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Sample records for mouse lung chemical

  1. Mouse lung adhesion assay for Bordetella pertussis

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    Burns, K A; Freer, J H [Department of Microbiology, Alexander Stone Building, Bearsden, Glasgow, Scotland

    1982-03-01

    The ability of Bordetella pertussis to adhere to cell surfaces has been demonstrated by adhesion to tissue culture cells and adhesion to chicken, hamster or rabbit trachea in organ culture. In this report a mouse lung assay for adhesion is described and the results obtained using two virulent strains of B. pertussis and their avirulent counterparts. These were a C modulation of one of the original virulent strains and a phase IV variant of the other virulent strain. Organisms were radiolabelled by adding 1 ..mu..Ci (37 K Bq) of (/sup 14/C)glutamic acid per 10 ml of culture medium before inoculation and incubation for 5 days. The lungs were washed by perfusion in situ with at least two volumes (1 ml) of sterile 1% (w/v) casamino acids. The percentage of the inoculated organisms retained in the lungs was determined, after removal of the lungs, by one of the following two methods: viable count or radioactive count. Results for both methods were expressed as the percentage of the inoculum retained in the lungs plus or minus one standard deviation.

  2. Mouse lung adhesion assay for Bordetella pertussis

    International Nuclear Information System (INIS)

    Burns, K.A.; Freer, J.H.

    1982-01-01

    The ability of Bordetella pertussis to adhere to cell surfaces has been demonstrated by adhesion to tissue culture cells and adhesion to chicken, hamster or rabbit trachea in organ culture. In this report a mouse lung assay for adhesion is described and the results obtained using two virulent strains of B. pertussis and their avirulent counterparts. These were a C modulation of one of the original virulent strains and a phase IV variant of the other virulent strain. Organisms were radiolabelled by adding 1 μCi (37 K Bq) of [ 14 C]glutamic acid per 10 ml of culture medium before inoculation and incubation for 5 days. The lungs were washed by perfusion in situ with at least two volumes (1 ml) of sterile 1% (w/v) casamino acids. The percentage of the inoculated organisms retained in the lungs was determined, after removal of the lungs, by one of the following two methods: viable count or radioactive count. Results for both methods were expressed as the percentage of the inoculum retained in the lungs plus or minus one standard deviation. (Auth.)

  3. Chemical Aspects of Lesser Mouse Deer Meat

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    Djalal Rosyidi

    2012-02-01

    Full Text Available An experiment aiming for studying chemical aspects of lesser mouse deer meat (Tragulus javanicus. This research explored the chemical aspects of lesser mouse deer meat (Tragulus javanicus. Eight lesser mouse deer (four female and four male were used in chemical aspects of lesser mouse deer meat. The parameters observed included proximate analysis, amino acid, fatty acid, cholesterol and EPA-DHA of the meat. The results showed that average meat chemical composition were content of water, protein, fat, ash and cholesterol were 76.33 %, 21.42 %, 0.51 %, 1.20% and 50.00 mg/100 g, respectively. Fatty acid consist of lauric acid, miristate, palmitate, stearic, oleic, linoleic, and linolenic were 1.04 % 3.09%, 30.97, 0.77%., 59.41%, 3.22% and 1.12%, respectively. The total EPA and DHA was 0.13% and 0.05%,   Keywords: amino acid, fatty acid, cholesterol and EPA-DHA

  4. Lung regeneration by fetal lung tissue implantation in a mouse pulmonary emphysema model.

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    Uyama, Koh; Sakiyama, Shoji; Yoshida, Mitsuteru; Kenzaki, Koichiro; Toba, Hiroaki; Kawakami, Yukikiyo; Okumura, Kazumasa; Takizawa, Hiromitsu; Kondo, Kazuya; Tangoku, Akira

    2016-01-01

    The mortality and morbidity of chronic obstructive pulmonary disease are high. However, no radical therapy has been developed to date. The purpose of this study was to evaluate whether fetal mouse lung tissue can grow and differentiate in the emphysematous lung. Fetal lung tissue from green fluorescent protein C57BL/6 mice at 16 days' gestation was used as donor material. Twelve-month-old pallid mice were used as recipients. Donor lungs were cut into small pieces and implanted into the recipient left lung by performing thoracotomy under anesthesia. The recipient mice were sacrificed at day 7, 14, and 28 after implantation and used for histological examination. Well-developed spontaneous pulmonary emphysema was seen in 12-month-old pallid mice. Smooth and continuous connection between implanted fetal lung tissue and recipient lung was recognized. Air space expansion and donor tissue differentiation were observed over time. We could clearly distinguish the border zones between injected tissue and native tissue by the green fluorescence of grafts. Fetal mouse lung fragments survived and differentiated in the emphysematous lung of pallid mice. Implantation of fetal lung tissue in pallid mice might lead to further lung regeneration research from the perspective of respiratory and exercise function. J. Med. Invest. 63: 182-186, August, 2016.

  5. Development of Mouse Lung Deposition Models

    Science.gov (United States)

    2015-07-01

    foot-pound-force gallon (U.S. liquid ) inch jerk joule/kilogram (J/kg) radiation dose absorbed kilotons kip (1000 lbf) kip/inch (ksi...AND PHYSIOLOGY PARAMETERS Lung ventilation is driven by the difference in pressure between the pleural space and the outside environment. The... pleural pressure 8 variation. However, lung expansion and contraction is uniform in rodents because rodents are typically positioned horizontally

  6. Methods of in-vivo mouse lung micro-CT

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    Recheis, Wolfgang A.; Nixon, Earl; Thiesse, Jacqueline; McLennan, Geoffrey; Ross, Alan; Hoffman, Eric

    2005-04-01

    Micro-CT will have a profound influence on the accumulation of anatomical and physiological phenotypic changes in natural and transgenetic mouse models. Longitudinal studies will be greatly facilitated, allowing for a more complete and accurate description of events if in-vivo studies are accomplished. The purpose of the ongoing project is to establish a feasible and reproducible setup for in-vivo mouse lung micro-computed tomography (μCT). We seek to use in-vivo respiratory-gated μCT to follow mouse models of lung disease with subsequent recovery of the mouse. Methodologies for optimizing scanning parameters and gating for the in-vivo mouse lung are presented. A Scireq flexiVent ventilated the gas-anesthetized mice at 60 breaths/minute, 30 cm H20 PEEP, 30 ml/kg tidal volume and provided a respiratory signal to gate a Skyscan 1076 μCT. Physiologic monitoring allowed the control of vital functions and quality of anesthesia, e.g. via ECG monitoring. In contrary to longer exposure times with ex-vivo scans, scan times for in-vivo were reduced using 35μm pixel size, 158ms exposure time and 18μm pixel size, 316ms exposure time to reduce motion artifacts. Gating via spontaneous breathing was also tested. Optimal contrast resolution was achieved at 50kVp, 200μA, applying an aluminum filter (0.5mm). There were minimal non-cardiac related motion artifacts. Both 35μm and 1μm voxel size images were suitable for evaluation of the airway lumen and parenchymal density. Total scan times were 30 and 65 minutes respectively. The mice recovered following scanning protocols. In-vivo lung scanning with recovery of the mouse delivered reasonable image quality for longitudinal studies, e.g. mouse asthma models. After examining 10 mice, we conclude μCT is a feasible tool evaluating mouse models of lung pathology in longitudinal studies with increasing anatomic detail available for evaluation as one moves from in-vivo to ex-vivo studies. Further developments include automated

  7. Immunohistochemical analysis of Clara cell secretory protein expression in a transgenic model of mouse lung carcinogenesis

    International Nuclear Information System (INIS)

    Hicks, Sarah M.; Vassallo, Jeffrey D.; Dieter, Matthew Z.; Lewis, Cindy L.; Whiteley, Laurence O.; Fix, Andrew S.; Lehman-McKeeman, Lois D.

    2003-01-01

    Immunohistochemical methods have been widely used to determine the histogenesis of spontaneous and chemically-induced mouse lung tumors. Typically, antigens for either alveolar Type II cells or bronchiolar epithelial Clara cells are studied. In the present work, the morphological and immunohistochemical phenotype of a transgenic mouse designed to develop lung tumors arising from Clara cells was evaluated. In this model, Clara cell-specific transformation is accomplished by directed expression of the SV40 large T antigen (TAg) under the mouse Clara cell secretory protein (CC10) promoter. In heterozygous mice, early lesions at 1 month of age consisted of hyperplastic bronchiolar epithelial cells. These progressed to adenoma by 2 months as proliferating epithelium extended into adjacent alveolar spaces. By 4 months, a large portion of the lung parenchyma was composed of tumor masses. Expression of constitutive CC10 was diminished in transgenic animals at all time points. Only the occasional cell or segment of the bronchiolar epithelium stained positively for CC10 by immunohistochemistry, and all tumors were found to be uniformly negative for staining. These results were corroborated by Western blotting, where CC10 was readily detectable in whole lung homogenate from nontransgenic animals, but not detected in lung from transgenic animals at any time point. Tumors were also examined for expression of surfactant apoprotein C (SPC), an alveolar Type II cell-specific marker, and found to be uniformly negative for staining. These results indicate that, in this transgenic model, expression of CC10, which is widely used to determine whether lung tumors arise from Clara cells, was reduced and subsequently lost during Clara cell tumor progression

  8. The Use of Chemical-Chemical Interaction and Chemical Structure to Identify New Candidate Chemicals Related to Lung Cancer.

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    Lei Chen

    Full Text Available Lung cancer causes over one million deaths every year worldwide. However, prevention and treatment methods for this serious disease are limited. The identification of new chemicals related to lung cancer may aid in disease prevention and the design of more effective treatments. This study employed a weighted network, constructed using chemical-chemical interaction information, to identify new chemicals related to two types of lung cancer: non-small lung cancer and small-cell lung cancer. Then, a randomization test as well as chemical-chemical interaction and chemical structure information were utilized to make further selections. A final analysis of these new chemicals in the context of the current literature indicates that several chemicals are strongly linked to lung cancer.

  9. The kinetics of repair in mouse lung after fractionated irradiation

    International Nuclear Information System (INIS)

    Travis, E.L.; Thames, H.D.; Watkins, T.L.; Kiss, I.

    1987-01-01

    The kinetics of repair of sublethal damage in mouse lung was studied after fractionated doses of 137 Cs γ-rays. A wide range of doses per fraction (1.7-12 Gy) was given with interfraction intervals ranging from 0.5 to 24 h. Data were analysed by a direct method of analysis using the incomplete repair model. The half-time of repair (Tsub(1/2)) was 0.76 h for the pneumonitis phase of damage (up to 8 months) and 0.65 h for the later phase of damage up to 12 months. Rate of repair was dependent on fraction size for both phases of lung damage and was faster after large dose fractions than after small fractions. Tsub(1/2) was 0.6 h (95% c.1. 0.53, 0.69) for doses per fraction greater than 5 Gy and 0.83 h (95% c.1. 0.76, 0.92) for doses per fraction of 2 Gy. Repair was nearly complete by 6 h at least for the pneumonitis phase of damage. If extrapolated to humans, these results imply that treatments with multiple fractions per day involving the lung will not be limited by the necessity for interfraction intervals much longer than 6 h. (author)

  10. Morphological Lesions in Mouse Liver and Lungs After Lung Exposure to Carbon Nanotubes

    DEFF Research Database (Denmark)

    Szarek, J.; Mortensen, Alicja; Jackson, P.

    2013-01-01

    Introduction: Engineered nanoparticles are smaller than 100 nm in at least one direction and designed to improve or achieve new physicochemical properties. Consequently, toxicological properties may also change. Carbon nanotubes have attracted industrial interest due to their unique properties....... Materials and Methods: One day before mating, 30 mice (C57BL/6BomTac, Taconic Europe, Denmark) were given 67 μg multi-walled carbon nanotubes (NM-400, Nanocyl, Belgium) intratracheally (group A). A further 30 control mice (group B) received vehicle (Millipore water with 2% mouse serum). Lungs and liver were...... taken from six animals from each group for histopathological examination (haematoxylin and eosin staining) 6 weeks (A1, B1 group) and 4 months (A2, B2) after exposure. Results: Lungs in A1 mice showed bronchiolar subepithelial oedema and perivascular oedema and sporadic hyperaemia and the presence...

  11. Multi-walled carbon nanotube-induced gene expression in the mouse lung: Association with lung pathology

    International Nuclear Information System (INIS)

    Pacurari, M.; Qian, Y.; Porter, D.W.; Wolfarth, M.; Wan, Y.; Luo, D.; Ding, M.; Castranova, V.; Guo, N.L.

    2011-01-01

    Due to the fibrous shape and durability of multi-walled carbon nanotubes (MWCNT), concerns regarding their potential for producing environmental and human health risks, including carcinogenesis, have been raised. This study sought to investigate how previously identified lung cancer prognostic biomarkers and the related cancer signaling pathways are affected in the mouse lung following pharyngeal aspiration of well-dispersed MWCNT. A total of 63 identified lung cancer prognostic biomarker genes and major signaling biomarker genes were analyzed in mouse lungs (n = 80) exposed to 0, 10, 20, 40, or 80 μg of MWCNT by pharyngeal aspiration at 7 and 56 days post-exposure using quantitative PCR assays. At 7 and 56 days post-exposure, a set of 7 genes and a set of 11 genes, respectively, showed differential expression in the lungs of mice exposed to MWCNT vs. the control group. Additionally, these significant genes could separate the control group from the treated group over the time series in a hierarchical gene clustering analysis. Furthermore, 4 genes from these two sets of significant genes, coiled-coil domain containing-99 (Ccdc99), muscle segment homeobox gene-2 (Msx2), nitric oxide synthase-2 (Nos2), and wingless-type inhibitory factor-1 (Wif1), showed significant mRNA expression perturbations at both time points. It was also found that the expression changes of these 4 overlapping genes at 7 days post-exposure were attenuated at 56 days post-exposure. Ingenuity Pathway Analysis (IPA) found that several carcinogenic-related signaling pathways and carcinogenesis itself were associated with both the 7 and 11 gene signatures. Taken together, this study identifies that MWCNT exposure affects a subset of lung cancer biomarkers in mouse lungs. - Research highlights: → Multi-Walled Carbon Nanotubes affect lung cancer biomarkers in mouse lungs. → The results suggest potentially harmful effects of MWCNT exposure on human lungs. → The results could potentially be used

  12. Urinary volatile compounds as biomarkers for lung cancer: a proof of principle study using odor signatures in mouse models of lung cancer.

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    Koichi Matsumura

    2010-01-01

    Full Text Available A potential strategy for diagnosing lung cancer, the leading cause of cancer-related death, is to identify metabolic signatures (biomarkers of the disease. Although data supports the hypothesis that volatile compounds can be detected in the breath of lung cancer patients by the sense of smell or through bioanalytical techniques, analysis of breath samples is cumbersome and technically challenging, thus limiting its applicability. The hypothesis explored here is that variations in small molecular weight volatile organic compounds ("odorants" in urine could be used as biomarkers for lung cancer. To demonstrate the presence and chemical structures of volatile biomarkers, we studied mouse olfactory-guided behavior and metabolomics of volatile constituents of urine. Sensor mice could be trained to discriminate between odors of mice with and without experimental tumors demonstrating that volatile odorants are sufficient to identify tumor-bearing mice. Consistent with this result, chemical analyses of urinary volatiles demonstrated that the amounts of several compounds were dramatically different between tumor and control mice. Using principal component analysis and supervised machine-learning, we accurately discriminated between tumor and control groups, a result that was cross validated with novel test groups. Although there were shared differences between experimental and control animals in the two tumor models, we also found chemical differences between these models, demonstrating tumor-based specificity. The success of these studies provides a novel proof-of-principle demonstration of lung tumor diagnosis through urinary volatile odorants. This work should provide an impetus for similar searches for volatile diagnostic biomarkers in the urine of human lung cancer patients.

  13. Modulation of epithelial sodium channel (ENaC expression in mouse lung infected with Pseudomonas aeruginosa

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    Radzioch Danuta

    2005-01-01

    Full Text Available Abstract Background The intratracheal instillation of Pseudomonas aeruginosa entrapped in agar beads in the mouse lung leads to chronic lung infection in susceptible mouse strains. As the infection generates a strong inflammatory response with some lung edema, we tested if it could modulate the expression of genes involved in lung liquid clearance, such as the α, β and γ subunits of the epithelial sodium channel (ENaC and the catalytic subunit of Na+-K+-ATPase. Methods Pseudomonas aeruginosa entrapped in agar beads were instilled in the lung of resistant (BalB/c and susceptible (DBA/2, C57BL/6 and A/J mouse strains. The mRNA expression of ENaC and Na+-K+-ATPase subunits was tested in the lung by Northern blot following a 3 hours to 14 days infection. Results The infection of the different mouse strains evoked regulation of α and β ENaC mRNA. Following Pseudomonas instillation, the expression of αENaC mRNA decreased to a median of 43% on days 3 and 7 after infection and was still decreased to a median of 45% 14 days after infection (p 1Na+-K+-ATPase mRNA, the catalytic subunit of the sodium pump, was recorded. The distinctive expression profiles of the three subunits were not different, between the susceptible and resistant mouse strains. Conclusions These results show that Pseudomonas infection, by modulating ENaC subunit expression, could influence edema formation and clearance in infected lungs.

  14. Lessons learned using different mouse models during space radiation-induced lung tumorigenesis experiments.

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    Wang, Jian; Zhang, Xiangming; Wang, Ping; Wang, Xiang; Farris, Alton B; Wang, Ya

    2016-06-01

    Unlike terrestrial ionizing radiation, space radiation, especially galactic cosmic rays (GCR), contains high energy charged (HZE) particles with high linear energy transfer (LET). Due to a lack of epidemiologic data for high-LET radiation exposure, it is highly uncertain how high the carcinogenesis risk is for astronauts following exposure to space radiation during space missions. Therefore, using mouse models is necessary to evaluate the risk of space radiation-induced tumorigenesis; however, which mouse model is better for these studies remains uncertain. Since lung tumorigenesis is the leading cause of cancer death among both men and women, and low-LET radiation exposure increases human lung carcinogenesis, evaluating space radiation-induced lung tumorigenesis is critical to enable safe Mars missions. Here, by comparing lung tumorigenesis obtained from different mouse strains, as well as miR-21 in lung tissue/tumors and serum, we believe that wild type mice with a low spontaneous tumorigenesis background are ideal for evaluating the risk of space radiation-induced lung tumorigenesis, and circulating miR-21 from such mice model might be used as a biomarker for predicting the risk. Copyright © 2016 The Committee on Space Research (COSPAR). Published by Elsevier Ltd. All rights reserved.

  15. Lessons learned using different mouse models during space radiation-induced lung tumorigenesis experiments

    Science.gov (United States)

    Wang, Jian; Zhang, Xiangming; Wang, Ping; Wang, Xiang; Farris, Alton B.; Wang, Ya

    2016-06-01

    Unlike terrestrial ionizing radiation, space radiation, especially galactic cosmic rays (GCR), contains high energy charged (HZE) particles with high linear energy transfer (LET). Due to a lack of epidemiologic data for high-LET radiation exposure, it is highly uncertain how high the carcinogenesis risk is for astronauts following exposure to space radiation during space missions. Therefore, using mouse models is necessary to evaluate the risk of space radiation-induced tumorigenesis; however, which mouse model is better for these studies remains uncertain. Since lung tumorigenesis is the leading cause of cancer death among both men and women, and low-LET radiation exposure increases human lung carcinogenesis, evaluating space radiation-induced lung tumorigenesis is critical to enable safe Mars missions. Here, by comparing lung tumorigenesis obtained from different mouse strains, as well as miR-21 in lung tissue/tumors and serum, we believe that wild type mice with a low spontaneous tumorigenesis background are ideal for evaluating the risk of space radiation-induced lung tumorigenesis, and circulating miR-21 from such mice model might be used as a biomarker for predicting the risk.

