, the role of baicalin in the treatment of pulmonary hypertension remains unknown. A disintegrin and metalloprotease with thrombospondin type-1 motif (ADAMTS-1) is a secreted enzyme that acts on a wide variety of extracellular matrix (ECM) substrates associated with vascular dise...

  7. A risk-adapted, response-based approach using ABVE-PC for children and adolescents with intermediate- and high-risk Hodgkin lymphoma: the results of P9425

    OpenAIRE

    Schwartz, Cindy L; Constine, Louis S.; Villaluna, Doojduen; London, Wendy B.; Hutchison, Robert E.; Sposto, Richard; Lipshultz, Steven E.; Turner, Charles S.; deAlarcon, Pedro A.; Chauvenet, Allen

    2009-01-01

    Current treatment strategies for Hodgkin lymphoma result in excellent survival but often confer significant long-term toxicity. We designed ABVE-PC (doxorubicin, bleomycin, vincristine, etoposide, prednisone, cyclophosphamide) to (1) enhance treatment efficacy by dose-dense drug delivery and (2) reduce risk of long-term sequelae by response-based reduction of cumulative chemotherapy. Efficient induction of early response by dose-dense drug delivery supported an early-response–adapted therapeu...

  8. Radiation therapy compared with chemotherapy for consolidation of chemotherapy-induced remission of advanced Hodgkin lymphoma: a study by the Eastern Co-operative Oncology Group (E1476) with > 20 years follow-up

    OpenAIRE

    Wiernik, Peter H.; Hong, Fangxin; GLICK, JOHN H.; Bennett, John M

    2009-01-01

    MOPP-Bleo (nitrogen mustard, vincristine, procarbazine, prednisone and bleomycin) induction therapy was given to 253 evaluable patients with Hodgkin lymphoma, stages IIIB, IIIs, or IV. Complete response (CR) occurred in 145 patients (57%) and partial response (PR) in 93 (37%). Of those 238 responders, 178 were randomized to consolidation therapy, and 164 were eligible and analyzable, including 114 CRs [55 patients randomized to ABVD and 59 to radiation therapy (RT)] and 50 partial responders ...

  9. Radiopharmaceuticals and tumor detection. [Evaluation of radiopharmaceuticals for tumor scintiscanning

    Energy Technology Data Exchange (ETDEWEB)

    Ansari, A.N.; Atkins, H.L.

    1976-01-01

    A number of radiopharmaceuticals are evaluated as to their usefulness for the reliable localization of malignant tumors by radioisotope scanning. Compounds discussed include /sup 75/Se-selenomethionine, /sup 32/P-phosphate, /sup 99m/Tc-phosphate, /sup 67/Ga-citrate, and /sup 111/In-bleomycin. It is pointed out that no ideal agent has yet been found and that considerable difficulties exist in comparing one clinical series with another. (CH)

  10. Concentration is more important than dose when using intralesional Pingyangmycin injection for treatment of vascular malformations

    Institute of Scientific and Technical Information of China (English)

    周琴; 郑家伟; 杨秀娟; 王延安

    2010-01-01

    @@ Vascular anomalies represent a wide spectrum of pathology with different clinico-pathological characteristics.Approximately 60% of them occur in the head and neck region.A variety of therapeutic modalities have been reported to manage vascular anomalies over the years,including surgical resection,laser therapy and sclerotherapy,etc.Bleomycin has been successfully used in intralesional injection treatment of cystic hydromas and haemangiomas,based specifically on a high sclerosing effect on vascular endothelium[1].

  11. Clinical study of COAD-B regimen in treatment of patients with relapsed /refractory nonHodgkin lymphoma

    Institute of Scientific and Technical Information of China (English)

    李明会

    2013-01-01

    Objective To investigate the efficacy,adverse events and long-term survival of cyclophosphamide,vindesine,cytarabine,dexamethasone and bleomycin (COAD-B) regimen for relapsed and refractory nonHodgkin lymphoma (NHL) .Methods Eighty six patients diagnosed with relapsed or refractory NHL were included in our study from January 2007 to January 2013.The chemotherapy regimen was COAD-B,the therapeutic efficacy was evaluated every 2 courses.Once the stable disease (SD) or progress of the disease (PD) achieved,

  12. Prognostic factors in the treatment of inoperable orofacial tumours with simultaneous radio- and intraarterial chemotherapy

    Energy Technology Data Exchange (ETDEWEB)

    Szepesi, T.; Stadler, B.; Hohenberg, G.; Hollmann, K.; Mailath, G.; Kuehboeck, J.

    1985-05-01

    Between January 1973 and April 1982 66 evaluable patients with advanced inoperable orofacial tumours underwent intraarterial Bleomycin and Methotrexate with simultaneous radiotherapy in a prospective study. 32 patients had no previous treatment, 34 patients had initial surgery, radiotherapy and/or chemotherapy. 15 mg Bleomycin were administered through a catheter into the arteria externa carotis daily in the morning. 25 mg Methotrexate were given in the same way at night followed by 3 mg Calcium-Leucovorin i.m. every 8 hours. The cumulative dose was 300 mg Bleomycin and 500 mg Methotrexate. Four hours after the administration of Bleomycin the target volume was irradiated (single fraction 2 Gy, total dose 60 to 65 Gy). The overall response rate was 65% containing 17% complete and 48% partial remission. Destruction of the bone appeared to be the most important index at the start of the therapy. Further prognostic determinants as previous treatment, localisation of the primary tumours (maxilla and start of the therapy. Further prognostic determinants as previous treatment, localisation of the primary tumours (maxilla and mandibula respectively oral cavity and oropharynx) and local regional lymphonode stage missed statistically significance in the survival time, may be due to a possible radiosensitizing effect of the simultaneous chemotherapy. Complete remission turned out to be the most important prognostic factor after the end of treatment. Patients responding with complete remission show a mediam disease free survival of 56+months and a median survival time of 82 months. Acute reactions were reversibel. Only in 14% of the patients the treatment could not be finished. Better results could be obtained by electron-affinic radiosensitizers and high LET radiation.

  13. Variability in micronucleus induction with different mutagens applied to several species of fish

    OpenAIRE

    2000-01-01

    Fish are often used for screening genotoxicity of water. For such programs, a knowledge of the sensitivity to clastogens, spontaneous micronucleus frequency and cell cycle kinetics of the target tissue is necessary. To investigate the pattern of inter-specific sensitivity to micronucleus induction three species of fish, Tilapia rendalli, Oreochromis niloticus and Cyprinus carpio, were exposed to the clastogens bleomycin (BLM), cyclophosphamide (CP), 5-fluorouracil (5-FU), and mitomycin C (MMC...

  14. Worm-like thrombus in left main coronary artery after cytostatic treatment.

    Science.gov (United States)

    Karavelioglu, Yusuf; Ekicibasi, Erkan; Tanalp, Ali C; Karapinar, Hekim; Aung, Soe M

    2010-07-01

    This paper reports a 43-year-old patient who had a large, mobile, worm-like thrombus in the left main coronary artery after receiving a chemotherapy regimen containing cisplatin, bleomycin and etoposide for a nonseminomatous testes tumor. The patient was successfully treated with thrombolytic therapy. Physicians should be aware that thrombotic events may be observed after the administration of certain chemotherapeutic agents, particularly cisplatin.

  15. Pulmonary damage caused by cytostatics and paraquat

    Energy Technology Data Exchange (ETDEWEB)

    Fischer, G.; Woeltjen, H.H.; Schauer, A.

    1981-09-01

    Substances which exercise a pulmonary toxic action will first of all produce alveolar and perivascular oedemas followed by fibrosis. Differential diagnosis is explained on the basis of two cases of a fatal mitomycin fibrosis of the lung, as well as the observation of fibrous changes following the administration of Bleomycin and Metothrexat. The course of pulmonary fibroses caused by paraquat is described for two cases of fatal paraquat intoxications.

  16. Intraperitoneal cytostatics impair early post-operative collagen synthesis in experimental intestinal anastomosesP6.

    OpenAIRE

    Martens, M F; Hendriks, T; Wobbes, T; DE PONT J.J.

    1992-01-01

    Collagen synthesis in intestinal anastomoses has been measured in rats after in vivo administration of cytostatics. The cytostatics were administered during 5 consecutive days either intravenously or intraperitoneally. On day 3 of the course the rats received both an ileal and a colonic anastomosis. The animals were sacrificed 3 and 7 days after operation. The cytostatics regimen used was a combination of 5-fluorouracil, bleomycin and cisplatinum in a dose of 10, 2 and 0.35 mg kg-1 day-1, res...

  17. mTOR Overactivation and Compromised Autophagy in the Pathogenesis of Pulmonary Fibrosis.

    Directory of Open Access Journals (Sweden)

    Yao-Song Gui

    Full Text Available The mammalian target of rapamycin (mTOR signaling pathway in pulmonary fibrosis was investigated in cell and animal models. mTOR overactivation in alveolar epithelial cells (AECs was achieved in the conditional and inducible Tsc1 knock-down mice SPC-rtTA/TetO-Cre/Tsc1(fx/+ (STT. Doxycycline caused Tsc1 knock-down and consequently mTOR activation in AECs for the STT mice. Mice treated with bleomycin exhibited increased mortality and pulmonary fibrosis compared with control mice. In wild-type C57BL/6J mice, pretreatment with rapamycin attenuated the bleomycin-mediated mortality and fibrosis. Rapamycin-mediated mouse survival benefit was inhibited by chloroquine, an autophagy inhibitor. Autophagosomes were decreased in the lungs after bleomycin exposure. Rapamycin induced the production of autophagosomes and diminished p62. We concluded that mTOR overactivation in AECs and compromised autophagy in the lungs are involved in the pathogenesis of pulmonary fibrosis. The suppression of mTOR and enhancement of autophagy may be used for treatment of pulmonary fibrosis.

  18. Adrenomedullin in inflammatory process associated with experimental pulmonary fibrosis

    Directory of Open Access Journals (Sweden)

    Bramanti Placido

    2011-04-01

    Full Text Available Abstract Background Adrenomedullin (AM, a 52-amino acid ringed-structure peptide with C-terminal amidation, was originally isolated from human pheochromocytoma. AM are widely distributed in various tissues and acts as a local vasoactive hormone in various conditions. Methods In the present study, we investigated the efficacy of AM on the animal model of bleomycin (BLM-induced lung injury. Mice were subjected to intratracheal administration of BLM and were assigned to receive AM daily by an intraperitoneal injection of 200 ngr/kg. Results and Discussion Myeloperoxidase activity, lung histology, immunohistochemical analyses for cytokines and adhesion molecules expression, inducible nitric oxide synthase (iNOS, nitrotyrosine, and poly (ADP-ribose polymerase (PARP were performed one week after fibrosis induction. Lung histology and transforming growth factor beta (TGF-β were performed 14 and 21 days after treatments. After bleomycin administration, AM-treated mice exhibited a reduced degree of lung damage and inflammation compared with BLM-treated mice, as shown by the reduction of (1 myeloperoxidase activity (MPO, (2 cytokines and adhesion molecules expression, (3 nitric oxide synthase expression, (4 the nitration of tyrosine residues, (5 poly (ADP-ribose (PAR formation, a product of the nuclear enzyme poly (ADP-ribose polymerase (PARP (6 transforming growth factor beta (TGF-β (7and the degree of lung injury. Conclusions Our results indicate that AM administration is able to prevent bleomycin induced lung injury through the down regulation of proinflammatory factors.

  19. Effect of P2X7 receptor knockout on AQP-5 expression of type I alveolar epithelial cells.

    Directory of Open Access Journals (Sweden)

    Georg Ebeling

    Full Text Available P2X7 receptors, ATP-gated cation channels, are specifically expressed in alveolar epithelial cells. The pathophysiological function of this lung cell type, except a recently reported putative involvement in surfactant secretion, is unknown. In addition, P2X7 receptor-deficient mice show reduced inflammation and lung fibrosis after exposure with bleomycin. To elucidate the role of the P2X7 receptor in alveolar epithelial type I cells we characterized the pulmonary phenotype of P2X7 receptor knockout mice by using immunohistochemistry, western blot analysis and real-time RT PCR. No pathomorphological signs of fibrosis were found. Results revealed, however, a remarkable loss of aquaporin-5 protein and mRNA in young knockout animals. Additional in vitro experiments with bleomycin treated precision cut lung slices showed a greater sensitivity of the P2X7 receptor knockout mice in terms of aquaporin-5 reduction as wild type animals. Finally, P2X7 receptor function was examined by using the alveolar epithelial cell lines E10 and MLE-12 for stimulation experiments with bleomycin. The in vitro activation of P2X7 receptor was connected with an increase of aquaporin-5, whereas the inhibition of the receptor with oxidized ATP resulted in down regulation of aquaporin-5. The early loss of aquaporin-5 which can be found in different pulmonary fibrosis models does not implicate a specific pathogenetic role during fibrogenesis.

  20. Clinical and laboratory assessment of a combination of drugs with radiation. Coordinated programme on improvement in radiotherapy of cancer using modifiers of radiosensitivity of cells

    International Nuclear Information System (INIS)

    Applications were clinically studied of misonidazole (MISO) as a hypoxic cell radiosensitizer with pharmacokinetic studies. Work with desmethylmisonidazole was focused on its penetration into the CNS because its low lipophilicity would predict poorer access than MISO. Laboratory work was focused on the interaction of hyperthermia with drugs. Cytotoxicity of MISO induced by hyperthermia was studied. Heat response following hypoxic pretreatment with MISO of EMT6 spheroids showed marked enhancement of subsequent heat killing dependent on the duration of the hypoxic pretreatment. The effect was studied in vitro of preheat temperature at modest temperatures (39 to 430C) on thermal tolerance and subsequent hyperthermic (43 to 440C) interaction with bleomycin, adriamycin and BCNU. Interaction between several cytotoxic drugs and two potentially critical normal tissues, skin and bone marrow was studied in the mouse. No increase in the heat reaction in the skin of the mouse foot was observed following single injections of adriamycin, bleomycin or 5 daily doses of bleomycin together with a single heat treatment. Single doses of BCNU and CTX increased the heat reaction. The radioprotector WR2721 failed to protect against either the heat or heat drug reactions from CTX and BCNU

  1. [Current treatment strategy in malignant pleural effusion].

    Science.gov (United States)

    Türler, A; Walter, M; Schmitz-Rixen, T

    1996-01-01

    Malignant pleural effusions are a grave consequence of advanced cancer disease. The successful suppression of pleural fluid reaccumulation can make a major contribution to the management and palliative care of patients with disseminated cancer. Many treatment concepts have been reported in the literature. The recommended therapy in malignant pleural effusions consists of intrapleural instillation of a sclerotic agent to produce pleurodesis. Different substances have been used, including tetracyclines, cytostatic agents, fibrin, talc, Corynebacterium parvum, cytokines and others. We reviewed the most frequently used techniques of pleurodesis in order to define the most effective treatment concept. In 15 prospective randomized trials the success rates varied from 13% with bleomycin to 100% with talc or Corynebacterium parvum. Talc was superior to other agents in 6 of 6, Corynebacterium parvum in 3 of 4 and bleomycin or tetracycline only in 3 of 8 studies. Adverse effects were frequently observed with cytostatic agents, but were very rare in the case of talc or fibrin instillation. Comparing the recently published data pleurodesis with talc appears to be the most effective treatment strategy, followed by Corynebacterium parvum, bleomycin and tetracycline. PMID:8686317

  2. Measurement of matrix metalloproteinase 9-mediated Collagen type III degradation fragment as a marker of skin fibrosis

    Directory of Open Access Journals (Sweden)

    Larsen Lise

    2011-03-01

    Full Text Available Abstract Background The current study utilized a Bleomycin-induced model of skin fibrosis to investigate the neo-epitope CO3-610 (KNGETGPQGP, a fragment of collagen III released during matrix metalloproteinase-9 (MMP9 degradation of the protein, we have previously described as a novel biomarker for liver fibrosis. The aim was to investigate CO3-610 levels in another well characterised model of fibrosis, to better describe the biomarker in relation to additional fibrotic pathologies. Methods Skin fibrosis was induced by daily injections of Bleomycin to a total of 52 female C3 H mice, while control mice (n = 28 were treated with phosphate buffered saline (PBS, for 2, 4, 6 or 8 weeks. Skin fibrosis was evaluated using Visiopharm software on Sirius-red stained skin sections. Urine ELISA assays and creatinine corrections were performed to measure CO3-610 levels. Results CO3-610 levels were significantly higher in Bleomycin-treated vs. PBS-treated mice at each time point of termination. The mean increases were: 59.2%, P Conclusion Increased levels in mouse urine of the MMP-9 mediated collagen III degradation fragment CO3-610 were correlated with skin fibrosis progression, suggesting that CO3-610 may be a potential positive biomarker to study the pathogenesis of skin fibrosis in mice.

  3. Results of a Prospective Study of High-Dose or Conventional Anthracycline-Cyclophosphamide Regimen Plus Radiotherapy for Localized Adult Non-Hodgkin’s Primary Bone Lymphoma

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    A. Schmidt-Tanguy

    2014-01-01

    Full Text Available Background. Primary bone lymphoma (PBL is a rare entity that has only been reviewed in one prospective and small retrospective studies, from which it is difficult to establish treatment guidelines. We prospectively evaluated high-dose or conventional anthracycline-cyclophosphamide dose and radiotherapy for PBL. Patients and Methods. The GOELAMS prospective multicenter study (1986–1998 enrolled adults with localized high-grade PBL according to age and performance status (PS. Patients <60 years received a high-dose CHOP regimen (VCAP and those ≥60 years a conventional anthracycline-cyclophosphamide regimen (VCEP-bleomycin; all received intrathecal chemotherapy and local radiotherapy. Results. Among the 26 patients included (VCAP: 19; VCEP-bleomycin: 7, 39% had poor PS ≥2. With a median follow-up of 8 years, overall survival, event-free survival, and relapse-free survival were 64%, 62%, and 65%, respectively, with no significant difference between treatment groups. Poor PS was significantly associated with shorter OS and EFS. Conclusions. Our results confirm the efficacy of our age-based therapeutic strategy. High-doses anthracycline-cyclophosphamide did not improve the outcome. VCEP-bleomycin is effective and well tolerated for old patients. The intensification must be considered for patients with PS ≥2, a poor prognostic factor.

  4. Progress in identifying a human ionizing-radiation repair gene using DNA-mediated gene transfer techniques

    International Nuclear Information System (INIS)

    The authors employing DNA-mediated gene transfer techniques in introducing human DNA into a DNA double-strand break (DSB) repair deficient Chinese hamster (CHO) cell mutant (xrs-6), which is hypersensitive to both X-rays (D0 = 0.39 Gy) and the antibiotic bleomycin (D0 = 0.01 μg/ml). High molecular weight DNA isolated from cultured human skin fibroblasts was partially digested with restriction enzyme Sau 3A to average sizes of 20 or 40 Kb, ligated with plasmid pSV2-gpt DNA, and transfected into xrs-6 cells. Colonies which developed under a bleomycin and MAX (mycophenolic acid/adenine/xanthine) double-selection procedure were isolated and further tested for X-ray sensitivity and DSB rejoining capacity. To date a total of six X-ray or bleomycin resistant transformants have been isolated. All express rejoining capacity for X-ray-induced DSB, similar to the rate observed for DSB repair in CHO wild type cells. DNA isolated from these primary transformants contain various copy numbers of pSV2-gpt DNA and also contain human DNA sequences as determined by Southern blot hybridization. Recently, a secondary transformant has been isolated using DNA from one of the primary transformants. Cellular and molecular characterization of this transformant is in progress. DNA from a genuine secondary transformant will be used in the construction of a DNA library to isolate human genomic DNA encoding this radiation repair gene

  5. Subcellular Distribution of Gallium-67 and other Auger-emitting Radionuclides in Human and Animal Tissues

    International Nuclear Information System (INIS)

    The subcellular distributions of the Auger-emitting radiopharmaceuticals 67Ga citrate, 111In-bleomycin, 63Zn-bleomycin, 123/125/I-Conray and 123/125I-Biligram in human and animal tumours and normal tissues were studied using differential centrifugation. For 67Ga, at 19 to 54 h after injection, the observed subcellular distribution patterns were similar in all the tissues studied with 2-5% of the total tissue radioactivity being associated with the cell nuclei. For 63Zn and 111In administered as the bleomycin complex or as chloride, as well as for the X ray contrast media 135/125I-Conray and 123/125I-Biligram the fraction associated with the nuclei was only 1-2%. The studies indicate that, for the 67Ga, 111In, 63Zn complexes or compounds studied, only γ1 to 4% of the Auger emissions are likely to arise in the cell nucleus. (author)

  6. Preliminary study of therapeutic effects of panax notoginside and methylprednisolone on pulmonary fibrosis in rats

    Institute of Scientific and Technical Information of China (English)

    CUI She-huai; LI Xue-jun

    2004-01-01

    Objective: To study the therapeutic effects of panax notoginside (PN) and methylprednisolone (MP) on pulmonary fibrosis in rats. Methods: Bleomycin was introduced into the bronchial tree of 75 Wistar male rats through a tracheal incision to establish a rat model of pulmonary fibrosis (PF). The rats were equally divided into 3 groups: PF group,PN treated group and MP treated group. Five rats of each group were killed 1, 3, 7, 14 and 28 d after the administration of bleomycin and the specimens of lung tissue and plasma were collected for the determination of content of collagen Ⅰ and Ⅲwith immunohistochemical method and the level of MIP-1α and MCP-1 with ELIZA. Results: The severity of PF, the content of collagen Ⅰ and Ⅲ and the level of MIP- 1 α and MCP- 1 were significantly decreased in PN and MP treated groups than in PF group ( P < 0.05). Conclusion: PN and MP are effective to control the development of PF induced with bleomycin in rats.

  7. Rare cavernous lymphangioma of the bladder in an adult female:treatment and review of the literature

    Institute of Scientific and Technical Information of China (English)

    Feng Qu; Jinyu Zheng; Yajun Xiao; Yifei Xing; Chuanguo Xiao

    2006-01-01

    Objective: Lymphangioma is a benign tumor representing a congenital malformation of the lymphatic channels. The cavernous lymphangioma of the bladder did not report before. Here we report 1 case of cavernous lymphangioma of the bladder in an adult female and review the literature in order to accumulate the experience of diagnosis and treatment for these diseases. Methods: In our case a 50-year-old woman presented with irritative voiding symptoms and had painless macroscopic hematuria at times. Cystoscopy showed a non-papillary tumor at apex vesicae and mucous membrane hyperaemia between the two orifices within the trigone. The pathologic diagnosis was cystitis glandularis with hyperplasia of urothelium and cavernous lymphangioma in lamina propria. Transurethral resection was performed and then bleomycin A5 was injected into lesion multipoint applying ureteral catheter with puncture needle. Results: Two months after operation the irritative voiding symptoms improved and the urine analysis was normal. Cystoscopy showed no residual tumor. Bleomycin A5 was injected into the lesion area again just like the operation before. All symptoms disappeared completely when the patient was examined a month later. There was no side effect after injection and no recurrence during the follow-up of 1 year. Conclusion: Lymphangioma of the bladder can be diagnosed exactly by cystoscopy and pathological examination. Surgery may be the best treatment. The bleomycin A5 intralesional sclerosant is also an effective therapy for the disease after surgical removal.

  8. Electrochemotherapy guided by intraoperative fluorescence imaging for the treatment of inoperable peritoneal micro-metastases.

    Science.gov (United States)

    Josserand, V; Kéramidas, M; Lavaud, J; Righini, C; Vollaire, J; Bellard, E; Rols, M P; Teissié, J; Coll, J L; Golzio, M

    2016-07-10

    Surgery is often the first therapeutic indication in cancer. Patient survival essentially depends on the completeness of tumor resection. This is a major challenge, particularly in patients with peritoneal carcinomatosis (PC), where tumors are widely disseminated in the large peritoneal cavity. These small tumors can be difficult to visualize and are often positioned in delicate locations, further increasing the risk of producing serious tissue/organ damage during their ablation. We propose an innovative therapeutic approach based on intraoperative fluorescence (IF) guided electrochemotherapy (ECT) for the treatment of peritoneal micro-metastases. ECT combines the effects of tissue electro-permeabilization (EP) with the administration of an antimitotic agent (bleomycin) that has poor permeability across intact membranes. IF significantly improves the detection of small tumor lesions. ECT is clinically validated for the treatment of cutaneous tumors in animals and humans, but this is the first time that it has been used along with IF imaging for the targeted treatment of peritoneal metastases in a preclinical model. We set up a murine model of PC that develops secondarily to the resection of a distant primary tumor. Tumor growth and metastasis were finely monitored by non-invasive multimodal imaging (bioluminescence and 3D fluorescence/microCT). Once metastases were detected, mice were randomized into three groups: the ECT group (bleomycin injected intravenously followed by EP) and 2 control groups (bleomycin alone and EP alone). Twenty four hours after the intravenous injection of the tumor targeting agent Angiostamp™700, mice in all groups underwent an abdominal surgery for metastases exploration assisted by fluorescence imaging with the Fluobeam®700 portative device. EP was applied to every nodule detected by IF, except in the bleomycin control group. After surgery, the metastatic invasion was tracked by bioluminescence imaging. In mice treated with bleomycin

  9. Enhancement of therapeutic drug and DNA delivery into cells by electroporation

    International Nuclear Information System (INIS)

    The effectiveness of potentially powerful therapeutics, including DNA, is often limited by their inability to permeate the cell membrane efficiently. Electroporation (EP) also referred to as 'electropermeabilization' of the outer cell membrane renders this barrier temporarily permeable by inducing 'pores' across the lipid bilayer. For in vivo EP, the drug or DNA is delivered into the interstitial space of the target tissue by conventional means, followed by local EP. EP pulses of micro- to millisecond duration and field strengths of 100-1500 V cm-1 generally enhance the delivery of certain chemotherapeutic drugs by three to four orders of magnitude and intracellular delivery of DNA several hundred-fold. We have used EP in clinical studies for human cancer therapy and in animals for gene therapy and DNA vaccination. Late stage squamous cell carcinomas of the head and neck were treated with intratumoural injection of bleomycin and subsequent EP. Of the 69 tumours treated, 25% disappeared completely and another 32% were reduced in volume by more than half. Residence time of bleomycin in electroporated tumours was significantly greater than in non-electroporated lesions. Histological findings and gene expression patterns after bleomycin-EP treatment indicated rapid apoptosis of the majority of tumour cells. In animals, we demonstrated the usefulness of EP for enhanced DNA delivery by achieving normalization of blood clotting times in haemophilic dogs, and by substantially increasing transgene expression in smooth muscle cells of arterial walls using a novel porous balloon EP catheter. Finally, we have found in animal experiments that the immune response to DNA vaccines can be dramatically enhanced and accelerated by EP and co-injection of micron-sized particles. We conclude that EP represents an effective, economical and safe approach to enhance the intracellular delivery, and thus potency, of important drugs and genes for therapeutic purposes. The safety and pharmaco

  10. Calcium Electroporation: Evidence for Differential Effects in Normal and Malignant Cell Lines, Evaluated in a 3D Spheroid Model.