  16. Novel mouse model of chronic Pseudomonas aeruginosa lung infection mimicking cystic fibrosis

    DEFF Research Database (Denmark)

    Hoffmann, Nadine; Rasmussen, Thomas Bovbjerg; Jensen, Peter Østrup

    2005-01-01

    (NH57388C) from the mucoid isolate (NH57388A) and a nonmucoid isolate (NH57388B) deficient in AHL were almost cleared from the lungs of the mice. This model, in which P. aeruginosa is protected against the defense system of the lung by alginate, is similar to the clinical situation. Therefore...... pulmonary mouse model without artificial embedding. The model is based on a stable mucoid CF sputum isolate (NH57388A) with hyperproduction of alginate due to a deletion in mucA and functional N-acylhomoserine lactone (AHL)-based quorum-sensing systems. Chronic lung infection could be established in both CF...

  17. SPECT/CT of lung nodules using 111In-DOTA-c(RGDfK) in a mouse lung carcinogenesis model.

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    Hayakawa, Takuya; Mutoh, Michihiro; Imai, Toshio; Tsuta, Koji; Yanaka, Akinori; Fujii, Hirofumi; Yoshimoto, Mitsuyoshi

    2013-08-01

    Lung cancer is one of the leading causes of cancer-related deaths worldwide, including Japan. Although computed tomography (CT) can detect small lung lesions such as those appearing as ground glass opacity, it cannot differentiate between malignant and non-malignant lesions. Previously, we have shown that single photon emission computed tomography (SPECT) imaging using (111)In-1,4,7,10-tetraazacyclododecane-N,N',N'',N'''-tetraacetic acid-cyclo-(Arg-Gly-Asp-D-Phe-Lys) (DOTA-c(RGDfK)), an imaging probe of αvβ3 integrin, is useful for the early detection of pancreatic cancer in a hamster pancreatic carcinogenesis model. In this study, we aimed to assess the usefulness of SPECT/CT with (111)In-DOTA-c(RGDfK) for the evaluation of the malignancy of lung cancer. Lung tumors were induced by a single intraperitoneal injection (250 mg/kg) of urethane in male A/J mice. Twenty-six weeks after the urethane treatment, SPECT was performed an hour after injection of (111)In-DOTA-c(RGDfK). Following this, the radioactivity ratios of tumor to normal lung tissue were measured by autoradiography (ARG) in the excised lung samples. We also examined the expression of αvβ3 integrin in mouse and human lung samples. Urethane treatment induced 5 hyperplasias, 41 adenomas and 12 adenocarcinomas in the lungs of 8 A/J mice. SPECT with (111)In-DOTA-c(RGDfK) could clearly visualize lung nodules, though we failed to detect small lung nodules like adenoma and hyperplasias (adenocarcinoma: 66.7%, adenoma: 33.6%, hyperplasia: 0.0%). ARG analysis revealed significant uptake of (111)In-DOTA-c(RGDfK) in all the lesions. Moreover, tumor to normal lung tissue ratios increased along with the progression of carcinogenesis. Histopathological examination using human lung tissue samples revealed clear up-regulation of αvβ3 integrin in well-differentiated adenocarcinoma (Noguchi type B and C) rather than atypical adenomatous hyperplasia. Although there are some limitations in evaluating the malignancy of

  18. Mouse lung contains endothelial progenitors with high capacity to form blood and lymphatic vessels

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    Barleon Bernhard

    2010-07-01

    Full Text Available Abstract Background Postnatal endothelial progenitor cells (EPCs have been successfully isolated from whole bone marrow, blood and the walls of conduit vessels. They can, therefore, be classified into circulating and resident progenitor cells. The differentiation capacity of resident lung endothelial progenitor cells from mouse has not been evaluated. Results In an attempt to isolate differentiated mature endothelial cells from mouse lung we found that the lung contains EPCs with a high vasculogenic capacity and capability of de novo vasculogenesis for blood and lymph vessels. Mouse lung microvascular endothelial cells (MLMVECs were isolated by selection of CD31+ cells. Whereas the majority of the CD31+ cells did not divide, some scattered cells started to proliferate giving rise to large colonies (> 3000 cells/colony. These highly dividing cells possess the capacity to integrate into various types of vessels including blood and lymph vessels unveiling the existence of local microvascular endothelial progenitor cells (LMEPCs in adult mouse lung. EPCs could be amplified > passage 30 and still expressed panendothelial markers as well as the progenitor cell antigens, but not antigens for immune cells and hematopoietic stem cells. A high percentage of these cells are also positive for Lyve1, Prox1, podoplanin and VEGFR-3 indicating that a considerabe fraction of the cells are committed to develop lymphatic endothelium. Clonogenic highly proliferating cells from limiting dilution assays were also bipotent. Combined in vitro and in vivo spheroid and matrigel assays revealed that these EPCs exhibit vasculogenic capacity by forming functional blood and lymph vessels. Conclusion The lung contains large numbers of EPCs that display commitment for both types of vessels, suggesting that lung blood and lymphatic endothelial cells are derived from a single progenitor cell.

  19. Synchrotron microradiography study on acute lung injury of mouse caused by PM2.5 aerosols

    International Nuclear Information System (INIS)

    Tong Yongpeng; Zhang Guilin; Li Yan; Tan Mingguan; Wang Wei; Chen Jianmin; Hwu Yeukuang; Hsu, Pei-Chebg; Je, Jung Ho; Margaritondo, Giorgio; Song Weiming; Jiang, Rongfang; Jiang Zhihai

    2006-01-01

    In order to investigate FeSO 4 , ZnSO 4 (the two of main metal compositions of Shanghai PM 2.5 (particle matter with those aerodynamical diameter 2.5 aerosol particles, FeSO 4 , ZnSO 4 and their mixtures were instilled intratracheally into mouse lungs for experiment. By 2 days after instillation, the live mice were checked in vivo by synchrotron refractive index microradiography. In addition after extracted and examined by dissection, the right lobes of lung were fixed by formalin, then imaged by synchrotron microradiography again. Corresponding parts of those lung tissues were embedded in paraffin for histopathologic study. The synchrotron X-ray microradiographs of live mouse lung showed different lung texture changes after instilled with different toxic solutions. Hemorrhage points in lung were observed more from those mice instilled by FeSO 4 contained toxin solutions groups. Bronchial epithelial hyperplasia can be observed in ZnSO 4 contained solution-instilled groups from histopathologic analysis. It was found that the acute lung injury of mice caused by solution of PM 2.5 + FeSO 4 + ZnSO 4 was more serious than other toxin solutions. Results suggested that FeSO 4 mainly induced hemorrhage and ZnSO 4 mainly induced inflammation and bronchiolar epithelial hyperplasia in the early toxicological effects of PM 2.5

  20. Morphological analysis of mouse lungs after treatment with magnetite-based magnetic fluid stabilized with DMSA

    International Nuclear Information System (INIS)

    Pereira Garcia, Monica; Miranda Parca, Renata; Braun Chaves, Sacha; Paulino Silva, Luciano; Djalma Santos, Antonio; Guerrero Marques Lacava, Zulmira; Cesar Morais, Paulo; Azevedo, Ricardo Bentes

    2005-01-01

    Mouse lungs injected with magnetic fluids based on magnetite nanoparticles stabilized by 2,3-dimercaptosuccinic acid were studied. We observed clusters of magnetic nanoparticles inside blood vessels, within the organ parenchyma and cells, as well as increased numbers of leukocytes in the organ. Both the particle concentration and organ inflammation diminished in a time-dependent manner

  1. Inhibition of Pyk2 blocks lung inflammation and injury in a mouse model of acute lung injury

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    Duan Yingli

    2012-01-01

    Full Text Available Abstract Background Proline-rich tyrosine kinase 2 (Pyk2 is essential in neutrophil degranulation and chemotaxis in vitro. However, its effect on the process of lung inflammation and edema formation during LPS induced acute lung injury (ALI remains unknown. The goal of the present study was to determine the effect of inhibiting Pyk2 on LPS-induced acute lung inflammation and injury in vivo. Methods C57BL6 mice were given either 10 mg/kg LPS or saline intratracheally. Inhibition of Pyk2 was effected by intraperitoneal administration TAT-Pyk2-CT 1 h before challenge. Bronchoalveolar lavage analysis of cell counts, lung histology and protein concentration in BAL were analyzed at 18 h after LPS treatment. KC and MIP-2 concentrations in BAL were measured by a mouse cytokine multiplex kit. The static lung compliance was determined by pressure-volume curve using a computer-controlled small animal ventilator. The extravasated Evans blue concentration in lung homogenate was determined spectrophotometrically. Results Intratracheal instillation of LPS induced significant neutrophil infiltration into the lung interstitium and alveolar space, which was attenuated by pre-treatment with TAT-Pyk2-CT. TAT-Pyk2-CT pretreatment also attenuated 1 myeloperoxidase content in lung tissues, 2 vascular leakage as measured by Evans blue dye extravasation in the lungs and the increase in protein concentration in bronchoalveolar lavage, and 3 the decrease in lung compliance. In each paradigm, treatment with control protein TAT-GFP had no blocking effect. By contrast, production of neutrophil chemokines MIP-2 and keratinocyte-derived chemokine in the bronchoalveolar lavage was not reduced by TAT-Pyk2-CT. Western blot analysis confirmed that tyrosine phosphorylation of Pyk2 in LPS-challenged lungs was reduced to control levels by TAT-Pyk2-CT pretreatment. Conclusions These results suggest that Pyk2 plays an important role in the development of acute lung injury in mice and

  2. Chemical clearing and dehydration of GFP expressing mouse brains.

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    Klaus Becker

    Full Text Available Generally, chemical tissue clearing is performed by a solution consisting of two parts benzyl benzoate and one part benzyl alcohol. However, prolonged exposure to this mixture markedly reduces the fluorescence of GFP expressing specimens, so that one has to compromise between clearing quality and fluorescence preservation. This can be a severe drawback when working with specimens exhibiting low GFP expression rates. Thus, we screened for a substitute and found that dibenzyl ether (phenylmethoxymethylbenzene, CAS 103-50-4 can be applied as a more GFP-friendly clearing medium. Clearing with dibenzyl ether provides improved tissue transparency and strikingly improved fluorescence intensity in GFP expressing mouse brains and other samples as mouse spinal cords, or embryos. Chemical clearing, staining, and embedding of biological samples mostly requires careful foregoing tissue dehydration. The commonly applied tissue dehydration medium is ethanol, which also can markedly impair GFP fluorescence. Screening for a substitute also for ethanol we found that tetrahydrofuran (CAS 109-99-9 is a more GFP-friendly dehydration medium than ethanol, providing better tissue transparency obtained by successive clearing. Combined, tetrahydrofuran and dibenzyl ether allow dehydration and chemical clearing of even delicate samples for UM, confocal microscopy, and other microscopy techniques.

  3. Chemical clearing and dehydration of GFP expressing mouse brains.

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    Becker, Klaus; Jährling, Nina; Saghafi, Saiedeh; Weiler, Reto; Dodt, Hans-Ulrich

    2012-01-01

    Generally, chemical tissue clearing is performed by a solution consisting of two parts benzyl benzoate and one part benzyl alcohol. However, prolonged exposure to this mixture markedly reduces the fluorescence of GFP expressing specimens, so that one has to compromise between clearing quality and fluorescence preservation. This can be a severe drawback when working with specimens exhibiting low GFP expression rates. Thus, we screened for a substitute and found that dibenzyl ether (phenylmethoxymethylbenzene, CAS 103-50-4) can be applied as a more GFP-friendly clearing medium. Clearing with dibenzyl ether provides improved tissue transparency and strikingly improved fluorescence intensity in GFP expressing mouse brains and other samples as mouse spinal cords, or embryos. Chemical clearing, staining, and embedding of biological samples mostly requires careful foregoing tissue dehydration. The commonly applied tissue dehydration medium is ethanol, which also can markedly impair GFP fluorescence. Screening for a substitute also for ethanol we found that tetrahydrofuran (CAS 109-99-9) is a more GFP-friendly dehydration medium than ethanol, providing better tissue transparency obtained by successive clearing. Combined, tetrahydrofuran and dibenzyl ether allow dehydration and chemical clearing of even delicate samples for UM, confocal microscopy, and other microscopy techniques.

  4. Genotoxicity of 3-nitrobenzanthrone and 3-aminobenzanthrone in MutaMouse and lung epithelial cells derived from MutaMouse.

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    Arlt, Volker M; Gingerich, John; Schmeiser, Heinz H; Phillips, David H; Douglas, George R; White, Paul A

    2008-11-01

    FE1 lung epithelial cells derived from MutaMouse are a new model system to provide in vitro mutagenicity data with the potential to predict the outcome of an in vivo MutaMouse test. 3-Nitrobenzanthrone (3-NBA) is a potent mutagen and suspected human carcinogen identified in diesel exhaust and urban air pollution. We investigated the mutagenicity and DNA binding of 3-NBA and its main metabolite 3-aminobenzanthrone (3-ABA) in vitro and in vivo in the MutaMouse assay. Mice were treated with 3-NBA or 3-ABA (0, 2 or 5 mg/kg body weight/day) by gavage for 28 days and 28 days later lacZ mutant frequency (MF) was determined in liver, lung and bone marrow. For both compounds, dose-related increases in MF were seen in liver and bone marrow, but not in lung; mutagenic activity was approximately 2-fold lower for 3-ABA than for 3-NBA. With 3-NBA, highest DNA adduct levels (measured by (32)P-post-labelling) were found in liver (approximately 230 adducts per 10(8) nucleotides) with levels 20- to 40-fold lower in bone marrow and lung. With 3-ABA, DNA adduct levels were again highest in the liver, but approximately 4-fold lower than for 3-NBA. FE1 cells were exposed to up to 10 microg/ml 3-NBA or 3-ABA for 6 h with or without exogenous activation (S9) and harvested after 3 days. For 3-NBA, there was a dose-related increase in MF both with and without S9 mix, which was >10 times higher than observed in vivo. At the highest concentration of 3-ABA (10 microg/ml), we found only around a 2-fold increase in MF relative to controls. DNA adduct formation in FE1 cells was dose-dependent for both compounds, but 10- to 20-fold higher for 3-NBA compared to 3-ABA. Collectively, our data indicate that MutaMouse FE1 cells are well suited for cost-effective testing of suspected mutagens with different metabolic activation pathways as a guide for subsequent in vivo MutaMouse testing.

  5. Failure of catalase to protect against aflatoxin B1-induced mouse lung tumorigenicity

    International Nuclear Information System (INIS)

    Guindon, Katherine A.; Foley, Julie F.; Maronpot, Robert R.; Massey, Thomas E.

    2008-01-01

    The carcinogenic mycotoxin aflatoxin B 1 (AFB 1 ) induces 8-hydroxy-2'-deoxyguanosine (8-OHdG) formation in mouse lung, an effect that can be prevented by treatment with polyethylene glycol-conjugated catalase (PEG-CAT). G → T transversion mutation in K-ras, an early event in AFB 1 -induced mouse lung carcinogenesis, is thought to result from AFB 1 -8,9-exo-epoxide binding to DNA to form AFB 1 -N 7 -guanine, but may also result from formation of 8-OHdG. Therefore, oxidative DNA damage may be important in AFB 1 carcinogenicity. The objective of this study was to determine whether PEG-CAT would prevent AFB 1 tumorigenicity. Mouse lung tumorigenesis was assessed following treatment of female A/J mice with 300 kU/kg PEG-CAT ip and/or 50 mg/kg AFB 1 . Mice were killed 7 months post-treatment and tumors greater than 1 mm in diameter were excised. Unexpectedly, the mean number of tumors per mouse in the PEG-CAT + AFB 1 group (8.81 ± 3.64, n = 47) was greater than that of the group treated with AFB 1 alone (7.05 ± 3.45, n = 42) (P 1 were larger than those from mice treated with AFB 1 alone (P 1 and PEG-CAT + AFB 1 groups (P > 0.05). In vitro incubation with mouse liver catalase (CAT) resulted in conversion of [ 3 H]AFB 1 into a DNA-binding species, a possible explanation for the results observed in vivo. These results demonstrate that PEG-CAT is not protective against AFB 1 carcinogenicity in mouse lung despite preventing DNA oxidation

  6. A human lung xenograft mouse model of Nipah virus infection.

    Directory of Open Access Journals (Sweden)

    Gustavo Valbuena

    2014-04-01

    Full Text Available Nipah virus (NiV is a member of the genus Henipavirus (family Paramyxoviridae that causes severe and often lethal respiratory illness and encephalitis in humans with high mortality rates (up to 92%. NiV can cause Acute Lung Injury (ALI in humans, and human-to-human transmission has been observed in recent outbreaks of NiV. While the exact route of transmission to humans is not known, we have previously shown that NiV can efficiently infect human respiratory epithelial cells. The molecular mechanisms of NiV-associated ALI in the human respiratory tract are unknown. Thus, there is an urgent need for models of henipavirus infection of the human respiratory tract to study the pathogenesis and understand the host responses. Here, we describe a novel human lung xenograft model in mice to study the pathogenesis of NiV. Following transplantation, human fetal lung xenografts rapidly graft and develop mature structures of adult lungs including cartilage, vascular vessels, ciliated pseudostratified columnar epithelium, and primitive "air" spaces filled with mucus and lined by cuboidal to flat epithelium. Following infection, NiV grows to high titers (10(7 TCID50/gram lung tissue as early as 3 days post infection (pi. NiV targets both the endothelium as well as respiratory epithelium in the human lung tissues, and results in syncytia formation. NiV infection in the human lung results in the production of several cytokines and chemokines including IL-6, IP-10, eotaxin, G-CSF and GM-CSF on days 5 and 7 pi. In conclusion, this study demonstrates that NiV can replicate to high titers in a novel in vivo model of the human respiratory tract, resulting in a robust inflammatory response, which is known to be associated with ALI. This model will facilitate progress in the fundamental understanding of henipavirus pathogenesis and virus-host interactions; it will also provide biologically relevant models for other respiratory viruses.

  7. TH-E-BRF-07: Raman Spectroscopy for Radiation Treatment Response Assessment in a Lung Metastases Mouse Model

    International Nuclear Information System (INIS)

    Devpura, S; Barton, K; Brown, S; Siddiqui, F; Chetty, I; Sethi, S; Klein, M

    2014-01-01

    Purpose: Raman spectroscopy is an optical spectroscopic method used to probe chemical information about a target tissue. Our goal was to investigate whether Raman spectroscopy is able to distinguish lung tumors from normal lung tissue and whether this technique can identify the molecular changes induced by radiation. Methods: 4T1 mouse breast cancer cells were implanted subcutaneously into the flanks of 6 Balb/C female mice. Four additional mice were used as “normal lung” controls. After 14 days, 3 mice bearing tumors received 6Gy to the left lung with 6MV photons and the other three were treated as “unirradiated tumor” controls. At a 24-hour time point, lungs were excised and the specimens were sectioned using a cryostat; alternating sections were either stained with hematoxylin and eosin (H and E) for evaluation by a pathologist or unstained for Raman measurements. 240 total Raman spectra were collected; 84 from normal lung controls; 63 from unirradiated tumors and 64 from tumors irradiated with 6Gy in a single fraction. Raman spectra were also collected from normal lung tissues of mice with unirradiated tumors. Principal component analysis (PCA) and discriminant function analysis (DFA) were performed to analyze the data. Results: Raman bands assignable to DNA/RNA showed prominent contributions in tumor tissues while Raman bands associated with hemoglobin showed strong contributions in normal lung tissue. PCA/DFA analysis identified normal lung tissue and tumor with 100% and 98.4% accuracy, respectively, relative to pathologic scoring. Additionally, normal lung tissues from unirradiated mice bearing tumors were classified as normal with 100% accuracy. In a model consisting of unirradiated and irradiated tumors identification accuracy was 79.4% and 93.8% respectively, relative to pathologic assessment. Conclusion: Initial results demonstrate the promise for Raman spectroscopy in the diagnosis normal vs. lung metastases as well as the assessment of

  8. TH-E-BRF-07: Raman Spectroscopy for Radiation Treatment Response Assessment in a Lung Metastases Mouse Model

    Energy Technology Data Exchange (ETDEWEB)

    Devpura, S; Barton, K; Brown, S; Siddiqui, F; Chetty, I [Henry Ford Health System, Detroit, MI (United States); Sethi, S [Karmanos Cancer Center, Detroit, MI (United States); Klein, M [Children' s Hospital of Michigan, Detroit, MI (United States)

    2014-06-15

    Purpose: Raman spectroscopy is an optical spectroscopic method used to probe chemical information about a target tissue. Our goal was to investigate whether Raman spectroscopy is able to distinguish lung tumors from normal lung tissue and whether this technique can identify the molecular changes induced by radiation. Methods: 4T1 mouse breast cancer cells were implanted subcutaneously into the flanks of 6 Balb/C female mice. Four additional mice were used as “normal lung” controls. After 14 days, 3 mice bearing tumors received 6Gy to the left lung with 6MV photons and the other three were treated as “unirradiated tumor” controls. At a 24-hour time point, lungs were excised and the specimens were sectioned using a cryostat; alternating sections were either stained with hematoxylin and eosin (H and E) for evaluation by a pathologist or unstained for Raman measurements. 240 total Raman spectra were collected; 84 from normal lung controls; 63 from unirradiated tumors and 64 from tumors irradiated with 6Gy in a single fraction. Raman spectra were also collected from normal lung tissues of mice with unirradiated tumors. Principal component analysis (PCA) and discriminant function analysis (DFA) were performed to analyze the data. Results: Raman bands assignable to DNA/RNA showed prominent contributions in tumor tissues while Raman bands associated with hemoglobin showed strong contributions in normal lung tissue. PCA/DFA analysis identified normal lung tissue and tumor with 100% and 98.4% accuracy, respectively, relative to pathologic scoring. Additionally, normal lung tissues from unirradiated mice bearing tumors were classified as normal with 100% accuracy. In a model consisting of unirradiated and irradiated tumors identification accuracy was 79.4% and 93.8% respectively, relative to pathologic assessment. Conclusion: Initial results demonstrate the promise for Raman spectroscopy in the diagnosis normal vs. lung metastases as well as the assessment of

  9. Alcohol Exposure Alters Mouse Lung Inflammation in Response to Inhaled Dust

    Directory of Open Access Journals (Sweden)

    Jill A. Poole

    2012-07-01

    Full Text Available Alcohol exposure is associated with increased lung infections and decreased mucociliary clearance. Occupational workers exposed to dusts from concentrated animal feeding operations (CAFOs are at risk for developing chronic inflammatory lung diseases. Agricultural worker co-exposure to alcohol and organic dust has been established, although little research has been conducted on the combination effects of alcohol and organic dusts on the lung. Previously, we have shown in a mouse model that exposure to hog dust extract (HDE collected from a CAFO results in the activation of protein kinase C (PKC, elevated lavage fluid cytokines/chemokines including interleukin-6 (IL-6, and the development of significant lung pathology. Because alcohol blocks airway epithelial cell release of IL-6 in vitro, we hypothesized that alcohol exposure would alter mouse lung inflammatory responses to HDE. To test this hypothesis, C57BL/6 mice were fed 20% alcohol or water ad libitum for 6 weeks and treated with 12.5% HDE by intranasal inhalation method daily during the final three weeks. Bronchoalveolar lavage fluid (BALF, tracheas and lungs were collected. HDE stimulated a 2–4 fold increase in lung and tracheal PKCε (epsilon activity in mice, but no such increase in PKCε activity was observed in dust-exposed mice fed alcohol. Similarly, alcohol-fed mice demonstrated significantly less IL-6 in lung lavage in response to dust than that observed in control mice instilled with HDE. TNFα levels were also inhibited in the alcohol and HDE-exposed mouse lung tissue as compared to the HDE only exposed group. HDE-induced lung inflammatory aggregates clearly present in the tissue from HDE only exposed animals were not visually detectable in the HDE/alcohol co-exposure group. Statistically significant weight reductions and 20% mortality were also observed in the mice co-exposed to HDE and alcohol. These data suggest that alcohol exposure depresses the ability

  10. Cadmium stimulates myofibroblast differentiation and mouse lung fibrosis

    International Nuclear Information System (INIS)

    Hu, Xin; Fernandes, Jolyn; Jones, Dean P.; Go, Young-Mi

    2017-01-01

    Highlights: • Low-dose Cd stimulates differentiation of human lung fibroblast to myofibroblast. • Cd-stimulated fibrosis signaling involves activation of SMAD transcription factor. • Low-dose Cd intake in mice activates myofibroblast differentiation. - Abstract: Increasing evidence suggests that Cd at levels found in the human diet can cause oxidative stress and activate redox-sensitive transcription factors in inflammatory signaling. Following inflammation, tissue repair often involves activation of redox-sensitive transcription factors in fibroblasts. In lungs, epithelial barrier remodeling is required to restore gas exchange and barrier function, and aberrant myofibroblast differentiation leads to pulmonary fibrosis. Contributions of exogenous exposures, such as dietary Cd, to pulmonary fibrosis remain inCompletely defined. In the current study, we tested whether Cd activates fibrotic signaling in human fetal lung fibroblasts (HFLF) at micromolar and submicromolar Cd concentrations that do not cause cell death. Exposure of HFLF to low-dose Cd (≤1.0 μM) caused an increase in stress fibers and increased protein levels of myofibroblast differentiation markers, including α-smooth muscle actin (α-SMA) and extra-domain-A-containing fibronectin (ED-A-FN). Assay of transcription factor (TF) activity using a 45-TF array showed that Cd increased activity of 12 TF, including SMAD2/3/4 (mothers against decapentaplegic homolog) signaling differentiation and fibrosis. Results were confirmed by real-time PCR and supported by increased expression of target genes of SMAD2/3/4. Immunocytochemistry of lungs of mice exposed to low-dose Cd (0.3 and 1.0 mg/L in drinking water) showed increased α-SMA protein level with lung Cd accumulation similar to lung Cd in non-smoking humans. Together, the results show that relatively low Cd exposures stimulate pulmonary fibrotic signaling and myofibroblast differentiation by activating SMAD2/3/4-dependent signaling. The results

  11. Development of a metastatic fluorescent Lewis Lung carcinoma mouse model

    DEFF Research Database (Denmark)

    Rask, Lene; Fregil, Marianne; Høgdall, Estrid

    2013-01-01

    Cancer metastasis is the foremost cause of death in cancer patients. A series of observable pathological changes takes place during progression and metastasis of cancer, but the underlying genetic changes remain unclear. Therefore, new approaches are required, including insights from cancer mouse...... and the model is well suited for the identification of novel microRNAs and mRNAs involved in malignant progression. Our results suggest that increases in metalloproteinase expression and impairment of microRNA processing are involved in the acquirement of metastatic ability....

  12. E-cigarette smoke damages DNA and reduces repair activity in mouse lung, heart, and bladder as well as in human lung and bladder cells

    OpenAIRE

    Lee, Hyun-Wook; Park, Sung-Hyun; Weng, Mao-wen; Wang, Hsiang-Tsui; Huang, William C.; Lepor, Herbert; Wu, Xue-Ru; Chen, Lung-Chi; Tang, Moon-shong

    2018-01-01

    Significance E-cigarette smoke (ECS) delivers nicotine through aerosols without burning tobacco. ECS is promoted as noncarcinogenic. We found that ECS induces DNA damage in mouse lung, bladder, and heart and reduces DNA-repair functions and proteins in lung. Nicotine and its nitrosation product 4-(methylnitrosamine)-1-(3-pyridyl)-1-butanone can cause the same effects as ECS and enhance mutations and tumorigenic cell transformation in cultured human lung and bladder cells. These results indica...

  13. High Frequency of Interactions between Lung Cancer Susceptibility Genes in the Mouse : Mapping of Sluc5 to Sluc14

    NARCIS (Netherlands)

    Fijneman, Remond J.A.; Jansen, Ritsert C.; Valk, Martin A. van der; Demant, Peter

    1998-01-01

    Although several genes that cause monogenic familial cancer syndromes have been identified, susceptibility to sporadic cancer remains unresolved. Animal experiments have demonstrated multigenic control of tumor susceptibility. Recently, we described four mouse lung cancer susceptibility (Sluc) loci,

  14. Lipopolysaccharide does not alter small airway reactivity in mouse lung slices.

    Science.gov (United States)

    Donovan, Chantal; Royce, Simon G; Vlahos, Ross; Bourke, Jane E

    2015-01-01

    The bacterial endotoxin, lipopolysaccharide (LPS) has been associated with occupational airway diseases with asthma-like symptoms and in acute exacerbations of COPD. The direct and indirect effects of LPS on small airway reactivity have not been fully elucidated. We tested the hypothesis that both in vitro and in vivo LPS treatment would increase contraction and impair relaxation of mouse small airways. Lung slices were prepared from naïve Balb/C mice and cultured in the absence or presence of LPS (10 μg/ml) for up to 48 h for measurement of TNFα levels in conditioned media. Alternatively, mice were challenged with PBS or LPS in vivo once a day for 4 days for preparation of lung slices or for harvest of lungs for Q-PCR analysis of gene expression of pro-inflammatory cytokines and receptors involved in airway contraction. Reactivity of small airways to contractile agonists, methacholine and serotonin, and bronchodilator agents, salbutamol, isoprenaline and rosiglitazone, were assessed using phase-contrast microscopy. In vitro LPS treatment of slices increased TNFα release 6-fold but did not alter contraction or relaxation to any agonists tested. In vivo LPS treatment increased lung gene expression of TNFα, IL-1β and ryanodine receptor isoform 2 more than 5-fold. However there were no changes in reactivity in lung slices from these mice, even when also incubated with LPS ex vivo. Despite evidence of LPS-induced inflammation, neither airway hyperresponsiveness or impaired dilator reactivity were evident. The increase in ryanodine receptor isoform 2, known to regulate calcium signaling in vascular smooth muscle, warrants investigation. Since LPS failed to elicit changes in small airway reactivity in mouse lung slices following in vitro or in vivo treatment, alternative approaches are required to define the potential contribution of this endotoxin to altered small airway reactivity in human lung diseases.

  15. Lipopolysaccharide does not alter small airway reactivity in mouse lung slices.

    Directory of Open Access Journals (Sweden)

    Chantal Donovan

    Full Text Available The bacterial endotoxin, lipopolysaccharide (LPS has been associated with occupational airway diseases with asthma-like symptoms and in acute exacerbations of COPD. The direct and indirect effects of LPS on small airway reactivity have not been fully elucidated. We tested the hypothesis that both in vitro and in vivo LPS treatment would increase contraction and impair relaxation of mouse small airways. Lung slices were prepared from naïve Balb/C mice and cultured in the absence or presence of LPS (10 μg/ml for up to 48 h for measurement of TNFα levels in conditioned media. Alternatively, mice were challenged with PBS or LPS in vivo once a day for 4 days for preparation of lung slices or for harvest of lungs for Q-PCR analysis of gene expression of pro-inflammatory cytokines and receptors involved in airway contraction. Reactivity of small airways to contractile agonists, methacholine and serotonin, and bronchodilator agents, salbutamol, isoprenaline and rosiglitazone, were assessed using phase-contrast microscopy. In vitro LPS treatment of slices increased TNFα release 6-fold but did not alter contraction or relaxation to any agonists tested. In vivo LPS treatment increased lung gene expression of TNFα, IL-1β and ryanodine receptor isoform 2 more than 5-fold. However there were no changes in reactivity in lung slices from these mice, even when also incubated with LPS ex vivo. Despite evidence of LPS-induced inflammation, neither airway hyperresponsiveness or impaired dilator reactivity were evident. The increase in ryanodine receptor isoform 2, known to regulate calcium signaling in vascular smooth muscle, warrants investigation. Since LPS failed to elicit changes in small airway reactivity in mouse lung slices following in vitro or in vivo treatment, alternative approaches are required to define the potential contribution of this endotoxin to altered small airway reactivity in human lung diseases.

  16. Hypothalamic digoxin, hemispheric chemical dominance, and interstitial lung disease.

    Science.gov (United States)

    Kurup, Ravi Kumar; Kurup, Parameswara Achutha

    2003-10-01

    The isoprenoid pathway produces three key metabolites--endogenous digoxin, dolichol, and ubiquinone. This was assessed in patients with idiopathic pulmonary fibrosis and in individuals of differing hemispheric dominance to find out the role of hemispheric dominance in the pathogenesis of idiopathic pulmonary fibrosis. All 15 cases of interstitial lung disease were right-handed/left hemispheric dominant by the dichotic listening test. The isoprenoidal metabolites--digoxin, dolichol, and ubiquinone, RBC membrane Na(+)-K+ ATPase activity, serum magnesium, tyrosine/tryptophan catabolic patterns, free radical metabolism, glycoconjugate metabolism, and RBC membrane composition--were assessed in idiopathic pulmonary fibrosis as well as in individuals with differing hemispheric dominance. In patients with idiopathic pulmonary fibrosis there was elevated digoxin synthesis, increased dolichol and glycoconjugate levels, and low ubiquinone and elevated free radical levels. There was also an increase in tryptophan catabolites and a reduction in tyrosine catabolites. There was an increase in cholesterol phospholipid ratio and a reduction in glycoconjugate level of RBC membrane in patients with idiopathic pulmonary fibrosis. Isoprenoid pathway dysfunction con tributes to the pathogenesis of idiopathic pulmonary fibrosis. The biochemical patterns obtained in interstitial lung disease are similar to those obtained in left-handed/right hemispheric chemically dominant individuals by the dichotic listening test. However, all the patients with interstitial lung disease were right-handed/left hemispheric dominant by the dichotic listening test. Hemispheric chemical dominance has no correlation with handedness or the dichotic listening test. Interstitial lung disease occurs in right hemispheric chemically dominant individuals and is a reflection of altered brain function.

  17. Anti-EGFR therapy radiosensitizes human lung adenocarcinoma xenograft in nude mouse

    International Nuclear Information System (INIS)

    Wang Hui; Li Tianran; Tian Jiahe; Qu Baolin; Zhu Hui

    2008-01-01

    Objective: To investigate the effect of Gefitinib on radiosensitivity of human lung adenocarcinoma xenograft in nude mouse. Methods: Human lung adenocarcinoma cell line A549 was used to establish nude mouse xenograft tumor model. The mice were derided into 4 groups: control, irradiation alone, Gefinitib alone and radiation combined with Genifitib. Radiation schedule was 3 fractions of 5 Gy, once daily. Gefitinib was daily administered by gavage at 100 mg/(kg·day -1 ) for 14 days. In the combination group, radiotherapy was performed 2 hours after Gefitinib administration. Tumor diameter was measured every other day. Percentage of tumor growth inhibition, growth delay time and regrowth delay time were evaluated. Results: For A549 xenografts in radiation alone, gefitinib alone and combination therapy groups, the percentage of tumor growth inhibition was 22.7%, 12.4% and 38.2%, respectively (F=25.75, P=0.000). Tumor growth delay time was 6.0, 7.8 and 21.6 days, respectively (F=70.49, P=0.000). Tumor regrowth delay time in combination therapy and irradiation alone groups was 23.4 and 10.2 days. (F=174.24, P= 0.000). Sensitizing enhancement ratio of combination group was 1.5 in growth and 1.7 in regrowth. Conclusions: Anti-EGFR therapy enhances the radiosensitivity of human lung adenocarcinoma xenograft in nude mouse. (authors)

  18. Biodistribution of gold nanoparticles following intratracheal instillation in mouse lung

    DEFF Research Database (Denmark)

    Sadauskas, Evaldas; Jacobsen, Nicklas R.; Danscher, Gorm

    2009-01-01

    plasma mass spectrometry (ICP-MS) and neutron activation analysis (NAA). The liver is the major site of deposition of circulating gold nanoparticles. Therefore the degree of translocation was determined by the hepatic deposition of gold. Mice were instilled with 5 intratracheal doses of gold...... repeatedly during 3 weeks, the load was substantial. Ultrastructurally, AMG silver enhanced gold nanoparticles were found in lysosome-/endosome-like organelles of the macrophages and analysis with AMG, ICP-MS and NAA of the liver revealed an almost total lack of translocation of nanoparticles. In mice given...... repeated instillations of 2 nm gold nanoparticles, 1.4‰ (by ICP-MS) to 1.9‰ (by NAA) of the instilled gold was detected in the liver. With the 40 nm gold, no gold was detected in the liver (detection level 2 ng, 0.1‰) except for one mouse in which 3‰ of the instilled gold was found in the liver. No gold...

  19. Establishment of Orthotopic Xuanwei Lung Cancer SCID Mouse Model 
and Analysis of Biological Properties

    Directory of Open Access Journals (Sweden)

    Yongchun ZHOU

    2012-08-01

    Full Text Available Background and objective The incidence of Xuanwei lung cancer ranks first in China, and its pathogenesis requires in-depth investigation. This study aims to establish an orthotopic Xuanwei lung cancer severe combined immunodeficiency (SCID mouse model and to provide a basic experimental platform for further study. Methods The Xuanwei lung cancer cell line XWLC-05 was inoculated into the lung tissue of SCID mice in high and low doses. The tumor formation rates, tumor characteristics, spontaneous metastases, and survival times of the mice were observed, taking a subcutaneously transplanted tumor as control. Results The tumor formation rates of the orthotopic transplantation of lung cancer cells in high and low doses were 81% and 83%, respectively, among which mice in the high-dose group appeared cachectic on day 13. Extensive invasion and adhesion were observed in the contralateral lung and thoracic cavity, but no distant metastasis was exhibited. Mice with low-dose cells in the orthotopic transplantation group appeared cachectic and distant metastasis occurred on day 25. The tumor formation rates in the subcutaneous inoculation group by the high and low doses of cells were 100% and 94.5%, respectively, and no distant metastasis was observed. The rate of metastasis within the orthotopic transplantation group and between the orthotopic and subcutaneous inoculation groups showed a significant difference (P<0.05. A significant difference was indicated by the survival rate within and between the groups (P<0.001. Conclusion We successfully established an orthotopic XWLC SCID mouse model, which lays the foundation for a more in-depth study.

  20. Gene expression profiling in mouse lung following polymeric hexamethylene diisocyanate exposure

    International Nuclear Information System (INIS)

    Lee, C.-T.; Ylostalo, Joni; Friedman, Mitchell; Hoyle, Gary W.

    2005-01-01

    Isocyanates are a common cause of occupational lung disease. Hexamethylene diisocyanate (HDI), a component of polyurethane spray paints, can induce respiratory symptoms, inflammation, lung function impairment, and isocyanate asthma. The predominant form of HDI in polyurethane paints is a nonvolatile polyisocyanate known as HDI biuret trimer (HDI-BT). Exposure of mice to aerosolized HDI-BT results in pathological effects, including pulmonary edema, lung inflammation, cellular proliferation, and fibrotic lesions, which occur with distinct time courses following exposure. To identify genes that mediate lung pathology in the distinct temporal phases after exposure, gene expression profiles in HDI-BT-exposed C57BL/6J mouse lungs were analyzed. RNase protection assay (RPA) of genes involved in apoptosis, cell survival, and inflammation revealed increased expression of IκBα, Fas, Bcl-X L , TNFα, KC, MIP-2, IL-6, and GM-CSF following HDI-BT exposure. Microarray analysis of approximately 10 000 genes was performed on lung RNA collected from mice 6, 18, and 90 h after HDI-BT exposure and from unexposed mice. Classes of genes whose expression was increased 6 h after exposure included those involved in stress responses (particularly oxidative stress and thiol redox balance), growth arrest, apoptosis, signal transduction, and inflammation. Types of genes whose expression was increased at 18 h included proteinases, anti-proteinases, cytoskeletal molecules, and inflammatory mediators. Transcripts increased at 90 h included extracellular matrix components, transcription factors, inflammatory mediators, and cell cycle regulators. This characterization of the gene expression profile in lungs exposed to HDI-BT will provide a basis for investigating injury and repair pathways that are operative during isocyanate-induced lung disease

  1. Effect of CPAP in a Mouse Model of Hyperoxic Neonatal Lung Injury

    Science.gov (United States)

    Reyburn, Brent; Fiore, Juliann M. Di; Raffay, Thomas; Martin, Richard J.; Y.S., Prakash; Jafri, Anjum; MacFarlane, Peter M.