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    Stine Krog Frandsen

    Full Text Available Calcium electroporation describes the use of high voltage electric pulses to introduce supraphysiological calcium concentrations into cells. This promising method is currently in clinical trial as an anti-cancer treatment. One very important issue is the relation between tumor cell kill efficacy-and normal cell sensitivity.Using a 3D spheroid cell culture model we have tested the effect of calcium electroporation and electrochemotherapy using bleomycin on three different human cancer cell lines: a colorectal adenocarcinoma (HT29, a bladder transitional cell carcinoma (SW780, and a breast adenocarcinoma (MDA-MB231, as well as on primary normal human dermal fibroblasts (HDF-n.The results showed a clear reduction in spheroid size in all three cancer cell spheroids three days after treatment with respectively calcium electroporation (p<0.0001 or electrochemotherapy using bleomycin (p<0.0001. Strikingly, the size of normal fibroblast spheroids was neither affected after calcium electroporation nor electrochemotherapy using bleomycin, indicating that calcium electroporation, like electrochemotherapy, will have limited adverse effects on the surrounding normal tissue when treating with calcium electroporation. The intracellular ATP level, which has previously been shown to be depleted after calcium electroporation, was measured in the spheroids after treatment. The results showed a dramatic decrease in the intracellular ATP level (p<0.01 in all four spheroid types-malignant as well as normal.In conclusion, calcium electroporation seems to be more effective in inducing cell death in cancer cell spheroids than in a normal fibroblast spheroid, even though intracellular ATP level is depleted in all spheroid types after treatment. These results may indicate an important therapeutic window for this therapy; although further studies are needed in vivo and in patients to investigate the effect of calcium electroporation on surrounding normal tissue when

  11. Jasmonates induce nonapoptotic death in high-resistance mutant p53-expressing B-lymphoma cells.

    Science.gov (United States)

    Fingrut, Orit; Reischer, Dorit; Rotem, Ronit; Goldin, Natalia; Altboum, Irit; Zan-Bar, Israel; Flescher, Eliezer

    2005-11-01

    Mutations in p53, a tumor suppressor gene, occur in more than half of human cancers. Therefore, we tested the hypothesis that jasmonates (novel anticancer agents) can induce death in mutated p53-expressing cells. Two clones of B-lymphoma cells were studied, one expressing wild-type (wt) p53 and the other expressing mutated p53. Jasmonic acid and methyl jasmonate (0.25-3 mM) were each equally cytotoxic to both clones, whereas mutant p53-expressing cells were resistant to treatment with the radiomimetic agent neocarzinostatin and the chemotherapeutic agent bleomycin. Neocarzinostatin and bleomycin induced an elevation in the p53 levels in wt p53-expressing cells, whereas methyl jasmonate did not. Methyl jasmonate induced mostly apoptotic death in the wt p53-expressing cells, while no signs of early apoptosis were detected in mutant p53-expressing cells. In contrast, neocarzinostatin and bleomycin induced death only in wt p53-expressing cells, in an apoptotic mode. Methyl jasmonate induced a rapid depletion of ATP in both clones. In both clones, oligomycin (a mitochondrial ATP synthase inhibitor) did not increase ATP depletion induced by methyl jasmonate, whereas inhibition of glycolysis with 2-deoxyglucose did. High glucose levels protected both clones from methyl jasmonate-induced ATP depletion (and reduced methyl jasmonate-induced cytotoxicity), whereas high levels of pyruvate did not. These results suggest that methyl jasmonate induces ATP depletion mostly by compromising oxidative phosphorylation in the mitochondria. In conclusion, jasmonates can circumvent the resistance of mutant p53-expressing cells towards chemotherapy by inducing a nonapoptotic cell death.

  12. Rosiglitazone attenuates pulmonary fibrosis and radiation-induced intestinal damage

    International Nuclear Information System (INIS)

    Full text of publication follows: Purpose.-The aim of the study was to evaluate radioprotective effect of rosiglitazone (RGZ) on a murine model of late pulmonary damage and of acute intestinal damage. Methods.- Lung fibrosis: C57 mice were treated with the radiomimetic agent bleomycin, with or without rosiglitazone (5 mg/kg/day). To obtain an independent qualitative and quantitative measure for lung fibrosis we used high resolution CT, performed twice a week during the entire observation period. Hounsfield Units (HU) of section slides from the upper and lower lung region were determined. On day 31 lungs were collected for histological analysis. Acute intestinal damage: mice underwent 12 Gy total body irradiation with or without rosiglitazone. Mice were sacrificed 24 or 72 h after total body irradiation and ileum and colon were collected. Results.- Lung fibrosis: after bleomycin treatment, mice showed typical CT features of lung fibrosis, including irregular septal thickening and patchy peripheral reticular abnormalities. Accordingly, HU lung density was dramatically increased. Rosiglitazone markedly attenuated the radiological signs of fibrosis and strongly inhibited HU lung density increase (60% inhibition at the end of the observation period). Histological analysis revealed that in bleomycin-treated mice, fibrosis involved 50-55% of pulmonary parenchyma and caused an alteration of the alveolar structures in 10% of parenchyma, while in rosiglitazone-treated mice, fibrosis involved only 20-25% of pulmonary parenchyma, without alterations of the alveolar structures. Acute intestinal damage: 24 h after 12 Gy of total body irradiation intestinal mucosa showed villi shortening, mucosal thickness and crypt necrotic changes. Rosiglitazone showed a histological improvement of tissue structure, with villi and crypts normalization and oedema reduction. Conclusion.- These results demonstrate that rosiglitazone displays a protective effect on pulmonary fibrosis and radiation

  13. Tandem mass spectrometry-based detection of c4'-oxidized abasic sites at specific positions in DNA fragments.

    Science.gov (United States)

    Chowdhury, Goutam; Guengerich, F Peter

    2009-07-01

    Oxidative damage to DNA has been linked to aging, cancer, and other biological processes. Reactive oxygen species and various antitumor agents including bleomycin and ionizing radiation have been shown to cause oxidative DNA sugar damage. Detection of DNA lesions is important for understanding the toxicological or therapeutic consequences associated with such agents. C4'-oxidized abasic sites (C4-AP) are produced by the antitumor drug bleomycin and ionizing radiation. The currently available methods for the detection of C4-AP cannot provide both structural and sequence information. We have developed an LC-ESI-MS-based approach for specific detection and mapping of C4-AP from a mixture of lesions. We show using Fe-bleomycin-damaged DNA that C4-AP can be detected at cytosine and thymine sites by direct MS analysis. Our results reveal that collision-induced dissociation of C4-AP-containing oligonucleotides results in preferential fragmentation at C4-AP sites with the formation of the unique a* ions (18 amu more than the a-B ions) that allow mapping of the C4-AP sites. Various chemical modification strategies (e.g., reduction with NaBH4 and NaBD4 and derivatization with methoxyamine and hydrazine, followed by LC-MS analysis) were also used for unambiguous detection of C4-AP sites. Finally, we show that the methods described here can detect the presence of C4-AP at specific sites in a complex sample such as hydroxyl radical-damaged DNA. The LC-MS approach was also used for the simultaneous detection of the other C4'-oxidation end product, 3'-phosphoglycolate, at a specific site in hydroxyl radical-damaged DNA. Thus, LC-MS provides a rapid and direct approach for the detection and mapping of oxidative DNA lesions. PMID:19496605

  14. Enhancement of therapeutic drug and DNA delivery into cells by electroporation* Enhancement of therapeutic drug and DNA delivery into cells by electroporation

    Science.gov (United States)

    Rabussay, Dietmar; Dev, Nagendu B.; Fewell, Jason; Smith, Louis C.; Widera, Georg; Zhang, Lei

    2003-02-01

    The effectiveness of potentially powerful therapeutics, including DNA, is often limited by their inability to permeate the cell membrane efficiently. Electroporation (EP) also referred to as `electropermeabilization' of the outer cell membrane renders this barrier temporarily permeable by inducing `pores' across the lipid bilayer. For in vivo EP, the drug or DNA is delivered into the interstitial space of the target tissue by conventional means, followed by local EP. EP pulses of micro- to millisecond duration and field strengths of 100-1500 V cm-1 generally enhance the delivery of certain chemotherapeutic drugs by three to four orders of magnitude and intracellular delivery of DNA several hundred-fold. We have used EP in clinical studies for human cancer therapy and in animals for gene therapy and DNA vaccination. Late stage squamous cell carcinomas of the head and neck were treated with intratumoural injection of bleomycin and subsequent EP. Of the 69 tumours treated, 25% disappeared completely and another 32% were reduced in volume by more than half. Residence time of bleomycin in electroporated tumours was significantly greater than in non-electroporated lesions. Histological findings and gene expression patterns after bleomycin-EP treatment indicated rapid apoptosis of the majority of tumour cells. In animals, we demonstrated the usefulness of EP for enhanced DNA delivery by achieving normalization of blood clotting times in haemophilic dogs, and by substantially increasing transgene expression in smooth muscle cells of arterial walls using a novel porous balloon EP catheter. Finally, we have found in animal experiments that the immune response to DNA vaccines can be dramatically enhanced and accelerated by EP and co-injection of micron-sized particles. We conclude that EP represents an effective, economical and safe approach to enhance the intracellular delivery, and thus potency, of important drugs and genes for therapeutic purposes. The safety and pharmaco

  15. Knockout of endothelial cell-derived endothelin-1 attenuates skin fibrosis but accelerates cutaneous wound healing.

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    Katsunari Makino

    Full Text Available Endothelin (ET-1 is known for the most potent vasoconstrictive peptide that is released mainly from endothelial cells. Several studies have reported ET-1 signaling is involved in the process of wound healing or fibrosis as well as vasodilation. However, little is known about the role of ET-1 in these processes. To clarify its mechanism, we compared skin fibrogenesis and wound repair between vascular endothelial cell-specific ET-1 knockout mice and their wild-type littermates. Bleomycin-injected fibrotic skin of the knockout mice showed significantly decreased skin thickness and collagen content compared to that of wild-type mice, indicating that bleomycin-induced skin fibrosis is attenuated in the knockout mice. The mRNA levels of transforming growth factor (TGF-β were decreased in the bleomycin-treated skin of ET-1 knockout mice. On the other hand, skin wound healing was accelerated in ET-1 knockout mice, which was indicated by earlier granulation tissue reduction and re-epithelialization in these mice. The mRNA levels of TGF-β, tumor necrosis factor (TNF-α and connective tissue growth factor (CTGF were reduced in the wound of ET-1 knockout mice. In endothelial ET-1 knockout mouse, the expression of TNF-α, CTGF and TGF-β was down-regulated. Bosentan, an antagonist of dual ET receptors, is known to attenuate skin fibrosis and accelerate wound healing in systemic sclerosis, and such contradictory effect may be mediated by above molecules. The endothelial cell-derived ET-1 is the potent therapeutic target in fibrosis or wound healing, and investigations of the overall regulatory mechanisms of these pathological conditions by ET-1 may lead to a new therapeutic approach.

  16. Experimental studies of metastases of esophageal carcinoma to lymph nodes

    International Nuclear Information System (INIS)

    Marked progress has been made in surgery for esophageal carcinoma, however, when compared to results of surgery for other carcinomas of the digestive tract, much research remains to be done. The author transplanted VX2 carcinoma, a transplantable tumor of the rabbit, to the esophagus in attempt to determine the mode of metastases of esophageal carcinoma to lymph nodes and also to observe the effect of chemotherapy (Bleomycin) and radiotherapy (Betatron). Carcinoma of the cervical esophagus metastasized to the cervical lymph nodes and then to the paratracheal lymph nodes. Carcinoma of the upper thoracic esophagus metastasized to the paratracheal lymph nodes and then to the cervical lymph nodes. Carcinoma of the mid-thoracic esophagus metastasized to the intrathoracic lymph nodes and then to the intraperitoneal lymph nodes. Carcinoma of the abdominal esophagus metastasized to the intraperitoneal lymph nodes and then to the intrathoracic lymph nodes. Skipping metastasis was rarely observed. Carcinoma of the thoracic esophagus with metastases of lymph nodes in the cervical or abdominal portion was considerably advanced, therefore it is considered that cleaning of the intrathoracic lymph nodes and simultaneous chemotherapy are required when such cases are encountered clinically. Irradiation resulted in regression in the size of the tumor and metastases to lymph nodes and there was a decrease in metastases to the distant lymph nodes. Effects of irradiation were similar on tumors and lymph nodes with positive metastases located within the field of irradiation. Bleomycin medication resulted in regression in the size of tumor and metastases to lymph nodes. Effects of Bleomycin medication were similar on tumors and lymph nodes with positive metastases. (auth.)

  17. The Effect of 217 Hz Magnetic Field of Cell Phone with Different Intensities on Apoptosis of Normal and Cancerous Cells Treated with Chemotherapy Drug

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    Mahsa Mansourian

    2012-03-01

    Full Text Available Background: According to the increasing development of home and business electronic equipment in today's world, the biological effects of ELF magnetic fields have been studied at two molecular-cellular and animal- human levels. Considering the therapeutic viewpoint of this study regarding the effects of low-frequency fields of mobile phone, the effect of acute exposure to this field on chemotherapy will be studied.Materials and Methods: In this experimental study, based on measurement of the intensity of the magnetic fields from mobile phones in another research, flux densities of magnetic field of 159.44, 93.25 and 120µ tesla with frequency of 217Hz was generated in magnetic field generator system, and the apoptosis level in K562 cancer cells and healthy cells of lymphocytes was assessed after exposure to field using flow cytometry method. This evaluation method was also performed for the cells treated with bleomycin after exposure to this field.Results: 217 Hz magnetic field exposure significantly increases the rate of apoptosis percentage (p > 0.05 in K562 cancer cells and in two intensities of 120 and 159.44µ tesla compared to the control group, but such effect is not observed in lymphocyte cells. Bleomycin-induced apoptosis percentage following exposure to the mentioned magnetic field shows no significant difference compared to the group of treatment with drug and without field exposure. This lack of significant difference is observed between the groups of drug after field exposure and field alone as well as between groups exposed to field and groups treated with bleomycin.Conclusion: Study results showed that 217 Hz magnetic field of mobile phone can induce apoptosis on cancer cells, but it has no effect on healthy cells. Thus, in order to use mobile phone as an effective factor in their treatment, some studies should be conducted at animal-human level.

  18. Validation of the 2nd Generation Proteasome Inhibitor Oprozomib for Local Therapy of Pulmonary Fibrosis.

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    Nora Semren

    Full Text Available Proteasome inhibition has been shown to prevent development of fibrosis in several organs including the lung. However, effects of proteasome inhibitors on lung fibrosis are controversial and cytotoxic side effects of the overall inhibition of proteasomal protein degradation cannot be excluded. Therefore, we hypothesized that local lung-specific application of a novel, selective proteasome inhibitor, oprozomib (OZ, provides antifibrotic effects without systemic toxicity in a mouse model of lung fibrosis. Oprozomib was first tested on the human alveolar epithelial cancer cell line A549 and in primary mouse alveolar epithelial type II cells regarding its cytotoxic effects on alveolar epithelial cells and compared to the FDA approved proteasome inhibitor bortezomib (BZ. OZ was less toxic than BZ and provided high selectivity for the chymotrypsin-like active site of the proteasome. In primary mouse lung fibroblasts, OZ showed significant anti-fibrotic effects, i.e. reduction of collagen I and α smooth muscle actin expression, in the absence of cytotoxicity. When applied locally into the lungs of healthy mice via instillation, OZ was well tolerated and effectively reduced proteasome activity in the lungs. In bleomycin challenged mice, however, locally applied OZ resulted in accelerated weight loss and increased mortality of treated mice. Further, OZ failed to reduce fibrosis in these mice. While upon systemic application OZ was well tolerated in healthy mice, it rather augmented instead of attenuated fibrotic remodelling of the lung in bleomycin challenged mice. To conclude, low toxicity and antifibrotic effects of OZ in pulmonary fibroblasts could not be confirmed for pulmonary fibrosis of bleomycin-treated mice. In light of these data, the use of proteasome inhibitors as therapeutic agents for the treatment of fibrotic lung diseases should thus be considered with caution.

  19. MMP28 promotes macrophage polarization toward M2 cells and augments pulmonary fibrosis

    Science.gov (United States)

    Gharib, Sina A.; Johnston, Laura K.; Huizar, Isham; Birkland, Timothy P.; Hanson, Josiah; Wang, Ying; Parks, William C.; Manicone, Anne M.

    2014-01-01

    Members of the MMP family function in various processes of innate immunity, particularly in controlling important steps in leukocyte trafficking and activation. MMP28 (epilysin) is a member of this family of proteinases, and we have found that MMP28 is expressed by macrophages and regulates their recruitment to the lung. We hypothesized that MMP28 regulates other key macrophage responses, such as macrophage polarization. Furthermore, we hypothesized that these MMP28-dependent changes in macrophage polarization would alter fibrotic responses in the lung. We examined the gene expression changes in WT and Mmp28−/− BMDMs, stimulated with LPS or IL-4/IL-13 to promote M1 and M2 cells, respectively. We also collected macrophages from the lungs of Pseudomonas aeruginosa-exposed WT and Mmp28−/− mice to evaluate changes in macrophage polarization. Lastly, we evaluated the macrophage polarization phenotypes during bleomycin-induced pulmonary fibrosis in WT and Mmp28−/− mice and assessed mice for differences in weight loss and total collagen levels. We found that MMP28 dampens proinflammatory macrophage function and promots M2 programming. In both in vivo models, we found deficits in M2 polarization in Mmp28−/− mice. In bleomycin-induced lung injury, these changes were associated with reduced fibrosis. MMP28 is an important regulator of macrophage polarization, promoting M2 function. Loss of MMP28 results in reduced M2 polarization and protection from bleomycin-induced fibrosis. These findings highlight a novel role for MMP28 in macrophage biology and pulmonary disease. PMID:23964118

  20. The use of chemotherapeutics for the treatment of keloid scars

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    Christopher David Jones

    2015-05-01

    Full Text Available Keloid scars are pathological scars, which develop as a result of exaggerated dermal tissue proliferation following cutaneous injury and often cause physical, psychological and cosmetic problems. Various theories regarding keloidogenesis exist, however the precise pathophysiological events remain unclear. Many different treatment modalities have been implicated in their management, but currently there is no entirely satisfactory method for treating all keloid lesions. We review a number of different chemotherapeutic agents which have been proposed for the treatment of keloid and hypertrophic scars while giving insight into some of the novel chemotherapeutic drugs which are currently being investigated. Non-randomized trials evaluating the influence of different chemotherapeutic agents, such as 5-fluorouracil (5-FU; mitomycin C; bleomycin and steroid injection, either alone or in combination with other chemotherapeutic agents or alternative treatment modalities, for the treatment of keloids were identified using a predefined PubMed search strategy. Twenty seven papers were identified. Scar improvement ≥50% was found in the majority of cases treated with 5-FU, with similar results found for mitomycin C, bleomycin and steroid injection. Combined intralesional 5-FU and steroid injection produced statistically significant improvements when compared to monotherapy. Monotherapy recurrence rates ranged from 0-47% for 5-FU, 0-15% for bleomycin and 0-50% for steroid injection. However, combined therapy in the form of surgical excision and adjuvant 5-FU or steroid injections demonstrated lower recurrence rates; 19% and 6% respectively. Currently, most of the literature supports the use of combination therapy (usually surgery and adjuvant chemotherapy as the mainstay treatment of keloids, however further investigation is necessary to determine success rates over longer time frames. Furthermore, there is the potential for novel therapies, but further

  1. MS80,a novel sulfated oligosaccharide,inhibits pulmonary fibrosis by targeting TGF-β1 both in vitro and in vivo

    Institute of Scientific and Technical Information of China (English)

    Han-dong JIANG; Hua-shi GUAN

    2009-01-01

    Aim:The pro-fibrogenic cytokine transforming growth factor-beta 1 (TGF-131) has attracted much attention for its potential role in the etiology of idiopathic pulmonary fibrosis (IPF).Here,we demonstrate that MS80,a novel sulfated oligosaccharide extracted from seaweed,can bind TGF-β1.The aim of the present study was to determine whether MSSO is capable of combating TGF-β1-mediated pulmonary fibrotic events both in vitro and in vivo,and to investigate the possible underlying mechanisms.Methods:Surface plasmon resonance was used to uncover the binding profiles between the compound and TGF-β.MTT assay,flow cytometry,Western blot analysis,BCA protein assay and SDS-PAGE gelatin zymography were used to probe the antifibrotic mechanisms of MS80.The in vivo fibrotic efficacy was evaluated in a bleomycin instillation-induced rat model.Results:We report that MS80,a new kind of sulfated oligosaccharide extracted from seaweed,inhibits TGF-β1-induced pulmonary fibrosis in vitro and bleomycin-induced pulmonary fibrosis in vivo.Our results indicated that MS80 competitively inhibited heparin/HS-TGF-β1 interaction through its high binding affinity for TGF-β1.Moreover,MS80 arrested TGF-β1-induced human embryo pulmonary fibroblast (HEPF) cell proliferation,collagen deposition and matrix metalloproteinase (MMP) activity.Intriguingly,MS80 deactivated both the ERK and p38 signaling pathways.MS80 was also a potent suppressor of bleomycin-induced rat pulmonary fibrosis in vivo,as evidenced by improved pathological settings and decreased lung collagen contents.Conclusion:MS80 in particular,and perhaps oligosaccharide in general,offer better pharmacological profiles with appreciably few side effects and represent a promising class of drug candidates for IPF therapy.

  2. Prospective analysis of DNA damage and repair markers of lung cancer risk from the Prostate, Lung, Colorectal and Ovarian (PLCO) Cancer Screening Trial.

    Science.gov (United States)

    Sigurdson, Alice J; Jones, Irene M; Wei, Qingyi; Wu, Xifeng; Spitz, Margaret R; Stram, Douglas A; Gross, Myron D; Huang, Wen-Yi; Wang, Li-E; Gu, Jian; Thomas, Cynthia B; Reding, Douglas J; Hayes, Richard B; Caporaso, Neil E

    2011-01-01

    Mutagen challenge and DNA repair assays have been used in case-control studies for nearly three decades to assess human cancer risk. The findings still engender controversy because blood was drawn after cancer diagnosis so the results may be biased, a type called 'reverse causation'. We therefore used Epstein-Barr virus-transformed lymphoblastoid cell lines established from prospectively collected peripheral blood samples to evaluate lung cancer risk in relation to three DNA repair assays: alkaline Comet assay, host cell reactivation (HCR) assay with the mutagen benzo[a]pyrene diol epoxide and the bleomycin mutagen sensitivity assay. Cases (n = 117) were diagnosed with lung cancer between 0.3 and 6 years after blood collection and controls (n = 117) were frequency matched on calendar year and age at blood collection, gender and smoking history; all races were included. Case and control status was unknown to laboratory investigators. In unconditional logistic regression analyses, statistically significantly increased lung cancer odds ratios (OR(adjusted)) were observed for bleomycin mutagen sensitivity as quartiles of chromatid breaks/cell [relative to the lowest quartile, OR = 1.2, 95% confidence interval (CI): 0.5-2.5; OR = 1.4, 95% CI: 0.7-3.1; OR = 2.1, 95% CI: 1.0-4.4, respectively, P(trend) = 0.04]. The magnitude of the association between the bleomycin assay and lung cancer risk was modest compared with those reported in previous lung cancer studies but was strengthened when we included only incident cases diagnosed more than a year after blood collection (P(trend) = 0.02), supporting the notion the assay may be a measure of cancer susceptibility. The Comet and HCR assays were unrelated to lung cancer risk. PMID:20929901

  3. Rosiglitazone attenuates pulmonary fibrosis and radiation-induced intestinal damage

    Energy Technology Data Exchange (ETDEWEB)

    Mangoni, M.; Gerini, C.; Sottili, M.; Cassani, S.; Stefania, G.; Biti, G. [Radiotherapy Unit, Clinical Physiopathology Department, University of Florence, Firenze (Italy); Castiglione, F. [Department of Human Pathology and Oncology, University of Florence, Firenze (Italy); Vanzi, E.; Bottoncetti, A.; Pupi, A. [Nuclear Medicine Unit, Clinical Physiopathology Department, University of Florence, Firenze (Italy)

    2011-10-15

    Full text of publication follows: Purpose.-The aim of the study was to evaluate radioprotective effect of rosiglitazone (RGZ) on a murine model of late pulmonary damage and of acute intestinal damage. Methods.- Lung fibrosis: C57 mice were treated with the radiomimetic agent bleomycin, with or without rosiglitazone (5 mg/kg/day). To obtain an independent qualitative and quantitative measure for lung fibrosis we used high resolution CT, performed twice a week during the entire observation period. Hounsfield Units (HU) of section slides from the upper and lower lung region were determined. On day 31 lungs were collected for histological analysis. Acute intestinal damage: mice underwent 12 Gy total body irradiation with or without rosiglitazone. Mice were sacrificed 24 or 72 h after total body irradiation and ileum and colon were collected. Results.- Lung fibrosis: after bleomycin treatment, mice showed typical CT features of lung fibrosis, including irregular septal thickening and patchy peripheral reticular abnormalities. Accordingly, HU lung density was dramatically increased. Rosiglitazone markedly attenuated the radiological signs of fibrosis and strongly inhibited HU lung density increase (60% inhibition at the end of the observation period). Histological analysis revealed that in bleomycin-treated mice, fibrosis involved 50-55% of pulmonary parenchyma and caused an alteration of the alveolar structures in 10% of parenchyma, while in rosiglitazone-treated mice, fibrosis involved only 20-25% of pulmonary parenchyma, without alterations of the alveolar structures. Acute intestinal damage: 24 h after 12 Gy of total body irradiation intestinal mucosa showed villi shortening, mucosal thickness and crypt necrotic changes. Rosiglitazone showed a histological improvement of tissue structure, with villi and crypts normalization and oedema reduction. Conclusion.- These results demonstrate that rosiglitazone displays a protective effect on pulmonary fibrosis and radiation

  4. Short History of Electroporation for the Study of Developmental Biology

    Science.gov (United States)

    Nakamura, Harukazu

    Electroporation at high voltage has been been applied for transformation of bacteria. Since it damages the tissue of higher organisms, it has been limited to bac teria trans formation. Nevertheless, electroporation in higher organisms has been carried out for the transfer of the drugs for treatment of cancer; bleomycin was successfully applied to hepatocellular carcinoma in the Donryu rat (Okino and Mohri, 1987). Mr. Hayakawa (Nepa Gene; Ichikawa, Japan) supplied the electroporator and helped to optimize the condition of electroporation with the BTX electropo rator, and Mr. Imada (Unique Medical-Imada, Natori, Japan) designed and prepared electrodes.

  5. Interstitial lung disease

    Institute of Scientific and Technical Information of China (English)

    1993-01-01

    930124 The effect of glycosaminoglycans inthe genesis of pulmonary interstitial fibrosis.LIBaoyu(李保玉),et al.Dept Pathol,Jilin MedColl,132001.Chin J Tuberc & Respir Dis 1992;15(4):204-205.The pulmonary interstitial fibrosis was causedby injecting Bleomycin into mouse trachea.Afterthe injection,the volume of glycosaminoglycans(GAG)in bronchoalveolar lavage fluid and lungtissues was increased.The observation underhistochemical stain and electron microscopeshowed that the distribution of GAG in lung tis-sues was varied at different time after the injec-tion,and related to the volume of collagen pro-teins and the formation of pulmonary interstitialfibrosis.

  6. Phase III randomised controlled trial of neoadjuvant chemotherapy plus radical surgery vs radical surgery alone for stages IB2, IIA2, and IIB cervical cancer: a Japan Clinical Oncology Group trial (JCOG 0102)

    OpenAIRE

    Katsumata, N; Yoshikawa, H; Kobayashi, H.; Saito, T.; Kuzuya, K; Nakanishi, T; Yasugi, T; Yaegashi, N; Yokota, H; Kodama, S.; Mizunoe, T; Hiura, M; Kasamatsu, T; Shibata, T.; Kamura, T

    2013-01-01

    Background: A phase III trial was conducted to determine whether neoadjuvant chemotherapy (NACT) before radical surgery (RS) improves overall survival. Methods: Patients with stage IB2, IIA2, or IIB squamous cell carcinoma of the uterine cervix were randomly assigned to receive either BOMP (bleomycin 7 mg days 1–5, vincristine 0.7 mg m−2 day 5, mitomycin 7 mg m−2 day 5, cisplatin 14 mg m−2 days 1–5, every 3 weeks for 2 to 4 cycles) plus RS (NACT group) or RS alone (RS group). Patients with pa...

  7. Radio-isotope uptake by tumours. Introduction to their clinical use

    International Nuclear Information System (INIS)

    Before each group of authors exposes his results, present tendencies and progress in research may be briefly recalled. The object is to make to clinicians, a technique which is both reliable and relatively easy to perform. The improvements are due to ease of recording with the gamma-camera, and, apart from Hg 197, the introduction of new radio-isotopes: Ga 67, bleomycin labelled with Co 57 and Cu 67 without a carrier. Tumours which escape detection have thus become rare and the specificity of the methods is reinforced. But the difficulties due to possible fixation on advanced inflammatory lesions have not yet been totally overcome

  8. Duration of the hidden chromosome instability persistence in peripheral blood lymphocytes of persons occupationally exposed to ionizing radiation

    International Nuclear Information System (INIS)

    With compatible use of tests 'G2-bleomycin sensitivity assay' and two-term (48 and 100 h) cultivation of human peripheral blood lymphocytes, the voluntary cytogenetic examination of persons who have occupational contact with ionizing radiation is carried out. The results are compared with those obtained in a similar observation of the unexposed group. Principal differences between the groups in the manifestation and the dynamics of the hidden chromosome instability (HCI) in time are found. Its indicators were significantly higher in the occupational group. The possibility of the persistence of radiation-associated HCI in successive generations of human somatic cells with significant interindividual differences is established

  9. [Talc--a standard drug in the treatment of malignant pleural effusion].

    Science.gov (United States)

    Bednár, M; Bezdícek, P

    1999-01-25

    Currently, talc is the most effective and widely-used agent for chemical pleurodesis in the treatment of both malignant pleural effusion and pneumothorax. Its popularity has been growing due to the low incidence of side effects, low cost and higher success rate in comparison with other agents (tetracyclines, bleomycin, Corynebacterium parvum). The guidelines for talc pleurodesis are summarized and the history of the Corynebacterium parvum as an agent for chemical pleurodesis is mentioned. Its production in the Czech Republic has been halted due to the increased interest in the talc as a chemical sclerosant. PMID:10376391

  10. Biosynthetic Gene Cluster of Cetoniacytone A, an Unusual Aminocyclitol from the Endosymbiotic Bacterium Actinomyces sp. Lu 9419

    OpenAIRE

    Wu, Xiumei; Flatt, Patricia M.; Xu, Hui; Mahmud, Taifo

    2009-01-01

    A gene cluster responsible for the biosynthesis of the antitumor agent cetoniacytone A was identified in Actinomyces sp. strain Lu 9419, an endosymbiotic bacteria isolated from the intestines of the rose chafer beetle (Cetonia aurata). The nucleotide sequence analysis of the 46 kb DNA region revealed the presence of 31 complete ORFs, including genes predicted to encode a 2-epi-5-epi-valiolone synthase (CetA), a glyoxalase/bleomycin resistance protein (CetB), an acyltransferase (CetD), an FAD-...

  11. Structure-Based Design of Tetrahydroisoquinoline-7-carboxamides as Selective Discoidin Domain Receptor 1 (DDR1) Inhibitors

    Science.gov (United States)

    2016-01-01

    The structure-based design of 1, 2, 3, 4-tetrahydroisoquinoline derivatives as selective DDR1 inhibitors is reported. One of the representative compounds, 6j, binds to DDR1 with a Kd value of 4.7 nM and suppresses its kinase activity with an IC50 value of 9.4 nM, but it is significantly less potent for a panel of 400 nonmutated kinases. 6j also demonstrated reasonable pharmacokinetic properties and a promising oral therapeutic effect in a bleomycin-induced mouse pulmonary fibrosis model. PMID:27219676

  12. Treatment of advanced head and neck cancer: multiple daily dose fractionated radiation therapy and sequential multimodal treatment approach.

    Science.gov (United States)

    Nissenbaum, M; Browde, S; Bezwoda, W R; de Moor, N G; Derman, D P

    1984-01-01

    Fifty-eight patients with advanced head and neck cancer were entered into a randomised trial comparing chemotherapy (DDP + bleomycin) alone, multiple daily fractionated radiation therapy, and multimodality therapy consisting of chemotherapy plus multiple fractionated radiation therapy. Multimodal therapy gave a significantly higher response rate (69%) than either single-treatment modality. The use of a multiple daily dose fractionation allowed radiation therapy to be completed over 10 treatment days, and the addition of chemotherapy to the radiation treatment did not significantly increase toxicity. Patients receiving multimodal therapy also survived significantly longer (median 50 weeks) than those receiving single-modality therapy (median 24 weeks).

  13. Juvenile laryngeal papillomatosis with pulmonary parenchymal spread

    Energy Technology Data Exchange (ETDEWEB)

    Kawanami, T.; Bowen, A.

    1985-02-01

    A 6.5-year-old boy developed laryngeal papillomas at 20 months of age and pulmonary parenchymal spread at age 3.5 years, the lung lesions beginning as solid nodules which rapidly cavitated. The cavitary lesions have stabilized in size but no appreciable improvement has resulted from trials of bleomycin, methotrexate, or interferon. A review of 14 other cases indicates that the lung lesions may develop many years after the onset of laryngeal papillomatosis, and the lung lesions do not tend to regress spontaneously as uncomplicated juvenile laryngeal papillomas often do. Three of 15 patients developed carcinomas in their lung lesions without prior therapeutic irradiation.

  14. Anti-inflammatory and antifibrotic effects of methyl palmitate

    International Nuclear Information System (INIS)

    Methyl palmitate (MP) has been shown earlier to inhibit Kupffer cells and rat peritoneal macrophages. To evaluate the potential of MP to inhibit the activation of other macrophages, RAW cells (macrophages of alveolar origin) were treated with varying concentrations of MP (0.25, 0.5, 1 mM). Assessment of cytotoxicity using MTT assay revealed that 0.25 and 0.5 mM are not toxic to RAW cells. MP was able to inhibit the phagocytic function of RAW cells. Treatment of cells with MP 24 hours prior to LPS stimulation significantly decreased nitric oxide release and altered the pattern of cytokines release; there was a significant decrease in TNF-α and a significant increase in IL-10 compared to the controls. However, there is a non-significant change in IL-6 level. Furthermore, phosphorylation of inhibitory kappa B (IκBα) protein was significantly decreased in RAW cells treated with 0.5 mM MP after LPS stimulation. Based upon the in-vitro results, it was examined whether MP treatment will be effective in preventing bleomycin-induced lung inflammation and fibrosis in-vivo. Bleomycin given by itself caused destruction of the lung architecture characterized by pulmonary fibrosis with collapse of air alveoli and emphysematous. Bleomycin induced a significant increase in hydroxyproline level and activated NF-κB, p65 expression in the lung. MP co-treatment significantly ameliorated bleomycin effects. These results suggest that MP has a potential of inhibiting macrophages in general. The present study demonstrated for the first time that MP has anti-inflammatory and antifibrotic effect that could be through NF-kB inhibition. Thus MP like molecule could be a promising anti-inflammatory and antifibrotic drug. - Research highlights: →Methyl palmitate is a universal macrophage inhibitor. →It could be a promising nucleus of anti-inflammatory and antifibrotic drugs. →The underlying mechanism of these effects could be through NF-kB inhibition.

  15. Involved Node Radiation Therapy

    DEFF Research Database (Denmark)

    Maraldo, Maja V; Aznar, Marianne C; Vogelius, Ivan R;

    2012-01-01

    PURPOSE: The involved node radiation therapy (INRT) strategy was introduced for patients with Hodgkin lymphoma (HL) to reduce the risk of late effects. With INRT, only the originally involved lymph nodes are irradiated. We present treatment outcome in a retrospective analysis using this strategy...... in a cohort of 97 clinical stage I-II HL patients. METHODS AND MATERIALS: Patients were staged with positron emission tomography/computed tomography scans, treated with adriamycin, bleomycin, vinblastine, and dacarbazine chemotherapy, and given INRT (prechemotherapy involved nodes to 30 Gy, residual masses...

  16. Electrochemotherapy of tumours

    International Nuclear Information System (INIS)

    Electrochemotherapy consists of chemotherapy followed by local application of electric pulses to the tumour to increase drug delivery into cells. Drug uptake can be increased by electroporation for only those drugs whose transport through the plasma membrane is impeded. Among many drugs that have been tested so far, only bleomycin and cisplatin found their way from preclinical testing to clinical trials. In vitro studies demonstrated several fold increase of their cytotoxicity after electroporation of cells. In vivo, electroporation of tumours after local or systemic administration of either of the drugs, i.e. electrochemotherapy, proved to be an effective antitumour treatment. In preclinical studies on several tumour models, electrochemotherapy either with bleomycin or cisplatin was elaborated and parameters for effective local tumour control were determined. In veterinary medicine, electrochemotherapy also proved to be effective in the treatment of primary tumours in cats, dogs and horses. In human clinical studies, electrochemotherapy was performed on the patients with progressive disease and accessible tumour nodules of different malignancies. All clinical studies demonstrated that electrochemotherapy is an effective treatment for local tumour control in cancer patients. (author)

  17. Chemotherapy agents and the induction of late lethal defects.

    Science.gov (United States)

    Seymour, C B; Mothersill, C

    1991-01-01

    Radiation is now known to be capable of producing both lethal and non lethal lesions in a variety of mammalian cells which may not be expressed for several cell divisions after the initial insult. The mechanism by which such an effect occurs is unknown. Because of the possible implications for cancer treatment, if such an effect also occurred following chemotherapy exposure, cells were exposed to various cytotoxic chemotherapy agents with known and well characterised effects on DNA or other areas of cell function or structure. The results indicate that late lethal defects are not detectable after treatment with appropriate ranges of doses of cisplatinum, vincristine, BCNU or adriamycin, but that they are induced by Bleomycin and to a lesser extent by 5-Fluorouracil. Bleomycin is known to cause strand breaks and is regarded as a radiomimetic agent. 5-Fluorouracil may act by preventing efficient and faithful synthesis of DNA, allowing mutations to become integrated into the genome. The occurrence of lethal mutations with both these agents supports previous suggestions that error-prone repair of DNA base sequence abnormalities may be fundamental to the process of late lethal damage production in mammalian cells. The cloning efficiency of cells which survived exposure to Vincristine or BCNU over a wide dose range was found to be significantly increased; this may represent an adaptive response to the drugs.

  18. A novel model of rheumatoid arthritis-associated interstitial lung disease in SKG mice.

    Science.gov (United States)

    Keith, Rebecca C; Powers, Jennifer L; Redente, Elizabeth F; Sergew, Amen; Martin, Richard J; Gizinski, Alison; Holers, V Michael; Sakaguchi, Shimon; Riches, David W H

    2012-03-01

    Rheumatoid arthritis-associated interstitial lung disease (RA-ILD) is associated with increased mortality in up to 10% of patients with rheumatoid arthritis. Lung exposure to cigarette smoke has been implicated in disease development. Little is known about the mechanisms underlying the development of RA-ILD, in part due to the lack of an appropriate mouse model. The objectives of this study were (i) to test the suitability of SKG mice as a model of cellular and fibrotic interstitial pneumonia in the setting of autoimmune arthritis, and (ii) to determine the role of lung injury in the development of arthritis in SKG mice. Lung tissues were evaluated in arthritic SKG mice by quantifying cell accumulation in bronchoalveolar lavage, static compliance, collagen levels, and infiltrating cell phenotypes by flow cytometry and histology. Lung injury was induced by exposure to cigarette smoke or bleomycin. Arthritic SKG mice developed a patchy cellular and fibrotic interstitial pneumonia associated with reduced static compliance, increased collagen levels, and accumulation of inflammatory cells. Infiltrating cells comprised CD4+ T cells, B cells, macrophages, and neutrophils. Chronic exposure to cigarette smoke or initiation of lung injury with bleomycin did not cause arthritis. The pattern of lung disease suggests that arthritic SKG mice represent an authentic model of nonspecific interstitial pneumonia in RA-ILD patients. The lack of arthritis development after cigarette smoke or lung injury suggests that a model where breaches in immunologic tolerance are induced by lung inflammation and injury alone may be overly simplistic.

  19. Vimentin regulates activation of the NLRP3 inflammasome

    Science.gov (United States)

    Dos Santos, Gimena; Rogel, Micah R.; Baker, Margaret A.; Troken, James R.; Urich, Daniela; Morales-Nebreda, Luisa; Sennello, Joseph A.; Kutuzov, Mikhail A.; Sitikov, Albert; Davis, Jennifer M.; Lam, Anna P.; Cheresh, Paul; Kamp, David; Shumaker, Dale K.; Budinger, G. R. Scott; Ridge, Karen M.

    2015-03-01

    Activation of the NLRP3 inflammasome and subsequent maturation of IL-1β have been implicated in acute lung injury (ALI), resulting in inflammation and fibrosis. We investigated the role of vimentin, a type III intermediate filament, in this process using three well-characterized murine models of ALI known to require NLRP3 inflammasome activation. We demonstrate that central pathophysiologic events in ALI (inflammation, IL-1β levels, endothelial and alveolar epithelial barrier permeability, remodelling and fibrosis) are attenuated in the lungs of Vim-/- mice challenged with LPS, bleomycin and asbestos. Bone marrow chimeric mice lacking vimentin have reduced IL-1β levels and attenuated lung injury and fibrosis following bleomycin exposure. Furthermore, decreased active caspase-1 and IL-1β levels are observed in vitro in Vim-/- and vimentin-knockdown macrophages. Importantly, we show direct protein-protein interaction between NLRP3 and vimentin. This study provides insights into lung inflammation and fibrosis and suggests that vimentin may be a key regulator of the NLRP3 inflammasome.

  20. Sustained PI3K Activation exacerbates BLM-induced Lung Fibrosis via activation of pro-inflammatory and pro-fibrotic pathways.

    Science.gov (United States)

    Kral, Julia Barbara; Kuttke, Mario; Schrottmaier, Waltraud Cornelia; Birnecker, Birgit; Warszawska, Joanna; Wernig, Christina; Paar, Hannah; Salzmann, Manuel; Sahin, Emine; Brunner, Julia Stefanie; Österreicher, Christoph; Knapp, Sylvia; Assinger, Alice; Schabbauer, Gernot

    2016-01-01

    Idiopathic pulmonary fibrosis (IPF) is a life-threatening disease with limited treatment options. Additionally, the lack of a complete understanding of underlying immunological mechanisms underscores the importance of discovering novel options for therapeutic intervention. Since the PI3K/PTEN pathway in myeloid cells influences their effector functions, we wanted to elucidate how sustained PI3K activity induced by cell-type specific genetic deficiency of its antagonist PTEN modulates IPF, in a murine model of bleomycin-induced pulmonary fibrosis (BIPF). We found that myeloid PTEN deficient mice (PTEN(MyKO)), after induction of BIPF, exhibit increased TGF-β1 activation, mRNA expression of pro-collagens and lysyl oxidase as well as augmented collagen deposition compared to wild-type littermates, leading to enhanced morbidity and decreased survival. Analysis of alveolar lavage and lung cell composition revealed that PTEN(MyKO) mice exhibit reduced numbers of macrophages and T-cells in response to bleomycin, indicating an impaired recruitment function. Interestingly, we found dysregulated macrophage polarization as well as elevated expression and release of the pro-fibrotic cytokines IL-6 and TNF-α in PTEN(MyKO) mice during BIPF. This might point to an uncontrolled wound healing response in which the inflammatory as well as tissue repair mechanisms proceed in parallel, thereby preventing resolution and at the same time promoting extensive fibrosis. PMID:26971883

  1. Dysregulated proinflammatory and fibrogenic phenotype of fibroblasts in cystic fibrosis.

    Directory of Open Access Journals (Sweden)

    François Huaux

    Full Text Available Morbi-mortality in cystic fibrosis (CF is mainly related to chronic lung infection and inflammation, uncontrolled tissue rearrangements and fibrosis, and yet the underlying mechanisms remain largely unknown. We evaluated inflammatory and fibrosis responses to bleomycin in F508del homozygous and wild-type mice, and phenotype of fibroblasts explanted from mouse lungs and skin. The effect of vardenafil, a cGMP-specific phosphodiesterase type 5 inhibitor, was tested in vivo and in culture. Responses of proinflammatory and fibrotic markers to bleomycin were enhanced in lungs and skin of CF mice and were prevented by treatment with vardenafil. Purified lung and skin fibroblasts from CF mice proliferated and differentiated into myofibroblasts more prominently and displayed higher sensitivity to growth factors than those recovered from wild-type littermates. Under inflammatory stimulation, mRNA and protein expression of proinflammatory mediators were higher in CF than in wild-type fibroblasts, in which CFTR expression reached similar levels to those observed in other non-epithelial cells, such as macrophages. Increased proinflammatory responses in CF fibroblasts were reduced by half with submicromolar concentrations of vardenafil. Proinflammatory and fibrogenic functions of fibroblasts are upregulated in CF and are reduced by vardenafil. This study provides compelling new support for targeting cGMP signaling pathway in CF pharmacotherapy.

  2. In vivo anticancer activity of vanillin semicarbazone

    Institute of Scientific and Technical Information of China (English)

    Shaikh M Mohsin Ali; M Abul Kalam Azad; Mele Jesmin; Shamim Ahsan; M Mijanur Rahman; Jahan Ara Khanam; M Nazrul Islam; Sha M Shahan Shahriar

    2012-01-01

    Objective:To evaluate the anticancer activity of vanillin semicarbazone (VSC) against Ehrlich ascites carcinoma (EAC) cells in Swiss albino mice. Methods:The compound VSC at three doses (5, 7.5 and 10 mg/kg i.p.) was administered into the intraperitoneal cavity of the EAC inoculated mice to observe its efficiency by studying the cell growth inhibition, reduction of tumour weight, enhancement of survival time as well as the changes in depleted hematological parameters. All such parameters were also studied with a known standard drug bleomycin at the dose of 0.3 mg/kg (i.p.). Results:Among the doses studied, 10 mg/kg (i.p.) was found to be quite comparable in potency to that of bleomycin at the dose of 0.3 mg/kg (i.p.). The host toxic effects of VSC was found to be negligible. Conclusions: It can be concluded that VSC can therefore be considered as potent anticancer agent.

  3. In vivo anticancer activity of vanillin, benzophenone and acetophenone thiosemicarbazones on Swiss albino mice

    Institute of Scientific and Technical Information of China (English)

    Sha Md. Shahan Shahriar; Shaikh M Mohsin Ali; Mele Jesmin; Md. Khairul Islam; Sarozit Mondal

    2014-01-01

    Objective: To study the anticancer activities of three schiff bases viz. vanillin thiosemicarbazone, benzophenone thiosemicarbazone and acetophenone thiosemicarbazone against Ehrlich ascites carcinoma (EAC) cells in Swiss albino mice. Methods: Synthesized compounds have administrated into the intraperitoneal cavity of the EAC inoculated mice at two doses. The anticancer activities have studied by monitoring the parameters such as cell growth inhibition, tumor weight measurement, survival time of EAC bearing mice as well as the changes in depleted hematological parameters due to tumorgenesis. All such data have been compared with those of a known standard drug bleomycin at the dose of 0.3 mg/kg (i.p.).Results:It has been found that these bases enhanced life span, reduced average tumor weight and inhibited tumor cell growth of EAC cell bearing mice remarkably. The results were similar in potency to those obtained with bleomycin. It was also found that the depleted hematological parameters (red blood count, white blood count and haemoglobin content) were found to be restored gradually towards normal within few weeks after ceasing the treatment.Conclusions:The compounds can be primarily considered more or less as potent anticancer agents.

  4. The circadian clock regulates rhythmic activation of the NRF2/glutathione-mediated antioxidant defense pathway to modulate pulmonary fibrosis

    Science.gov (United States)

    Pekovic-Vaughan, Vanja; Gibbs, Julie; Yoshitane, Hikari; Yang, Nan; Pathiranage, Dharshika; Guo, Baoqiang; Sagami, Aya; Taguchi, Keiko; Bechtold, David; Loudon, Andrew; Yamamoto, Masayuki; Chan, Jefferson; van der Horst, Gijsbertus T.J.; Fukada, Yoshitaka; Meng, Qing-Jun

    2014-01-01

    The disruption of the NRF2 (nuclear factor erythroid-derived 2-like 2)/glutathione-mediated antioxidant defense pathway is a critical step in the pathogenesis of several chronic pulmonary diseases and cancer. While the mechanism of NRF2 activation upon oxidative stress has been widely investigated, little is known about the endogenous signals that regulate the NRF2 pathway in lung physiology and pathology. Here we show that an E-box-mediated circadian rhythm of NRF2 protein is essential in regulating the rhythmic expression of antioxidant genes involved in glutathione redox homeostasis in the mouse lung. Using an in vivo bleomycin-induced lung fibrosis model, we reveal a clock “gated” pulmonary response to oxidative injury, with a more severe fibrotic effect when bleomycin was applied at a circadian nadir in NRF2 levels. Timed administration of sulforaphane, an NRF2 activator, significantly blocked this phenotype. Moreover, in the lungs of the arrhythmic ClockΔ19 mice, the levels of NRF2 and the reduced glutathione are constitutively low, associated with increased protein oxidative damage and a spontaneous fibrotic-like pulmonary phenotype. Our findings reveal a pivotal role for the circadian control of the NRF2/glutathione pathway in combating oxidative/fibrotic lung damage, which might prompt new chronotherapeutic strategies for the treatment of human lung diseases, including idiopathic pulmonary fibrosis. PMID:24637114

  5. Vascular effects of sildenafil in patients with pulmonary fibrosis and pulmonary hypertension: an ex vivo/in vitro study.

    Science.gov (United States)

    Milara, Javier; Escrivá, Juan; Ortiz, José Luis; Juan, Gustavo; Artigues, Enrique; Morcillo, Esteban; Cortijo, Julio

    2016-06-01

    Sildenafil improves the 6-min walking distance in patients with idiopathic pulmonary fibrosis (IPF) and right-sided ventricular systolic dysfunction.We analysed the previously unexplored role of sildenafil on vasoconstriction and remodelling of pulmonary arteries from patients with IPF and pulmonary hypertension (PH) ex vivo Pulmonary arteries from 18 donors without lung disease, nine IPF, eight PH+IPF and four PH patients were isolated to measure vasodilator and anti-contractile effects of sildenafil in isometric organ bath. Ventilation/perfusion was explored in an animal model of bleomycin lung fibrosis.Sildenafil relaxed serotonin (5-HT) pre-contracted pulmonary arteries in healthy donors and IPF patients and, to a lesser extent, in PH+IPF and PH. Sildenafil inhibited 5-HT dose-response contraction curve mainly in PH+IPF and PH, but not in healthy donors. Sildenafil did not impair the ventilation/perfusion mismatching induced by bleomycin. Pulmonary arteries from PH+IPF patients showed a marked expression of phosphodiesterse-5 and extracellular matrix components. Sildenafil inhibited pulmonary artery endothelial and smooth muscle cell to mesenchymal transition by inhibition of extracellular regulated kinases 1 and 2 (ERK1/2) and SMAD3 phosphorylation.These results suggest an absence of direct relaxant effect and a prominent anti-contractile and anti-remodelling role of sildenafil in PH+IPF pulmonary arteries that could explain the beneficial effects of sildenafil in IPF with PH phenotype. PMID:27009174

  6. Targeted inhibition of disheveled PDZ domain via NSC668036 depresses fibrotic process

    International Nuclear Information System (INIS)

    In this study, we determined the effects of transforming growth factor-beta (TGF-β) and Wnt/β-catenin signaling on myofibroblast differentiation of NIH/3T3 fibroblasts in vitro and evaluated the therapeutic efficacy of NSC668036 in bleomycin-induced pulmonary fibrosis murine model. In vitro study, NSC668036, a small organic inhibitor of the PDZ domain in Dvl, suppressed β-catenin-driven gene transcription and abolished TGF-β1-induced migration, expression of collagen I and α-smooth muscle actin (α-SMA) in fibroblasts. In vivo study, we found that NSC668036 significantly suppressed accumulation of collagen I, α-SMA, and TGF-β1 but increased the expression of CK19, Occludin and E-cadherin that can inhibit pulmonary fibrogenesis. Because fibrotic lung exhibit aberrant activation of Wnt/β-catenin signaling, these data collectively suggest that inhibition of Wnt/β-catenin signaling at the Dvl level may be an effective approach to the treatment of fibrotic lung diseases. - Highlights: • NSC668036 inhibited the proliferation and migration of NIH/3T3 fibroblasts. • NSC668036 suppressed the Wnt/β-catenin signaling pathway. • TGF-β-induced stimulation of profibrotic responses were inhibited by NSC668036. • NSC668036 can inhibit the development of bleomycin-induced pulmonary fibrosis

  7. Present state of the combined treatment with radiation and chemicals

    International Nuclear Information System (INIS)

    Of malignancies in which the results have been markedly improved by combined treatment with radiation and chemicals for the past decade, non-Hodgkin's lymphoma localized in head and neck and intra-oral carcinoma are presented. In the management of non-Hodgkin's lymphoma, the authors stressed the following: 1) Rappaport's classification has been a help to evaluate the prognosis; 2) lymphoma of the Waldeyer's ring should not be included in nodal lymphoma, and also it should be separated from extranodal lymphoma as well, because of different prognosis; 3) It seems that some kinds of chemotherapy would have a role in improving the results of radiotherapy in the management of radiotherapy, even in localized cases. In some types of intra-oral carcinomas, bleomycin was found to be useful in the combined treatment with radiation as follows: 1) A minimum required dose for local control of intra-oral carcinomas could be a combination of 30Gy in 3 weeks and 100mg bleomycin during the same period. 2) Although the end results of patients with carcinoma of tongue or floor of mouth have not been improved by this approach, there was marked improvement in patients with carcinoma of the lower gum. 3) For the treatment, the side effect as limiting factor was mucositis, and none of the cases of the series developed pulmonary complication. In the cases controlled by initial combined treatment, no one developed troubles of the mandible, in the follow-up study for the past 10 years. (author)

  8. Cytotoxicity of probiotics from Philippine commercial dairy products on cancer cells and the effect on expression of cfos and cjun early apoptotic-promoting genes and Interleukin-1 β and Tumor Necrosis Factor-α proinflammatory cytokine genes.

    Science.gov (United States)

    Shyu, Peter T; Oyong, Glenn G; Cabrera, Esperanza C

    2014-01-01

    This study determined cytotoxicity of probiotic Lactobacillus spp. from Philippine dairy products on cancer cells and normal fibroblasts and their effects on expression of early apoptotic-promoting cfos, cjun and proinflammatory cytokine IL-1β, TNF-α genes. Cultures were from Yakult, Bear Brand Probiotic Drink, Nido3+ Powdered Milk. Filter-sterilized supernatants from cultures of Lactobacillus spp. were evaluated for cytotoxicity to colon cancer cells (HT-29 and HCT116), leukemia cells (THP-1), and normal human dermal fibroblasts (HDFn) using PrestoBlue. Bleomycin was the positive control. Absolute quantification of transcript levels was conducted using qRT-PCR. Cytotoxicity index profiles on HDFn, THP-1 of all probiotic supernatants and negative controls suggest nontoxicity to the cells when compared to bleomycin, whereas all probiotic supernatants were found to be cytotoxic to HT-29 and HCT-116 colon cancer cell lines. Expression of cfos, cjun transcripts was significantly upregulated in HT-29 and HCT116 cells treated with probiotic supernatants compared to untreated baseline levels (P probiotic supernatants compared to those exposed to MRS medium (P < 0.05). Results provide strong support for the role of Lactobacillus spp. studied in anticancer therapy and in prevention of inflammation that may act as precursor to carcinogenesis. PMID:25276792

  9. Cytotoxicity of Probiotics from Philippine Commercial Dairy Products on Cancer Cells and the Effect on Expression of cfos and cjun Early Apoptotic-Promoting Genes and Interleukin-1β and Tumor Necrosis Factor-α Proinflammatory Cytokine Genes

    Directory of Open Access Journals (Sweden)

    Peter T. Shyu

    2014-01-01

    Full Text Available This study determined cytotoxicity of probiotic Lactobacillus spp. from Philippine dairy products on cancer cells and normal fibroblasts and their effects on expression of early apoptotic-promoting cfos, cjun and proinflammatory cytokine IL-1β, TNF-α genes. Cultures were from Yakult, Bear Brand Probiotic Drink, Nido3+ Powdered Milk. Filter-sterilized supernatants from cultures of Lactobacillus spp. were evaluated for cytotoxicity to colon cancer cells (HT-29 and HCT116, leukemia cells (THP-1, and normal human dermal fibroblasts (HDFn using PrestoBlue. Bleomycin was the positive control. Absolute quantification of transcript levels was conducted using qRT-PCR. Cytotoxicity index profiles on HDFn, THP-1 of all probiotic supernatants and negative controls suggest nontoxicity to the cells when compared to bleomycin, whereas all probiotic supernatants were found to be cytotoxic to HT-29 and HCT-116 colon cancer cell lines. Expression of cfos, cjun transcripts was significantly upregulated in HT-29 and HCT116 cells treated with probiotic supernatants compared to untreated baseline levels (P<0.05. Expression of IL-1β and TNF-α by lipopolysaccharide-treated macrophages was significantly downregulated in cells with probiotic supernatants compared to those exposed to MRS medium (P<0.05. Results provide strong support for the role of Lactobacillus spp. studied in anticancer therapy and in prevention of inflammation that may act as precursor to carcinogenesis.