    2015-01-01

    Background Continuous positive airway pressure [CPAP] and supplemental oxygen have become the mainstay of neonatal respiratory support in preterm infants. Although oxygen therapy is associated with respiratory morbidities including bronchopulmonary dysplasia [BPD], the long-term effects of CPAP on lung function are largely unknown. We used a hyperoxia-induced mouse model of BPD to explore the effects of daily CPAP during the first week of life on later respiratory system mechanics. Objective To test the hypothesis that daily CPAP in a newborn mouse model of BPD improves longer term respiratory mechanics. Methods Mouse pups from C57BL/6 pregnant dams were exposed to room air [RA] or hyperoxia [50% O2, 24hrs/day] for the first postnatal week with or without exposure to daily CPAP [6cmH2O, 3hrs/day]. Respiratory system resistance [Rrs] and compliance [Crs] were measured following a subsequent 2 week period of room RA recovery. Additional measurements included radial alveolar counts and macrophage counts. Results Mice exposed to hyperoxia had significantly elevated Rrs, decreased Crs, reduced alveolarization, and increased macrophage counts at three weeks compared to RA treated mice. Daily CPAP treatment significantly improved Rrs, Crs and alveolarization, and decreased lung macrophage infiltration in hyperoxia-exposed pups. Conclusions We have demonstrated that daily CPAP had a longer term benefit on baseline respiratory system mechanics in a neonatal mouse model of BPD. We speculate that this beneficial effect of CPAP was the consequence of a decrease in the inflammatory response and resultant alveolar injury associated with hyperoxic newborn lung injury. PMID:26394387

  2. Low-frequency ultrasound increases non-viral gene transfer to the mouse lung.

    Science.gov (United States)

    Xenariou, Stefania; Liang, Hai-Dong; Griesenbach, Uta; Zhu, Jie; Farley, Raymond; Somerton, Lucinda; Singh, Charanjit; Jeffery, Peter K; Scheule, Ronald K; Cheng, Seng H; Geddes, Duncan M; Blomley, Martin; Alton, Eric W F W

    2010-01-01

    The aim of the study was to assess if low-frequency ultrasound (US), in the range of 30-35 kHz, increases non-viral gene transfer to the mouse lung. US is greatly attenuated in the lung due to large energy losses at the air/tissue interfaces. The advantages of low-frequency US, compared with high-frequency US are: (i) increased cavitation (responsible for the formation of transient pores in the cell membrane) and (ii) reduced energy losses during lung penetration. Cationic lipid GL67/plasmid DNA (pDNA), polyethylenimine (PEI)/pDNA and naked pDNA were delivered via intranasal instillation and the animals were then exposed to US (sonoporation) at 0.07 or 0.1 MPa for 10 min. Under these conditions, US did not enhance GL67 or PEI-mediated transfection. It did, however, increase naked pDNA gene transfer by approximately 4 folds. Importantly, this was achieved in the absence of microbubbles, which are crucial for the commonly used high-frequency (1 MHz) sonoporation but may not be able to withstand nebulization in a clinically relevant setup. Lung hemorrhage was also assessed and shown to increase with US pressure in a dose-dependent manner. We have thus, established that low-frequency US can enhance lung gene transfer with naked pDNA and this enhancement is more effective than the previously reported 1 MHz US.

  3. Pharmacokinetic and Genomic Effects of Arsenite in Drinking Water on Mouse Lung in a 30-Day Exposure

    Directory of Open Access Journals (Sweden)

    Jaya Chilakapati

    2015-06-01

    Full Text Available The 2 objectives of this subchronic study were to determine the arsenite drinking water exposure dependent increases in female C3H mouse liver and lung tissue arsenicals and to characterize the dose response (to 0, 0.05, 0.25, 1, 10, and 85 ppm arsenite in drinking water for 30 days and a purified AIN-93M diet for genomic mouse lung expression patterns. Mouse lungs were analyzed for inorganic arsenic, monomethylated, and dimethylated arsenicals by hydride generation atomic absorption spectroscopy. The total lung mean arsenical levels were 1.4, 22.5, 30.1, 50.9, 105.3, and 316.4 ng/g lung tissue after 0, 0.05, 0.25, 1, 10, and 85 ppm, respectively. At 85 ppm, the total mean lung arsenical levels increased 14-fold and 131-fold when compared to either the lowest noncontrol dose (0.05 ppm or the control dose, respectively. We found that arsenic exposure elicited minimal numbers of differentially expressed genes (DEGs; 77, 38, 90, 87, and 87 DEGs after 0.05, 0.25, 1, 10, and 85 ppm, respectively, which were associated with cardiovascular disease, development, differentiation, apoptosis, proliferation, and stress response. After 30 days of arsenite exposure, this study showed monotonic increases in mouse lung arsenical (total arsenic and dimethylarsinic acid concentrations but no clear dose-related increases in DEG numbers.

  4. Modification of radiation damage in mouse lung by DNA-binding radioprotectors

    International Nuclear Information System (INIS)

    Budd, R.; D'Abrew, S.; Coultas, P.; Martin, R.F.

    1996-01-01

    Full text: The limited diffusion of Hoechst 33342 through cell layers, which has been exploited in mapping the location of cells in multi-cellular spheroids, and in vivo, reflects a general characteristic of DNA-ligands. This property may confer special advantages on DNA-binding radioprotectors in the context of radiotherapy, where it is important to minimise delivery of the radioprotector to the tumour. For example, one might expect limited diffusion to capillaries and systemic uptake following topical application to epithelial cells, which can be dose-limiting tissues in radiotherapy. These potential applications will require delivery of sufficient concentrations of the DNA-binding radioprotectors to cells in vivo. In this context, the findings of Young and Hill, who could not detect any radioprotective effect in an in vivo setting, is of concern. We have re-examined this question by investigating radioprotection in the mouse lung model. A single intravenous injection of Hoechst 33342 (80mg/kg) given 30min prior to the lung irradiation, extends the radiation dose required for death in 50% of mice at 16 weeks post irradiation, from 19Gy to 23Gy (ie: a DMF of 1.2). This is similar to the extent of radioprotection reported by Travis et al for WR2721 (300 mg/kg) in this model. These results auger well for the potential of the more potent radioprotectors, and indeed preliminary experiments with methylproamine in the mouse lung model suggests a DMF of 1.35

  5. Multitracer Stable Isotope Quantification of Arginase and Nitric Oxide Synthase Activity in a Mouse Model of Pseudomonas Lung Infection

    Directory of Open Access Journals (Sweden)

    Hartmut Grasemann

    2014-01-01

    Full Text Available Cystic fibrosis airways are deficient for L-arginine, a substrate for nitric oxide synthases (NOSs and arginases. The rationale for this study was to quantify NOS and arginase activity in the mouse lung. Anesthetized unventilated mice received a primed constant stable isotope intravenous infusion containing labeled L-arginine, ornithine, and citrulline. The isotopic enrichment of each of the infused isotopomers and its product amino acids were measured in plasma and organ homogenates using liquid chromatography-tandem mass spectrometry. The effect of infection was studied three days after direct tracheal instillation of Pseudomonas-coated agar beads. In the infusion model, lung infection resulted in a significant (28-fold increase in NOS activity in lung but not in trachea, kidney, liver, or plasma. Absolute rates of arginase activity in solid tissues could not be calculated in this model. In an isolated lung perfusion model used for comparison increased NOS activity in infected lungs was confirmed (28.5-fold and lung arginase activity was increased 9.7-fold. The activity of L-arginine metabolizing enzymes can be measured using stable isotope conversion in the mouse. Accumulation of L-ornithine in the whole mouse model hindered the exact quantification of arginase activity in the lung, a problem that was overcome utilizing an isolated lung perfusion model.

  6. Biochemical changes in mouse lung after subcutaneous injection of the sulfur mustard 2-chloroethyl 4-chlorobutyl sulfide.

    Science.gov (United States)

    Elsayed, Nabil M; Omaye, Stanley T

    2004-07-01

    Sulfur mustard (HD) is a vesicant-type chemical warfare agent (CWA) introduced in World War I which continues to be produced, stockpiled, and occasionally deployed by some countries, and could be used potentially by terrorists. Exposure to HD can cause erythema, blisters, corneal opacity, and airway damage. We have reported previously that subcutaneous (SC) injection of immunodeficient athymic nude mice with the half mustard butyl 2-chloroethyl sulfide (BCS) causes systemic biochemical changes in several organs distal to the exposure site. In the present study, we examined the response of non-immunodeficient Swiss Webster mice to the mustard, 2-chloroethyl 4-chlorobutyl sulfide (CECBS). In a pilot study, we found that a single SC injection of 20-25 microl/mouse causes death within 24h. Consequently, we used 5 microl/mouse (approx. 0.017 mg/kg body weight) of neat CECBS or an equal volume of saline as control. We examined the lungs after 1, 24, and 48 h for biochemical changes including total and oxidized glutathione, protein, DNA, and lipid peroxidation contents in tissue homogenate, and superoxide dismutase, catalase, glucose-6-phosphate dehydrogenase, and glutathione S-transferases activities in the cytosol. After 1h and/or 24h, we found statistically significant changes that were resolved by 48 h. These changes mimicked those of HD and BCS and were generally consistent with free radical-mediated oxidative stress. The implications of these observations are two-fold. First, dermal exposure to low-dose mustard gas could elicit systemic changes impacting distal organs such as the lungs. It also suggests that antioxidants could potentially modulate the response and reduce the damage. Second, although the use of known CWAs such as HD is prohibited, analogs that are not recognized as agents are as toxic and could be dangerous if acquired and used by potential terrorists.

  7. Stereotactic Body Radiation Therapy Delivery in a Genetically Engineered Mouse Model of Lung Cancer

    Energy Technology Data Exchange (ETDEWEB)

    Du, Shisuo; Lockamy, Virginia [Department of Radiation Oncology, Thomas Jefferson University, Philadelphia, Pennsylvania (United States); Zhou, Lin [Department of Thoracic Oncology, Cancer Center and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, Sichuan (China); Xue, Christine; LeBlanc, Justin [Department of Radiation Oncology, Thomas Jefferson University, Philadelphia, Pennsylvania (United States); Glenn, Shonna [Xstrahl, Inc, Suwanee, Georgia (United States); Shukla, Gaurav; Yu, Yan; Dicker, Adam P.; Leeper, Dennis B. [Department of Radiation Oncology, Thomas Jefferson University, Philadelphia, Pennsylvania (United States); Lu, You [Department of Thoracic Oncology, Cancer Center and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, Sichuan (China); Lu, Bo, E-mail: bo.lu@jefferson.edu [Department of Radiation Oncology, Thomas Jefferson University, Philadelphia, Pennsylvania (United States)

    2016-11-01

    Purpose: To implement clinical stereotactic body radiation therapy (SBRT) using a small animal radiation research platform (SARRP) in a genetically engineered mouse model of lung cancer. Methods and Materials: A murine model of multinodular Kras-driven spontaneous lung tumors was used for this study. High-resolution cone beam computed tomography (CBCT) imaging was used to identify and target peripheral tumor nodules, whereas off-target lung nodules in the contralateral lung were used as a nonirradiated control. CBCT imaging helps localize tumors, facilitate high-precision irradiation, and monitor tumor growth. SBRT planning, prescription dose, and dose limits to normal tissue followed the guidelines set by RTOG protocols. Pathologic changes in the irradiated tumors were investigated using immunohistochemistry. Results: The image guided radiation delivery using the SARRP system effectively localized and treated lung cancer with precision in a genetically engineered mouse model of lung cancer. Immunohistochemical data confirmed the precise delivery of SBRT to the targeted lung nodules. The 60 Gy delivered in 3 weekly fractions markedly reduced the proliferation index, Ki-67, and increased apoptosis per staining for cleaved caspase-3 in irradiated lung nodules. Conclusions: It is feasible to use the SARRP platform to perform dosimetric planning and delivery of SBRT in mice with lung cancer. This allows for preclinical studies that provide a rationale for clinical trials involving SBRT, especially when combined with immunotherapeutics.

  8. Repair capacity of mouse lung after total body irradiation alone or combined with cyclophosphamide

    International Nuclear Information System (INIS)

    Safwat, Akmal; Bentzen, Soeren M.; Nielsen, Ole S.; Mahmoud, Hossam K.; Overgaard, Jens

    1996-01-01

    Purpose. Cyclophosphamide (CTX) combined with fractionated total body irradiation (TBI) is frequently used in the conditioning of patients prior to bone marrow transplantation (BMT). This study was performed to investigate the effect of CTX on the repair capacity of lung tissue after TBI in a mouse model for BMT. Materials and methods. TBI was given as a single fraction, 3 fractions in 3 days (Fx 3) or 9 fractions in 3 days (Fx 9) either alone or 24 h after a single dose of CTX. The single fraction TBI was given at either high dose rate (HDR) of 0.71 Gy/min or low dose rate (LDR) of 0.08 Gy/min. All mice were transplanted 4-6 h after the last TBI fraction. Lung damage was assessed using ventilation rate (VR) and lethality between 28 and 180 days. The repair capacity of lung tissue was estimated using the direct analysis method with the probability of reaching the end point described by a logistic formulation of the linear quadratic model. Results. The VR data confirmed the high repair capacity of lung tissue with an α/β ratio of 4.4 Gy though with a wide 95% confidence interval (CI = 0.03-10.5). Giving CTX before fractionated TBI marked reduced the doses needed to cause response in 50% of the animals. The sparing effect of using fractionated TBI was still evident in the combined CTX-TBI schedules. The estimated α/β ratio was 1.6 Gy (CI = 0.01-4.7) which is within the range of values reported after thoracic radiation only. On the other hand, the sparing effect seen in going from single fraction HDR to LDR was completely abolished when CTX was given 24 h before TBI. The same pattern was repeated when lethality between 28-180 days was used. Yet, the use of lethality to estimate lung damage in a TBI model, markedly underestimated the repair capacity. Conclusions. These results confirm the high repair capacity of lung tissue after TBI and emphasize the value of using a specific end point in testing lung damage after TBI. It also shows that there can be a negative

  9. INDUCTION OF DNA ADDUCTS, TUMORS, AND KI-RAS ONCOGENE MUTATIONS IN STRAIN A/J MOUSE LUNG BY IP. ADMINISTRATION OF DIBENZ[A,H]ANTHRACENE

    Science.gov (United States)

    Induction of DNA adducts, tumors, and Ki-ras oncogene mutations in strain AlJ mouse lung by ip. administration of dibenz[a,h]anthracene Previous studies of polycyclic aromatic hydrocarbon (P AH) induced lung tumors in the strain NJ mouse model system have demonstrated qua...

  10. Modulation of lung inflammation by vessel dilator in a mouse model of allergic asthma

    Directory of Open Access Journals (Sweden)

    Cormier Stephania A

    2009-07-01

    Full Text Available Abstract Background Atrial natriuretic peptide (ANP and its receptor, NPRA, have been extensively studied in terms of cardiovascular effects. We have found that the ANP-NPRA signaling pathway is also involved in airway allergic inflammation and asthma. ANP, a C-terminal peptide (amino acid 99–126 of pro-atrial natriuretic factor (proANF and a recombinant peptide, NP73-102 (amino acid 73–102 of proANF have been reported to induce bronchoprotective effects in a mouse model of allergic asthma. In this report, we evaluated the effects of vessel dilator (VD, another N-terminal natriuretic peptide covering amino acids 31–67 of proANF, on acute lung inflammation in a mouse model of allergic asthma. Methods A549 cells were transfected with pVD or the pVAX1 control plasmid and cells were collected 24 hrs after transfection to analyze the effect of VD on inactivation of the extracellular-signal regulated receptor kinase (ERK1/2 through western blot. Luciferase assay, western blot and RT-PCR were also performed to analyze the effect of VD on NPRA expression. For determination of VD's attenuation of lung inflammation, BALB/c mice were sensitized and challenged with ovalbumin and then treated intranasally with chitosan nanoparticles containing pVD. Parameters of airway inflammation, such as airway hyperreactivity, proinflammatory cytokine levels, eosinophil recruitment and lung histopathology were compared with control mice receiving nanoparticles containing pVAX1 control plasmid. Results pVD nanoparticles inactivated ERK1/2 and downregulated NPRA expression in vitro, and intranasal treatment with pVD nanoparticles protected mice from airway inflammation. Conclusion VD's modulation of airway inflammation may result from its inactivation of ERK1/2 and downregulation of NPRA expression. Chitosan nanoparticles containing pVD may be therapeutically effective in preventing allergic airway inflammation.

  11. Interactions between ethanol and cigarette smoke in a mouse lung carcinogenesis model

    International Nuclear Information System (INIS)

    Balansky, Roumen; Ganchev, Gancho; Iltcheva, Marietta; Nikolov, Manasi; La Maestra, S.; Micale, Rosanna T.; Steele, Vernon E.; De Flora, Silvio

    2016-01-01

    Highlights: • Cigarette smoke and ethanol are known to synergize in the upper aerodigestive tract. • Their interactions in the lower respiratory tract have poorly been explored. • Prenatal and postnatal treatments of mice with ethanol caused pulmonary alterations. • However, ethanol attenuated smoke-induced preneoplastic and neoplastic lesions in lung. • The interaction between smoke and alcohol depends on life stage and target tissue. - Abstract: Both ethanol and cigarette smoke are classified as human carcinogens. They can synergize, especially in tissues of the upper aerodigestive tract that are targeted by both agents. The main objective of the present study was to evaluate the individual and combined effects of ethanol and smoke in the respiratory tract, either following transplacental exposure and/or postnatal exposure. We designed two consecutive studies in mouse models by exposing Swiss H mice to oral ethanol and/or inhaled mainstream cigarette smoke for up to 4 months, at various prenatal and postnatal life stages. Clastogenic effects and histopathological alterations were evaluated after 4 and 8 months, respectively. Ethanol was per se devoid of clastogenic effects in mouse peripheral blood erythrocytes. However, especially in mice exposed both transplacentally throughout pregnancy and in the postnatal life, ethanol administration was associated not only with liver damage but also with pro-angiogenetic effects in the lung by stimulating the proliferation of blood vessels. In addition, these mice developed pulmonary emphysema, alveolar epithelial hyperplasias, microadenomas, and benign tumors. On the other hand, ethanol interfered in the lung carcinogenesis process resulting from the concomitant exposure of mice to smoke. In fact, ethanol significantly attenuated some smoke-related preneoplastic and neoplastic lesions in the respiratory tract, such as alveolar epithelial hyperplasia, microadenomas, and even malignant tumors. In addition, ethanol

  12. Strain-dependent Damage in Mouse Lung After Carbon Ion Irradiation

    Energy Technology Data Exchange (ETDEWEB)

    Moritake, Takashi [Advanced Radiation Biology Research Program, Research Center for Charged Particle Therapy, National Institute of Radiological Sciences, Chiba (Japan); Proton Medical Research Center, University of Tsukuba, Tsukuba (Japan); Fujita, Hidetoshi; Yanagisawa, Mitsuru; Nakawatari, Miyako; Imadome, Kaori; Nakamura, Etsuko; Iwakawa, Mayumi [Advanced Radiation Biology Research Program, Research Center for Charged Particle Therapy, National Institute of Radiological Sciences, Chiba (Japan); Imai, Takashi, E-mail: imait@nirs.go.jp [Advanced Radiation Biology Research Program, Research Center for Charged Particle Therapy, National Institute of Radiological Sciences, Chiba (Japan)

    2012-09-01

    Purpose: To examine whether inherent factors produce differences in lung morbidity in response to carbon ion (C-ion) irradiation, and to identify the molecules that have a key role in strain-dependent adverse effects in the lung. Methods and Materials: Three strains of female mice (C3H/He Slc, C57BL/6J Jms Slc, and A/J Jms Slc) were locally irradiated in the thorax with either C-ion beams (290 MeV/n, in 6 cm spread-out Bragg peak) or with {sup 137}Cs {gamma}-rays as a reference beam. We performed survival assays and histologic examination of the lung with hematoxylin-eosin and Masson's trichrome staining. In addition, we performed immunohistochemical staining for hyaluronic acid (HA), CD44, and Mac3 and assayed for gene expression. Results: The survival data in mice showed a between-strain variance after C-ion irradiation with 10 Gy. The median survival time of C3H/He was significantly shortened after C-ion irradiation at the higher dose of 12.5 Gy. Histologic examination revealed early-phase hemorrhagic pneumonitis in C3H/He and late-phase focal fibrotic lesions in C57BL/6J after C-ion irradiation with 10 Gy. Pleural effusion was apparent in C57BL/6J and A/J mice, 168 days after C-ion irradiation with 10 Gy. Microarray analysis of irradiated lung tissue in the three mouse strains identified differential expression changes in growth differentiation factor 15 (Gdf15), which regulates macrophage function, and hyaluronan synthase 1 (Has1), which plays a role in HA metabolism. Immunohistochemistry showed that the number of CD44-positive cells, a surrogate marker for HA accumulation, and Mac3-positive cells, a marker for macrophage infiltration in irradiated lung, varied significantly among the three mouse strains during the early phase. Conclusions: This study demonstrated a strain-dependent differential response in mice to C-ion thoracic irradiation. Our findings identified candidate molecules that could be implicated in the between-strain variance to early

  13. Mutational landscape of EGFR-, MYC-, and Kras-driven genetically engineered mouse models of lung adenocarcinoma.

    Science.gov (United States)

    McFadden, David G; Politi, Katerina; Bhutkar, Arjun; Chen, Frances K; Song, Xiaoling; Pirun, Mono; Santiago, Philip M; Kim-Kiselak, Caroline; Platt, James T; Lee, Emily; Hodges, Emily; Rosebrock, Adam P; Bronson, Roderick T; Socci, Nicholas D; Hannon, Gregory J; Jacks, Tyler; Varmus, Harold

    2016-10-18

    Genetically engineered mouse models (GEMMs) of cancer are increasingly being used to assess putative driver mutations identified by large-scale sequencing of human cancer genomes. To accurately interpret experiments that introduce additional mutations, an understanding of the somatic genetic profile and evolution of GEMM tumors is necessary. Here, we performed whole-exome sequencing of tumors from three GEMMs of lung adenocarcinoma driven by mutant epidermal growth factor receptor (EGFR), mutant Kirsten rat sarcoma viral oncogene homolog (Kras), or overexpression of MYC proto-oncogene. Tumors from EGFR- and Kras-driven models exhibited, respectively, 0.02 and 0.07 nonsynonymous mutations per megabase, a dramatically lower average mutational frequency than observed in human lung adenocarcinomas. Tumors from models driven by strong cancer drivers (mutant EGFR and Kras) harbored few mutations in known cancer genes, whereas tumors driven by MYC, a weaker initiating oncogene in the murine lung, acquired recurrent clonal oncogenic Kras mutations. In addition, although EGFR- and Kras-driven models both exhibited recurrent whole-chromosome DNA copy number alterations, the specific chromosomes altered by gain or loss were different in each model. These data demonstrate that GEMM tumors exhibit relatively simple somatic genotypes compared with human cancers of a similar type, making these autochthonous model systems useful for additive engineering approaches to assess the potential of novel mutations on tumorigenesis, cancer progression, and drug sensitivity.