  10. Refractory Classical Hodgkin Lymphoma Presenting with Atypical Cutaneous Involvement and Diagnosis of ZZ Phenotype Alpha-1 Antitrypsin Deficiency

    Directory of Open Access Journals (Sweden)

    Mohamad Khawandanah

    2014-01-01

    Full Text Available Cutaneous Hodgkin lymphoma is a rare condition. Specific neoplastic involvement can be primary (confined to the skin or secondary to systemic involvement (metastatic. Cutaneous involvement by HL usually occurs late in the course and is associated with poor prognosis; however in some cases it can exhibit indolent behavior. Skin involvement with nonspecific cutaneous findings may represent a paraneoplastic syndrome. We describe a case of 46-year-old white male patient presented with rash and lymphadenopathy which led to the diagnosis of stage IVE mixed cellularity classical Hodgkin lymphoma with skin involvement. His disease was refractory to multiple lines of chemotherapy including (1 AVD (doxorubicin/bleomycin/dacarbazine, (2 brentuximab, and (3 bendamustine, he later achieved complete remission with (4 GCD (gemcitabine/carboplatin/dexamethasone salvage regimen. Bleomycin was not given secondary to poor pulmonary function tests. His treatment was complicated after AVD with multiple pneumothoraces which unmasked the diagnosis of ZZ phenotype alpha-1 antitrypsin (ATT deficiency. Simultaneous existence of Hodgkin lymphoma and ATT is rarely reported.

  11. An Innovative Cell Microincubator for Drug Discovery Based on 3D Silicon Structures

    Directory of Open Access Journals (Sweden)

    Francesca Aredia

    2016-01-01

    Full Text Available We recently employed three-dimensional (3D silicon microstructures (SMSs consisting in arrays of 3 μm-thick silicon walls separated by 50 μm-deep, 5 μm-wide gaps, as microincubators for monitoring the biomechanical properties of tumor cells. They were here applied to investigate the in vitro behavior of HT1080 human fibrosarcoma cells driven to apoptosis by the chemotherapeutic drug Bleomycin. Our results, obtained by fluorescence microscopy, demonstrated that HT1080 cells exhibited a great ability to colonize the narrow gaps. Remarkably, HT1080 cells grown on 3D-SMS, when treated with the DNA damaging agent Bleomycin under conditions leading to apoptosis, tended to shrink, reducing their volume and mimicking the normal behavior of apoptotic cells, and were prone to leave the gaps. Finally, we performed label-free detection of cells adherent to the vertical silicon wall, inside the gap of 3D-SMS, by exploiting optical low coherence reflectometry using infrared, low power radiation. This kind of approach may become a new tool for increasing automation in the drug discovery area. Our results open new perspectives in view of future applications of the 3D-SMS as the core element of a lab-on-a-chip suitable for screening the effect of new molecules potentially able to kill tumor cells.

  12. Polycomb-group histone methyltransferase CLF is required for proper somatic recombination in Arabidopsis

    Institute of Scientific and Technical Information of China (English)

    Na Chen; Wang-Bin Zhou; Ying-Xiang Wang; Ai-Wu Dong; Yu Yu

    2014-01-01

    Homologous recombination (HR) is a key process during meiosis in reproductive cells and the DNA damage repair process in somatic cells. Although chromatin structure is thought to be crucial for HR, only a smal number of chromatin modifiers have been studied in HR regulation so far. Here, we investigated the function of CURLY LEAF (CLF), a Polycomb-group (PcG) gene responsible for histone3 lysine 27 trimethy-lation (H3K27me3), in somatic and meiotic HR in Arabidopsis thaliana. Although fluorescent protein reporter assays in pol en and seeds showed that the frequency of meiotic cross-over in the loss-of-function mutant clf-29 was not significantly different from that in wild type, there was a lower frequency of HR in clf-29 than in wild type under normal conditions and under bleomycin treatment. The DNA damage levels were compara-ble between clf-29 and wild type, even though several DNA damage repair genes (e.g. ATM, BRCA2a, RAD50, RAD51, RAD54,and PARP2) were expressed at lower levels in clf-29. Under bleomycin treatment, the expression levels of DNA repair genes were similar in clf-29 and wild type, thus CLF may also regulate HR via other mechanisms. These findings expand the current knowledge of PcG function and contribute to general interests of epigenetic regulation in genome stability regulation.

  13. Targeting of the pulmonary capillary vascular niche promotes lung alveolar repair and ameliorates fibrosis.

    Science.gov (United States)

    Cao, Zhongwei; Lis, Raphael; Ginsberg, Michael; Chavez, Deebly; Shido, Koji; Rabbany, Sina Y; Fong, Guo-Hua; Sakmar, Thomas P; Rafii, Shahin; Ding, Bi-Sen

    2016-02-01

    Although the lung can undergo self-repair after injury, fibrosis in chronically injured or diseased lungs can occur at the expense of regeneration. Here we study how a hematopoietic-vascular niche regulates alveolar repair and lung fibrosis. Using intratracheal injection of bleomycin or hydrochloric acid in mice, we show that repetitive lung injury activates pulmonary capillary endothelial cells (PCECs) and perivascular macrophages, impeding alveolar repair and promoting fibrosis. Whereas the chemokine receptor CXCR7, expressed on PCECs, acts to prevent epithelial damage and ameliorate fibrosis after a single round of treatment with bleomycin or hydrochloric acid, repeated injury leads to suppression of CXCR7 expression and recruitment of vascular endothelial growth factor receptor 1 (VEGFR1)-expressing perivascular macrophages. This recruitment stimulates Wnt/β-catenin-dependent persistent upregulation of the Notch ligand Jagged1 (encoded by Jag1) in PCECs, which in turn stimulates exuberant Notch signaling in perivascular fibroblasts and enhances fibrosis. Administration of a CXCR7 agonist or PCEC-targeted Jag1 shRNA after lung injury promotes alveolar repair and reduces fibrosis. Thus, targeting of a maladapted hematopoietic-vascular niche, in which macrophages, PCECs and perivascular fibroblasts interact, may help to develop therapy to spur lung regeneration and alleviate fibrosis.

  14. Targeted inhibition of disheveled PDZ domain via NSC668036 depresses fibrotic process

    Energy Technology Data Exchange (ETDEWEB)

    Wang, Cong, E-mail: wangcongweihai@126.com [Immunology and Reproduction Biology Laboratory, Medical School, Nanjing University, Nanjing, Hankou Road 22, Jiangsu 210093 (China); Jiangsu Key Laboratory of Molecular Medicine, Nanjing University, Nanjing, Jiangsu 210093 (China); State Key Laboratory of Analytical Chemistry for Life Science, Nanjing University, Nanjing, Jiangsu 210093 (China); Dai, Jinghong, E-mail: daijinghongnew@163.com [Department of Respiratory Medicine, Nanjing Drum Tower Hospital Affiliated to Medical School of Nanjing University (China); Sun, Zhaorui, E-mail: lanseyunduan@163.com [Immunology and Reproduction Biology Laboratory, Medical School, Nanjing University, Nanjing, Hankou Road 22, Jiangsu 210093 (China); Jiangsu Key Laboratory of Molecular Medicine, Nanjing University, Nanjing, Jiangsu 210093 (China); State Key Laboratory of Analytical Chemistry for Life Science, Nanjing University, Nanjing, Jiangsu 210093 (China); Department of Emergency, Jinling Hospital, Medical School, Nanjing University, Nanjing, Jiangsu 210093 (China); Shi, Chaowen, E-mail: willscw@live.cn [Immunology and Reproduction Biology Laboratory, Medical School, Nanjing University, Nanjing, Hankou Road 22, Jiangsu 210093 (China); Jiangsu Key Laboratory of Molecular Medicine, Nanjing University, Nanjing, Jiangsu 210093 (China); State Key Laboratory of Analytical Chemistry for Life Science, Nanjing University, Nanjing, Jiangsu 210093 (China); Cao, Honghui, E-mail: caohonghui92@gmail.com [Immunology and Reproduction Biology Laboratory, Medical School, Nanjing University, Nanjing, Hankou Road 22, Jiangsu 210093 (China); Jiangsu Key Laboratory of Molecular Medicine, Nanjing University, Nanjing, Jiangsu 210093 (China); State Key Laboratory of Analytical Chemistry for Life Science, Nanjing University, Nanjing, Jiangsu 210093 (China); and others

    2015-02-01

    In this study, we determined the effects of transforming growth factor-beta (TGF-β) and Wnt/β-catenin signaling on myofibroblast differentiation of NIH/3T3 fibroblasts in vitro and evaluated the therapeutic efficacy of NSC668036 in bleomycin-induced pulmonary fibrosis murine model. In vitro study, NSC668036, a small organic inhibitor of the PDZ domain in Dvl, suppressed β-catenin-driven gene transcription and abolished TGF-β1-induced migration, expression of collagen I and α-smooth muscle actin (α-SMA) in fibroblasts. In vivo study, we found that NSC668036 significantly suppressed accumulation of collagen I, α-SMA, and TGF-β1 but increased the expression of CK19, Occludin and E-cadherin that can inhibit pulmonary fibrogenesis. Because fibrotic lung exhibit aberrant activation of Wnt/β-catenin signaling, these data collectively suggest that inhibition of Wnt/β-catenin signaling at the Dvl level may be an effective approach to the treatment of fibrotic lung diseases. - Highlights: • NSC668036 inhibited the proliferation and migration of NIH/3T3 fibroblasts. • NSC668036 suppressed the Wnt/β-catenin signaling pathway. • TGF-β-induced stimulation of profibrotic responses were inhibited by NSC668036. • NSC668036 can inhibit the development of bleomycin-induced pulmonary fibrosis.

  15. [Electrochemotherapy: mechanism of action and clinical results in the locoregional treatment of patients with skin cancers and superficial metastases].

    Science.gov (United States)

    Campana, Luca Giovanni; Marconato, Roberto; Sieni, Elisabetta; Valpione, Sara; Corti, Luigi; Mocellin, Simone; Rossi, Carlo Riccardo

    2016-08-01

    Electrochemotherapy (ECT) has emerged among European centers as an innovative locoregional treatment for patients with unresectable skin cancers or superficial metastases from any histotype. The combined administration of a cytotoxic agent (bleomycin or cisplatin) with properly tuned electric pulses results in locally-enhanced drug delivery (reversible electroporation) into malignant cells and sustained tumor response. Reversible electroporation represents the basis of ECT and allows the potentiation of two low permeant cytotoxic agents such as bleomycin (~8000 fold) and cisplatin (~80 fold). The procedure was standardized in 2006 - thanks to a European project - and shortly after introduced in the clinical practice. In recent years, experience with ECT has accumulated mainly in melanoma and breast cancer patients with cutaneous metastases, in whom complete response rates of 20-50% and 40-75% have been reported, respectively, depending on tumor size. Currently, this therapy is being investigated in deep-seated (i.e. bone, soft tissue) metastases and visceral malignancies (i.e. locally advanced pancreatic cancer), with encouraging results. PMID:27571558

  16. Feasibility and safety of electrochemotherapy (ECT) in the pancreas: a pre-clinical investigation

    International Nuclear Information System (INIS)

    Pancreatic ductal adenocarcinoma (PDAC) is a lethal disease generally refractory to standard chemotherapeutic agents; therefore improvements in anticancer therapies are mandatory. A major determinant of therapeutic resistance in PDAC is the poor drug delivery to neoplastic cells, mainly due to an extensive fibrotic reaction. Electroporation can be used in vivo to increase cancer cells’ local uptake of chemotherapeutics (electrochemotherapy, ECT), thus leading to an enhanced tumour response rate. In the present study, we evaluated the in vivo effects of reversible electroporation in normal pancreas in a rabbit experimental model. We also tested the effect of electroporation on pancreatic cancer cell lines in order to evaluate their increased sensitivity to chemotherapeutic agents. The application in vivo of the European Standard Operating Procedure of Electrochemotherapy (ESOPE) pulse protocol (1000 V/cm, 8 pulses, 100 μs, 5 KHz) was tested on the pancreas of normal New Zealand White Rabbits and short and long-term toxicity were assessed. PANC1 and MiaPaCa2 cell lines were tested for in vitro electrochemotherapy experiments with and without electroporation. Levels of cell permeabilization were determined by flow cytometry, whereas cell viability and drug (cisplatin and bleomycin) sensitivity of pulsed cells were measured by 3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl) -2H-tetrazolium (MTS) assay. In healthy rabbits, neither systemic nor local toxic effects due to the electroporation procedure were observed, demonstrating the safety of the optimized electric parameters in the treatment of the pancreas in vivo. In parallel, we established an optimized protocol for ECT in vitro that determined an enhanced anti-cancer effect of bleomycin and cisplatin with respect to treatment without electroporation. Our data suggest that electroporation is a safe procedure in the treatment of PDAC because it does not affect normal pancreatic parenchyma

  17. Quantification of lung fibrosis and emphysema in mice using automated micro-computed tomography.

    Directory of Open Access Journals (Sweden)

    Ellen De Langhe

    Full Text Available BACKGROUND: In vivo high-resolution micro-computed tomography allows for longitudinal image-based measurements in animal models of lung disease. The combination of repetitive high resolution imaging with fully automated quantitative image analysis in mouse models of lung fibrosis lung benefits preclinical research. This study aimed to develop and validate such an automated micro-computed tomography analysis algorithm for quantification of aerated lung volume in mice; an indicator of pulmonary fibrosis and emphysema severity. METHODOLOGY: Mice received an intratracheal instillation of bleomycin (n = 8, elastase (0.25 U elastase n = 9, 0.5 U elastase n = 8 or saline control (n = 6 for fibrosis, n = 5 for emphysema. A subset of mice was scanned without intervention, to evaluate potential radiation-induced toxicity (n = 4. Some bleomycin-instilled mice were treated with imatinib for proof of concept (n = 8. Mice were scanned weekly, until four weeks after induction, when they underwent pulmonary function testing, lung histology and collagen quantification. Aerated lung volumes were calculated with our automated algorithm. PRINCIPAL FINDINGS: Our automated image-based aerated lung volume quantification method is reproducible with low intra-subject variability. Bleomycin-treated mice had significantly lower scan-derived aerated lung volumes, compared to controls. Aerated lung volume correlated with the histopathological fibrosis score and total lung collagen content. Inversely, a dose-dependent increase in lung volume was observed in elastase-treated mice. Serial scanning of individual mice is feasible and visualized dynamic disease progression. No radiation-induced toxicity was observed. Three-dimensional images provided critical topographical information. CONCLUSIONS: We report on a high resolution in vivo micro-computed tomography image analysis algorithm that runs fully automated and allows quantification of aerated lung volume in mice. This

  18. Paeoniflorin suppresses TGF-β mediated epithelial-mesenchymal transition in pulmonary fibrosis through a Smad-dependent pathway

    Science.gov (United States)

    Ji, Yu; Dou, Yan-nong; Zhao, Qian-wen; Zhang, Ji-zhou; Yang, Yan; Wang, Ting; Xia, Yu-feng; Dai, Yue; Wei, Zhi-feng

    2016-01-01

    Aim: Paeoniflorin has shown to attenuate bleomycin-induced pulmonary fibrosis (PF) in mice. Because the epithelial-mesenchymal transition (EMT) in type 2 lung endothelial cells contributes to excessive fibroblasts and myofibroblasts during multiple fibrosis of tissues, we investigated the effects of paeoniflorin on TGF-β mediated pulmonary EMT in bleomycin-induced PF mice. Methods: PF was induced in mice by intratracheal instillation of bleomycin (5 mg/kg). The mice were orally treated with paeoniflorin or prednisone for 21 d. After the mice were sacrificed, lung tissues were collected for analysis. An in vitro EMT model was established in alveolar epithelial cells (A549 cells) incubated with TGF-β1 (2 ng/mL). EMT identification and the expression of related proteins were performed using immunohistochemistry, transwell assay, ELISA, Western blot and RT-qPCR. Results: In PF mice, paeoniflorin (50, 100 mg·kg−1·d−1) or prednisone (6 mg·kg−1·d−1) significantly decreased the expression of FSP-1 and α-SMA, and increased the expression of E-cadherin in lung tissues. In A549 cells, TGF-β1 stimulation induced EMT, as shown by the changes in cell morphology, the increased cell migration, and the increased vimentin and α-SMA expression as well as type I and type III collagen levels, and by the decreased E-cadherin expression. In contrast, effects of paeoniflorin on EMT disappeared when the A549 cells were pretreated with TGF-β1 for 24 h. TGF-β1 stimulation markedly increased the expression of Snail and activated Smad2/3, Akt, ERK, JNK and p38 MAPK in A549 cells. Co-incubation with paeoniflorin (1–30 μmol/L) dose-dependently attenuated TGF-β1-induced expression of Snail and activation of Smad2/3, but slightly affected TGF-β1-induced activation of Akt, ERK, JNK and p38 MAPK. Moreover, paeoniflorin markedly increased Smad7 level, and decreased ALK5 level in A549 cells. Conclusion: Paeoniflorin suppresses the early stages of TGF-β mediated EMT in alveolar

  19. Ovarian function after removal of an entire ovary for cryopreservation of pieces of cortex prior to gonadotoxic treatment: a follow-up study

    DEFF Research Database (Denmark)

    Rosendahl, M.; Andersen, Claus Yding; Ernst, E.;

    2008-01-01

    BACKGROUND: Ovarian function was studied in Danish patients who had ovarian tissue cryopreserved, and the patients' experiences with the procedure were investigated. METHODS: There were 92 women who had an entire ovary removed for cryopreservation 18-75 months earlier. Reasons included: breast......) were performed in 73 women. RESULTS: In total, 11% of the BMT patients had normal ovarian function. Hodgkin's patients who only received ABVD (doxorubicin, bleomycin, vinblastine and dacarbazine) (n = 12) and 60% of the breast cancer patients showed little evidence of ovarian damage. Regular...... menstruation was shown to be a good indicator of ovarian function. The cryopreservation procedure rarely complicated cancer treatment (5%) and 84% felt comforted because they had potentially secured their fertility. CONCLUSIONS: Cryopreservation of ovarian tissue should be considered in young female patients...

  20. ESR of copper and iron complexes with antitumor and cytotoxic properties

    Energy Technology Data Exchange (ETDEWEB)

    Antholine, W.E.; Kalyanaraman, B.; Petering, D.H.

    1985-12-01

    The relatively few iron and copper metal complexes which have been examined in cells and tissues for their redox properties, radical generation properties, and antitumor activity are discussed for studies which utilized electron spin resonance spectroscopy (ESR). A common property of a number of metal complexes, which include bleomycin, adriamycin, and thiosemicarbazones described in this review, is that they are readily reduced by thiol compounds and oxidized by oxygen or reduced species of oxygen to produce radicals. Structural features of these reactions are identified by ESR spectroscopy in model systems and often in cells. Furthermore, ESR spectroscopy has been most useful to probe the environment of the complexes in cells and to measure the rate of reduction of their oxidized forms. As a result of these studies, it is anticipated that more attention will be given to the exploration of redox-active metal complexes as drugs. 95 references.

  1. Experimental Study on the Radiosensitivity and Chemosensitivity of A-431 Cell Line

    International Nuclear Information System (INIS)

    The purpose of this study was to aid in the prediction of tumor cell tolerance to radiotherapy and/or chemotherapy. Human epidermoid carcinoma A-431 cell line were irradiated by 2, 4, 6, 8, 10 Gy at a dose rate of 210 cGy/min using 60Co Irradiator ALDORADO 8 and then were exposed to bleomycin or cisplatin at concentration of 2 μg/ml for 1 hour. The viable cells were determined for each radiation dose and/or each drug at the 4th day and cell surviving curves were obtained using semiautomated MTT assay. The surviving fraction after irradiation of 2 Gy was 0.99, and there was not significant difference of surviving fraction in comparison with the control group on A-431 cell line (p>0.05). But there were significant differences of surviving fractions at doses of 4, 6, 8, 10 Gy in comparison with the control group (p0.05).

  2. Hodgkin lymphoma in Tyrol-a population-based study.

    Science.gov (United States)

    Fong, Dominic; Steurer, Michael; Greil, Richard; Gunsilius, Eberhard; Spizzo, Gilbert; Gastl, Guenther; Tzankov, Alexandar

    2009-05-01

    We aimed to analyze the epidemiology, clinical characteristics, and outcome of patients with Hodgkin lymphoma (HL) diagnosed in Tyrol. All patients with newly diagnosed HL between 1993 and 2005 were included in this study. Among the 158 cases included, nodular lymphocytic predominant HL (nodular paragranuloma) was identified in ten cases (6%) whereas the majority of patients had classical Hodgkin lymphoma. Age (p Tyrol is comparable to other Western countries. Modern risk-adapted treatment results in excellent long-term prognosis but may be complicated by serious nonhematological side effects, in particular, infections and bleomycin-induced lung toxicity. Furthermore, 3% of HL patients had an antecedent malignant hematological disease before occurrence of HL.

  3. Lung scans and malignancy

    International Nuclear Information System (INIS)

    An experience of pulmonary isotope scanning carried out with mercury 197 labelled mercury chloride and acetate, cobalt 57-labelled bleomycin, and Cu67 and Cu64 labelled copper citrate was presented. The scans were carried out with various isotopes supplied by the French Atomic Energy Authority, and gave comparable results, which may be summarised as follows: increased uptake in more than 90% of cases of carcinoma, absent uptake in all cases of benign tumour, frequent increased uptake in acute or advanced inflammatory lesions, absence of uptake, very commonly, in tuberculoma and chronic lesions with scar formation. Radio-isotope scan using Cu67 labelled copper citrate permitted discrimination of malignant tumours (increased fixation which showed up best at the 24th hour) from inflammatory lesions (increased fixation which was reduced on the 24th hour). The positive or negative character of the fixation in a given lesions remains the same, whatever the isotope used in our experience

  4. General considerations on the use of radio-active substances for the study of lung tumours

    International Nuclear Information System (INIS)

    Among the numerous substances proposed for the study of lung tumours, three are more commonly used, 67Ga, 57Co labelled bleomycin and 197Hg. With these three substances, the uptake is high on malignant tumours and also on active inflammatory lesions, it is normal in the case of benign tumours and cooled inflammatory lesions. In spite of this lack of specificity in carcinoma, these three radio-active substances are useful in practice for they permit to distinguish benign from malignant tumours, often they permit to make the diagnosis of cancer with a high degree of probability and, finally, they are of use in permitting, for example, to judge the efficiency of treatment. New compounds are under study, they may permit true detection of cancer

  5. Experimental basis for the combination of irradiation with cytotoxic drugs

    International Nuclear Information System (INIS)

    For the treatment of therapy resistant tumours the combination of irradiation with chemical substances, especially cytotoxic drugs, can have advantages. In order to obtain supraadditive effects it is reasonable to know the mechanism of interaction. In this respect interactions are very important on the level of intracellular recovery processes, of repopulation, and of hypoxic cells. Substances have been discussed which interact with ionizing radiation on these levels. Especially the modification of recovery processes can increase the radiation effects efficiently. In this connection substances like actinomycin D, bleomycin, adriamycin, and newer drugs like aclacinomycin are of interest. For such a treatment tumours with a high capacity of recovery must be considered. An individual selection would have great advantages therefore. (orig.)

  6. Bilateral Sertoli-Leydig cell tumor in a primigravida: a rare case

    Directory of Open Access Journals (Sweden)

    Ruchita Tyagi

    2014-06-01

    Full Text Available We present a unique case of incidentally discovered bilateral Sertoli Leydig cell tumor in a primigravida who displayed no features of virilization. The apha fetoprotein levels were elevated. Magnetic resonance imaging was suggestive of ovarian tumors, possibly germ cell tumor. Bilateral salpingo-oophorectomy was performed and histopathology showed features of Sertoli Leydig cell tumor with intermediate to poor differentiation. Immunohistochemistry was positive for calretinin and inhibin, while cytokeratin was negative. Four courses of bleomycin-, etoposide- and cisplatin-based chemotherapy regimen was started, but the patient aborted while receiving the second cycle of chemotherapy. She received the remaining two cycles of chemotherapy and is now on close follow up with monitoring of serum inhibin levels to detect any tumor recurrence. Bilateral Sertloli Leydig cell tumor has not been reported previously in a pregnant female. The aim of this article is to describe the clinical, radiological and pathological features and management of this rare entity.

  7. "MAXIMAL FERTILITY SPARING SURGERY IN A PATIENT WITH A RARE MIXED GERM CELL TUMOR"

    Directory of Open Access Journals (Sweden)

    F. Ghaemmaghami

    2004-10-01

    Full Text Available Ovarian mixed germ cell tumors consisting of endodermal sinus tumor and immature teratoma are very rare and have been reported only in a few case reports. Here we report a rare mixed germ cell tumor of ovary which was consisted of endodermal sinus tumor and immature teratoma components with an unusual intraabdominal location. Patient was a 21 years old girl with the chief compliant of abdominal pain. Ultrasound and CT scan showed a lobulated cystic mass. Laparotomy was performed and due to unusual localization, in which tumor was localized as a tumoral bridge between two ovaries, we performed maximal fertility sparing surgery by preserving ovaries, tubes and uterus. After surgery, 4 courses of chemotherapy with bleomycin, etoposide, and cis-platinum were done. Alfa feto-protein became negative after 3 courses of chemotherapy and she was under observation and in good health during follow up period.

  8. Primary omental yolk sac tumor.

    Science.gov (United States)

    Lim, Seon Hwa; Kim, Yon Hee; Yim, Ga Won; Nam, Eun Ji; Kim, Young Tae; Kim, Sunghoon

    2013-11-01

    Extra-ovarian yolk sac tumor arising in the omentum is extremely rare. As yolk sac tumor originated from the omentum has been rarely reported, its clinical information is very limited. The authors encountered a case of yolk sac tumor originated from the omentum, and reported the case herein. A 32-year-old woman was presented with developed low abdominal distension for a month. Magnetic resonance imaging findings were suggestive of ovarian malignancy with ascites and peritoneal seeding nodules. Explorative laparotomy was performed and then the findings from frozen biopsy of omentum were suggestive of poorly differentiated tumor though whether it was primary or metastatic was uncertain. Thus, staging laparotomy were performed. Histopathology confirmed that the tumor was a yolk sac tumor of omentum origin. Then, 6 cycles of postoperative adjuvant chemotherapy at intervals of 3 weeks were performed using bleomycin, etoposide, and cisplatin regimen. Four-year outpatient follow-up thereafter showed no relapse. PMID:24396822

  9. Reliability of estimated glomerular filtration rate in patients treated with platinum containing therapy

    DEFF Research Database (Denmark)

    Lauritsen, Jakob; Gundgaard, Maria G; Mortensen, Mette S;

    2014-01-01

    Estimates of glomerular filtration rate (eGFR) are widely used when administering nephrotoxic chemotherapy. No studies performed in oncology patients have shown whether eGFR can safely substitute a measured GFR (mGFR) based on a marker method. We aimed to assess the validity of four major formulas...... based on PCr (Cockcroft-Gault, MDRD, Wright and CKD-EPI) in comparison to mGFR in an oncology setting. Patients included had disseminated germ cell cancer and received conventional chemotherapy: bleomycin, etoposide and cisplatin. The mGFR of the patients was compared to all estimates with focus on bias...... (median percentage error), precision (median absolute percentage error) and accuracy (p10 and p30). The precision of carboplatin dosage based on eGFR was calculated. Data on mGFR, eGFR, and PCr were available in 390 patients, with a total of ∼ 1,600 measurements. Median PCr and mGFR synchronically...