  14. Lipid peroxidation in radiation pneumonitis in mouse lung and its preventation

    International Nuclear Information System (INIS)

    Kodama, Akihisa; Tsujino, Kayoko; Kono, Michio

    1998-01-01

    Lipid peroxidation of the lung in irradiated C57BL6J mice was analyzed by gas chromatography. Among six major fatty acids in the mouse lung tissue, the amounts of two unsaturated fatty acids, arachidonic acid and DHA reduced one day after irradiation, and then recovered up to the level of in the control group four weeks after irradiation. In contrast, the amounts of stearic and palmitic acid did not change significantly. The mice fed with vitamin E-enriched food showed no significant changes of fatty acids which were compatible with pathophysiological findings 4 weeks after irradiation. Reduction of both arachidonic acid and DHA following lipid peroxidation in lung tissue, was assumed to play an important role in development of radiation pneumonitis. Vitamin E seems to enable to prevent or reduce the occurrence and progression of radiation pneumonitis, but as a radical scavenger, it may also weaken the anti-tumor growth effect of low linear energy transfer (LET) irradiation as photon. (author)

  15. Double-hit mouse model of cigarette smoke priming for acute lung injury.

    Science.gov (United States)

    Sakhatskyy, Pavlo; Wang, Zhengke; Borgas, Diana; Lomas-Neira, Joanne; Chen, Yaping; Ayala, Alfred; Rounds, Sharon; Lu, Qing

    2017-01-01

    Epidemiological studies indicate that cigarette smoking (CS) increases the risk and severity of acute lung injury (ALI)/acute respiratory distress syndrome (ARDS). The mechanism is not understood, at least in part because of lack of animal models that reproduce the key features of the CS priming process. In this study, using two strains of mice, we characterized a double-hit mouse model of ALI induced by CS priming of injury caused by lipopolysaccharide (LPS). C57BL/6 and AKR mice were preexposed to CS briefly (3 h) or subacutely (3 wk) before intratracheal instillation of LPS and ALI was assessed 18 h after LPS administration by measuring lung static compliance, lung edema, vascular permeability, inflammation, and alveolar apoptosis. We found that as little as 3 h of exposure to CS enhanced LPS-induced ALI in both strains of mice. Similar exacerbating effects were observed after 3 wk of preexposure to CS. However, there was a strain difference in susceptibility to CS priming for ALI, with a greater effect in AKR mice. The key features we observed suggest that 3 wk of CS preexposure of AKR mice is a reproducible, clinically relevant animal model that is useful for studying mechanisms and treatment of CS priming for a second-hit-induced ALI. Our data also support the concept that increased susceptibility to ALI/ARDS is an important adverse health consequence of CS exposure that needs to be taken into consideration when treating critically ill individuals.

  16. Mutational landscape of EGFR-, MYC-, and Kras-driven genetically engineered mouse models of lung adenocarcinoma

    Science.gov (United States)

    McFadden, David G.; Politi, Katerina; Bhutkar, Arjun; Chen, Frances K.; Song, Xiaoling; Pirun, Mono; Santiago, Philip M.; Kim-Kiselak, Caroline; Platt, James T.; Lee, Emily; Hodges, Emily; Rosebrock, Adam P.; Bronson, Roderick T.; Socci, Nicholas D.; Hannon, Gregory J.; Jacks, Tyler; Varmus, Harold

    2016-01-01

    Genetically engineered mouse models (GEMMs) of cancer are increasingly being used to assess putative driver mutations identified by large-scale sequencing of human cancer genomes. To accurately interpret experiments that introduce additional mutations, an understanding of the somatic genetic profile and evolution of GEMM tumors is necessary. Here, we performed whole-exome sequencing of tumors from three GEMMs of lung adenocarcinoma driven by mutant epidermal growth factor receptor (EGFR), mutant Kirsten rat sarcoma viral oncogene homolog (Kras), or overexpression of MYC proto-oncogene. Tumors from EGFR- and Kras-driven models exhibited, respectively, 0.02 and 0.07 nonsynonymous mutations per megabase, a dramatically lower average mutational frequency than observed in human lung adenocarcinomas. Tumors from models driven by strong cancer drivers (mutant EGFR and Kras) harbored few mutations in known cancer genes, whereas tumors driven by MYC, a weaker initiating oncogene in the murine lung, acquired recurrent clonal oncogenic Kras mutations. In addition, although EGFR- and Kras-driven models both exhibited recurrent whole-chromosome DNA copy number alterations, the specific chromosomes altered by gain or loss were different in each model. These data demonstrate that GEMM tumors exhibit relatively simple somatic genotypes compared with human cancers of a similar type, making these autochthonous model systems useful for additive engineering approaches to assess the potential of novel mutations on tumorigenesis, cancer progression, and drug sensitivity. PMID:27702896

  17. Dissecting epigenetic silencing complexity in the mouse lung cancer suppressor gene Cadm1.

    Directory of Open Access Journals (Sweden)

    Stella Marie Reamon-Buettner

    Full Text Available Disease-oriented functional analysis of epigenetic factors and their regulatory mechanisms in aberrant silencing is a prerequisite for better diagnostics and therapy. Yet, the precise mechanisms are still unclear and complex, involving the interplay of several effectors including nucleosome positioning, DNA methylation, histone variants and histone modifications. We investigated the epigenetic silencing complexity in the tumor suppressor gene Cadm1 in mouse lung cancer progenitor cell lines, exhibiting promoter hypermethylation associated with transcriptional repression, but mostly unresponsive to demethylating drug treatments. After predicting nucleosome positions and transcription factor binding sites along the Cadm1 promoter, we carried out single-molecule mapping with DNA methyltransferase M.SssI, which revealed in silent promoters high nucleosome occupancy and occlusion of transcription factor binding sites. Furthermore, M.SssI maps of promoters varied within and among the different lung cancer cell lines. Chromatin analysis with micrococcal nuclease also indicated variations in nucleosome positioning to have implications in the binding of transcription factors near nucleosome borders. Chromatin immunoprecipitation showed that histone variants (H2A.Z and H3.3, and opposing histone modification marks (H3K4me3 and H3K27me3 all colocalized in the same nucleosome positions that is reminiscent of epigenetic plasticity in embryonic stem cells. Altogether, epigenetic silencing complexity in the promoter region of Cadm1 is not only defined by DNA hypermethylation, but high nucleosome occupancy, altered nucleosome positioning, and 'bivalent' histone modifications, also likely contributed in the transcriptional repression of this gene in the lung cancer cells. Our results will help define therapeutic intervention strategies using epigenetic drugs in lung cancer.

  18. Mutation spectrum in FE1-MUTA(TM) Mouse lung epithelial cells exposed to nanoparticulate carbon black

    DEFF Research Database (Denmark)

    Jacobsen, Nicklas Raun; White, Paul A; Gingerich, John

    2011-01-01

    It has been shown previously that carbon black (CB), Printex 90 exposure induces cII and lacZ mutants in the FE1-Muta(TM) Mouse lung epithelial cell line and causes oxidatively damaged DNA and the production of reactive oxygen species (ROS). The purpose of this study was to determine the mutation...

  19. Redox Disrupting Potential of ToxCast™Chemicals Ranked by Activity in Mouse Embryonic Stem Cells

    Science.gov (United States)

    Little is known regarding the adverse outcome pathways responsible for developmental toxicity following exposure to chemicals. An evaluation of Toxoast™ Phase I chemicals in an adherent mouse embryonic stem cell (mESC) assay revealed a redox sensitive pathway that correlated with...

  20. REDOX DISRUPTING POTENTIAL OF TOXCAST CHEMICALS RANKED BY ACTIVITY IN MOUSE EMBRYONIC STEM CELLS

    Science.gov (United States)

    To gain insight regarding the adverse outcome pathways leading to developmental toxicity following exposure to chemicals, we evaluated ToxCast™ Phase I chemicals in an adherent mouse embryonic stem cell (mESC) assay and identified a redox sensitive pathway that correlated with al...

  1. Effects of nickel-oxide nanoparticle pre-exposure dispersion status on bioactivity in the mouse lung.

    Science.gov (United States)

    Sager, Tina; Wolfarth, Michael; Keane, Michael; Porter, Dale; Castranova, Vincent; Holian, Andrij

    2016-01-01

    Nanotechnology is emerging as one of the world's most promising new technologies. From a toxicology perspective, nanoparticles possess two features that promote their bioactivity. The first involves physical-chemical characteristics of the nanoparticle, which include the surface area of the nanoparticle. The second feature is the ability of the nanoparticle to traverse cell membranes. These two important nanoparticle characteristics are greatly influenced by placing nanoparticles in liquid medium prior to animal exposure. Nanoparticles tend to agglomerate and clump in suspension, making it difficult to reproducibly deliver them for in vivo or in vitro experiments, possibly affecting experimental variability. Thus, we hypothesize that nanoparticle dispersion status will correlate with the in vivo bioactivity/toxicity of the particle. To test our hypothesis, nano-sized nickel oxide was suspended in four different dispersion media (phosphate-buffered saline (PBS), dispersion medium (DM), a combination of dipalmitoyl-phosphatidyl choline (DPPC) and albumin in concentrations that mimic diluted alveolar lining fluid), Survanta®, or pluronic (Pluronic F-68). Well-dispersed and poorly dispersed suspensions were generated in each media by varying sonication time on ice utilizing a Branson Sonifer 450 (25W continuous output, 20 min or 5 min, respectively). Mice (male, C57BL/6J, 7-weeks-old) were given 0-80 µg/mouse of nano-sized nickel oxide in the different states of dispersion via pharyngeal aspiration. At 1 and 7 d post-exposure, mice underwent whole lung lavage to assess pulmonary inflammation and injury as a function of dispersion status, dose and time. The results show that pre-exposure dispersion status correlates with pulmonary inflammation and injury. These results indicate that a greater degree of pre-exposure dispersion increases pulmonary inflammation and cytotoxicity, as well as decreases in the integrity of the blood-gas barrier in the lung.

  2. A Comparative Study of Rat Lung Decellularization by Chemical Detergents for Lung Tissue Engineering

    Directory of Open Access Journals (Sweden)

    Hamid Tebyanian

    2017-12-01

    CONCLUSION: Decellularized lung tissue can be used in the laboratory to study various aspects of pulmonary biology and physiology and also, these results can be used in the continued improvement of engineered lung tissue.

  3. PCR detection of retinoblastoma gene deletions in radiation-induced mouse lung adenocarcinomas

    International Nuclear Information System (INIS)

    Churchill, M.E.; Gemmell, M.A.; Woloschak, G.E.

    1994-01-01

    From 1971--1986, Argonne National Laboratory conducted a series of large-scale studies of tumor incidence in 40,000 BCF 1 mice irradiated with 60 Co γ-rays or JANUS fission-spectrum neutrons. Polymerase chain reaction (PCR) technique was used to detect deletions in the mouse retinoblastoma (mRb) gene. Six mRb gene exon fragments were amplified in a 40-cycle, 3-temperature PCR protocol. Absence of any of these fragments on a Southern blot indicated a deletion of that portion of the mRb gene. Tumors chosen for analysis were lung adenocarcinomas that were judged to be the cause of death in post-mortem analyses. Spontaneous tumors as well as those from irradiated mice were analyzed for mRb deletions. In all normal mouse tissues studies all six mRb exon fragments were present on Southern blots. Tumors in six neutron-irradiated mice also had no mRb deletions. However, 1 of 6 tumors from γ-irradiated mice and 6 of 18 spontaneous tumors from unirradiated mice showed a deletion in one or both mRb alleles. All deletions detected were in the 5' region of the mRb gene

  4. PCR detection of retinoblastoma gene deletions in radiation-induced mouse lung adenocarcinomas

    International Nuclear Information System (INIS)

    Churchill, M.E.; Gemmell, M.A.; Woloschak, G.E.

    1993-01-01

    From 1971 to 1986, Argonne National Laboratory conducted a series of large-scale studies of tumor incidence in 40,000 BCF 1 mice irradiated with 60 Co γ rays or JANUS fission-spectrum neutrons; normal and tumor tissues from mice in these studies were preserved in paraffin blocks. A polymerase chain reaction (PCR) technique has been developed to detect deletions in the mouse retinoblastoma (mRb) gene in the paraffin-embedded tissues. Microtomed sections were used as the DNA source in PCR reaction mixtures. Six mRb gene exon fragments were amplified in a 40-cycle, 3-temperature PCR protocol. The absence of any of these fragments (relative to control PCR products) on a Southern blot indicated a deletion of that portion of the mRb gene. The tumors chosen for analysis were lung adenocarcinomas that were judged to be the cause of death in post-mortem analyses. Spontaneous tumors as well as those from irradiated mice (569 cGy of 60 Co γ rays or 60 cGy of JANUS neutrons, doses that have been found to have approximately equal biological effectiveness in the BCF, mouse) were analyzed for mRb deletions. In all normal mouse tissues studies, all six mRb exon fragments were present on Southem blots. Tumors in six neutron-irradiated mice also had no mRb deletions. However, I of 6 tumors from γ-irradiated mice and 6 of 18 spontaneous tumors from unirradiated mice had a deletion in one or both mRb alleles. All deletions detected were in the 5' region of the mRb gene

  5. Interactions between the otitis media gene, Fbxo11, and p53 in the mouse embryonic lung.

    Science.gov (United States)

    Tateossian, Hilda; Morse, Susan; Simon, Michelle M; Dean, Charlotte H; Brown, Steve D M

    2015-12-01

    Otitis media with effusion (OME) is the most common cause of hearing loss in children, and tympanostomy (ear tube insertion) to alleviate the condition remains the commonest surgical intervention in children in the developed world. Chronic and recurrent forms of otitis media (OM) are known to have a very substantial genetic component; however, until recently, little was known of the underlying genes involved. The Jeff mouse mutant carries a mutation in the Fbxo11 gene, a member of the F-box family, and develops deafness due to a chronic proliferative OM. We previously reported that Fbxo11 is involved in the regulation of transforming growth factor beta (TGF-β) signalling by regulating the levels of phospho-Smad2 in the epithelial cells of palatal shelves, eyelids and airways of the lungs. It has been proposed that FBXO11 regulates the cell's response to TGF-β through the ubiquitination of CDT2. Additional substrates for FBXO11 have been identified, including p53. Here, we have studied both the genetic and biochemical interactions between FBXO11 and p53 in order to better understand the function of FBXO11 in epithelial development and its potential role in OM. In mice, we show that p53 (also known as Tp53) homozygous mutants and double heterozygous mutants (Jf/+ p53/+) exhibit similar epithelial developmental defects to Fbxo11 homozygotes. FBXO11 and p53 interact in the embryonic lung, and mutation in Fbxo11 prevents the interaction with p53. Both p53 and double mutants show raised levels of pSMAD2, recapitulating that seen in Fbxo11 homozygotes. Overall, our results support the conclusion that FBXO11 regulates the TGF-β pathway in the embryonic lung via cross-talk with p53. © 2015. Published by The Company of Biologists Ltd.

  6. Bilirubin nanoparticles ameliorate allergic lung inflammation in a mouse model of asthma.

    Science.gov (United States)

    Kim, Dong Eon; Lee, Yonghyun; Kim, MinGyo; Lee, Soyoung; Jon, Sangyong; Lee, Seung-Hyo

    2017-09-01

    Although asthma, a chronic inflammatory airway disease, is relatively well-managed by inhaled corticosteroids, the side effects associated with the long-term use of these agents precipitate the need for alternative therapeutic options based on differing modes of action. Bilirubin, a potent endogenous antioxidant, and anti-inflammatory molecule have been shown to ameliorate asthmatic symptoms; however, its clinical translation has been limited owing to its water insolubility and associated potential toxicity. Here we report the first application of bilirubin-based nanoparticles (BRNPs) as a nanomedicine for the treatment of allergic lung inflammatory disease. BRNPs were prepared directly from self-assembly of PEGylated bilirubin in aqueous solution and had a hydrodynamic diameter of ∼100 nm. Because allergen-specific type 2 T-helper (Th2) cells play a key role in the pathogenesis and progression of allergic asthma, the effects of BRNPs on Th2 immune responses were investigated both in vivo and in vitro. BRNPs after intravenous injection (i.v.) showed much higher serum concentration and a longer circulation time of bilirubin than the intraperitoneal injection (i.p.) of BRNPs or unconjugated bilirubin (UCB). The anti-asthmatic effects of BRNPs were assessed in a mouse model of allergen-induced asthma. Compared with UCB, treatment with BRNPs suppressed the symptoms of experimental allergic asthma and dramatically ameliorated Th2-related allergic lung inflammation. Consistent with these results, BRNPs caused a reduction of Th2 cell populations and the expression of related cytokines by antibody-stimulated CD4 + T cells in vitro. Therefore, our results establish BRNPs as an important immunomodulatory agent that may be useful as a therapeutic for allergic lung inflammatory disease and other immune-mediated disorders. Copyright © 2017 Elsevier Ltd. All rights reserved.

  7. Identification of new candidate drugs for lung cancer using chemical-chemical interactions, chemical-protein interactions and a K-means clustering algorithm.

    Science.gov (United States)

    Lu, Jing; Chen, Lei; Yin, Jun; Huang, Tao; Bi, Yi; Kong, Xiangyin; Zheng, Mingyue; Cai, Yu-Dong

    2016-01-01

    Lung cancer, characterized by uncontrolled cell growth in the lung tissue, is the leading cause of global cancer deaths. Until now, effective treatment of this disease is limited. Many synthetic compounds have emerged with the advancement of combinatorial chemistry. Identification of effective lung cancer candidate drug compounds among them is a great challenge. Thus, it is necessary to build effective computational methods that can assist us in selecting for potential lung cancer drug compounds. In this study, a computational method was proposed to tackle this problem. The chemical-chemical interactions and chemical-protein interactions were utilized to select candidate drug compounds that have close associations with approved lung cancer drugs and lung cancer-related genes. A permutation test and K-means clustering algorithm were employed to exclude candidate drugs with low possibilities to treat lung cancer. The final analysis suggests that the remaining drug compounds have potential anti-lung cancer activities and most of them have structural dissimilarity with approved drugs for lung cancer.

  8. Detection of retinoblastoma gene deletions in spontaneous and radiation-induced mouse lung adenocarcinomas by polymerase chain reaction

    International Nuclear Information System (INIS)

    Churchill, M.E.; Gemmell, M.A.; Woloschak, G.E.

    1994-01-01

    A polymerase chain reaction (PCR) technique has been developed to detect deletions in the mouse retinoblastoma gene using histological sections from radiation-induced and spontaneous tumors as the DNA source. Six mouse Rb gene exon fragments were amplified in a 40-cycle, 3-temperature PCR protocol. The absence of any of these fragments relative to control PCR products on a Southern blot indicated a deletion of that portion of the mouse Rb gene. Tumors chosen for analysis were lung adenocarcinomas that were judged to be the cause of death. Spontaneous tumors as well as those from irradiated mice (5.69 Gy 60 Co γ rays or 0.6 Gy JANUS neutrons, which have been found to have approximately equal radiobiological effectiveness) were analyzed for mouse Rb deletions. Tumors in 6 neutron-irradiated mice had no mouse Rb deletions. However, 1 of 6 tumors from γ-irradiated mice (17%) and 6 of 18 spontaneous tumors from unirradiated mice (33%) showed a deletion in one or both mouse Rb alleles. All deletions detected were in the 5' region of the mouse Rb gene. 36 refs., 2 figs., 2 tabs

  9. Synchrotron microradiography study on acute lung injury of mouse caused by PM{sub 2.5} aerosols

    Energy Technology Data Exchange (ETDEWEB)

    Tong Yongpeng [Shanghai Institute of Applied Physics, Chinese Academy of Sciences, Shanghai 201800 (China); Zhang Guilin [Shanghai Institute of Applied Physics, Chinese Academy of Sciences, Shanghai 201800 (China)]. E-mail: glzhang@sinap.ac.cn; Li Yan [Shanghai Institute of Applied Physics, Chinese Academy of Sciences, Shanghai 201800 (China); Tan Mingguan [Shanghai Institute of Applied Physics, Chinese Academy of Sciences, Shanghai 201800 (China); Wang Wei [Shanghai Institute of Applied Physics, Chinese Academy of Sciences, Shanghai 201800 (China); Chen Jianmin [Shanghai Institute of Applied Physics, Chinese Academy of Sciences, Shanghai 201800 (China); Hwu Yeukuang [Institute of Physics, Academia Sinica, Nankang, Taipei (China); Hsu, Pei-Chebg [Institute of Physics, Academia Sinica, Nankang, Taipei, Taiwan (China); Je, Jung Ho [Department of Material Science and Engineering, Pohang University of Science and Technology, Pohang (Korea, Republic of); Margaritondo, Giorgio [Faculte des sciences de base, CH-1015 Lausanne, Ecole Polytechnique Federale de Lausanne (EPFL) (Switzerland); Song Weiming [School of Public Health, Fudan University, Shanghai 200032 (China); Jiang, Rongfang [School of Public Health, Fudan University, Shanghai 200032 (China); Jiang Zhihai [School of Public Health, Fudan University, Shanghai 200032 (China)

    2006-05-15

    In order to investigate FeSO{sub 4}, ZnSO{sub 4} (the two of main metal compositions of Shanghai PM{sub 2.5} (particle matter with those aerodynamical diameter <2.5 {mu}m)) effects on acute lung injury, six solutions contained PM{sub 2.5} aerosol particles, FeSO{sub 4}, ZnSO{sub 4} and their mixtures were instilled intratracheally into mouse lungs for experiment. By 2 days after instillation, the live mice were checked in vivo by synchrotron refractive index microradiography. In addition after extracted and examined by dissection, the right lobes of lung were fixed by formalin, then imaged by synchrotron microradiography again. Corresponding parts of those lung tissues were embedded in paraffin for histopathologic study. The synchrotron X-ray microradiographs of live mouse lung showed different lung texture changes after instilled with different toxic solutions. Hemorrhage points in lung were observed more from those mice instilled by FeSO{sub 4} contained toxin solutions groups. Bronchial epithelial hyperplasia can be observed in ZnSO{sub 4} contained solution-instilled groups from histopathologic analysis. It was found that the acute lung injury of mice caused by solution of PM{sub 2.5} + FeSO{sub 4} + ZnSO{sub 4} was more serious than other toxin solutions. Results suggested that FeSO{sub 4} mainly induced hemorrhage and ZnSO{sub 4} mainly induced inflammation and bronchiolar epithelial hyperplasia in the early toxicological effects of PM{sub 2.5}.

  10. Phase-contrast computed tomography for quantification of structural changes in lungs of asthma mouse models of different severity

    International Nuclear Information System (INIS)

    Dullin, Christian; Larsson, Emanuel; Tromba, Giuliana; Markus, Andrea M.; Alves, Frauke

    2015-01-01

    Synchrotron inline phase-contrast computed tomography in combination with single-distance phase retrieval enables quantification of morphological alterations in lungs of mice with mild and severe experimental allergic airways disease in comparison with healthy controls. Lung imaging in mouse disease models is crucial for the assessment of the severity of airway disease but remains challenging due to the small size and the high porosity of the organ. Synchrotron inline free-propagation phase-contrast computed tomography (CT) with its intrinsic high soft-tissue contrast provides the necessary sensitivity and spatial resolution to analyse the mouse lung structure in great detail. Here, this technique has been applied in combination with single-distance phase retrieval to quantify alterations of the lung structure in experimental asthma mouse models of different severity. In order to mimic an in vivo situation as close as possible, the lungs were inflated with air at a constant physiological pressure. Entire mice were embedded in agarose gel and imaged using inline free-propagation phase-contrast CT at the SYRMEP beamline (Synchrotron Light Source, ‘Elettra’, Trieste, Italy). The quantification of the obtained phase-contrast CT data sets revealed an increasing lung soft-tissue content in mice correlating with the degree of the severity of experimental allergic airways disease. In this way, it was possible to successfully discriminate between healthy controls and mice with either mild or severe allergic airway disease. It is believed that this approach may have the potential to evaluate the efficacy of novel therapeutic strategies that target airway remodelling processes in asthma

  11. Phase-contrast computed tomography for quantification of structural changes in lungs of asthma mouse models of different severity

    Energy Technology Data Exchange (ETDEWEB)

    Dullin, Christian, E-mail: christian.dullin@med.uni-goettingen.de [University Medical Center Goettingen, Robert Koch Strasse 40, Goettingen, Lower Saxony 37075 (Germany); Larsson, Emanuel [Elettra-Sincrotrone Trieste, Strada Statale 14, km 163,5 in AREA Science Park, Basovizza (Trieste) 34149 (Italy); University of Trieste, Trieste (Italy); Linkoeping University, SE-581 83 Linkoeping (Sweden); Tromba, Giuliana [Elettra-Sincrotrone Trieste, Strada Statale 14, km 163,5 in AREA Science Park, Basovizza (Trieste) 34149 (Italy); Markus, Andrea M. [University Medical Center Goettingen, Robert Koch Strasse 40, Goettingen, Lower Saxony 37075 (Germany); Alves, Frauke [University Medical Center Goettingen, Robert Koch Strasse 40, Goettingen, Lower Saxony 37075 (Germany); University Medical Center Goettingen, Robert Koch Strasse 40, Goettingen, Lower Saxony 37075 (Germany); Max Planck Institut for Experimental Medicine, Hermann-Rein-Strasse 3, Goettingen, Lower Saxony 37075 (Germany)

    2015-06-17

    Synchrotron inline phase-contrast computed tomography in combination with single-distance phase retrieval enables quantification of morphological alterations in lungs of mice with mild and severe experimental allergic airways disease in comparison with healthy controls. Lung imaging in mouse disease models is crucial for the assessment of the severity of airway disease but remains challenging due to the small size and the high porosity of the organ. Synchrotron inline free-propagation phase-contrast computed tomography (CT) with its intrinsic high soft-tissue contrast provides the necessary sensitivity and spatial resolution to analyse the mouse lung structure in great detail. Here, this technique has been applied in combination with single-distance phase retrieval to quantify alterations of the lung structure in experimental asthma mouse models of different severity. In order to mimic an in vivo situation as close as possible, the lungs were inflated with air at a constant physiological pressure. Entire mice were embedded in agarose gel and imaged using inline free-propagation phase-contrast CT at the SYRMEP beamline (Synchrotron Light Source, ‘Elettra’, Trieste, Italy). The quantification of the obtained phase-contrast CT data sets revealed an increasing lung soft-tissue content in mice correlating with the degree of the severity of experimental allergic airways disease. In this way, it was possible to successfully discriminate between healthy controls and mice with either mild or severe allergic airway disease. It is believed that this approach may have the potential to evaluate the efficacy of novel therapeutic strategies that target airway remodelling processes in asthma.

  12. Failure of the cultivated mushroom (Agaricus bisporus) to induce tumors in the A/J mouse lung tumor model

    DEFF Research Database (Denmark)

    Pilegaard, Kirsten; Kristiansen, E.; Meyer, Otto A.

    1997-01-01

    We studied whether the cultivated mushroom (Agaricus bisporus) or 4-(carboxy)phenylhydrazine (CP) induce lung adenomas in the A/J mouse lung tumor model. For 26 weeks female mice were fed a semisynthetic diet where 11 or 22% of the diet was replaced by freeze-dried mushrooms. The intake...... of the mushroom diets was equivalent to an intake of agaritine, the major phenylhydrazine derivative occurring in the mushroom, of 92 or 166 mg/kg body weight per day. The intake of CP was 106 mg/kg body weight per day. Neither the;freeze-dried mushroom nor CP induced statistically significant increased numbers...

  13. Antitumor effect of cordycepin (3'-deoxyadenosine) on mouse melanoma and lung carcinoma cells involves adenosine A3 receptor stimulation.

    Science.gov (United States)

    Nakamura, Kazuki; Yoshikawa, Noriko; Yamaguchi, Yu; Kagota, Satomi; Shinozuka, Kazumasa; Kunitomo, Masaru

    2006-01-01

    An attempt was made to elucidate the molecular targetfor the antitumor effects of cordycepin (3'-deoxyadenosine) using non-selective and selective adenosine A1, A2a, A2b and A3 receptor agonists and antagonists. Although adenosine and 2'-deoxyadenosine (up to 100 microM) had no effect, cordycepin showed remarkable inhibitory effects on the growth curves of B16-BL6 mouse melanoma (IC50= 39 microM) and mouse Lewis lung carcinoma (IC50 = 48 microM) cell lines in vitro. Among the adenosine receptor agonists and antagonists used (up to 100 microM), only 2-chloro-N6-(3-iodobenzyl)-adenosine-5'-N-methyluronamide (Cl-IB-MECA), a selective adenosine A3 receptor agonist, notably inhibited the growth of both mouse tumor cell lines (B16-BL6; IC50 = 5 microM, LLC; 14 microM). In addition, the tumor growth inhibitory effect of cordycepin was antagonized by 3-ethyl 5-benzyl 2-methyl-6-phenyl-4-phenylethynyl-1,4-(+/-)-dihydropyridine-3,5-dicarboxylate (MRS1191), a selective adenosine A3 receptor antagonist. These results suggest that cordycepin exerts inhibitory effects on the growth of mouse melanoma and lung carcinoma cells by stimulating adenosine A3 receptors on tumor cells.

  14. Polymerase chain reaction detection of retinoblastoma gene deletions in paraffin-embedded mouse lung adenocarcinomas

    International Nuclear Information System (INIS)

    Churchill, M.E.; Gemmell, M.A.; Woloschak, G.E.

    1991-01-01

    A Polymerase chain reaction (PCR) technique was used to detect deletions in the mouse retinoblastoma (mRb) gene using microtomed sections from paraffin-embedded radiation-induced and spontaneous tumors as the DNA source. Six mRb gene exon fragments were amplified in a 40-cycle, 3-temperature PCR protocol. Absence of any of these fragments relative to control PCR products on a Southern blot indicated a deletion of that portion of the mRb gene. Tumors chosen for analysis were lung adenocarcinomas that were judged to be the cause of death. Spontaneous tumors as well as those from irradiated mice (569 cGy of 60 Co γ rays or 60 cGy of JANUS neutrons) were analyzed. Tumors in six neutron-irradiated mice also had no mRb deletions. However, one of six tumors from γ-irradiated mice and 6 of 18 spontaneous tumors from unirradiated mice showed a deletion in one or both mRb alleles. All deletions detected were in the 5' region of the mRb gene

  15. Mastic Oil Inhibits the Metastatic Phenotype of Mouse Lung Adenocarcinoma Cells

    International Nuclear Information System (INIS)

    Loutrari, Heleni; Magkouta, Sophia; Papapetropoulos, Andreas; Roussos, Charis

    2011-01-01

    Mastic oil from Pistacia lentiscus variation chia, a natural combination of bioactive terpenes, has been shown to exert anti-tumor growth effects against a broad spectrum of cancers including mouse Lewis lung adenocarcinomas (LLC). However, no studies have addressed its anti-metastatic actions. In this study, we showed that treatment of LLC cells with mastic oil within a range of non-toxic concentrations (0.01–0.04% v/v): (a) abrogated their Matrigel invasion and migration capabilities in transwell assays; (b) reduced the levels of secreted MMP-2; (c) restricted phorbol ester-induced actin remodeling and (d) limited the length of neo-vessel networks in tumor microenvironment in the model of chick embryo chorioallantoic membrane. Moreover, exposure of LLC and endothelial cells to mastic oil impaired their adhesive interactions in a co-culture assay and reduced the expression of key adhesion molecules by endothelial cells upon their stimulation with tumor necrosis factor-alpha. Overall, this study provides novel evidence supporting a multipotent role for mastic oil in prevention of crucial processes related to cancer metastasis

  16. Induction of MHC-mismatched Mouse Lung Allograft Acceptance with Combined Donor Bone Marrow: Lung Transplant using a 12-Hour Nonmyeloablative Conditioning Regimen

    Science.gov (United States)

    Vulic, Ante; Panoskaltsis-Mortari, Angela; McDyer, John F.; Luznik, Leo

    2016-01-01

    Background Despite broad and intense conventional immunosuppression, long-term survival after lung transplantation lags behind that for other solid organ transplants, primarily because of allograft rejection. Therefore, new strategies to promote lung allograft acceptance are urgently needed. The purpose of the present study was to induce allograft tolerance with a protocol compatible with deceased donor organ utilization. Methods Using the MHC-mismatched mouse orthotopic lung transplant model, we investigated a conditioning regimen consisting of pretransplant T cell depletion, low dose total body irradiation and posttransplant (donor) bone marrow and splenocyte infusion followed by posttransplantation cyclophosphamide (PTTT-PTB/PTCy). Results Our results show that C57BL/6 recipients of BALB/c lung allografts undergoing this complete short-duration nonmyeloablative conditioning regimen had durable lung allograft acceptance. Mice that lacked 1 or more components of this regimen exhibited significant graft loss. Mechanistically, animals with lung allograft acceptance had established higher levels of donor chimerism, lymphocyte responses which were attenuated to donor antigens but maintained to third-party antigens, and clonal deletion of donor-reactive host Vβ T cells. Frequencies of Foxp3+ T regulatory cells were comparable in both surviving and rejected allografts implying that their perturbation was not a dominant cell-regulatory mechanism. Donor chimerism was indispensable for sustained tolerance, as evidenced by acute rejection of allografts in established chimeric recipients of PTTT-PTB/PTCy following a chimerism-ablating secondary recipient lymphocyte infusion. Conclusion Together, these data provide proof-of-concept for establishing lung allograft tolerance with tandem donor bone marrow transplantation (BMT) using a short-duration nonmyeloablative conditioning regimen and PTCy. PMID:27861294

  17. Development of new mouse lung tumor models expressing EGFR T790M mutants associated with clinical resistance to kinase inhibitors.

    Science.gov (United States)

    Regales, Lucia; Balak, Marissa N; Gong, Yixuan; Politi, Katerina; Sawai, Ayana; Le, Carl; Koutcher, Jason A; Solit, David B; Rosen, Neal; Zakowski, Maureen F; Pao, William

    2007-08-29

    The EGFR T790M mutation confers acquired resistance to kinase inhibitors in human EGFR mutant lung adenocarcinoma, is occasionally detected before treatment, and may confer genetic susceptibility to lung cancer. To study further its role in lung tumorigenesis, we developed mice with inducible expression in type II pneumocytes of EGFR(T790M) alone or together with a drug-sensitive L858R mutation. Both transgenic lines develop lung adenocarcinomas that require mutant EGFR for tumor maintenance but are resistant to an EGFR kinase inhibitor. EGFR(L858R+T790M)-driven tumors are transiently targeted by hsp90 inhibition. Notably, EGFR(T790M)-expressing animals develop tumors with longer latency than EGFR(L858R+T790M)-bearing mice and in the absence of additional kinase domain mutations. These new mouse models of mutant EGFR-dependent lung adenocarcinomas provide insight into clinical observations. The models should also be useful for developing improved therapies for patients with lung cancers harboring EGFR(T790M) alone or in conjunction with drug-sensitive EGFR kinase domain mutations.

  18. Development of new mouse lung tumor models expressing EGFR T790M mutants associated with clinical resistance to kinase inhibitors.

    Directory of Open Access Journals (Sweden)

    Lucia Regales

    2007-08-01

    Full Text Available The EGFR T790M mutation confers acquired resistance to kinase inhibitors in human EGFR mutant lung adenocarcinoma, is occasionally detected before treatment, and may confer genetic susceptibility to lung cancer.To study further its role in lung tumorigenesis, we developed mice with inducible expression in type II pneumocytes of EGFR(T790M alone or together with a drug-sensitive L858R mutation. Both transgenic lines develop lung adenocarcinomas that require mutant EGFR for tumor maintenance but are resistant to an EGFR kinase inhibitor. EGFR(L858R+T790M-driven tumors are transiently targeted by hsp90 inhibition. Notably, EGFR(T790M-expressing animals develop tumors with longer latency than EGFR(L858R+T790M-bearing mice and in the absence of additional kinase domain mutations.These new mouse models of mutant EGFR-dependent lung adenocarcinomas provide insight into clinical observations. The models should also be useful for developing improved therapies for patients with lung cancers harboring EGFR(T790M alone or in conjunction with drug-sensitive EGFR kinase domain mutations.

  19. In vivo tomographic imaging of lung colonization of tumour in mouse with simultaneous fluorescence and X-ray CT.

    Science.gov (United States)

    Zhang, Bin; Gao, Fuping; Wang, Mengjiao; Cao, Xu; Liu, Fei; Wang, Xin; Luo, Jianwen; Wang, Guangzhi; Bai, Jing

    2014-01-01

    Non-invasive in vivo imaging of diffuse and wide-spread colonization within the lungs, rather than distinct solid primary tumors, is still a challenging work. In this work, a lung colonization mouse model bearing A549 human lung tumor was simultaneously scanned by a dual-modality fluorescence molecular tomography (FMT) and X-ray computed tomography (CT) system in vivo. A two steps method which incorporates CT structural information into the FMT reconstruction procedure is employed to provide concurrent anatomical and functional information. By using the target-specific fluorescence agent, the fluorescence tomographic results show elevated fluorescence intensity deep within the lungs which is colonized with diffuse and wide-spread tumors. The results were confirmed with ex vivo fluorescence reflectance imaging and histological examination of the lung tissues. With FMT reconstruction combined with the CT information, the dual-modality FMT/micro-CT system is expected to offer sensitive and noninvasive imaging of diffuse tumor colonization within the lungs in vivo. Copyright © 2014 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  20. Ceramide synthases expression and role of ceramide synthase-2 in the lung: insight from human lung cells and mouse models.