  10. Effects of Long-Term Exposure to 60 GHz Millimeter-Wavelength Radiation on the Genotoxicity and Heat Shock Protein (Hsp Expression of Cells Derived from Human Eye

    Directory of Open Access Journals (Sweden)

    Shin Koyama

    2016-08-01

    Full Text Available Human corneal epithelial (HCE-T and human lens epithelial (SRA01/04 cells derived from the human eye were exposed to 60 gigahertz (GHz millimeter-wavelength radiation for 24 h. There was no statistically significant increase in the micronucleus (MN frequency in cells exposed to 60 GHz millimeter-wavelength radiation at 1 mW/cm2 compared with sham-exposed controls and incubator controls. The MN frequency of cells treated with bleomycin for 1 h provided positive controls. The comet assay, used to detect DNA strand breaks, and heat shock protein (Hsp expression also showed no statistically significant effects of exposure. These results indicate that exposure to millimeter-wavelength radiation has no effect on genotoxicity in human eye cells.

  11. Adaptive Response in Animals Exposed to Non-Ionizing Radiofrequency Fields: Some Underlying Mechanisms

    Directory of Open Access Journals (Sweden)

    Yi Cao

    2014-04-01

    Full Text Available During the last few years, our research group has been investigating the phenomenon of adaptive response in animals exposed to non-ionizing radiofrequency fields. The results from several separate studies indicated a significant increase in survival, decreases in genetic damage as well as oxidative damage and, alterations in several cellular processes in mice pre-exposed to radiofrequency fields and subsequently subjected to sub-lethal or lethal doses of γ-radiation or injected with bleomycin, a radiomimetic chemical mutagen. These observations indicated the induction of adaptive response providing the animals the ability to resist subsequent damage. Similar studies conducted by independent researchers in mice and rats have supported our observation on increased survival. In this paper, we have presented a brief review of all of our own and other independent investigations on radiofrequency fields-induced adaptive response and some underlying mechanisms discussed.

  12. Modifying effects of pre-existing fibrosis in rats exposed to aerosols of 239PuO2. II

    International Nuclear Information System (INIS)

    We have initiated a study using rats to determine the modifying effects of pre-existing pulmonary fibrosis on the retention and biological effects of inhaled 239PuO2. Pulmonary fibrosis was induced by intratracheal instillation of 8.5 IU/kg body weight of bleomycin at 45 to 49 days before inhalation exposure to an aerosol of 239PuO2. The clearance of 239Pu from the lungs of rats was decreased significantly (p 239Pu, apparently by entrapping the particles in fibrotic areas of the lung. The life span of the rats with pulmonary fibrosis was decreased by up to 25% compared with control rats having similar initial lung burdens of 239Pu. (author)

  13. Intra-abdominal seminoma found incidentally during trauma workup in a man with bilateral cryptorchidism

    Directory of Open Access Journals (Sweden)

    Danielle Velez

    2015-01-01

    Full Text Available Bilateral cryptorchidism is a rare occurrence and seminoma is the most common germ cell tumor found in undescended testes when they occur. We present the case of a patient with bilateral cryptorchidism who presented to our trauma center after a motor vehicle collision and was found incidentally to have a 17-cm intra-abdominal mass. The mass was subsequently biopsied and proven to be seminoma. The patient completed three cycles of bleomycin/etoposide/cisplatin chemotherapy and successfully underwent a postchemo retroperitoneal lymph node dissection with no viable residual tumor or positive lymph nodes found in the surgical specimen. He also had an orchiopexy of the contralateral testicle. The patient recovered fully and has been found to be recurrence-free four months postoperatively. We highlight the importance of cisplatin-based chemotherapy and extensive tumor resection as the mainstay of initial cancer control.

  14. Changes in protein expression in p53 deleted spontaneous thymic lymphomas

    DEFF Research Database (Denmark)

    Honoré, Bent; Vorum, Henrik; Pedersen, Anders Elm;

    2004-01-01

    spontaneous p53-/- thymic lymphomas, SM5 and SM7. A total of around 1500 proteins were detected on individual gels. Only changes in protein expression by a factor of 2 or more were considered. In the thymic lymphoma cells 3-5% of the proteins were found to be differentially regulated when compared...... with the protein expression in p53+/+ and p53-/- thymocytes. Only a minority (13 proteins) of the quantitatively changed proteins were common for the two thymic lymphoma cell lines, suggesting that the p53 deficiency mainly results in genetic dysfunctions which are individual for a given tumor. Two of the detected...... structure containing motifs of the glyoxalase-bleomycin resistance protein family (MDR) as deduced from the cDNA....

  15. Lung Surfactant Protein D (SP-D) Response and Regulation During Acute and Chronic Lung Injury

    DEFF Research Database (Denmark)

    Gaunsbaek, Maria Quisgaard; Rasmussen, Karina Juhl; Beers, Michael F.;

    2013-01-01

    lung injury, with a sustained increment during chronic inflammation compared with acute inflammation. A quick upregulation of SP-D in serum in response to acute airway inflammation supports the notion that SP-D translocates from the airways into the vascular system, in favor of being synthesized......BACKGROUND: Surfactant protein D (SP-D) is a collection that plays important roles in modulating host defense functions and maintaining phospholipid homeostasis in the lung. The aim of current study was to characterize comparatively the SP-D response in bronchoalveolar lavage (BAL) and serum in...... three murine models of lung injury, using a validated ELISA technology for estimation of SP-D levels. METHODS: Mice were exposed to lipopolysaccharide, bleomycin, or Pneumocystis carinii (Pc) and sacrificed at different time points. RESULTS: In lipopolysaccharide-challenged mice, the level of SP-D in...

  16. Effects of connective tissue growth factor and collagen type Ⅰ scleroderma

    Institute of Scientific and Technical Information of China (English)

    Xiaoning Yan; Jie Feng; Bingjun Shi

    2007-01-01

    Objective: To investigate the effects of connective tissue growth factor(CTGF) and collagen type Ⅰ(COL-I) on the pathogenesis of scleroderma and explore the relationship between the level of COL-I and CTGF. Methods: 12 mice model of scleroderma was established by the injection of Bleomycin. The level of CTGF and COL-I were detected by immunohistochemical method. The relationship was analyzed between CTGF and COL-I level. As control group, 12 healthy mice were selected. Results: The levels of CTGF and COL-I in sclerotic models were higher than in normal controls (P < 0.05). It was found that there was a correlation between the level of CTGF and COL-I. Conclusion: CTGF and COL-I played an important role in the hardening process of the skin lesions of the mice model, which may be involved in the pathogenesis of scleroderma.

  17. The predictive role of interim positron emission tomography for Hodgkin lymphoma treatment outcome is confirmed using the interpretation criteria of the Deauville five-point scale

    DEFF Research Database (Denmark)

    Gallamini, Andrea; Barrington, Sally F; Biggi, Alberto;

    2014-01-01

    reported the scans using the Deauville five-point scale, blinded to treatment outcome. Forty-five scans were scored as positive (17.3%) and 215 (82.7%) as negative. After a median follow up of 37.0 (2-110) months, 252 patients are alive and eight have died. The 3-year progression-free survival rate was 83...... of the Deauville five-point scale for the interpretation of interim positron emission tomography scan. Two hundred and sixty patients with newly diagnosed Hodgkin lymphoma were enrolled. Fifty-three patients with early unfavorable and 207 with advanced-stage disease were treated with doxorubicin, bleomycin......% for the whole study population, 28% for patients with interim positive scans and 95% for patients with interim negative scans (Poutcome were 0.73, 0.94, 0...

  18. Concurrent Presentation of Hodgkin Lymphoma and Multiple Myeloma

    Directory of Open Access Journals (Sweden)

    Rekha Chandran

    2013-01-01

    Full Text Available The simultaneous presentation of the Hodgkin lymphoma and multiple myeloma in the absence of prior chemotherapy or radiation is very rare. Here, we discuss a 72-year-old patient who initially presented with generalized pruritis. Workup led to a diagnosis of multiple myeloma which progressed and required treatment. As part of his pretreatment workup, an MRI was performed to evaluate skeletal lesions. This revealed diffuse and bulky adenopathy which was confirmed by PET. A biopsy of an axillary node was consistent with the nodular sclerosing type Hodgkin lymphoma. He was treated with adriamycin, bleomycin, vinblastine, and dacarbazine (ABVD chemotherapy × 6 resulting in complete resolution of his adenopathy and pruritis as well as improvement in his myeloma.

  19. The adaptive response of human lymphocytes to very low doses of ionizing radiation: a case of induced chromosomal repair with the induction of specific proteins

    International Nuclear Information System (INIS)

    It appears that the adaptive response of human lymphocytes to low doses of X-rays can be mimicked by exposure to low levels of a truly radiomimetic compound, bleomycin, that induces double-strand breaks in DNA. Similarly, the adaptive response can be induced by exposure to low levels of H2O2, which produces reactive species similar to those induced by ionizing radiation. This adaptive response, which is attributed to the induction of a repair mechanism, i.e. repair enzymes, can be prevented if protein synthesis, and thus enzyme synthesis, is inhibited by cycloheximide at the crucial time (4-6 h) after exposure to the adaptive dose. Two-dimensional gel electrophoresis has shown that 1 cGy of X-rays can reproducibly induce several proteins not found in unirradiated lymphocytes. These proteins are considered to be excellent candidates for the actual repair enzyme(s). (author)

  20. Photothermal enhancement of chemotherapy mediated by gold-silica nanoshell-loaded macrophages: in vitro squamous cell carcinoma study

    Science.gov (United States)

    Madsen, Steen J.; Shih, En-Chung; Peng, Qian; Christie, Catherine; Krasieva, Tatiana; Hirschberg, Henry

    2016-01-01

    Moderate hyperthermia (MHT) has been shown to enhance the effects of chemotherapeutic agents in a wide variety of cancers. The purpose of this study was to investigate the combined effects of commonly used chemotherapeutic agents with MHT induced by near-infrared (NIR) activation of gold nanoshell (AuNS)-loaded macrophages (Ma). AuNS-loaded murine Ma combined with human FaDu squamous cells, in hybrid monolayers, were subjected to three cytotoxic drugs (doxorubicin, bleomycin, cisplatin) with or without NIR laser irradiation. For all three drugs, efficacy was increased by NIR activation of AuNS-loaded Ma. The results of this in vitro study provide proof-of-concept for the use of AuNS-loaded Ma for photothermal enhancement of the effects of chemotherapy on squamous cell carcinoma.

  1. Long-term cognitive function following chemotherapy in patients with testicular cancer

    DEFF Research Database (Denmark)

    Pedersen, Anders Degn; Rossen, Philip; Mehlsen, Mimi Yung;

    2009-01-01

    Cancer patients frequently report cognitive complaints following chemotherapy, but the results from the available studies, mainly of women with breast cancer, are inconsistent. Our aim was to compare cognitive function of men with testicular cancer (TC) who had orchiectomy and chemotherapy...... (bleomycin, etoposide, cisplatin) with men who had orchiectomy only or orchiectomy and radiotherapy. Thirty-six chemotherapy patients and 36 nonchemotherapy patients were tested 2-7 years after treatment for TC with standardized neuropsychological tests. Chemotherapy and nonchemotherapy patients displayed...... similar performances on cognitive tests (p values adjusted for multiple comparisons: .63-1.00). Moreover, there was no difference in the proportion of cognitively impaired patients in the chemotherapy group (5.6%) compared to the nonchemotherapy group (8.3%) (chi2 = 0.22, p = .64). Our results...

  2. Resistant metastatic penile carcinoma and response to biochemotherapy with paclitaxel and epidermal growth factor receptor monoclonal antibody, nimotuzumab

    Directory of Open Access Journals (Sweden)

    Avinash Pandey

    2013-01-01

    Full Text Available Carcinoma penis is one of the common malignancies in developing world especially among rural population. Multimodality treatment with surgery, radiation and chemotherapy for advanced penile carcinoma with groin nodal metastasis is crucial to optimise the outcome. Cisplatin, fluorouracil, methotrexate, vinorelbine, bleomycin and paclitaxel are the common chemotherapeutic agents used along with local therapy. Paucity of data to show superiority of one chemotherapeutic regime over another and only modest response to any combination chemotherapy. Progression of disease after surgery, radiation and chemotherapy is associated with poor outcome and quality of life. Nimotuzumab, Anti EGFR monoclonal antibody, along with paclitaxel in our case of resistant metastatic penile carcinoma has shown good symptomatic palliation and clinical response.

  3. Survival and Toxicity in Patients With Disseminated Germ CellCancer Aged 40 Years and Older

    DEFF Research Database (Denmark)

    Thomsen, Frederik B; Bandak, Mikkel; Thomsen, Maria F;

    2014-01-01

    , treatment related toxicity and survival in patients aged ≥40 years treated with standard chemotherapy for GCC compared with a younger control group that received similar treatment during the same period. METHODS: From 1984 to 2011, 135 patients aged ≥40 years with disseminated GCC treated with bleomycin...... the two groups were found regarding bone marrow toxicity or mean percentage changes in lung- or renal function. Patients aged ≥40 year had increased cancer specific mortality, HR = 4.8 (P = 0.005). In particular patients with disease progression after first line chemotherapy had increased mortality (P = 0.......015). Moreover, the 5-year overall survival for patients aged ≥40 years was 82.5% compared to the expected 5-year survival of the background population of 96.3% (P

  4. Treatment-related risk factors for premature menopause following Hodgkin lymphoma

    DEFF Research Database (Denmark)

    De Bruin, Marie L; Huisbrink, Jeannine; Hauptmann, Michael;

    2008-01-01

    We conducted a cohort-study among 518 female 5-year Hodgkin lymphoma (HL) survivors, aged 14 to 40 years (median: 25 years) at treatment (1965-1995). Multivariable Cox regression was used to quantify treatment effects on risk of premature menopause, defined as cessation of menses before age 40...... years. After a median follow up of 9.4 years, 97 women had reached menopause before age 40 years. Chemotherapy was associated with a 12.3-fold increased risk of premature menopause compared with radiotherapy alone. Treatment with MOPP (mechlorethamine, vincristine, procarbazine, prednisone......)/ABV (doxorubicine, bleomycine, vinblastine) significantly increased the risk of premature menopause (hazard ratio [HR]: 2.9), although to a lesser extent than MOPP treatment (HR: 5.7). Alkylating agents, especially procarbazine (HR: 8.1) and cyclophosphamide (HR: 3.5), showed the strongest associations. Ten years...

  5. An old patient with growing teratoma syndrome of the ovary

    Institute of Scientific and Technical Information of China (English)

    Sadiman Kiykac Altinbas; Taner Turan; Namik Kemal Altinbas; Ahmet Ozfuttu; Nurettin Boran; Gokhan Tulunay

    2013-01-01

    Growing teratoma syndrome (GTS) is a rare complication of malignant ovarian germ cell tumors. A 52-year old woman was admitted to our Gynecological Oncology Department with metastatic multiple abdominal masses. Her initial gynecological history presented an immature teratoma of the ovary 3 years previously, and she underwent total abdominal hysterectomy, bilateral salpingo-oophorectomy, bilateral pelvic-paraaortic lymphadenectomy and omentectomy. She received three cycles of bleomycin, etoposide and cisplatin (BEP) regimen after surgery. Although the tumor markers were within normal limits, multiple metastatic lesions were detected in the 3rd month of follow-up. The patient was referred to our gynecological oncology department, optimal debulking including resection of the tumoral lesions localized on the liver, diaphragm, peritoneum, sigmoid colon, omentum and retroperitoneum was performed. Histopathology of all samples revealed mature teratoma. This syndrome should be remembered when a tumor is refractory to chemotherapy and growth of the tumor still continues after resection of the initial tumor.

  6. Scleroderma in a Patient on Capecitabine: Is this a Variant of Hand-Foot Syndrome?

    Science.gov (United States)

    Agarwal, Archana; Hellinger, James; Park, Dorothy J; Volkmann, Elizabeth

    2016-01-01

    Drug-induced scleroderma is a rare adverse effect of some chemotherapeutic drugs, such as taxanes and bleomycin. Capecitabine, an oral fluoropyrimidine approved for the treatment of metastatic breast and colon cancer, commonly causes cutaneous side effects including the hand-and-foot syndrome (HFS). Scleroderma-like skin changes associated with HFS associated with capecitabine is rare. However, diffuse scleroderma has never before been reported. We report a case of capecitabine-induced diffuse/systemic scleroderma in an 86-year-old female treated with capecitabine for metastatic colorectal cancer. She developed progressive skin and visceral sclerosis involving the lungs. We discuss the association between chemotherapy and scleroderma. We believe this is the first case of diffuse/systemic capecitabine-induced scleroderma without the presence of HFS. Early diagnosis is essential as fibrosis might be prevented in early stages. The capecitabine should be discontinued as early as possible. PMID:27493845

  7. Cross-sensitivity of X-ray-hypersensitive cells derived from LEC strain rats to DNA-damaging agents

    International Nuclear Information System (INIS)

    The cross-sensitivity of X-ray-hypersensitive lung fibroblasts from LEC strain (LEC) rats to other DNA-damaging agents was examined. The LEC cells were 2- to 3-fold more sensitive to bleomycin (BLM) that induces DNA double-strand breaks, and to a cross-linking agent, mitomycin C, than the cells from WKAH strain (WKAH) rats, while they were slightly sensitive to alkylating agents, ethyl nitrosourea and N-methyl-N'-nitro-N-nitrosoguanidine, but not to UV-irradiation. Although no difference was observed in the initial yields of DNA double-strand breaks induced by BLM between LEC and WKAH cells, the repair process of DNA double-strand breaks was significantly slower in LEC cells than in WKAH cells

  8. Genotoxin Induced Mutagenesis in the Model Plant Physcomitrella patens

    Directory of Open Access Journals (Sweden)

    Marcela Holá

    2013-01-01

    Full Text Available The moss Physcomitrella patens is unique for the high frequency of homologous recombination, haploid state, and filamentous growth during early stages of the vegetative growth, which makes it an excellent model plant to study DNA damage responses. We used single cell gel electrophoresis (comet assay to determine kinetics of response to Bleomycin induced DNA oxidative damage and single and double strand breaks in wild type and mutant lig4 Physcomitrella lines. Moreover, APT gene when inactivated by induced mutations was used as selectable marker to ascertain mutational background at nucleotide level by sequencing of the APT locus. We show that extensive repair of DSBs occurs also in the absence of the functional LIG4, whereas repair of SSBs is seriously compromised. From analysis of induced mutations we conclude that their accumulation rather than remaining lesions in DNA and blocking progression through cell cycle is incompatible with normal plant growth and development and leads to sensitive phenotype.

  9. INTERVENTION CHEMOTHERAPY IN COMPREHENSIVE TREATMENT OF ADVANCED NASOPHARYNGEAL CARCINOMA

    Institute of Scientific and Technical Information of China (English)

    2000-01-01

    Objective: To study the use of interventional chemotherapy in comprehensive treatment for advanced nasopharyngeal carcinoma. Methods: Interventional chemotherapy with multi-drugs including cisplatin (DDP) 100 mg, 5-fluorouracil (5-FU) 1000 mg and bleomycin (BLM) 16 mg was used to treat 30 cases with advanced nasopharyngeal carcinoma before radiotherapy. 50 cases that received radiotherapy alone were used as a control group. The methods, time and dose schedule of radiotherapy were similar in the two groups. Results: The primary lesions in 16 cases and the cervical lymph nodes in 12 cases were reduced in size after interventional chemotherapy. Radiation doses of those in complete response in their primary lesion and cervical lymph nodes were lower than that of the control group (P<0.05). The complete response rate of study group was 83.3% and that of control group was 72.0% (P<0.05). Conclusion: Interventional chemotherapy plus radiotherapy is a valuable treatment method in advanced nasopharyngeal carcinoma.

  10. Hemolytic-Uremic Syndrome Associated with Gemcitabine: A Case Report and Review of Literature

    Directory of Open Access Journals (Sweden)

    McGee PJ

    2005-07-01

    Full Text Available CONTEXT: Hemolytic uremic syndrome is a rare condition compromising the clinical triad of acute renal failure, microangiopathic hemolytic anemia, and thrombocytopenia. Hemolytic uremic syndrome may be associated with a variety of etiologies, and chemotherapeutic agents have also been reported to be associated with hemolytic uremic syndrome, including mitomycin, cisplatin, bleomycin, and most recently gemcitabine. CASE REPORT: A 72-year-old Caucasian male treated with four cycles of gemcitabine at 1,000 mg/m2 developed clinical and laboratory findings compatible with hemolytic uremic syndrome. He developed microangiopathic hemolysis, rapidly declining renal function with proteinuria and hematuria, and renal biopsy revealed thrombotic microangiopathy. Hemodialysis, plasmapheresis, and corticosteroid therapy were utilized but the process ultimately was irreversible. CONCLUSION: With multiple reports of hemolytic uremic syndrome complicating gemcitabine therapy, it is imperative that clinicians heighten their awareness of this potentially lethal complication.

  11. Calcium Electroporation

    DEFF Research Database (Denmark)

    Frandsen, Stine Krog; Gibot, Laure; Madi, Moinecha;

    2015-01-01

    BACKGROUND: Calcium electroporation describes the use of high voltage electric pulses to introduce supraphysiological calcium concentrations into cells. This promising method is currently in clinical trial as an anti-cancer treatment. One very important issue is the relation between tumor cell kill...... efficacy-and normal cell sensitivity. METHODS: Using a 3D spheroid cell culture model we have tested the effect of calcium electroporation and electrochemotherapy using bleomycin on three different human cancer cell lines: a colorectal adenocarcinoma (HT29), a bladder transitional cell carcinoma (SW780......), and a breast adenocarcinoma (MDA-MB231), as well as on primary normal human dermal fibroblasts (HDF-n). RESULTS: The results showed a clear reduction in spheroid size in all three cancer cell spheroids three days after treatment with respectively calcium electroporation (p

  12. [Biphasic pulmonary blastoma with germ cell differentiation: a challenge in diagnosis and treatment].

    Science.gov (United States)

    Teixeira, Alexandra; Vieira, Claúdia; Sousa, Nuno; Begonha, Rosa; Afonso, Mariana; Amaro, Teresina; Maurício, Joaquina

    2011-12-01

    Serviço de Oncologia Médica. Instituto Português de Oncologia Francisco Gentil. Porto. Portugal. A 27-year-old man, smoker, presented with three months history of fever. A left pulmonary mass inseparable from the heart was identified and serum alpha-fetoprotein was 4160 ng/ml. The morphologic aspects and immunohistochemistry of the biopsy specimen, in conjunction with the clinical findings were compatible with a diagnosis of pulmonary blastoma with germ cell differentiation. The tumour was considered unresectable. The patient was submitted to two cycles of primary chemotherapy with bleomycin, etoposide and cisplatin. Despite a reduction in serum alpha-fetoprotein, the tumor did not regress. Second line chemotherapy (with paclitaxel, ifosfamide and cisplatin) was instituted, but progressive disease was identified after 2 cycles. Six months after the diagnosis cerebral metastases were found and the patient died. This case illustrates a rare situation of difficult diagnosis and treatment.

  13. Effects of artichoke (Cynara scolymus) leaf and bloom head extracts on chemically induced DNA lesions in Drosophila melanogaster

    Science.gov (United States)

    Jacociunas, Laura Vicedo; Dihl, Rafael Rodrigues; Lehmann, Mauricio; de Barros Falcão Ferraz, Alexandre; Richter, Marc François; da Silva, Juliana; de Andrade, Heloísa Helena Rodrigues

    2014-01-01

    The genotoxicity of bloom head (BHE) and leaf (LE) extracts from artichoke (Cynara scolymus L.), and their ability to modulate the mutagenicity and recombinogenicity of two alkylating agents (ethyl methanesulfonate – EMS and mitomycin C – MMC) and the intercalating agent bleomycin (BLM), were examined using the somatic mutation and recombination test (SMART) in Drosophila melanogaster. Neither the mutagenicity nor the recombinogenicity of BLM or MMC was modified by co- or post-treatment with BHE or LE. In contrast, co-treatment with BHE significantly enhanced the EMS-induced genotoxicity involving mutagenic and/or recombinant events. Co-treatment with LE did not alter the genotoxicity of EMS whereas post-treatment with the highest dose of LE significantly increased this genotoxicity. This enhancement included a synergistic increase restricted to somatic recombination. These results show that artichoke extracts promote homologous recombination in proliferative cells of D. melanogaster. PMID:24688296

  14. A pre-validation trial - testing genotoxicity of several chemicals using standard, medium- and high-throughput comet formats.

    Directory of Open Access Journals (Sweden)

    Kristine Bjerve Gutzkow

    2015-06-01

    Results obtained with the three systems (standard, medium- and high-throughput were essentially the same. The 96-minigel format was analysed with the fully automated scoring system IMSTAR and comparable results were achieved with the semi-automated scoring system from Perceptives. The known genotoxic chemicals MNU, B(aP, 4-NQO and cyclophosphamide showed little consistent sign of genotoxicity at concentrations causing limited cytotoxicity. D-mannitol and Triton X-100 were, as expected, non-genotoxic (though Triton X-100, at high concentrations, caused DNA breaks as an apparent secondary effect of cytotoxicity. Etoposide and bleomycin gave significant increase in DNA strand break at borderline cytotoxic concentrations. The limitation of the assay to detect damaged bases by known genotoxins may be overcome by incorporating a DNA repair enzyme, such as formamidopyrimidine-DNA-glycosylase (FPG, to convert damaged bases into breaks as shown by Azqueta A et al., Mutagenesis vol. 28 no. 3 pp. 271–277, 2013 .

  15. Early interim 2-[18F]fluoro-2-deoxy-D-glucose positron emission tomography is prognostically superior to international prognostic score in advanced-stage Hodgkin's lymphoma: a report from a joint Italian-Danish study

    DEFF Research Database (Denmark)

    Loft, Annika; Gallamini, Andrea; Hutchings, Martin;

    2007-01-01

    PURPOSE: Starting from November 2001, 260 newly diagnosed patients with Hodgkin's lymphoma (HL) were consecutively enrolled in parallel Italian and Danish prospective trials to evaluate the prognostic role of an early interim 2-[(18)F]fluoro-2-deoxy-D-glucose positron emission tomography (FDG......-PET) scan and the International Prognostic Score (IPS) in advanced HL, treated with conventional ABVD (doxorubicin, bleomycin, vinblastine, and dacarbazine) therapy. PATIENTS AND METHODS: Most patients (n = 190) presented with advanced disease (stages IIB through IVB), whereas 70 presented in stage IIA...... with adverse prognostic factors. All but 11 patients were treated with standard ABVD therapy followed by consolidation radiotherapy in case of bulky presentation or residual tumor mass. Conventional radiologic staging was performed at baseline. FDG-PET scan was performed at baseline and after two courses...

  16. Adaptive response induced by occupational exposures to ionizing radiation

    International Nuclear Information System (INIS)

    We have found a significant decreased sensitivity to the cytogenetic effects of ionizing radiation (IR) and bleomycin (BLM) in lymphocytes from individuals occupationally exposed to IR when compared with a control population. These results suggest that occupational exposures to IR can induce adaptive response that can be detected by a subsequent treatment by IR or by BLM. However, no correlation between the results obtained with both treatments was observed. A great heterogeneity in the frequencies of chromatid aberrations induced by BLM was observed. The study of the influence of different harvesting times showed that there was no correlation with the frequencies of chromatid breaks. Our results indicate that the use of BLM to detect adaptive response has several difficulties at the individual level. (author)

  17. A Case of Recalcitrant Plantar Warts Associated with Statin Use

    Directory of Open Access Journals (Sweden)

    Aaron G. Wernham

    2015-01-01

    Full Text Available Background. Plantar warts are a common presenting skin complaint caused by the human papillomavirus. 1st line therapies include cryotherapy and topical salicylic acid. Where there is resistance to these treatments, consideration is made for 2nd line therapies, including intralesional bleomycin, imiquimod, 5-fluorouracil, and photodynamic therapy. We present a case of bilateral persistent plantar warts, resistant to treatment with repeated cryotherapy and topical salicylic acid over a 6-year period. Following a patient initiated decision to discontinue their statin medication, we observed rapid clearance of plantar warts without change to standard therapy or their environment. This case correlates with emerging literature demonstrating a link between statin medication and proliferation of HPV through increased levels of FOXP3+ regulatory T cells.

  18. Effect of TGF-β/Smad signaling pathway on lung myofibroblast differentiation

    Institute of Scientific and Technical Information of China (English)

    Li GU; Yuan-jue ZHU; Xiao YANG; Zi-Jian GUO; Wen-bing XU; Xin-lun TIAN

    2007-01-01

    Aim: Myofibroblasts play important roles in the pathogenesis of lung fibrosis.Transforming growth factor (TGF)-β1 has been widely recognized as a key fibrogenic cytokine. The major signaling pathway of TGF-β1 is through cytoplas-mic Smad proteins. Our study investigated the role of individual TGF-β1/Smad signal proteins in mediating α-smooth muscle actin (α-SMA) gene expression,which is a well-known key marker of myofibroblast differentiation. Methods: We transiently cotransfected α-SMA promoter-luciferase fusion plasmid (p895-Luc)and Smad expression plasmids and measured Luc activity in TGF-β1-treated hu-man fetal lung fibroblasts. We induced Smad3 knockout mice lung fibrosis by bleomycin, α-SMA protein expression was assessed by Western blotting. Col-lagen protein was analyzed by measuring hydroxyprolin. Myofibroblast morphol-ogy was assessed by immunohistochemistry. Results: We found that the overexpression of Smad3, not Smad2 markedly increased TGF-β1-induced α-SMA promoter activity and α-SMA protein expression in vitro, whereas the over-expression of dominant negative mutant Smad3 and Smad7 repressed TGF-β1 induced α-SMA gene expression. Compared to wild-type mice, Smad3 knockout mice showed attenuated lung fibrosis after bleomycin treatment, manifested by lower collagen production and myofibroblast differentiation. Conclusion: Our study suggested TGF-β1/Smad3 is a major pathway which regulated the myofibroblast differentiation. This result indicates a potential significance for future attempts of attenuating the progression of human lung fibrosis by the inhibition of the Smad3 cascade.

  19. IL-1 and IL-23 mediate early IL-17A production in pulmonary inflammation leading to late fibrosis.

    Directory of Open Access Journals (Sweden)

    Paméla Gasse

    Full Text Available BACKGROUND: Idiopathic pulmonary fibrosis is a devastating as yet untreatable disease. We demonstrated recently the predominant role of the NLRP3 inflammasome activation and IL-1β expression in the establishment of pulmonary inflammation and fibrosis in mice. METHODS: The contribution of IL-23 or IL-17 in pulmonary inflammation and fibrosis was assessed using the bleomycin model in deficient mice. RESULTS: We show that bleomycin or IL-1β-induced lung injury leads to increased expression of early IL-23p19, and IL-17A or IL-17F expression. Early IL-23p19 and IL-17A, but not IL-17F, and IL-17RA signaling are required for inflammatory response to BLM as shown with gene deficient mice or mice treated with neutralizing antibodies. Using FACS analysis, we show a very early IL-17A and IL-17F expression by RORγt(+ γδ T cells and to a lesser extent by CD4αβ(+ T cells, but not by iNKT cells, 24 hrs after BLM administration. Moreover, IL-23p19 and IL-17A expressions or IL-17RA signaling are necessary to pulmonary TGF-β1 production, collagen deposition and evolution to fibrosis. CONCLUSIONS: Our findings demonstrate the existence of an early IL-1β-IL-23-IL-17A axis leading to pulmonary inflammation and fibrosis and identify innate IL-23 and IL-17A as interesting drug targets for IL-1β driven lung pathology.

  20. Pulmonary complications of bone marrow transplantation: a comparison of total body irradiation and cyclophosphamide to busulfan and cyclophosphamide

    International Nuclear Information System (INIS)

    Purpose: To retrospectively compare the acute and long-term pulmonary toxicities of total body irradiation and busulfan in bone marrow transplantation. Methods and Materials: From March 1984 through February 1991, 144 patients received high-dose therapy with cyclophosphamide plus either total body irradiation (TBI-CY) or busulfan (BU-CY) followed by bone marrow rescue. Treatment protocols were based on disease type. Cyclophosphamide dose was 120-200 mg/kg, given in 2-4 days. Total body irradiation was given as 12 Gy in four fractions over 4 days, or 14.4 Gy in eight fractions over 4 days. Busulfan dose was 16 mg/kg given over 4 days. Results: Seventy-nine patients were treated with TBI-CY and 65 patients with BU-CY. More patients in the TBI group had allogeneic transplants (40 vs. 18). Pulmonary events occurred in 48 patients, 19 in BU-CY and 29 in TBI-CY. Of the 58 patients with allogeneic transplants, 21 (36%) developed chronic graft-vs.-host disease (GVHD), and 10 of those patients developed pulmonary complications (including 2 with obliterative bronchitis and 1 with asthma). Interstitial pneumonitis (IP) occurred in 14 patients, 12 in the TBI-CY group and 2 in the BU-CY group. Cytomegalovirus and pneumocystis infections were associated with IP in 11 of those patients. Fatal idiopathic IP occurred in one patient in each of the TBI-CY and BU-CY groups. Multivariate analysis showed that only chronic GVHD and prior bleomycin use were significant predictors of interstitial pneumonitis; no difference was seen between TBI-CY and BU-CY. Conclusions: Pulmonary complications were most commonly associated with GVHD and prior bleomycin use. The incidence of cytomegalovirus or pneumocystis carinii pneumonitis was greater in the patients receiving the TBI regimen; fatal pulmonary complications were not significantly different between TBI and nonTBI regimens

  1. Posttranslational modifications in microcin B17 define an additional class of DNA gyrase inhibitor.

    Science.gov (United States)

    Yorgey, P; Lee, J; Kördel, J; Vivas, E; Warner, P; Jebaratnam, D; Kolter, R

    1994-05-10

    Drugs that inhibit the activity of DNA gyrase fall almost exclusively into two structural classes, the quinolones and the coumarins. A third class of DNA gyrase inhibitor is defined by the ribosomally synthesized peptide antibiotic microcin B17 (MccB17). MccB17 contains 43 amino acid residues, but 14 of these are posttranslationally modified. Here we describe the characterization of the structure of these modifications. We propose that four cysteine and four serine side chains undergo condensation with the carbonyl group of the preceding residue, followed by alpha/beta dehydrogenation to yield four thiazole and four oxazole rings, respectively. The three proteins implicated in catalyzing these modifications (McbBCD) would constitute the only thiazole/oxazole biosynthetic enzymes identified. These results open up possibilities for the design of DNA gyrase inhibitors and add to the repertoire of posttranslational modifications with potential for protein engineering. Escherichia coli sbmA mutants, which lack the inner membrane protein (SbmA) involved in MccB17 uptake, were found to be resistant to bleomycin. Bleomycin is structurally unrelated to MccB17 except for the fact that it contains two thiazole rings. This suggests that thiazole rings are part of the MccB17 structure recognized by SbmA. This observation and the finding that SbmA homologs are widely conserved and can play developmental roles [Glazebrook, J., Ichige, A. & Walker, G. C. (1993) Genes Dev. 7, 1485-1497] suggest that thiazole- and oxazole-containing compounds may serve as signaling molecules for a wide variety of bacteria in diverse environments, including pathogen interactions with plant and animal hosts.

  2. Experimental study on combination of chemotherapy and radiotherapy

    International Nuclear Information System (INIS)

    Recently, by applying multidrug therapy using cisplatin and bleomycin to the treatment of head and neck cancer, the response rate of chemotherapy has been markedly increased and thus, chemotherapy has taken an important part in the treatment of head and neck cancer. In this paper a clinical application of chemotherapy in combination with radiotherapy was evaluated from the point of the cure rate and also preservation of the structures and the functions of the head and neck region. In order to test the advantage or usefulness of initial chemotherapy followed by radiotherapy (= pre-radiation chemotherapy), the experimental study on combination of chemotherapy and radiotherapy was designed by using ICR mice and Ehrlich solid carcinoma. Cisplatin and peplomycin, a newly developed derivative of bleomycin, were used as chemotherapeutic agents. Tumor growth delay rate was chosen as a parameter to indicate the effectiveness. Results obtained are as follows. 1. Combination chemotherapy of cisplatin and peplomycin was more effective than each single agent on Ehrlich solid carcinoma. Synergistic effect was obtained by higher dose. So, the combination of cisplatin and peplomycin was proved to be eligible for pre-radiation chemotherapy. 2. Synergistic effect of chemotherapy and radiotherapy was observed when chemotherapy was used prior to radiotherapy on Ehrlich solid carcinoma. 3. Even their additional effect was not recognized when radiotherapy preceded to chemotherapy on Ehrlich solid carcinoma. 4. No severe toxic effect was seen in the mice. The experimental results made it clear that pre-radiation chemotherapy is beneficial to the treatment of head and neck cancer. (author)

  3. The role of mitoxantrone in non-Hodgkin's lymphoma.

    Science.gov (United States)

    Armitage, James O

    2002-04-01

    The development of doxorubicin was an important advance in the treatment of patients with non-Hodgkin's lymphoma (NHL). Alternatives to doxorubicin, such as mitoxantrone (Novantrone), have less nonhematologic toxicity and could offer a therapeutic advantage in some situations if similar antilymphoma activity exists. Several combination regimens that include mitoxantrone have been shown to be active. These include mitoxantrone/ifosfamide (Ifex) and mitoxantrone/etoposide combinations as salvage therapy for aggressive lymphomas. Mitoxantrone in combination with fludarabine (Fludara) for the treatment of newly diagnosed follicular lymphomas and in combination with fludarabine and dexamethasone for relapsed/refractory follicular lymphomas has produced high complete response rates. Other evolving uses of mitoxantrone include combination therapy with cladribine (Leustatin) or rituximab (Rituxan), and as part of conditioning regimens for hematopoietic stem cell transplantation. In diffuse aggressive lymphoma, mitoxantrone, 10 mg/m2, substituted for doxorubicin, 50 mg/m2, results in a poorer response when CNOP (cyclophosphamide [Cytoxan, Neosar], mitoxantrone [Novantrone], vincristine [Oncovin], prednisone) is compared to CHOP (cyclophosphamide, doxorubicin HCl vincristine, prednsione); however, increasing the mitoxantrone dose to 12 mg/m2 in either the CNOP or CMP-BOP (cyclophosphamide, mitoxantrone, procarbazine [Matulane], bleomycin [Blenoxane], vincristine, prednisone) regimens yields results comparable to those achieved with the doxorubicin-containing regimen. Comparable results have also been observed when 10 mg/M2 of mitoxantrone was substituted for 45 mg/M2 of doxorubicin in the m-BACOD (methorexate, bleomycin, doxorubicin [Adriamycin], cyclophosphamide, vincristine, dexamethasone) regimen. Mitoxantrone is active in NHL, and combinations including mitoxantrone can be used effectively and may provide an advantage in the elderly. PMID:12017536

  4. ABVE-PC and modified BEACOPP regimen in Indian children with Hodgkin lymphoma: Feasibility and efficacy

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    Somasundaram Jayabose

    2016-01-01

    Full Text Available Aims: To study the toxicity of ABVE-PC (doxorubicin, bleomycin, vincristine, etoposide, prednisone and cyclophosphamide and modified-BEACOPP (bleomycin, etoposide, doxorubicin, cyclophosphamide,vincristine, procarbazine, prednisone in intermediate-risk and high-risk Hodgkin lymphoma patients. Methods: High-risk patients received 4 cycles of modified-BEACOPP (m-BEACOPP plus 4 cycles of ABVD. Intermediate-risk patients received 4 cycles of ABVE-PC plus 2 cycles of ABVD. Results: From 2010 to 2014, 17 patients received 66 cycles of m-BEACOPP and 9 patients received 40 cycles of ABVE-PC. In the m-BEACOPP and ABVE-PC courses, respectively, significant thrombocytopenia (<50,000/mm3 occurred in 10.6% vs 0% of courses; anemia (Hb. <8 gm/dl in 27.3% vs 15%; neutropenia (ANC<500/mm3 in 46.9% vs 32.5%; and febrile neutropenia in 33.3% vs. 22.5%. Only episode of documented infection (hepatic abscess occurred in ABVE-PC. There were no episodes of sepsis, typhlitis or pneumonia in either group. All 26 patients are in remission with a median follow-up of 35 months (range, 17-61; and there have been no relapses. Two of 26 (7.7% patients failed to achieve rapid early response after 2 cycles and complete remission after 4 cycles of chemotherapy; both achieved remission with more intensive regimens followed by radiation. The remaining 24 patients did not receive radiation therapy. Conclusions: Both m-BEACOPP and ABVE-PC regimens have acceptable toxicity; and thus can be used in most centres with optimum supportive care facilities. They offer promising response rate and relapse free survival without the need for radiation therapy in most patients; and thus may be considered for children with high-risk and intermediate-risk Hodgkin lymphoma.

  5. Prospective randomized study on inductive chemotherapy plus radiotherapy for patients with upper and middle esophageal carcinoma

    International Nuclear Information System (INIS)

    Objective: To evaluate the effect of radiotherapy combined with inductive chemotherapy for patients with upper and middle esophageal cancer. Methods: 162 patients with upper and middle esophageal cancer were randomized into two groups, with 82 treated by inductive chemotherapy combined with radiotherapy (C + R) and 80 by radiotherapy alone (R). The chemotherapy regimen included 5-fluorouracil 500 mg/m2 on d1-d5 by continuous infusion for 120 hours, cisplatin 60 mg/m2 on dl and bleomycin A5 8 mg on d1, d3, d5 intravenously. Three to seven days after chemotherapy, the patients were irradiated with anteroposterior (AP) and posteroanterior (PA) fields to a dose of 40-44 Gy in 4.0-4.4 weeks followed by a boost of 24-28 Gy in 2.4-2.8 weeks through oblique fields. Results: The 5- and 10-year survival rates were 22.0%, 15.9% for the C + R group and 13.8%, 8.8% for the R group. The difference was statistically significant (P = 0.034). The toxic and side effects were tolerable and similar in the two groups. Nineteen patients (23%) in the C + R group and thirty-one (39%) in the R group died from distant metastasis and/or lymph node metastasis, even though the difference was not statistically significant (x2 = 3.47, P > 0.05). Conclusions: Inductive chemotherapy with 5-fluorouracil, cisplatin, bleomycin A5 plus radiotherapy may improve the outcome of esophageal cancer, with the toxic and side effects of the combined modality severer than radiation along, but they are well tolerated

  6. Superiority of second over first generation chemotherapy in a randomized trial for stage III-IV intermediate and high-grade non-Hodgkin's lymphoma (NHL): the 1980-1985 EORTC trial. The EORTC Lymphoma Group.

    Science.gov (United States)

    Carde, P; Meerwaldt, J H; van Glabbeke, M; Somers, R; Monconduit, M; Thomas, J; de Wolf-Peeters, C; de Pauw, B; Tanguy, A; Kluin-Nelemans, J C

    1991-06-01

    A first-generation CHOP-like cyclic combination chemotherapy (CT) regimen using cyclophosphamide 600 mg/m2 IV d1, hydroxorubicin (doxorubicin) 50 mg/m2 IV d1, VM26 60 mg/m2 IV d1, and prednisone 40 mg/m2 PO d1-5 (CHVmP) was compared to a second-generation combination wherein vincristine 1.4 mg/m2 IV and bleomycin 6 mg/m2 IM/IV were added at mid-interval (d15) to the former drugs (CHVmP + VB) in the treatment of intermediate- and high-grade malignant NHL. From April 1980 to January 1986, 141 eligible patients with stage III-IV unfavorable histologies (except T lymphoblastic NHL) entered this EORTC randomized trial. In both arms adjuvant radiotherapy (30 Gy) was given in instances of bulky or residual disease. In all patient subsets the outcome favored the second-generation regimen. The difference was even greater in patients with Diffuse Large Cell Lymphoma (DLCL). At 5 years, overall survival was 53% with CHVmP + VB versus 29% (p = 0.002). The advantage was due to a higher complete remission (CR) rate (80% versus 50%, p = 0.01). Indeed, once CR was achieved the relapse-free survival (RFS) was not significantly influenced (59% versus 49%). No significant additional toxicity could be attributed to vincristine and bleomycin. This study demonstrates a clear benefit for intermediate- and high-risk malignant NHL and particularly DLCL from intercalating non-myelotoxic drugs at mid-cycle intervals, without adverse effects.

  7. Correlation of Clinical and Dosimetric Factors With Adverse Pulmonary Outcomes in Children After Lung Irradiation

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    Venkatramani, Rajkumar, E-mail: rvenkatramani@chla.usc.edu [Division of Hematology/Oncology, Children' s Hospital Los Angeles, Los Angeles, California (United States); Department of Pediatrics, Keck School of Medicine, University of Southern California, Los Angeles, California (United States); Kamath, Sunil [Department of Pulmonology, Children' s Hospital Los Angeles, Los Angeles, California (United States); Wong, Kenneth [Division of Hematology/Oncology, Children' s Hospital Los Angeles, Los Angeles, California (United States); Olch, Arthur J. [Division of Hematology/Oncology, Children' s Hospital Los Angeles, Los Angeles, California (United States); Department of Radiation Oncology, University of Southern California, Los Angeles, California (United States); Malvar, Jemily [Department of Preventive Medicine, Keck School of Medicine, University of Southern California, Los Angeles, California (United States); Sposto, Richard [Division of Hematology/Oncology, Children' s Hospital Los Angeles, Los Angeles, California (United States); Department of Preventive Medicine, Keck School of Medicine, University of Southern California, Los Angeles, California (United States); Goodarzian, Fariba [Department of Radiology, Children' s Hospital Los Angeles, Los Angeles, California (United States); Freyer, David R. [Division of Hematology/Oncology, Children' s Hospital Los Angeles, Los Angeles, California (United States); Department of Pediatrics, Keck School of Medicine, University of Southern California, Los Angeles, California (United States); Keens, Thomas G. [Department of Pediatrics, Keck School of Medicine, University of Southern California, Los Angeles, California (United States); Department of Pulmonology, Children' s Hospital Los Angeles, Los Angeles, California (United States); and others

    2013-08-01

    Purpose: To identify the incidence and the risk factors for pulmonary toxicity in children treated for cancer with contemporary lung irradiation. Methods and Materials: We analyzed clinical features, radiographic findings, pulmonary function tests, and dosimetric parameters of children receiving irradiation to the lung fields over a 10-year period. Results: We identified 109 patients (75 male patients). The median age at irradiation was 13.8 years (range, 0.04-20.9 years). The median follow-up period was 3.4 years. The median prescribed radiation dose was 21 Gy (range, 0.4-64.8 Gy). Pulmonary toxic chemotherapy included bleomycin in 58.7% of patients and cyclophosphamide in 83.5%. The following pulmonary outcomes were identified and the 5-year cumulative incidence after irradiation was determined: pneumonitis, 6%; chronic cough, 10%; pneumonia, 35%; dyspnea, 11%; supplemental oxygen requirement, 2%; radiographic interstitial lung disease, 40%; and chest wall deformity, 12%. One patient died of progressive respiratory failure. Post-irradiation pulmonary function tests available from 44 patients showed evidence of obstructive lung disease (25%), restrictive disease (11%), hyperinflation (32%), and abnormal diffusion capacity (12%). Thoracic surgery, bleomycin, age, mean lung irradiation dose (MLD), maximum lung dose, prescribed dose, and dosimetric parameters between V{sub 22} (volume of lung exposed to a radiation dose ≥22 Gy) and V{sub 30} (volume of lung exposed to a radiation dose ≥30 Gy) were significant for the development of adverse pulmonary outcomes on univariate analysis. MLD, maximum lung dose, and V{sub dose} (percentage of volume of lung receiving the threshold dose or greater) were highly correlated. On multivariate analysis, MLD was the sole significant predictor of adverse pulmonary outcome (P=.01). Conclusions: Significant pulmonary dysfunction occurs in children receiving lung irradiation by contemporary techniques. MLD rather than prescribed

  8. Inhomogeneity of local stiffness in the extracellular matrix scaffold of fibrotic mouse lungs.

    Science.gov (United States)

    Melo, Esther; Cárdenes, Nayra; Garreta, Elena; Luque, Tomas; Rojas, Mauricio; Navajas, Daniel; Farré, Ramon

    2014-09-01

    Lung disease models are useful to study how cell engraftment, proliferation and differentiation are modulated in lung bioengineering. The aim of this work was to characterize the local stiffness of decellularized lungs in aged and fibrotic mice. Mice (2- and 24-month old; 14 of each) with lung fibrosis (N=20) and healthy controls (N=8) were euthanized after 11 days of intratracheal bleomycin (fibrosis) or saline (controls) infusion. The lungs were excised, decellularized by a conventional detergent-based (sodium-dodecyl sulfate) procedure and slices of the acellular lungs were prepared to measure the local stiffness by means of atomic force microscopy. The local stiffness of the different sites in acellular fibrotic lungs was very inhomogeneous within the lung and increased according to the degree of the structural fibrotic lesion. Local stiffness of the acellular lungs did not show statistically significant differences caused by age. The group of mice most affected by fibrosis exhibited local stiffness that were ~2-fold higher than in the control mice: from 27.2±1.64 to 64.8±7.1kPa in the alveolar septa, from 56.6±4.6 to 99.9±11.7kPa in the visceral pleura, from 41.1±8.0 to 105.2±13.6kPa in the tunica adventitia, and from 79.3±7.2 to 146.6±28.8kPa in the tunica intima. Since acellular lungs from mice with bleomycin-induced fibrosis present considerable micromechanical inhomogeneity, this model can be a useful tool to better investigate how different degrees of extracellular matrix lesion modulate cell fate in the process of organ bioengineering from decellularized lungs.

  9. 3D MRI of impaired hyperpolarized 129Xe uptake in a rat model of pulmonary fibrosis.

    Science.gov (United States)

    Cleveland, Zackary I; Virgincar, Rohan S; Qi, Yi; Robertson, Scott H; Degan, Simone; Driehuys, Bastiaan

    2014-12-01

    A variety of pulmonary pathologies, in particular interstitial lung diseases, are characterized by thickening of the pulmonary blood-gas barrier, and this thickening results in reduced gas exchange. Such diffusive impairment is challenging to quantify spatially, because the distributions of the metabolically relevant gases (CO2 and O2) cannot be detected directly within the lungs. Hyperpolarized (HP) (129)Xe is a promising surrogate for these metabolic gases, because MR spectroscopy and imaging allow gaseous alveolar (129)Xe to be detected separately from (129)Xe dissolved in the red blood cells (RBCs) and the adjacent tissues, which comprise blood plasma and lung interstitium. Because (129)Xe reaches the RBCs by diffusing across the same barrier tissues (blood plasma and interstitium) as O2, barrier thickening will delay (129)Xe transit and, thus, reduce RBC-specific (129)Xe MR signal. Here we have exploited these properties to generate 3D, MR images of (129)Xe uptake by the RBCs in two groups of rats. In the experimental group, unilateral fibrotic injury was generated prior to imaging by instilling bleomycin into one lung. In the control group, a unilateral sham instillation of saline was performed. Uptake of (129)Xe by the RBCs, quantified as the fraction of RBC signal relative to total dissolved (129)Xe signal, was significantly reduced (P = 0.03) in the injured lungs of bleomycin-treated animals. In contrast, no significant difference (P = 0.56) was observed between the saline-treated and untreated lungs of control animals. Together, these results indicate that 3D MRI of HP (129)Xe dissolved in the pulmonary tissues can provide useful biomarkers of impaired diffusive gas exchange resulting from fibrotic thickening. PMID:24816478

  10. The evolving role of response-adapted PET imaging in Hodgkin lymphoma.

    Science.gov (United States)

    Coyle, Michael; Kostakoglu, Lale; Evens, Andrew M

    2016-04-01

    (18)F-fluorodeoxyglucose positron emission tomography with (FDG-PET) has a well-established role in the pre- and post-treatment staging of Hodgkin lymphoma (HL), however its use as a predictive therapeutic tool via responded-adapted therapy continues to evolve. There have been a multitude of retrospective and noncontrolled clinical studies showing that early (or interim) FDG-PET is highly prognostic in HL, particularly in the advanced-stage setting. Response-adapted treatment approaches in HL are attempting to diminish toxicity for low-risk patients by minimizing therapy, and conversely, intensify treatment for high-risk patients. Results from phase III noninferiority studies in early-stage HL with negative interim FDG-PET that randomized patients to chemotherapy alone versus combined modality therapy showed a continued small improvement in progression-free survival for patients who did not receive radiation. Preliminary reports of data escalating therapy for positive interim FDG-PET in early-stage HL and for de-escalation of therapy [i.e. bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine and prednisone (BEACOPP)] for negative interim FDG-PET in advanced stage HL (i.e. deletion of bleomycin) have demonstrated improved outcomes. Maturation of these studies and continued follow up of all response-adapted studies are needed. Altogether, the treatment of HL remains an individualized clinical management choice for physicians and patients. Continued refinement and optimization of FDG-PET is needed, including within the context of targeted therapeutic agents. In addition, a number of new and novel techniques of functional imaging, including metabolic tumor volume and tumor proliferation, are being explored in order to enhance staging, characterization, prognostication and ultimately patient outcome. PMID:27054026

  11. Artesunate modulates expression of matrix metalloproteinases and their inhibitors as well as collagen-IV to attenuate pulmonary fibrosis in rats.

    Science.gov (United States)

    Wang, Y; Huang, G; Mo, B; Wang, C

    2016-01-01

    The aim of this study was to determine the effect of artesunate on extracellular matrix (ECM) accumulation and the expression of collagen-IV, matrix metalloproteinase (MMP), and tissue inhibitor of matrix metalloproteinase (TIMP) to understand the pharmacological role of artesunate in pulmonary fibrosis. Eighty Sprague-Dawley rats were randomly assigned to four groups that were administered saline alone, bleomycin (BLM) alone, BLM + artesunate, or artesunate alone for 28 days. Lung tissues from 10 rats in each group were used to obtain lung fibroblast (LF) primary cells, and the rest were used to analyze protein expression. The mRNA expression of collagen-IV, MMP-2, MMP-9, TIMP-1, and TIMP-2 in lung fibroblasts was detected by real-time quantitative reverse transcriptase polymerase chain reaction. The protein levels of collagen-IV, MMP-2, MMP-9, TIMP-1, and TIMP-2 protein in lung tissues were analyzed by western blotting. Artesunate treatment alleviated alveolitis and pulmonary fibrosis induced by bleomycin in rats, as indicated by a decreased lung coefficient and improvement of lung tissue morphology. Artesunate treatment also led to decreased collagen-IV protein levels, which might be a result of its downregulated expression and increased MMP-2 and MMP-9 protein and mRNA levels. Increased TIMP-1 and TIMP- 2 protein and mRNA levels were detected after artesunate treatment in lung tissues and primary lung fibroblast cells and may contribute to enhanced activity of MMP-2 and -9. These findings suggested that artesunate attenuates alveolitis and pulmonary fibrosis by regulating expression of collagen-IV, TIMP-1 and 2, as well as MMP-2 and -9, to reduce ECM accumulation. PMID:27323108

  12. Pyrrhocoricin, a proline-rich antimicrobial peptide derived from insect, inhibits the translation process in the cell-free Escherichia coli protein synthesis system.