    Directory of Open Access Journals (Sweden)

    Irina Petrache

    Full Text Available Increases in ceramide levels have been implicated in the pathogenesis of both acute or chronic lung injury models. However, the role of individual ceramide species, or of the enzymes that are responsible for their synthesis, in lung health and disease has not been clarified. We now show that C24- and C16-ceramides are the most abundant lung ceramide species, paralleled by high expression of their synthetic enzymes, ceramide synthase 2 (CerS2 and CerS5, respectively. Furthermore, the ceramide species synthesis in the lung is homeostatically regulated, since mice lacking very long acyl chain C24-ceramides due to genetic deficiency of CerS2 displayed a ten-fold increase in C16-ceramides and C16-dihydroceramides along with elevation of acid sphingomyelinase and CerS5 activities. Despite relatively preserved total lung ceramide levels, inhibition of de novo sphingolipid synthesis at the level of CerS2 was associated with significant airflow obstruction, airway inflammation, and increased lung volumes. Our results suggest that ceramide species homeostasis is crucial for lung health and that CerS2 dysfunction may predispose to inflammatory airway and airspace diseases.

  1. Lung-Derived Microscaffolds Facilitate Diabetes Reversal after Mouse and Human Intraperitoneal Islet Transplantation.

    Science.gov (United States)

    Abualhassan, Nasser; Sapozhnikov, Lena; Pawlick, Rena L; Kahana, Meygal; Pepper, Andrew R; Bruni, Antonio; Gala-Lopez, Boris; Kin, Tatsuya; Mitrani, Eduardo; Shapiro, A M James

    2016-01-01

    There is a need to develop three-dimensional structures that mimic the natural islet tissue microenvironment. Endocrine micro-pancreata (EMPs) made up of acellular organ-derived micro-scaffolds seeded with human islets have been shown to express high levels of key beta-cell specific genes and secrete quantities of insulin per cell similar to freshly isolated human islets in a glucose-regulated manner for more than three months in vitro. The aim of this study was to investigate the capacity of EMPs to restore euglycemia in vivo after transplantation of mouse or human islets in chemically diabetic mice. We proposed that the organ-derived EMPs would restore the extracellular components of the islet microenvironment, generating favorable conditions for islet function and survival. EMPs seeded with 500 mouse islets were implanted intraperitoneally into streptozotocin-induced diabetic mice and reverted diabetes in 67% of mice compared to 13% of controls (p = 0.018, n = 9 per group). Histological analysis of the explanted grafts 60 days post-transplantation stained positive for insulin and exhibited increased vascular density in a collagen-rich background. EMPs were also seeded with human islets and transplanted into the peritoneal cavity of immune-deficient diabetic mice at 250 islet equivalents (IEQ), 500 IEQ and 1000 IEQ. Escalating islet dose increased rates of normoglycemia (50% of the 500 IEQ group and 75% of the 1000 IEQ group, n = 3 per group). Human c-peptide levels were detected 90 days post-transplantation in a dose-response relationship. Herein, we report reversal of diabetes in mice by intraperitoneal transplantation of human islet seeded on EMPs with a human islet dose as low as 500 IEQ.

  2. Serial micro-CT assessment of the therapeutic effects of rosiglitazone in a bleomycin-induced lung fibrosis mouse model

    Energy Technology Data Exchange (ETDEWEB)

    Choi, Eun Jung; Jin, Gong Yong; Bok, Se Mi; Han, Young Min; Lee, Young Sun; Jung, Myung Ja; Kwon, Keun Sang [Research Institute of Clinical Medicine of Chonbuk National University, Biomedical Research Institute of Chonbuk National University Hospital, Institute for Medical Sciences, Jeonju (Korea, Republic of)

    2014-08-15

    The aim of this study was to assess the therapeutic effects of rosiglitazone with serial micro-CT findings before and after rosiglitazone administration in a lung fibrosis mouse model induced with bleomycin. We instilled the bleomycin solution directly into the trachea in twenty mice (female, C57BL/6 mice). After the instillation with bleomycin, mice were closely observed for 3 weeks and then all mice were scanned using micro-CT without sacrifice. At 3 weeks, the mice were treated with rosiglitazone on days 21 to 27 if they had abnormal CT findings (n = 9, 45%). For the mice treated with rosiglitazone, we performed micro-CT with mouse sacrifice 2 weeks after the rosiglitazone treatment completion. We assessed the abnormal CT findings (ground glass attenuation, consolidation, bronchiectasis, reticular opacity, and honeycombing) using a five-point scale at 3 and 6 weeks using Wilcoxon-signed ranked test. The micro-CT findings were correlated with the histopathologic results. One out of nine (11.1%) mice improved completely. In terms of consolidation, all mice (100%) showed marked decrease from 3.1 ± 1.4 at 3 weeks to 0.9 ± 0.9 at 6 weeks (p = 0.006). At 6 weeks, mild bronchiectasis (n = 6, 66.7%), mild reticular opacity (n 7, 77.8%) and mild honeycomb patterns (n = 3, 33.3%) appeared. A serial micro-CT enables the evaluation of drug effects in a lung fibrosis mouse model.

  3. Study on the protective effect of ethyl pyruvate on mouse models of sepsis-induced lung injury

    International Nuclear Information System (INIS)

    Ti Dongdong; Deng Zihui; Xue Hui; Wang Luhuan; Lin Ji; Yan Guangtao

    2008-01-01

    Objective: To investigate the protective role of ethyl pyruvate on mouse models of lung injury from sepsis. Methods: Mouse sepsis models were established by cecal ligation-perforation. Four enzyme parameters related to synthesis of free radicals in lung homogenized fluids namely malonaldehyde (MDA), pyruvate acid, lactic acid and total anti-oxidative capacity (TAOC) were determined with spectrophotometry, and serum leptin levels were detected with radioimmunoassay at 3, 6, 9, 12h after operation in these models. Half of the models were treated with intraperitoneal injection of ethyl pyruvate (EP) (75mg/kg). Results: In the models treated with ethyl pyruvate injection, the activity of malonaldehyde, pyruvate acid, lactic acid and total anti-oxidative capacity were affected to certain extent, at some time frames but the results were not unanimously inhibitive or promotive. Serum leptin levels in EP injection models at 6h and 12h after sepsis were significantly higher than those in non-treated models. Conclusion: Ethyl pyruvate perhaps exerted its protective effect on sepsis-induced lung injury through increase of leptin levels in the models. (authors)

  4. Evaluation of an adherent mouse embryonic stem cell in vitro assay to predict developmental toxicity of ToxCast chemicals.

    Science.gov (United States)

    The potential for most environmental chemicals to produce developmental toxicity is unknown. Mouse embryonic stem cell (mESC) assays are an alternative in vitro model to assess chemicals. The chemical space evaluated using mESC and compared to in vivo is limited. We used an adher...

  5. The effects of exogenous surfactant administration on ventilation-induced inflammation in mouse models of lung injury.

    Science.gov (United States)

    Puntorieri, Valeria; Hiansen, Josh Qua; McCaig, Lynda A; Yao, Li-Juan; Veldhuizen, Ruud A W; Lewis, James F

    2013-11-20

    Mechanical ventilation (MV) is an essential supportive therapy for acute lung injury (ALI); however it can also contribute to systemic inflammation. Since pulmonary surfactant has anti-inflammatory properties, the aim of the study was to investigate the effect of exogenous surfactant administration on ventilation-induced systemic inflammation. Mice were randomized to receive an intra-tracheal instillation of a natural exogenous surfactant preparation (bLES, 50 mg/kg) or no treatment as a control. MV was then performed using the isolated and perfused mouse lung (IPML) set up. This model allowed for lung perfusion during MV. In experiment 1, mice were exposed to mechanical ventilation only (tidal volume =20 mL/kg, 2 hours). In experiment 2, hydrochloric acid or air was instilled intra-tracheally four hours before applying exogenous surfactant and ventilation (tidal volume =5 mL/kg, 2 hours). For both experiments, exogenous surfactant administration led to increased total and functional surfactant in the treated groups compared to the controls. Exogenous surfactant administration in mice exposed to MV only did not affect peak inspiratory pressure (PIP), lung IL-6 levels and the development of perfusate inflammation compared to non-treated controls. Acid injured mice exposed to conventional MV showed elevated PIP, lung IL-6 and protein levels and greater perfusate inflammation compared to air instilled controls. Instillation of exogenous surfactant did not influence the development of lung injury. Moreover, exogenous surfactant was not effective in reducing the concentration of inflammatory cytokines in the perfusate. The data indicates that exogenous surfactant did not mitigate ventilation-induced systemic inflammation in our models. Future studies will focus on altering surfactant composition to improve its immuno-modulating activity.

  6. Validation of Tuba1a as Appropriate Internal Control for Normalization of Gene Expression Analysis during Mouse Lung Development

    Directory of Open Access Journals (Sweden)

    Aditi Mehta

    2015-02-01

    Full Text Available The expression ratio between the analysed gene and an internal control gene is the most widely used normalization method for quantitative RT-PCR (qRT-PCR expression analysis. The ideal reference gene for a specific experiment is the one whose expression is not affected by the different experimental conditions tested. In this study, we validate the applicability of five commonly used reference genes during different stages of mouse lung development. The stability of expression of five different reference genes (Tuba1a, Actb Gapdh, Rn18S and Hist4h4 was calculated within five experimental groups using the statistical algorithm of geNorm software. Overall, Tuba1a showed the least variability in expression among the different stages of lung development, while Hist4h4 and Rn18S showed the maximum variability in their expression. Expression analysis of two lung specific markers, surfactant protein C (SftpC and Clara cell-specific 10 kDA protein (Scgb1a1, normalized to each of the five reference genes tested here, confirmed our results and showed that incorrect reference gene choice can lead to artefacts. Moreover, a combination of two internal controls for normalization of expression analysis during lung development will increase the accuracy and reliability of results.

  7. The genetic basis of strain-dependent differences in the early phase of radiation injury in mouse lung

    International Nuclear Information System (INIS)

    Franko, A.J.; Sharplin, J.; Ward, W.F.; Hinz, J.M.

    1991-01-01

    Substantial differences between mouse strains have been reported in the lesions present in the lung during the early phase of radiation injury. Some strains show only classical pneumonitis, while other strains develop substantial fibrosis and hyaline membranes which contribute appreciably to respiratory insufficiency, in addition to pneumonitis. Other strains are intermediate between these extremes. These differences correlate with intrinsic differences in activities of lung plasminogen activator and angiotensin converting enzyme. The genetic basis of these differences was assessed by examining histologically the early reaction in lungs of seven murine hybrids available commercially after whole-thorax irradiation. Crosses between fibrosing and nonfibrosing parents were uniformly nonfibrosing, and crosses between fibrosing and intermediate parents were uniformly intermediate. No evidence of sex linkage was seen. Thus the phenotype in which fibrosis is found is controlled by autosomal recessive determinants. Strains prone to radiation-induced pulmonary fibrosis and hyaline membranes exhibited intrinsically lower activities of lung plasminogen activator and angiotensin converting enzyme than either the nonfibrosing strains or the nonfibrosing hybrid crosses. The median time of death of the hybrids was genetically determined primarily by the longest-lived parent regardless of the types of lesions expressed

  8. Imaging of lung metastasis tumor mouse model using [{sup 18}F]FDG small animal PET and CT

    Energy Technology Data Exchange (ETDEWEB)

    Kim, June Youp; Woo, Sang Keun; Lee, Tae Sup [Korea Institute of Radiological and Medical Sciences (KIRAMS), Seoul (Korea, Republic of)] (and others)

    2007-02-15

    The purpose of this study is to image metastaic lung melanoma model with optimal pre-conditions for animal handling by using [{sup 18}F]FDG small animal PET and clinical CT. The pre-conditions for lung region tumor imaging were 16-22 h fasting and warming temperature at 30 .deg. C. Small animal PET image was obtained at 60 min postinjection of 7.4 MBq [{sup 18}F]FDG and compared pattern of [{sup 18}F]FDG uptake and glucose standard uptake value (SUVG) of lung region between Ketamine/Xylazine (Ke/Xy) and Isoflurane (Iso) anesthetized group in normal mice. Metastasis tumor mouse model to lung was established by intravenous injection of B16-F10 cells in C57BL/6 mice. In lung metastasis tumor model, [{sup 18}F]FDG image was obtained and fused with anatomical clinical CT image. Average blood glucose concentration in normal mice were 128.0 {+-} 22.87 and 86.0 {+-} 21.65 mg/dL in Ke/Xy group and Iso group, respectively. Ke/Xy group showed 1.5 fold higher blood glucose concentration than Iso group. Lung to Background ratio (L/B) in SUVG image was 8.6 {+-} 0.48 and 12.1 {+-}0.63 in Ke/Xy group and Iso group, respectively. In tumor detection in lung region, [{sup 18}F]FDG image of Iso group was better than that of Ke/Xy group, because of high L/B ratio. Metastatic tumor location in [{sup 18}F]FDG small animal PET image was confirmed by fusion image using clinical CT. Tumor imaging in small animal lung region with [{sup 18}F]FDG small animal PET should be considered pre-conditions which fasting, warming and an anesthesia during [{sup 18}F]FDG uptake. Fused imaging with small animal PET and CT image could be useful for the detection of metastatic tumor in lung region.

  9. Deficiency of CCAAT/enhancer binding protein family DNA binding prevents malignant conversion of adenoma to carcinoma in NNK-induced lung carcinogenesis in the mouse

    Directory of Open Access Journals (Sweden)

    Kimura Shioko

    2012-12-01

    Full Text Available Abstract Background The CCAAT/enhancer binding proteins (C/EBPs play important roles in carcinogenesis of many tumors including the lung. Since multiple C/EBPs are expressed in lung, the combinatorial expression of these C/EBPs on lung carcinogenesis is not known. Methods A transgenic mouse line expressing a dominant negative A-C/EBP under the promoter of lung epithelial Clara cell secretory protein (CCSP gene in doxycycline dependent fashion was subjected to 4-(methylnitrosamino-1-(3-pyridyl-1-butanone (NNK-induced lung carcinogenesis bioassay in the presence and absence of doxycycline, and the effect of abolition of DNA binding activities of C/EBPs on lung carcinogenesis was examined. Results A-C/EBP expression was found not to interfere with tumor development; however, it suppressed the malignant conversion of adenoma to carcinoma during NNK-induced lung carcinogenesis. The results suggested that Ki67 may be used as a marker for lung carcinomas in mouse. Conclusions The DNA binding of C/EBP family members can be used as a potential molecular target for lung cancer therapy.

  10. Multi-Modal Imaging in a Mouse Model of Orthotopic Lung Cancer

    OpenAIRE

    Patel, Priya; Kato, Tatsuya; Ujiie, Hideki; Wada, Hironobu; Lee, Daiyoon; Hu, Hsin-pei; Hirohashi, Kentaro; Ahn, Jin Young; Zheng, Jinzi; Yasufuku, Kazuhiro

    2016-01-01

    Background Investigation of CF800, a novel PEGylated nano-liposomal imaging agent containing indocyanine green (ICG) and iohexol, for real-time near infrared (NIR) fluorescence and computed tomography (CT) image-guided surgery in an orthotopic lung cancer model in nude mice. Methods CF800 was intravenously administered into 13 mice bearing the H460 orthotopic human lung cancer. At 48 h post-injection (peak imaging agent accumulation time point), ex vivo NIR and CT imaging was performed. A cli...

  11. Mouse mammary tumor virus-like gene sequences are present in lung patient specimens

    Directory of Open Access Journals (Sweden)

    Rodríguez-Padilla Cristina

    2011-09-01

    Full Text Available Abstract Background Previous studies have reported on the presence of Murine Mammary Tumor Virus (MMTV-like gene sequences in human cancer tissue specimens. Here, we search for MMTV-like gene sequences in lung diseases including carcinomas specimens from a Mexican population. This study was based on our previous study reporting that the INER51 lung cancer cell line, from a pleural effusion of a Mexican patient, contains MMTV-like env gene sequences. Results The MMTV-like env gene sequences have been detected in three out of 18 specimens studied, by PCR using a specific set of MMTV-like primers. The three identified MMTV-like gene sequences, which were assigned as INER6, HZ101, and HZ14, were 99%, 98%, and 97% homologous, respectively, as compared to GenBank sequence accession number AY161347. The INER6 and HZ-101 samples were isolated from lung cancer specimens, and the HZ-14 was isolated from an acute inflammatory lung infiltrate sample. Two of the env sequences exhibited disruption of the reading frame due to mutations. Conclusion In summary, we identified the presence of MMTV-like gene sequences in 2 out of 11 (18% of the lung carcinomas and 1 out of 7 (14% of acute inflamatory lung infiltrate specimens studied of a Mexican Population.

  12. On the tear proteome of the house mouse (Mus musculus musculus in relation to chemical signalling

    Directory of Open Access Journals (Sweden)

    Romana Stopkova

    2017-07-01

    Full Text Available Mammalian tears are produced by lacrimal glands to protect eyes and may function in chemical communication and immunity. Recent studies on the house mouse chemical signalling revealed that major urinary proteins (MUPs are not individually unique in Mus musculus musculus. This fact stimulated us to look for other sexually dimorphic proteins that may—in combination with MUPs—contribute to a pool of chemical signals in tears. MUPs and other lipocalins including odorant binding proteins (OBPs have the capacity to selectively transport volatile organic compounds (VOCs in their eight-stranded beta barrel, thus we have generated the tear proteome of the house mouse to detect a wider pool of proteins that may be involved in chemical signalling. We have detected significant male-biased (7.8% and female-biased (7% proteins in tears. Those proteins that showed the most elevated sexual dimorphisms were highly expressed and belong to MUP, OBP, ESP (i.e., exocrine gland-secreted peptides, and SCGB/ABP (i.e., secretoglobin families. Thus, tears may have the potential to elicit sex-specific signals in combination by different proteins. Some tear lipocalins are not sexually dimorphic—with MUP20/darcin and OBP6 being good examples—and because all proteins may flow with tears through nasolacrimal ducts to nasal and oral cavities we suggest that their roles are wider than originally thought. Also, we have also detected several sexually dimorphic bactericidal proteins, thus further supporting an idea that males and females may have adopted alternative strategies in controlling microbiota thus yielding different VOC profiles.

  13. In vitro mouse spermatogenesis with an organ culture method in chemically defined medium.

    Directory of Open Access Journals (Sweden)

    Hiroyuki Sanjo

    Full Text Available We previously reported the successful induction and completion of mouse spermatogenesis by culturing neonatal testis tissues. The culture medium consisted of α-minimum essential medium (α-MEM, supplemented with Knockout serum replacement (KSR or AlbuMAX, neither of which were defined chemically. In this study, we formulated a chemically defined medium (CDM that can induce mouse spermatogenesis under organ culture conditions. It was found that bovine serum albumin (BSA purified through three different procedures had different effects on spermatogenesis. We also confirmed that retinoic acid (RA played crucial roles in the onset of spermatogonial differentiation and meiotic initiation. The added lipids exhibited weak promoting effects on spermatogenesis. Lastly, luteinizing hormone (LH, follicle stimulating hormone (FSH, triiodothyronine (T3, and testosterone (T combined together promoted spermatogenesis until round spermatid production. The CDM, however, was not able to produce elongated spermatids. It was also unable to induce spermatogenesis from the very early neonatal period, before 2 days postpartum, leaving certain factors necessary for spermatogenic induction in mice unidentified. Nonetheless, the present study provided important basic information on testis organ culture and spermatogenesis in vitro.

  14. MWCNTs of different physicochemical properties cause similar inflammatory responses, but differences in transcriptional and histological markers of fibrosis in mouse lungs

    DEFF Research Database (Denmark)

    Poulsen, Sarah S.; Saber, Anne T.; Williams, Andrew

    2015-01-01

    Multi-walled carbon nanotubes (MWCNTs) are an inhomogeneous group of nanomaterials that vary in lengths, shapes and types of metal contamination, which makes hazard evaluation difficult. Here we present a toxicogenomic analysis of female C57BL/6 mouse lungs following a single intratracheal instil...