    Science.gov (United States)

    Taniguchi, Masayuki; Ochiai, Akihito; Kondo, Hiroshi; Fukuda, Shun; Ishiyama, Yohei; Saitoh, Eiichi; Kato, Tetsuo; Tanaka, Takaaki

    2016-05-01

    Previous studies have shown that pyrrhocoricin, a proline-rich antimicrobial peptide (PrAMP), killed sensitive species in a dose-dependent manner by specifically binding to DnaK. Here, on the basis of the finding that DnaK-deficient Escherichia coli strains are susceptible to PrAMPs, we used pyrrhocoricin to investigate internal targets other than DnaK. Using conventional antibiotics (bleomycin, streptomycin, and fosfomycin) that have known modes of action, first, we validated the availability of an assay using a cell-free rapid translation system (RTS), which is an in vitro protein synthesis system based on E. coli lysate, for evaluating inhibition of protein synthesis. We found that, similarly to bleomycin and streptomycin, pyrrhocoricin inhibited GFP synthesis in RTS in a concentration-dependent manner. In addition, blockage of transcription and translation steps in RTS was individually estimated using RT-PCR after gene expression to determine mRNA products and using sodium dodecyl sulfate-polyacrylamide gel electrophoresis to determine the amounts of GFP expressed from purified mRNA, respectively. The results demonstrated that this inhibition of GFP synthesis by pyrrhocoricin did not occur at the transcription step but rather at the translation step, in a manner similar to that of GFP synthesis by streptomycin, an inhibitor of the translation step by causing misreading of tRNA. These results suggest that RTS is a powerful assay system for determining if antimicrobial peptides inhibit protein synthesis and its transcription and/or translation steps. This is the first study to have shown that pyrrhocoricin inhibited protein synthesis by specifically repressing the translation step. PMID:26472128

  13. The Transcriptional Response to DNA-Double-Strand Breaks in Physcomitrella patens

    Science.gov (United States)

    Kamisugi, Yasuko; Whitaker, John W.

    2016-01-01

    The model bryophyte Physcomitrella patens is unique among plants in supporting the generation of mutant alleles by facile homologous recombination-mediated gene targeting (GT). Reasoning that targeted transgene integration occurs through the capture of transforming DNA by the homology-dependent pathway for DNA double-strand break (DNA-DSB) repair, we analysed the genome-wide transcriptomic response to bleomycin-induced DNA damage and generated mutants in candidate DNA repair genes. Massively parallel (Illumina) cDNA sequencing identified potential participants in gene targeting. Transcripts encoding DNA repair proteins active in multiple repair pathways were significantly up-regulated. These included Rad51, CtIP, DNA ligase 1, Replication protein A and ATR in homology-dependent repair, Xrcc4, DNA ligase 4, Ku70 and Ku80 in non-homologous end-joining and Rad1, Tebichi/polymerase theta, PARP in microhomology-mediated end-joining. Differentially regulated cell-cycle components included up-regulated Rad9 and Hus1 DNA-damage-related checkpoint proteins and down-regulated D-type cyclins and B-type CDKs, commensurate with the imposition of a checkpoint at G2 of the cell cycle characteristic of homology-dependent DNA-DSB repair. Candidate genes, including ATP-dependent chromatin remodelling helicases associated with repair and recombination, were knocked out and analysed for growth defects, hypersensitivity to DNA damage and reduced GT efficiency. Targeted knockout of PpCtIP, a cell-cycle activated mediator of homology-dependent DSB resection, resulted in bleomycin-hypersensitivity and greatly reduced GT efficiency. PMID:27537368

  14. Alveolar derecruitment and collapse induration as crucial mechanisms in lung injury and fibrosis.

    Science.gov (United States)

    Lutz, Dennis; Gazdhar, Amiq; Lopez-Rodriguez, Elena; Ruppert, Clemens; Mahavadi, Poornima; Günther, Andreas; Klepetko, Walter; Bates, Jason H; Smith, Bradford; Geiser, Thomas; Ochs, Matthias; Knudsen, Lars

    2015-02-01

    Idiopathic pulmonary fibrosis (IPF) and bleomycin-induced pulmonary fibrosis are associated with surfactant system dysfunction, alveolar collapse (derecruitment), and collapse induration (irreversible collapse). These events play undefined roles in the loss of lung function. The purpose of this study was to quantify how surfactant inactivation, alveolar collapse, and collapse induration lead to degradation of lung function. Design-based stereology and invasive pulmonary function tests were performed 1, 3, 7, and 14 days after intratracheal bleomycin-instillation in rats. The number and size of open alveoli was correlated to mechanical properties. Active surfactant subtypes declined by Day 1, associated with a progressive alveolar derecruitment and a decrease in compliance. Alveolar epithelial damage was more pronounced in closed alveoli compared with ventilated alveoli. Collapse induration occurred on Day 7 and Day 14 as indicated by collapsed alveoli overgrown by a hyperplastic alveolar epithelium. This pathophysiology was also observed for the first time in human IPF lung explants. Before the onset of collapse induration, distal airspaces were easily recruited, and lung elastance could be kept low after recruitment by positive end-expiratory pressure (PEEP). At later time points, the recruitable fraction of the lung was reduced by collapse induration, causing elastance to be elevated at high levels of PEEP. Surfactant inactivation leading to alveolar collapse and subsequent collapse induration might be the primary pathway for the loss of alveoli in this animal model. Loss of alveoli is highly correlated with the degradation of lung function. Our ultrastructural observations suggest that collapse induration is important in human IPF. PMID:25033427

  15. Expression of human carcinoembryonic antigen-related cell adhesion molecule 6 and alveolar progenitor cells in normal and injured lungs of transgenic mice.

    Science.gov (United States)

    Lin, Shin-E; Barrette, Anne Marie; Chapin, Cheryl; Gonzales, Linda W; Gonzalez, Robert F; Dobbs, Leland G; Ballard, Philip L

    2015-12-01

    Carcinoembryonic antigen-related cell adhesion molecule 6 (CEACAM6) is expressed in the epithelium of various primate tissues, including lung airway and alveoli. In human lung, CEACAM6 is developmentally and hormonally regulated, protects surfactant function, has anti-apoptotic activity and is dysregulated in cancers. We hypothesized that alveolar CEACAM6 expression increases in lung injury and promotes cell proliferation during repair. Studies were performed in CEABAC transgenic mice-containing human CEACAM genes. The level of CEACAM6 in adult CEABAC lung was comparable to that in human infants; expression occurred in epithelium of airways and of some alveoli but rarely co-localized with markers of type I or type II cells. Ten days after bleomycin instillation, both the number of CEACAM6(+) cells and immunostaining intensity were elevated in injured lung areas, and there was increased co-localization with type I and II cell markers. To specifically address type II cells, we crossed CEABAC mice with animals expressing EGFP driven by the SP-C promoter. After bleomycin injury, partially flattened, elongated epithelial cells were observed that expressed type I cell markers and were primarily either EGFP(+) or CEACAM6(+). In cell cycle studies, mitosis was greater in CEACAM6(+) non-type II cells versus CEACAM6(+)/EGFP(+) cells. CEACAM6 epithelial expression was also increased after hyperoxic exposure and LPS instillation, suggesting a generalized response to acute lung injuries. We conclude that CEACAM6 expression is comparable in human lung and the CEABAC mouse. CEACAM6 in this model appears to be a marker of a progenitor cell population that contributes to alveolar epithelial cell replenishment after lung injury. PMID:26702074

  16. Correlation of Clinical and Dosimetric Factors With Adverse Pulmonary Outcomes in Children After Lung Irradiation

    International Nuclear Information System (INIS)

    Purpose: To identify the incidence and the risk factors for pulmonary toxicity in children treated for cancer with contemporary lung irradiation. Methods and Materials: We analyzed clinical features, radiographic findings, pulmonary function tests, and dosimetric parameters of children receiving irradiation to the lung fields over a 10-year period. Results: We identified 109 patients (75 male patients). The median age at irradiation was 13.8 years (range, 0.04-20.9 years). The median follow-up period was 3.4 years. The median prescribed radiation dose was 21 Gy (range, 0.4-64.8 Gy). Pulmonary toxic chemotherapy included bleomycin in 58.7% of patients and cyclophosphamide in 83.5%. The following pulmonary outcomes were identified and the 5-year cumulative incidence after irradiation was determined: pneumonitis, 6%; chronic cough, 10%; pneumonia, 35%; dyspnea, 11%; supplemental oxygen requirement, 2%; radiographic interstitial lung disease, 40%; and chest wall deformity, 12%. One patient died of progressive respiratory failure. Post-irradiation pulmonary function tests available from 44 patients showed evidence of obstructive lung disease (25%), restrictive disease (11%), hyperinflation (32%), and abnormal diffusion capacity (12%). Thoracic surgery, bleomycin, age, mean lung irradiation dose (MLD), maximum lung dose, prescribed dose, and dosimetric parameters between V22 (volume of lung exposed to a radiation dose ≥22 Gy) and V30 (volume of lung exposed to a radiation dose ≥30 Gy) were significant for the development of adverse pulmonary outcomes on univariate analysis. MLD, maximum lung dose, and Vdose (percentage of volume of lung receiving the threshold dose or greater) were highly correlated. On multivariate analysis, MLD was the sole significant predictor of adverse pulmonary outcome (P=.01). Conclusions: Significant pulmonary dysfunction occurs in children receiving lung irradiation by contemporary techniques. MLD rather than prescribed dose should be used

  17. Application of Translational Medicine Concept in Chinese Materia Medica:Effect and Mechanism of Mahuang and Wuweizi on Pulmonary Fibrosis

    Institute of Scientific and Technical Information of China (English)

    QIN Hai-zhi; DONG Wei-tao

    2015-01-01

    Objective:To explore the effect and mechanism of Mahuang (Herba Ephedra) and Wuweizi (Schisandra Chinesis) on pulmonary ifbrosis based on translation medicine theory. Methods: Totally 90 Wistar rats were divided into 6 groups. Pulmonary ifbrosis models of rats were established by drip of bleomycin A5 through trachea while sham-operation group was infused with equivalent normal saline instead of bleomycin A5 into trachea. Sham-operation group and negative control group were performed with normal saline gavage while positive control group with subcutaneous injection of hydrocortisone, Mahuang group and Wuweizi group with gavage of Mahuang and Wuweizi concentrated decoction, respectively, whereas combined group was treated with gavage of Mahuang concentrated decoction during the ifrst 7 days and with Wuweizi concentrated decoction in the ensuing 21 days. On the 7th day and 28th day, pulmonary alveolitis and fibrosis in different groups were observed and the expression levels of serum vascular endothelial growth factor (VEGF), angiopoietin-2 (Ang-2), thrombospondin-1 (TSP-1), monocyte chemoattractant protein-1 (MCP-1), and macrophage inflammatory protein-1α (MIP-1α) were detected and compared. Results: All models of groups were successfully established. Compared with negative control group, the levels of VEGF, Ang-2, MCP-1 and MIP-1α decreased in different degrees but TSP-1 increased in other groups after medication for 7 days and 28 days. Conclusion: Mahuang and Wuweizi have intervention effects on pulmonary fibrosis, the mechanism of which might be related to the inhibition of excessive angiogenesis through inhibiting the expression of MCP-1 and MIP-1α, lowering the level of proangiogenic factors (Ang-2 and BEGF), and enhancing the level of angiogenesis inhibiting factor (TSP-1).

  18. Tumor necrosis factor-α accelerates the resolution of established pulmonary fibrosis in mice by targeting profibrotic lung macrophages.

    Science.gov (United States)

    Redente, Elizabeth F; Keith, Rebecca C; Janssen, William; Henson, Peter M; Ortiz, Luis A; Downey, Gregory P; Bratton, Donna L; Riches, David W H

    2014-04-01

    Idiopathic pulmonary fibrosis (IPF) is a relentless, fibrotic parenchymal lung disease in which alternatively programmed macrophages produce profibrotic molecules that promote myofibroblast survival and collagen synthesis. Effective therapies to treat patients with IPF are lacking, and conventional therapy may be harmful. We tested the hypothesis that therapeutic lung delivery of the proinflammatory cytokine tumor necrosis factor (TNF)-α into wild-type fibrotic mice would reduce the profibrotic milieu and accelerate the resolution of established pulmonary fibrosis. Fibrosis was assessed in bleomycin-instilled wild-type and TNF-α(-/-) mice by measuring hydroxyproline levels, static compliance, and Masson's trichrome staining. Macrophage infiltration and programming status was assessed by flow cytometry of enzymatically digested lung and in situ immunostaining. Pulmonary delivery of TNF-α to wild-type mice with established pulmonary fibrosis was found to reduce their fibrotic burden, to improve lung function and architecture, and to reduce the number and programming status of profibrotic alternatively programmed macrophages. In contrast, fibrosis and alternative macrophage programming were prolonged in bleomycin-instilled TNF-α(-/-) mice. To address the role of the reduced numbers of alternatively programmed macrophages in the TNF-α-induced resolution of established pulmonary fibrosis, we conditionally depleted macrophages in MAFIA (MAcrophage Fas-Induced Apoptosis) mice. Conditional macrophage depletion phenocopied the resolution of established pulmonary fibrosis observed after therapeutic TNF-α delivery. Taken together, our results show for the first time that TNF-α is involved in the resolution of established pulmonary fibrosis via a mechanism involving reduced numbers and programming status of profibrotic macrophages. We speculate that pulmonary delivery of TNF-α or augmenting its signaling pathway represent a novel therapeutic strategy to resolve

  19. Treatment of vascular tumors and vascular malformations with Pingyangmycin%平阳霉素治疗血管瘤与脉管畸形临床观察

    Institute of Scientific and Technical Information of China (English)

    卢新华; 刘海涛; 叶明华; 夏刚; 陈羿

    2011-01-01

    目的 总结平阳霉素治疗血管瘤及脉管畸形所致不良反应及并发症,探讨其发生的原因及防治措施.方法 用平阳霉素或平阳霉素联合其他药物瘤内注射治疗血管瘤及脉管畸形234例,治疗期间观察并防治不良反应及并发症.结果 234例患者中28例出现不良反应,不良反应率为12.0%,主要为发热、食欲不振、皮疹、局部溃疡、过敏性休克.结论 注射平阳霉素前肌内注射地塞米松或平阳霉素混合地塞米松注射,可预防或减少平阳霉素发热反应,注射前平阳霉素皮肤试验可预防过敏反应发生.%Objective To evaluate the treatment of vascular tumors and vascular malformations with Pingyangmycin, including adverse reactions and complications. Methods Totally 234 cases of vascular tumors and vascular malformations were treated by Pingyangmycin or intratumoral injection in combination with other drugs. Adverse reactions and complications during treatment were observed. Results Two hundred thirty-four patients had adverse reactions( 12.0% ) which included fever, loss of appetite, rash, local ulceration and anaphylactic shock.Conclusion The intramuscular injection of dexamethasone or Pingyangmycin before mixing dexamethasone injection can prevent or reduce fever bleomycin. Meanwhile bleomycin skin test prior to injection can prevent allergic reactions.

  20. Effect of Ibuprofen on the Expression of TGF-β and MyD88 in Mice with Pulmonary Fibrosis%布洛芬对肺纤维化小鼠TGF-β和MyD88表达的影响

    Institute of Scientific and Technical Information of China (English)

    王春雷; 吕飞; 张烨

    2013-01-01

    Objective To study the effect of ibuprofen on the protective effect of bleomycin-induced pulmonary fibrosis in mice.Methods By copying the model of pulmonary fibrosis in mice by intratracheal instillation of bleomycin,the treatment group underwent intraperitoneal injection of different doses of ibuprofen.In collection of lavage fluid,TNF-α and IL-6 levels were analyzed by flow cytometry of intracellular and ROS levels were determined by ELISA;Lavage fluid TGF-β1 and MyD88 expression levels were detected by Western blot. Results Compared with normal control group,model group,bronchoalveolar lavage fluid ROS,TNF-α and IL-6 were significantly increased(P<0.01).Ibuprofen treatment of inflammatory factors in bronchoalveolar lavage fluid of ROS,TNF-αand of IL-6 decreased significantly(P<0.01).Ibuprofen can alleviate the phenomenon of increased ROS and inflammatory cytokines in pulmonary fibrosis caused by Western blot results showed that TGF-β and MyD88 protein expression with the increase in ibuprofen concentration decreased,20mg/kg ibuprofen significantly decreased(P<0.01).Conclusion Our study showed that ibuprofen reduce bleomycin-induced pulmonary fibrosis cytokine levels and lowered TGF-β and MyD88 expression.%  目的研究布洛芬对博莱霉素诱导的小鼠肺纤维化的保护作用与TGF-β和MyD88的关系。方法通过气管内滴注博莱霉素复制小鼠肺纤维化模型,治疗组行腹腔注射给予不同剂量的布洛芬。收集肺泡灌洗液用ELISA方法测定TNF-α和IL-6含量,用流式细胞仪测定细胞内ROS的水平;用Western blot方法检测肺泡灌洗液TGF-β1和MyD88的表达水平。结果与正常对照组比较,模型组支气管肺泡灌洗液ROS、TNF-α和IL-6含量显著增加(P<0.01),经布洛芬处理肺泡灌洗液中炎症因子ROS、TNF-α和IL-6明显降低(P<0.01),说明布洛芬可缓解肺纤维化所引起的ROS和炎症因子增高的现象。Western blot结果显示 TGF

  1. 不同诱导剂致慢性阻塞性肺疾病模型小鼠氧化应激损伤的实验研究%Experimental Observation of Lung Oxidative Stress Injury in Mice Model of Chronic Obstructive Pulmonary Disease Induced by Different Inducers

    Institute of Scientific and Technical Information of China (English)

    覃文慧; 杨柯; 邓家刚; 张帅; 黄思诗

    2014-01-01

    This study was aimed to observe the intervention effect of oxidation/antioxidation at different time point among mice induced by lipopolysaccharide (LPS) and bleomycin. It provided experimental basis for the establishment of chronic obstructive pulmonary disease (COPD) animal model with qi-deficiency and phlegm-obstructing pattern with inducers mentioned above. A total of 96 mice were randomly divided into the normal control group, bleomycin group, and LPS group, with 32 mice in each group. In the bleomycin group and LPS group, 40 μL of nasal drops were given with bleomycin at the concentration of 3.75 μg/μL or LPS at the concentration of 5 μg/μL, respectively to establish the COPD animal model with qi-deficiency and phlegm-obstructing pattern. On the 1st day, 7th day, 14th day and 28th day after the model establishment, the general status and activities of mice were recorded. And traditional Chinese medicine (TCM) signs such as skin color of the four limbs, skin color under the tongue and color of the tail were also collected when the animal model was sacrificed. At each time point, 8 mice were sacrificed. The lung tissues were removed. And the contents of GSH, MDA, SOD and T-AOC were detected in the homogenate of lung tissues. The results showed that compared with the normal control group, mice in the bleomycin group had slightly dull eyes, dry hair without burnish, upright and fluffy hair, dark purple skin color of the auricle and four claws, tiredness, inactivity, occasional cough, asthma or rapid breathing. The GSH content of lung tissues on the 7th day, 14th day and 28th day was obviously reduced (P< 0.05, or P< 0.01). The MDA, SOD and T-AOC contents on the 1st day, 7th day, 14th day and 28th day were obviously reduced (P< 0.05, or P< 0.01). Compared with the normal control group, mice in the LPS group had slightly dull eyes, soft hair with slight burnish, pale red skin color of the auricle and four claws, tiredness; some mice preferred to gather

  2. Surgical Treatment Combined with Postoperative Adjuvant Chemotherapy Offer a Viable Option to the Cervical Cancer in Stage ⅠB ~ⅡA with Moderate and High-Risk Factor for Recurrence

    Institute of Scientific and Technical Information of China (English)

    MA Ke; LIU Tongyu; HUANG Weiping; WEN Hongwu; LIAO Qinping

    2012-01-01

    To determine the effectiveness of surgical therapy combined with postoperative adjuvant chemotherapy for cervical cancer with moderate and high-risk factors.Methods:68 patients with cervical cancer in stage Ⅰ B ~ ⅡA were enrolled and initially treated with radical hysterectomy and pelvic lymphadenectomy from January 1999 to December 2009.37 patients were assigned into moderate-risk group (stromal invasion > 50%,poor differentiation,max diameter of tumor ≥ 4 cm,positive LVSI,n =37),and 31patients assigned into high-risk group (positive surgical margin,parametrial invasion,lymph node involvement,n =31).In all cases,chemotherapy was administered adjuvantly:three to four courses of chemotherapy were administered adjuvantly to patients in moderate-risk group and four to six courses to patients in high-risk group.Chemotherapy regimen was BIP (Bleomycin + Ifosfamide + Cisplatin/Carboplatin)for squamous and adenosquamous cancer,and TP (Paclitaxel + Cisplatin/Carboplatin) for adenocarcinoma.Disease-free survival rates and complications of the combined therapy were recorded in follow-up.Results:Estimated 3-year disease-free survival rate was 93.1% for the patientsin moderate-risk group,and 85.4% for the patients in high-risk group (P > 0.05).The recurrence rate was 10.3% for the total 68 patients,and was 8.1% and 12.9% for the patients in moderate-risk group and high-risk group,respectively.The incidence of locoregional recurrence was 5.4% and 6.5% in the moderate-risk group and the high-risk group,respectively.Side effects of chemotherapy and complications of the combined therapy were limited,and no severe bleomycin-related pulmonary toxicity was observed.Conclusions:our results indicate that surgical therapy combined with postoperative adjuvant chemotherapy offers a viable option to the cervical cancer in stage Ⅰ B ~ Ⅱ A.Patients can tolerate the side effects of chemotherapy and get better efficacy.

  3. Involved-Node Proton Therapy in Combined Modality Therapy for Hodgkin Lymphoma: Results of a Phase 2 Study

    Energy Technology Data Exchange (ETDEWEB)

    Hoppe, Bradford S., E-mail: bhoppe@floridaproton.org [Radiation Oncology, University of Florida Proton Therapy Institute, Jacksonville, Florida (United States); Flampouri, Stella [Radiation Oncology, University of Florida Proton Therapy Institute, Jacksonville, Florida (United States); Zaiden, Robert [Department of Medicine, Division of Hematology and Oncology, University of Florida College of Medicine, Jacksonville, Florida (United States); Slayton, William [Department of Pediatrics, Division of Hematology and Oncology, University of Florida College of Medicine, Gainesville, Florida (United States); Sandler, Eric [Department of Pediatrics, Division of Hematology/Oncology Nemours Children' s Clinic, Jacksonville, Florida (United States); Ozdemir, Savas [Department of Radiology, Division of Functional and Molecular Imaging, University of Florida College of Medicine, Jacksonville, Florida (United States); Dang, Nam H.; Lynch, James W. [Department of Medicine, Division of Hematology and Oncology, University of Florida College of Medicine, Gainesville, Florida (United States); Li, Zuofeng; Morris, Christopher G.; Mendenhall, Nancy P. [Radiation Oncology, University of Florida Proton Therapy Institute, Jacksonville, Florida (United States)

    2014-08-01

    Purpose: This study describes the early clinical outcomes of a prospective phase 2 study of consolidative involved-node proton therapy (INPT) as a component of combined-mode therapy in patients with stages I to III Hodgkin lymphoma (HL) with mediastinal involvement. Methods and Materials: Between September 2009 and June 2013, 15 patients with newly diagnosed HL received INPT after completing chemotherapy in an institutional review board-approved protocol comparing the dosimetric impact of PT with those of three-dimensional conformal radiation therapy (3DCRT) and intensity modulated RT. Based on {sup 18}F-Fluorodeoxyglucose positron emission tomography/computed tomography ({sup 18}F-FDG PET/CT) response, 5 children received 15 to 25.5 cobalt Gy equivalent (CGE) of INPT after receiving 4 cycles of Adriamycin, Bleomycin, Vincristine, Etoposide, Prednisone, Cyclophosphamide or Vincristine, adriamycin, methotrexate, Prednisone chemotherapy, and 10 adults received 30.6 to 39.6 CGE of INPT after 3 to 6 cycles of Adriamycin, Bleomycine, Vinblastine, Dacarbazine. Patients were routinely evaluated for toxicity during and after treatment, using Common Terminology Criteria for Adverse Events, version 3.0, and for relapse by physical examination and routine imaging. Relapse-free survival (RFS) and event-free survival (EFS) rates were calculated using the Kaplan-Meier method from the time of diagnosis. Results: The median follow-up was 37 months (range, 26-55). Two events occurred during follow-up: 1 relapse (inside and outside the targeted field) and 1 transformation into a primary mediastinal large B cell lymphoma. The 3-year RFS rate was 93%, and the 3-year EFS rate was 87%. No acute or late grade 3 nonhematologic toxicities were observed. Conclusions: Although decades of follow-up will be needed to realize the likely benefit of PT in reducing the risk of radiation-induced late effects, PT following chemotherapy in patients with HL is well-tolerated, and disease outcomes

  4. Efficacy of neoadjuvant chemotherapy and radiotherapy for the histology-confirmed intracranial germinoma-preliminary report

    Energy Technology Data Exchange (ETDEWEB)

    Noh, Young Ju; Kim, Hak Jae; Heo, Dae Seog; Shin, Hee Yung; Kim, Il Han [Seoul National University College of Medicine, Seoul (Korea, Republic of)

    2002-06-15

    We intended to decrease late CNS reaction after radical radiotherapy for an intracranial germinoma by using combined neoadjuvant chemotherapy and involved-field radiotherapy. The efficacy in terms of its acute toxicity and short-term relapse patterns was analyzed. Eighteen patients were treated with combined neoadjuvant chemotherapy and radiotherapy between 1995 and 2001. The chemotherapy regimen used was the Children's Cancer Group (CCG) 9921A (cisplatin, cyclophosphamide, VP-16, vincristine) for 5 patients younger than 16 years, BEP(bleomycin, VP-16, cisplatin) for 12 patients, and EP (VP-16, cisplatin) for 1 patient. The radiotherapy covered the whole craniospinal axis for 5 patients, the whole brain for 1, and the partial brain (involved field) for 12. the primary lesion received tumour doses between 3,960 and 5,400 cGy. The male to female ratio was 16:2 and the median age was 16 years old. The tumors were located in the pineal gland in 12 patients, in the suprasellar region in 1, in the basal ganglia in 1, in the thalamus in 1. Three patients had multiple lesions and ventricular seedings were shown at MRI. In 3 patients, tumor cells were detected in the cerebrospinal fluid and MRI detected a spinal seeding in 2 patients. The response to neoadjuvant chemotherapy was complete remission in 5 patients, partial remission in 12, and no response in 1. However, after radiotherapy, all except 1 patient experienced complete remission. The toxicity during or after chemotherapy greater than or equal to grade III was remarkable; hematologic toxicity was observed in 11 patients, liver toxicity in none, kidney toxicity in none, and gastrointestinal toxicity in one. One patient suffered from bleomycin-induced pneumonitis. Radiotherapy was therefore stopped and the patient eventually died of respiratory failure. The other 17 are alive without any evidence of disease or relapse during an average of 20 months follow-up. A high response rate and disease control was

  5. miR-19a, -19b, and -26b Mediate CTGF Expression and Pulmonary Fibroblast Differentiation.

    Science.gov (United States)

    Chen, Yen-Chou; Chen, Bing-Chang; Yu, Chung-Chi; Lin, Shin-Hua; Lin, Chien-Huang

    2016-10-01

    Although microRNA (miRNA) dysregulation with intracellular signaling cascade disruption has been demonstrated in the pathophysiology of pulmonary fibrosis, the relationship between miRNAs and intracellular signaling cascades in pulmonary fibrosis remains unclear. Using the human embryonic lung fibroblast cell line WI-38, we observed endothelin-1 (ET-1)- and thrombin-induced expression of the differentiation markers α-smooth muscle actin (α-SMA) and vimentin along with increased connective tissue growth factor (CTGF) protein expression. Decreased CTGF protein expression by CTGF siRNA significantly blocked ET-1- and thrombin-induced α-SMA and vimentin expression in WI-38 cells. Activation of the mitogen-activated protein kinases (MAPKs) extracellular signal-regulated kinase ERK, c-Jun N-terminal kinase (JNK), and p38 contributed to ET-1- and thrombin-induced CTGF, α-SMA, and vimentin expression in WI-38 cells. TargetScan Human, miRanda, and PicTar prediction algorithms were used to predict miRNAs with binding sites in the 3' untranslated region (UTR) of CTGF mRNA. miR-19a, -19b, and -26b were candidate miRNAs of CTGF. Direct binding of the candidate miRNAs to the 3'-UTR of CTGF mRNA was verified through luciferase assay by using SV40-promoter-IRES-driven luciferase containing the 3'-UTR of CTGF mRNA as a reporter plasmid. ET-1 and thrombin reduced candidate miRNA levels. Candidate miRNA overexpression significantly suppressed ET-1- and thrombin-induced CTGF expression and reduced α-SMA and vimentin expression in the WI-38 cells. Furthermore, candidate miRNA levels were decreased in the lung tissues of mice with bleomycin-induced pulmonary fibrosis, and intratracheal application of miR-19a, -19b, and 26b reduced the pulmonary fibrotic severity induced by bleomycin. This study is the first to demonstrate crosstalk between MAPK activation and reduction in miR-19a, -19b, and -26b expression leading to lung fibroblast differentiation. J. Cell. Physiol. 231: 2236

  6. Construction of Marker-Free Transgenic Strains of Chlamydomonas reinhardtii Using a Cre/loxP-Mediated Recombinase System.

    Science.gov (United States)

    Kasai, Yuki; Harayama, Shigeaki

    2016-01-01

    The Escherichia coli bacteriophage P1 encodes a site-specific recombinase called Cre and two 34-bp target sites of Cre recombinase called loxP. The Cre/loxP system has been used to achieve targeted insertion and precise deletion in many animal and plant genomes. The Cre/loxP system has particularly been used for the removal of selectable marker genes to create marker-free transgenic organisms. For the first time, we applied the Cre/loxP-mediated site-specific recombination system to Chlamydomonas reinhardtii to construct marker-free transgenic strains. Specifically, C. reinhardtii strains cc4350 and cc124 carrying an aphVIII expression cassette flanked by two direct repeats of loxP were constructed. Separately, a synthetic Cre recombinase gene (CrCRE), the codons of which were optimized for expression in C. reinhardtii, was synthesized, and a CrCRE expression cassette was introduced into strain cc4350 carrying a single copy of the loxP-flanked aphVIII expression cassette. Among 46 transformants carrying the CrCRE expression cassette stably, the excision of aphVIII by CrCre recombinase was observed only in one transformant. We then constructed an expression cassette of an in-frame fusion of ble to CrCRE via a short linker peptide. The product of ble (Ble) is a bleomycin-binding protein that confers resistance to bleomycin-related antibiotics such as Zeocin and localizes in the nucleus. Therefore, the ble-(linker)-CrCRE fusion protein is expected to localize in the nucleus. When the ble-(linker)-CrCRE expression cassette was integrated into the genome of strain cc4350 carrying a single copy of the loxP-flanked aphVIII expression cassette, CrCre recombinase-mediated excision of the aphVIII expression cassette was observed at a frequency higher than that in stable transformants of the CrCRE expression cassette. Similarly, from strain cc124 carrying a single loxP-flanked aphVIII expression cassette, the aphVIII expression cassette was successfully excised after

  7. Treatment Results and prognostic Factors in Patients with Esophageal Cancer

    Energy Technology Data Exchange (ETDEWEB)

    Chung, Weon Kuu; Kim, Soo Kon; Kim, Min Chul; Jang, Myoung [Presbyterian Medical Center, Chonju (Korea, Republic of); Moon, Sun Rock [Wonkwang Univ., Medical School, Iksan (Korea, Republic of)

    1995-09-15

    Purpose : To analyse clinical outcome and prognostic factors according to treatment modality, this paper report our experience of retrospective study of patients with esophageal cancer. Materials and Methods : One hundred and ten patients with primary esophageal cancer who were treated in Presbyterian Medical Center from May 1985 to December 1992. We analysed these patients retrospectively with median follow up time of 28 months, one hundred and four patients(95%) were followed up from 15 to 69 months. In methods, twenty-eight patients were treated with median radiation dose irradiated 54.3Gy only. Fifty-six patients were treated with combined chemoradiotherapy. Sixteen cases of these patients were treated with concurrent chemoradiation and the other patients(forty cases) were treated sequential chemoradiotherapy. In concurrent chemoradiotherapy group, patients received 5-FU continuous IV infusion for 4 days. Cisplatin IV bolus, and concurrent esophageal irradiation to 30 Gy. After that patients received ?Fu continuous IV, Cisplatin bolus injection and Mitomycin-C bolus IV, Bleomycin continuous IV, and irradiation to 20 Gy. In sequential chemoradiotherapy group, the chemotherapy consisted of 5-FU 1,000 mg/m2 administered as a continuous 24 hour intravenous infusion during five days and Cisplatin 80-100 mg/m2 bolus injected, or Bleomycin, Vinblastine, Cisplatin, Methotrexate were used of 1 or 2 cycles. After preoperative concurrent chemoradiation, twenty-six patients underwent radical esophagectomy. Results ; ninety-three patients could be examined for response assessment. By treatment modality, response rates were 85.1% for radiation alone group and 86.3% for combined chemoradiation group. But in operation group, after one cycle of concurrent chemoradiation treatment, response rate was 61.9%. The pathologic complete response were 15.4% in operation group. Overall median survival was 11 months and actuarial 5-year survival rate was 8%. The median survival interval

  8. Regenerative medicine in the treatment of idiopathic pulmonary fibrosis: current position

    Directory of Open Access Journals (Sweden)

    Álvarez D

    2015-04-01

    Full Text Available Diana Álvarez,1,2 Melanie Levine,1 Mauricio Rojas1–3 1Dorothy P and Richard P Simmons Center for Interstitial Lung Disease, 2Pulmonary, Allergy, and Critical Care Medicine, 3McGowan Institute for Regenerative Medicine, University of Pittsburgh Medical Center, Pittsburgh, PA, USA Abstract: Idiopathic pulmonary fibrosis (IPF is a progressive, irreversible disease of the lung that has no lasting option for therapy other than transplantation. It is characterized by replacement of the normal lung tissue by fibrotic scarring, honeycombing, and increased levels of myofibroblasts. The underlying causes of IPF are still largely unknown. The focus of the current review is the possible use of stem cell therapy, specifically mesenchymal stem cells (MSCs, a multipotent stromal cell population, which have demonstrated promising data in multiple animal models of pulmonary fibrosis (PF. The most studied source of MSCs is the bone marrow, although they can be found also in the adipose tissue and umbilical cord, as well as in the placenta. MSCs have immunomodulatory and tissue-protective properties that allow them to manipulate the local environment of the injured tissue, ameliorating the inflammation and promoting repair. Because IPF primarily affects older patients, the issue of aging is intrinsically linked to many aspects of the disease, including the age of the stem cells. Animal models have shown the success of MSC therapy in mitigating the fibrotic effects of bleomycin-induced PF. However, bleomycin, the most commonly used model for PF, is imperfect in mimicking IPF as it presents in humans, as the duration of the illness is not parallel or reversible, and honeycombing is not produced. Furthermore, the time of MSC dosage has proven to be critical in determining whether the cells will ultimately have a positive or negative effect on disease progression, since it has been demonstrated that the maximal beneficial effect of MSCs occurs during the early

  9. Patterns of Relapse From a Phase 3 Study of Response-Based Therapy for Intermediate-Risk Hodgkin Lymphoma (AHOD0031): A Report From the Children's Oncology Group

    Energy Technology Data Exchange (ETDEWEB)

    Dharmarajan, Kavita V. [Mount Sinai Medical Center, New York, New York (United States); Friedman, Debra L. [Vanderbilt University, Nashville, Tennessee (United States); Schwartz, Cindy L. [MD Anderson Cancer Center, Houston, Texas (United States); Chen, Lu [Children' s Oncology Group, Arcadia, California (United States); FitzGerald, T.J. [Quality Assurance Review Center, Lincoln, Rhode Island (United States); McCarten, Kathleen M. [Rhode Island Hospital/Warren Alpert Medical School at Brown University, Providence, Rhode Island (United States); Kessel, Sandy K.; Iandoli, Matt [Quality Assurance Review Center, Lincoln, Rhode Island (United States); Constine, Louis S. [University of Rochester Medical Center, Rochester, New York (United States); Wolden, Suzanne L., E-mail: woldens@mskcc.org [Memorial Sloan-Kettering Cancer Center, New York, New York (United States)

    2015-05-01

    Purpose: The study was designed to determine whether response-based therapy improves outcomes in intermediate-risk Hodgkin lymphoma. We examined patterns of first relapse in the study. Patients and Methods: From September 2002 to July 2010, 1712 patients <22 years old with stage I-IIA with bulk, I-IIAE, I-IIB, and IIIA-IVA with or without doxorubicin, bleomycin, vincristine, etoposide, prednisone, and cyclophosphamide were enrolled. Patients were categorized as rapid (RER) or slow early responders (SER) after 2 cycles of doxorubicin, bleomycin, vincristine, etoposide, prednisone, and cyclophosphamide (ABVE-PC). The SER patients were randomized to 2 additional ABVE-PC cycles or augmented chemotherapy with 21 Gy involved field radiation therapy (IFRT). RER patients were stipulated to undergo 2 additional ABVE-PC cycles and were then randomized to 21 Gy IFRT or no further treatment if complete response (CR) was achieved. RER without CR patients were non-randomly assigned to 21 Gy IFRT. Relapses were characterized without respect to site (initial, new, or both; and initial bulk or initial nonbulk), and involved field radiation therapy field (in-field, out-of-field, or both). Patients were grouped by treatment assignment (SER; RER/no CR; RER/CR/IFRT; and RER/CR/no IFRT). Summary statistics were reported. Results: At 4-year median follow-up, 244 patients had experienced relapse, 198 of whom were fully evaluable for review. Those who progressed during treatment (n=30) or lacked relapse imaging (n=16) were excluded. The median time to relapse was 12.8 months. Of the 198 evaluable patients, 30% were RER/no CR, 26% were SER, 26% were RER/CR/no IFRT, 16% were RER/CR/IFRT, and 2% remained uncategorized. The 74% and 75% relapses involved initially bulky and nonbulky sites, respectively. First relapses rarely occurred at exclusively new or out-of-field sites. By contrast, relapses usually occurred at nodal sites of initial bulky and nonbulky disease. Conclusion: Although

  10. Fibrocytes in the Fibrotic Lung: Altered Phenotype Detected by Flow Cytometry

    Directory of Open Access Journals (Sweden)

    Charles eReese

    2014-06-01

    Full Text Available Fibrocytes are bone marrow hematopoietic-derived cells that also express a mesenchymal cell marker (commonly collagen I and participate in fibrotic diseases of multiple organs. Given their origin, they or their precursors must be circulating cells before recruitment into target tissues. While most previous studies focused on circulating fibrocytes, here we focus on the fibrocyte phenotype in fibrotic tissue. The study’s relevance to human disease is heightened by use of a model in which bleomycin is delivered systemically, recapitulating several features of human scleroderma including multi-organ fibrosis not observed when bleomycin is delivered directly into the lungs. Using flow cytometry, we find in the fibrotic lung a large population of CD45high fibrocytes (called Region I rarely found in vehicle-treated control mice. A second population of CD45+ fibrocytes (called Region II is observed in both control and fibrotic lung. The level of CD45 in circulating fibrocytes is far lower than in either Region I or II lung fibrocytes. The chemokine receptors CXCR4 and CCR5 are expressed at higher levels in Region I than in Region II and are present at very low levels in all other lung cells including CD45+/collagen I- leucocytes. The collagen chaperone HSP47 is present at similar high levels in both Regions I and II, but at a higher level in fibrotic lung than in control lung. There is also a major population of HSP47high/CD45- cells in fibrotic lung not present in control lung. CD44 is present at higher levels in Region I than in Region II and at much lower levels in all other cells including CD45+/collagen I- leucocytes. When lung fibrosis is inhibited by restoring caveolin-1 activity using a caveolin-1 scaffolding domain peptide (CSD, a strong correlation is observed between fibrocyte number and fibrosis score. In summary, the distinctive phenotype of fibrotic lung fibrocytes suggests that fibrocyte differentiation occurs primarily within the

  11. Involved-Node Proton Therapy in Combined Modality Therapy for Hodgkin Lymphoma: Results of a Phase 2 Study

    International Nuclear Information System (INIS)

    Purpose: This study describes the early clinical outcomes of a prospective phase 2 study of consolidative involved-node proton therapy (INPT) as a component of combined-mode therapy in patients with stages I to III Hodgkin lymphoma (HL) with mediastinal involvement. Methods and Materials: Between September 2009 and June 2013, 15 patients with newly diagnosed HL received INPT after completing chemotherapy in an institutional review board-approved protocol comparing the dosimetric impact of PT with those of three-dimensional conformal radiation therapy (3DCRT) and intensity modulated RT. Based on 18F-Fluorodeoxyglucose positron emission tomography/computed tomography (18F-FDG PET/CT) response, 5 children received 15 to 25.5 cobalt Gy equivalent (CGE) of INPT after receiving 4 cycles of Adriamycin, Bleomycin, Vincristine, Etoposide, Prednisone, Cyclophosphamide or Vincristine, adriamycin, methotrexate, Prednisone chemotherapy, and 10 adults received 30.6 to 39.6 CGE of INPT after 3 to 6 cycles of Adriamycin, Bleomycine, Vinblastine, Dacarbazine. Patients were routinely evaluated for toxicity during and after treatment, using Common Terminology Criteria for Adverse Events, version 3.0, and for relapse by physical examination and routine imaging. Relapse-free survival (RFS) and event-free survival (EFS) rates were calculated using the Kaplan-Meier method from the time of diagnosis. Results: The median follow-up was 37 months (range, 26-55). Two events occurred during follow-up: 1 relapse (inside and outside the targeted field) and 1 transformation into a primary mediastinal large B cell lymphoma. The 3-year RFS rate was 93%, and the 3-year EFS rate was 87%. No acute or late grade 3 nonhematologic toxicities were observed. Conclusions: Although decades of follow-up will be needed to realize the likely benefit of PT in reducing the risk of radiation-induced late effects, PT following chemotherapy in patients with HL is well-tolerated, and disease outcomes were similar to

  12. Patterns of Relapse From a Phase 3 Study of Response-Based Therapy for Intermediate-Risk Hodgkin Lymphoma (AHOD0031): A Report From the Children's Oncology Group

    International Nuclear Information System (INIS)

    Purpose: The study was designed to determine whether response-based therapy improves outcomes in intermediate-risk Hodgkin lymphoma. We examined patterns of first relapse in the study. Patients and Methods: From September 2002 to July 2010, 1712 patients <22 years old with stage I-IIA with bulk, I-IIAE, I-IIB, and IIIA-IVA with or without doxorubicin, bleomycin, vincristine, etoposide, prednisone, and cyclophosphamide were enrolled. Patients were categorized as rapid (RER) or slow early responders (SER) after 2 cycles of doxorubicin, bleomycin, vincristine, etoposide, prednisone, and cyclophosphamide (ABVE-PC). The SER patients were randomized to 2 additional ABVE-PC cycles or augmented chemotherapy with 21 Gy involved field radiation therapy (IFRT). RER patients were stipulated to undergo 2 additional ABVE-PC cycles and were then randomized to 21 Gy IFRT or no further treatment if complete response (CR) was achieved. RER without CR patients were non-randomly assigned to 21 Gy IFRT. Relapses were characterized without respect to site (initial, new, or both; and initial bulk or initial nonbulk), and involved field radiation therapy field (in-field, out-of-field, or both). Patients were grouped by treatment assignment (SER; RER/no CR; RER/CR/IFRT; and RER/CR/no IFRT). Summary statistics were reported. Results: At 4-year median follow-up, 244 patients had experienced relapse, 198 of whom were fully evaluable for review. Those who progressed during treatment (n=30) or lacked relapse imaging (n=16) were excluded. The median time to relapse was 12.8 months. Of the 198 evaluable patients, 30% were RER/no CR, 26% were SER, 26% were RER/CR/no IFRT, 16% were RER/CR/IFRT, and 2% remained uncategorized. The 74% and 75% relapses involved initially bulky and nonbulky sites, respectively. First relapses rarely occurred at exclusively new or out-of-field sites. By contrast, relapses usually occurred at nodal sites of initial bulky and nonbulky disease. Conclusion: Although

  13. Effects of benzo(a)pyrene on telomere length in human bronchial epithelial cells%苯并(a)芘对人支气管上皮细胞端粒长度的影响

    Institute of Scientific and Technical Information of China (English)

    宾萍; 段化伟; 王亚东; 戴宇飞; 牛勇; 刘清君; 陈泓; 刘庆; 郑玉新

    2011-01-01

    Objective To investigate the effects of Benzo(a) pyrene[B(a) P] on telomere length in human bronchial epithelial cells in vitro. Methods Human bronchial epithelial cell lines(16HBE) were treated with B(a) P in vitro. Real-time polymerase chain reaction (RT-PCR) was used to evaluate the telomere length of genomic DNA in cells, and the changes of relative telomere length were marked. The positive control was 4 μg/ml Bleomycin (BLM). Results Compared to the group of 0μmol/L B(a) P, the groups of 1 μmol/L,4μmol/L and positive control group, the telomere length were significantly shorter (P < 0. 05 ), but no significant difference was found between group of 16 μmol/L B(a) P and control. Conclusion The data showed that B(a) P had influence on the telomere length of genomic DNA in 16HBE cells. It might lead to short telomere length in a certain range of dosage.%目的 体外探讨苯并(a)芘[Benzo(a)pyrene,B(a)P]对人支气管上皮细胞端粒长度的影响.方法 应用人支气管上皮细胞株16HBE,给予不同浓度的B(a)P处理,采用定量PCR方法测定细胞全基因组DNA的相对端粒长度,观察细胞全基因组DNA相对端粒长度的变化情况.以4μg/ml博来霉素(Bleomycin,BLM)为阳性对照.结果 与0μmol/L组比较,1和4μmol/L B(a)P染毒组,以及阳性对照组的相对端粒长度较短,差异有统计学意义(P0.05).结论 B(a)P可对人支气管上皮细胞16HBE的全基因组DNA端粒长度产生影响,在一定剂量内会导致细胞全基因组DNA端粒长度缩短.

  14. 微创技术在口腔颌面的应用研究%MinimallyInvasiveTechniquesintheApplicationofOralandMaxillofacialRegion

    Institute of Scientific and Technical Information of China (English)

    刘韬

    2013-01-01

    Objective:Minimally invasive techniques oral and maxillofacial vascular malformation clinical research. Methods:According to the actual situation of vascular malformations, Adopt a"color Doppler ultrasound to guide minimally invasive treatment line bleomycin injection, digital subtraction angiography is mediated super-selective arterial embolization minimally invasive treatment, super-selective arterial embolization combined pingyangmycin minimally invasive treatment“and other means comprehensive treatment of oral and maxillofacial vascular malformations. Results: Interrupted after 1 year, Comprehensive treatment of the total efficiency 76.19%, Including color Doppler ultrasound to guide the line bleomycin injection minimally invasive treatment group was 71.43%, Digital subtraction angiography is mediated by a selective arterial embolization minimally invasive treatment group was 71.43%, Intervention super-selective intra-arterial embolization combined pingyangmycin minimally invasive treatment group was 85.71%.Conclusion:Color Doppler ultrasound guidance, super-selective arterial embolization is safe and effective oral and maxillofacial vascular malformations, Simplify treatment procedures, Reduce tissue trauma.%目的:探讨微创技术对口腔颌面处血管畸形的临床治疗研究。方法:依血管畸形实际状况,采取“CDU为引导行PYM注射的微创治疗、DSA为介导行SAE微创治疗、SAE+PYM联合微创治疗”等手段综合治疗口腔颌面血管畸形。结果:术后追访1年,综合治疗总有效率76.19%,其中CDU为引导行PYM注射的微创治疗组为71.43%,DSA为介导行SAE微创治疗组为71.43%,介入SAE+PYM联合微创治疗组为85.71%。结论:CDU引导、SAE治疗口腔颌面血管畸形安全有效,简化治疗程序,降低组织创伤。

  15. Primary yolk sac tumor of the gluteus: a case report and literature review

    Directory of Open Access Journals (Sweden)

    Li B

    2016-08-01

    Full Text Available Bo Li,1 Qianqian Jiang,1 Shitai Zhang,1 Yang Zhou,1 Qing-Fu Zhang,2 Ling OuYang1 1Department of Obstetrics and Gynecology, Shengjing Hospital of China Medical University, Shenyang, 2Department of Pathology, the First Affiliated Hospital and College of Basic Medical Sciences, China Medical University, Shenyang, People’s Republic of China Abstract: Yolk sac tumor (YST is a common malignant primitive germ cell tumor that often exhibits differentiation into endodermal structures. They most commonly occur in childhood and adolescence and are rare after the age of 40 years. Derived from the yolk sac during the embryonic period, YSTs can occur in the gonads and germ cells because the tumor cells migrate from the yolk sac toward the gonads. Here, we present a rare case of primary gluteus YST in a 3-year-old girl. She received BEP chemotherapy (bleomycin + etoposide + cisplatin after surgical resection. There was no evidence of recurrence 7 months after primary treatment. Keywords: immunohistochemistry, yolk sac tumor, germ cell tumor

  16. In vitro chemosensitivity of head and neck cancer cell lines

    Directory of Open Access Journals (Sweden)

    Schuler PJ

    2010-08-01

    Full Text Available Abstract Background Systemic treatment of head and neck squamous cell carcinoma (HNSCC includes a variety of antineoplastic drugs. However, drug-resistance interferes with the effectiveness of chemotherapy. Preclinical testing models are needed in order to develop approaches to overcome chemoresistance. Methods Ten human cell lines were obtained from HNSCC, including one with experimentally-induced cisplatin resistance. Inhibition of cell growth by seven chemotherapeutic agents (cisplatin, carboplatin, 5- fluorouracil, methotrexate, bleomycin, vincristin, and paclitaxel was measured using metabolic MTT-uptake assay and correlated to clinically-achievable plasma concentrations. Results All drugs inhibited cell growth in a concentration-dependent manner with an IC50 comparable to that achievable in vivo. However, response curves for methotrexate were unsatisfactory and for paclitaxel, the solubilizer cremophor EL was toxic. Cross-resistance was observed between cisplatin and carboplatin. Conclusion Chemosensitivity of HNSCC cell lines can be determined using the MTT-uptake assay. For DNA-interfering cytostatics and vinca alkaloids this is a simple and reproducible procedure. Determined in vitro chemosensitivity serves as a baseline for further experimental approaches aiming to modulate chemoresistance in HNSCC with potential clinical significance.

  17. Preoperative Arterial Interventional Chemotherapy on Cervical Cancer

    Institute of Scientific and Technical Information of China (English)

    WANG Hui; LING HU-Hua; TANG Liang-dan; ZHANG Xing-hua

    2008-01-01

    Objective:To discuss the therapeutic effect of preoperative interventional chemotherapy on cervical cancer.Methods:Preoperative interventional chemotherapy by femoral intubation was performed in 25 patients with bulky cervical cancer.The patients received bleomycin 45 mg and cisplatin or oxaliplatin 80 mg/m2.Results:25 cases(including 8 cases with stage Ⅰ and 17 cases with stage Ⅱ)received one or two courses of preoperative interventional chemotherapy.The size of the focal lesions was decreased greatly and radical hysterectomy and lymphadenectomy were performed successfully in all the patients.All of the specimens were sent for pathological examination.Lymphocyte infiltration was found more obvious in the cancer tissues as compared with their counterpart before treatment.As a result,relevant vaginal bleeding was stopped completely shortly after the treatment.Conclusion:Arterial interventional chemotherapy was proved to reduce the local size of cervical cancer and thus control the hemorrhage efficiently.The patients with cervical cancer can receive radical hysterectomy therapy after the interventional chemotherapy.

  18. DNaseI Protects against Paraquat-Induced Acute Lung Injury and Pulmonary Fibrosis Mediated by Mitochondrial DNA

    Directory of Open Access Journals (Sweden)

    Guo Li

    2015-01-01

    Full Text Available Background. Paraquat (PQ poisoning is a lethal toxicological challenge that served as a disease model of acute lung injury and pulmonary fibrosis, but the mechanism is undetermined and no effective treatment has been discovered. Methods and Findings. We demonstrated that PQ injures mitochondria and leads to mtDNA release. The mtDNA mediated PBMC recruitment and stimulated the alveolar epithelial cell production of TGF-β1 in vitro. The levels of mtDNA in circulation and bronchial alveolar lavage fluid (BALF were elevated in a mouse of PQ-induced lung injury. DNaseI could protect PQ-induced lung injury and significantly improved survival. Acute lung injury markers, such as TNFα, IL-1β, and IL-6, and marker of fibrosis, collagen I, were downregulated in parallel with the elimination of mtDNA by DNaseI. These data indicate a possible mechanism for PQ-induced, mtDNA-mediated lung injury, which may be shared by other causes of lung injury, as suggested by the same protective effect of DNaseI in bleomycin-induced lung injury model. Interestingly, increased mtDNA in the BALF of patients with amyopathic dermatomyositis-interstitial lung disease can be appreciated. Conclusions. DNaseI targeting mtDNA may be a promising approach for the treatment of PQ-induced acute lung injury and pulmonary fibrosis that merits fast tracking through clinical trials.

  19. Metabolic fate of endogenous molecular damage: Urinary glutathione conjugates of DNA-derived base propenals as markers of inflammation

    Science.gov (United States)

    Jumpathong, Watthanachai; Chan, Wan; Taghizadeh, Koli; Babu, I. Ramesh; Dedon, Peter C.

    2015-01-01

    Although mechanistically linked to disease, cellular molecules damaged by endogenous processes have not emerged as significant biomarkers of inflammation and disease risk, due in part to poor understanding of their pharmacokinetic fate from tissue to excretion. Here, we use systematic metabolite profiling to define the fate of a common DNA oxidation product, base propenals, to discover such a biomarker. Based on known chemical reactivity and metabolism in liver cell extracts, 15 candidate metabolites were identified for liquid chromatography-coupled tandem mass spectrometry (LC-MS/MS) quantification in urine and bile of rats treated with thymine propenal (Tp). Analysis of urine revealed three metabolites (6% of Tp dose): thymine propenoate and two mercapturate derivatives of glutathione conjugates. Bile contained an additional four metabolites (22% of Tp dose): cysteinylglycine and cysteine derivatives of glutathione adducts. A bis-mercapturate was observed in urine of untreated rats and increased approximately three- to fourfold following CCl4-induced oxidative stress or treatment with the DNA-cleaving antitumor agent, bleomycin. Systematic metabolite profiling thus provides evidence for a metabolized DNA damage product as a candidate biomarker of inflammation and oxidative stress in humans. PMID:26283391

  20. Rapid, noninvasive quantitation of skin disease in systemic sclerosis using optical coherence elastography

    Science.gov (United States)

    Du, Yong; Liu, Chih-Hao; Lei, Ling; Singh, Manmohan; Li, Jiasong; Hicks, M. John; Larin, Kirill V.; Mohan, Chandra

    2016-04-01

    Systemic sclerosis (SSc) is a connective tissue disease that results in excessive accumulation of collagen in the skin and internal organs. Overall, SSc has a rare morbidity (276 cases per million adults in the United States), but has a 10-year survival rate of 55%. Currently, the modified Rodnan skin score (mRSS) is assessed by palpation on 17 sites on the body. However, the mRSS assessed score is subjective and may be influenced by the experience of the rheumatologists. In addition, the inherent elasticity of skin may bias the mRSS assessment in the early stage of SSc, such as oedematous. Optical coherence elastography (OCE) is a rapidly emerging technique, which can assess mechanical contrast in tissues with micrometer spatial resolution. In this work, the OCE technique is applied to assess the mechanical properties of skin in both control and bleomycin (BLM) induced SSc-like disease noninvasively. Young's modulus of the BLM-SSc skin was found be significantly higher than that of normal skin, in both the in vivo and in vitro studies (p<0.05). Thus, OCE is able to differentiate healthy and fibrotic skin using mechanical contrast. It is a promising new technology for quantifying skin involvement in SSc in a rapid, unbiased, and noninvasive manner.