  15. Multi-Modal Imaging in a Mouse Model of Orthotopic Lung Cancer.

    Science.gov (United States)

    Patel, Priya; Kato, Tatsuya; Ujiie, Hideki; Wada, Hironobu; Lee, Daiyoon; Hu, Hsin-Pei; Hirohashi, Kentaro; Ahn, Jin Young; Zheng, Jinzi; Yasufuku, Kazuhiro

    2016-01-01

    Investigation of CF800, a novel PEGylated nano-liposomal imaging agent containing indocyanine green (ICG) and iohexol, for real-time near infrared (NIR) fluorescence and computed tomography (CT) image-guided surgery in an orthotopic lung cancer model in nude mice. CF800 was intravenously administered into 13 mice bearing the H460 orthotopic human lung cancer. At 48 h post-injection (peak imaging agent accumulation time point), ex vivo NIR and CT imaging was performed. A clinical NIR imaging system (SPY®, Novadaq) was used to measure fluorescence intensity of tumor and lung. Tumor-to-background-ratios (TBR) were calculated in inflated and deflated states. The mean Hounsfield unit (HU) of lung tumor was quantified using the CT data set and a semi-automated threshold-based method. Histological evaluation using H&E, the macrophage marker F4/80 and the endothelial cell marker CD31, was performed, and compared to the liposomal fluorescence signal obtained from adjacent tissue sections. The fluorescence TBR measured when the lung is in the inflated state (2.0 ± 0.58) was significantly greater than in the deflated state (1.42 ± 0.380 (n = 7, p<0.003). Mean fluorescent signal in tumor was highly variable across samples, (49.0 ± 18.8 AU). CT image analysis revealed greater contrast enhancement in lung tumors (a mean increase of 110 ± 57 HU) when CF800 is administered compared to the no contrast enhanced tumors (p = 0.0002). Preliminary data suggests that the high fluorescence TBR and CT tumor contrast enhancement provided by CF800 may have clinical utility in localization of lung cancer during CT and NIR image-guided surgery.

  16. CYP2F2-generated metabolites, not styrene oxide, are a key event mediating the mode of action of styrene-induced mouse lung tumors.

    Science.gov (United States)

    Cruzan, G; Bus, J; Hotchkiss, J; Harkema, J; Banton, M; Sarang, S

    2012-02-01

    Styrene induces lung tumors in mice but not in rats. Although metabolism of styrene to 7,8-styrene oxide (SO) by CYP2E1 has been suggested as a mediator of styrene toxicity, lung toxicity is not attenuated in CYP2E1 knockout mice. However, styrene and/or SO metabolism by mouse lung Clara cell-localized CYP2F2 to ring-oxidized cytotoxic metabolite(s) has been postulated as a key metabolic gateway responsible for both lung toxicity and possible tumorigenicity. To test this hypothesis, the lung toxicity of styrene and SO was evaluated in C57BL/6 (WT) and CYP2F2⁻/⁻ knockout mice treated with styrene (400 mg/kg/day, gavage, or 200 or 400 mg/kg/day, ip) or S- or R-SO (200 mg/kg/day, ip) for 5 days. Styrene treated WT mice displayed significant necrosis and exfoliation of Clara cells, and cumulative BrdU-labeling index of S-phase cells was markedly increased in terminal bronchioles of WT mice exposed to styrene or S- or RSO. In contrast, Clara and terminal bronchiole cell toxicity was not observed in CYP2F2⁻/⁻ mice exposed to either styrene or SO. This study clearly demonstrates that the mouse lung toxicity of both styrene and SO is critically dependent on metabolism by CYP2F2. Importantly, the human isoform of CYP2F, CYP2F1, is expressed at much lower levels and likely does not catalyze significant styrene metabolism, supporting the hypothesis that styrene-induced mouse lung tumors may not quantitatively, or possibly qualitatively, predict lung tumor potential in humans. Copyright © 2011 Elsevier Inc. All rights reserved.

  17. The radioprotective effects of methylprednisolone and Sho-Saikoto on mouse lung

    Energy Technology Data Exchange (ETDEWEB)

    Kure, Fumio [Kyoto Prefectural Univ. of Medicine (Japan)

    1992-01-01

    The radioprotective effects of methylprednisolone and Sho-Saikoto (a herbal medicine) on radiation damage to lung tissue were evaluated in four main groups of female Slc-ICR mice, one control group and three groups irradiated with single doses (6 Gy, 12 Gy, 18 Gy) of {sup 60}Co gamma rays. Subgroups were established with administration of methylprednisolone and Sho-Saikoto, alone and together. Direct quantitative measurements of collagen accumulation in lung (lung fibrosis) were made by analysis of digitally processed microscopic images of Azan-Mallory stained sections 24 weeks after irradiation. Administration of methylprednisolone supressed the expected development of fibrotic lung tissue in each of the irradiated groups. In a further study, peplomycin, a lung fibrosis enhancing agent, was administered to all four groups in addition to methylprednisolone and Sho-Saikoto, alone and together. Methylprednisolone was demonstrated to be effective only in 12 Gy group. Overall, Sho-Saikoto showed a lesser degree of effect in the prevention of the fibrosis than methylprednisolone, but the administration of both was demonstrated to be more effective than either alone. (author).

  18. The response of mouse skin and lung to fractionated x-rays

    International Nuclear Information System (INIS)

    Field, S.B.; Hornsey, S.

    1975-01-01

    The relationship between total dose and number of fractions has been investigated for damage to lung and skin in mice. Single doses and various numbers of fractions have been given and the results are analysed in two ways: (i) by comparing the fractionated treatment with a single dose. With this approach, and assuming that the observed damage to lung and skin is the result of cell killing, it is estimated that the ratio of initial to final slope of the cell survival curve is about 7:1; (ii) by measuring the additional dose required when the number of fractions is doubled. These results are roughly fitted by a single-hit times multitarget survival-curve model, with the ratio of slopes about 3:1. It is concluded from this discrepancy that the two-component model is an inadequate description of the survival curve for the cells of either skin or lung. (author)

  19. Chemical Cocktails Enable Hepatic Reprogramming of Mouse Fibroblasts with a Single Transcription Factor

    Directory of Open Access Journals (Sweden)

    Ren Guo

    2017-08-01

    Full Text Available Liver or hepatocytes transplantation is limited by the availability of donor organs. Functional hepatocytes independent of the donor sources may have wide applications in regenerative medicine and the drug industry. Recent studies have demonstrated that chemical cocktails may induce reprogramming of fibroblasts into a range of functional somatic cells. Here, we show that mouse fibroblasts can be transdifferentiated into the hepatocyte-like cells (iHeps using only one transcription factor (TF (Foxa1, Foxa2, or Foxa3 plus a chemical cocktail. These iHeps show typical epithelial morphology, express multiple hepatocyte-specific genes, and acquire hepatocyte functions. Genetic lineage tracing confirms the fibroblast origin of these iHeps. More interestingly, these iHeps are expandable in vitro and can reconstitute the damaged hepatic tissues of the fumarylacetoacetate hydrolase-deficient (Fah−/− mice. Our study provides a strategy to generate functional hepatocyte-like cells by using a single TF plus a chemical cocktail and is one step closer to generate the full-chemical iHeps.

  20. Genetic effects of combined chemical-X-ray treatments in male mouse germ cells

    International Nuclear Information System (INIS)

    Cattanach, B.M.; Rasberry, C.

    1987-01-01

    Several studies have shown that the yield of genetic damage induced by radiation in male mouse germ cells can be modified by chemical treatments. Pre-treatments with radio-protecting agents have given contradictory results but this appears to be largely attributable to the different germ cell stages tested and dependent upon the level of radiation damage induced. Pre-treatments which enhance the yield of genetic damage have been reported although, as yet, no tests have been conducted with radio-sensitizers. Another form of interaction between chemicals and radiation is specifically found with spermatogonial stem cells. Chemicals that kill cells can, by population depletion, substantially and predictably modify the genetic response to subsequent radiation exposure over a period of several days, or even weeks. Enhancement and reduction in the genetic yield can be attained, dependent upon the interval between treatments, with the modification also varying with the type of genetic damage scored. Post-treatment with one chemical (TEM) has been shown to reduce the genetic response to radiation exposure. (author)

  1. Quantifying morphological parameters of the terminal branching units in a mouse lung by phase contrast synchrotron radiation computed tomography.

    Directory of Open Access Journals (Sweden)

    Jeongeun Hwang

    Full Text Available An effective technique of phase contrast synchrotron radiation computed tomography was established for the quantitative analysis of the microstructures in the respiratory zone of a mouse lung. Heitzman's method was adopted for the whole-lung sample preparation, and Canny's edge detector was used for locating the air-tissue boundaries. This technique revealed detailed morphology of the respiratory zone components, including terminal bronchioles and alveolar sacs, with sufficiently high resolution of 1.74 µm isotropic voxel size. The technique enabled visual inspection of the respiratory zone components and comprehension of their relative positions in three dimensions. To check the method's feasibility for quantitative imaging, morphological parameters such as diameter, surface area and volume were measured and analyzed for sixteen randomly selected terminal branching units, each consisting of a terminal bronchiole and a pair of succeeding alveolar sacs. The four types of asymmetry ratios concerning alveolar sac mouth diameter, alveolar sac surface area, and alveolar sac volume are measured. This is the first ever finding of the asymmetry ratio for the terminal bronchioles and alveolar sacs, and it is noteworthy that an appreciable degree of branching asymmetry was observed among the alveolar sacs at the terminal end of the airway tree, despite the number of samples was small yet. The series of efficient techniques developed and confirmed in this study, from sample preparation to quantification, is expected to contribute to a wider and exacter application of phase contrast synchrotron radiation computed tomography to a variety of studies.

  2. Influenza A virus infection and cigarette smoke impair bronchodilator responsiveness to β-adrenoceptor agonists in mouse lung.

    Science.gov (United States)

    Donovan, Chantal; Seow, Huei Jiunn; Bourke, Jane E; Vlahos, Ross

    2016-05-01

    β2-adrenoceptor agonists are the mainstay therapy for patients with asthma but their effectiveness in cigarette smoke (CS)-induced lung disease such as chronic obstructive pulmonary disease (COPD) is limited. In addition, bronchodilator efficacy of β2-adrenoceptor agonists is decreased during acute exacerbations of COPD (AECOPD), caused by respiratory viruses including influenza A. Therefore, the aim of the present study was to assess the effects of the β2-adrenoceptor agonist salbutamol (SALB) on small airway reactivity using mouse precision cut lung slices (PCLS) prepared from CS-exposed mice and from CS-exposed mice treated with influenza A virus (Mem71, H3N1). CS exposure alone reduced SALB potency and efficacy associated with decreased β2-adrenoceptor mRNA expression, and increased tumour necrosis factor α (TNFα) and interleukin-1β (IL-1β) expression. This impaired relaxation was restored by day 12 in the absence of further CS exposure. In PCLS prepared after Mem71 infection alone, responses to SALB were transient and were not well maintained. CS exposure prior to Mem71 infection almost completely abolished relaxation, although β2-adrenoceptor and TNFα and IL-1β expression were unaltered. The present study has shown decreased sensitivity to SALB after CS or a combination of CS and Mem71 occurs by different mechanisms. In addition, the PCLS technique and our models of CS and influenza infection provide a novel setting for assessment of alternative bronchodilators. © 2016 The Author(s).

  3. Combination Effect of Regulatory T-Cell Depletion and Ionizing Radiation in Mouse Models of Lung and Colon Cancer

    Energy Technology Data Exchange (ETDEWEB)

    Son, Cheol-Hun [Dongnam Institute of Radiological and Medical Sciences, Busan (Korea, Republic of); Department of Biochemistry, Pusan National University School of Medicine, Yangsan (Korea, Republic of); Bae, Jae-Ho [Department of Biochemistry, Pusan National University School of Medicine, Yangsan (Korea, Republic of); Shin, Dong-Yeok; Lee, Hong-Rae; Jo, Wol-Soon; Yang, Kwangmo [Dongnam Institute of Radiological and Medical Sciences, Busan (Korea, Republic of); Park, You-Soo, E-mail: biotek01@hanmail.net [Dongnam Institute of Radiological and Medical Sciences, Busan (Korea, Republic of)

    2015-06-01

    Purpose: To investigate the potential of low-dose cyclophosphamide (LD-CTX) and anti-CD25 antibody to prevent activation of regulatory T cells (Tregs) during radiation therapy. Methods and Materials: We used LD-CTX and anti-CD25 monoclonal antibody as a means to inhibit Tregs and improve the therapeutic effect of radiation in a mouse model of lung and colon cancer. Mice were irradiated on the tumor mass of the right leg and treated with LD-CTX and anti-CD25 antibody once per week for 3 weeks. Results: Combined treatment of LD-CTX or anti-CD25 antibody with radiation significantly decreased Tregs in the spleen and tumor compared with control and irradiation only in both lung and colon cancer. Combinatorial treatments resulted in a significant increase in the effector T cells, longer survival rate, and suppressed irradiated and distal nonirradiated tumor growth. Specifically, the combinatorial treatment of LD-CTX with radiation resulted in outstanding regression of local and distant tumors in colon cancer, and almost all mice in this group survived until the end of the study. Conclusions: Our results suggest that Treg depletion strategies may enhance radiation-mediated antitumor immunity and further improve outcomes after radiation therapy.

  4. Increased cytosine DNA-methyltransferase activity in A/J mouse lung cells following carcinogen exposure and during tumor progression

    International Nuclear Information System (INIS)

    Belinsky, S.A.; Issa, J.-P.J.; Baylin, S.B.

    1994-01-01

    Considerable evidence has accumulated that 5-methylcytosine modification of mammalian DNA, both in exons and CpG rich islands located in promoter regions, is important in gene regulation. For example, a decrease of 5-methylcytosine in 5' flanking regions or exons of genes has been associated with increased gene transcription. In addition, hypermethylation at specific regions of chromosomes 17p and 3p have also been observed in lung and colon cancer. During colon cancer development, these hypermethylation changes precede allelic loss. In addition, the activity of the enzyme which maintains the methylation status at CpG dinucleotides, DNA methyltransferase (MT), has been shown to increase during colon cancer progression. These observations suggest changes in methylation patterns within specific genes could result in either inappropriate gene expression or gene deletion, both of which would contribute to the establishment of the malignant phenotype. The purpose of this investigation was to determine if DNA MT activity is elevated in target (alveolar type II), but not in nontarget (Clara, endothelial, macrophage) lung cells isolated from the A/J mouse following exposure to nitrosamine 4-methylnitrosamino-1-(3-pyridyl)-1-butanone (NNK). In addition, the activity of this enzyme during tumor progression was examined

  5. Irradiation induces increased production of haemopoietic and proinflammatory cytokines in the mouse lung

    Czech Academy of Sciences Publication Activity Database

    Fedoročko, P.; Agyed, A.; Vacek, Antonín

    2002-01-01

    Roč. 78, č. 4 (2002), s. 305-313 ISSN 0955-3002 Grant - others:VEGA MŠ SR(SK) 1/6026/99 Institutional research plan: CEZ:AV0Z5004920 Keywords : colony-stimulating activity (CSA) * lung-conditioned media (LCM) * mice Subject RIV: BO - Biophysics Impact factor: 2.119, year: 2002

  6. Impact of Cigarette Smoke on the Human and Mouse Lungs : A Gene-Expression Comparison Study

    NARCIS (Netherlands)

    Morissette, Mathieu C.; Lamontagne, Maxime; Berube, Jean-Christophe; Gaschler, Gordon; Williams, Andrew; Yauk, Carole; Couture, Christian; Laviolette, Michel; Hogg, James C.; Timens, Wim; Halappanavar, Sabina; Stampfli, Martin R.; Bosse, Yohan

    2014-01-01

    Cigarette smoke is well known for its adverse effects on human health, especially on the lungs. Basic research is essential to identify the mechanisms involved in the development of cigarette smoke-related diseases, but translation of new findings from pre-clinical models to the clinic remains

  7. Nanotitanium dioxide toxicity in mouse lung is reduced in sanding dust from paint

    DEFF Research Database (Denmark)

    Saber, Anne Thoustrup; Jacobsen, Nicklas Raun; Mortensen, Alicja

    2012-01-01

    with severity similar to Printex 90. The inflammatory response of NanoTiO(2) and Printex 90 correlated with the instilled surface area. None of the materials, except of Printex 90, induced DNA damage in lung lining fluid cells. The highest dose of NanoTiO(2) caused DNA damage in hepatic tissue 1 day after...

  8. Intermittent hypoxia increases melanoma metastasis to the lung in a mouse model of sleep apnea.

    Science.gov (United States)

    Almendros, Isaac; Montserrat, Josep M; Torres, Marta; Dalmases, Mireia; Cabañas, Maria L; Campos-Rodríguez, Francisco; Navajas, Daniel; Farré, Ramon

    2013-05-01

    Obstructive sleep apnea (OSA) has recently been associated with an increased risk of cancer incidence and mortality in humans. Experimental data in mice have also shown that intermittent hypoxia similar to that observed in OSA patients enhances tumor growth. The aim of this study was to test the hypothesis that intermittent hypoxia mimicking OSA enhances lung metastasis. A total of 75 C57BL/6J male mice (10-week-old) were subjected to either spontaneous or induced melanoma lung metastasis. Normoxic animals breathed room air and intermittent hypoxic animals were subjected to cycles of 20s of 5% O2 followed by 40s of room air for 6h/day. Spontaneous and induced lung metastases were studied after subcutaneous and intravenous injection of B16F10 melanoma cells, respectively. Compared with normoxia, intermittent hypoxia induced a significant increase in melanoma lung metastasis. These animal model results suggest that intermittent hypoxia could contribute to cancer metastasis in patients with OSA. Copyright © 2013 Elsevier B.V. All rights reserved.

  9. Quantitative study of late injury in the irradiated mouse lung using computer graphics

    International Nuclear Information System (INIS)

    Tanabe, Masahiro; Furuse, Takeshi; Rapachietta, D.R.; Kallman, R.F.

    1990-01-01

    It is reported that quantitative histological analysis using current imaging technology and computer graphics is useful in studying late injury in the irradiated lung (with and without added chemotherapy), and that it correlated closely with results of the functional breathing rate test. (author). 7 refs.; 1 fig

  10. Dietary vitamin A and lung cancer: results of a case-control study among chemical workers.

    Science.gov (United States)

    Bond, G G; Thompson, F E; Cook, R R

    1987-01-01

    A nested case-control study conducted among a cohort of chemical manufacturing employees provided an opportunity to test the hypothesis that lung cancer risk is inversely related to dietary intake of vitamin A. Eligible for study were 308 former male employees who had died of lung cancer between 1940 and 1980. Two control groups, one a decedent and the other a "living" series, were individually matched to the cases one-for-one. Interviews were completed with 734 subjects or their next-of-kin and included a food frequency list. A vitamin A index was developed for each subject based on the frequency of consumption of 29 food items. After adjustment for a number of potentially confounding variables (e.g., smoking, educational level, and use of vitamin supplements), there was evidence that vitamin A intake was inversely associated with lung cancer risk. The effect was most pronounced in the comparisons with the "living" controls and appeared strongest among cigarette smokers. Subjects in the lowest tertile of vitamin A intake had approximately twice the risk of lung cancer as those in the highest. Analyses of an index of carotenoids and of individual food items suggested that plant sources of vitamin A may play a more important role in producing the effect than do animal sources.

  11. [Pulmonary apoptosis and necrosis in hyperoxia-induced acute mouse lung injury].

    Science.gov (United States)

    Zhang, Xiang-feng; Foda, Hussein D

    2004-07-01

    To investigate the pathways to cell death in hyperoxia-induced lung injury and the functional significance of apoptosis in vivo in response to hyperoxia. Seventy-two mice were exposed in sealed cages > 98% oxygen (for 24 - 72 h) or room air, and the severity of lung injury and epithelium sloughing was evaluated. The extent and location of apoptosis in injured lung tissues were studied by terminal transferase dUTP end labeling assay (TUNEL), reverse transcript-polymerase chain reaction (RT-PCR) and immunohistochemistry. Hyperoxia caused acute lung injury; the hyperoxic stress resulted in marked epithelium sloughing. TUNEL assay exhibited increased apoptosis index both in alveolar epithelial cells and bronchial epithelial cells in sections from mice after 48 h hyperoxia compared with their control group (0.51 +/- 0.10, 0.46 +/- 0.08 verse 0.04 +/- 0.02, 0.02 +/- 0.01). This was accompanied by increased expression of caspase-3 mRNA in lung tissues after 48 h hyperoxia compared with their control group (0.53 +/- 0.09 verse 0.34 +/- 0.07), the expression was higher at 72 h of hyperoxia (0.60 +/- 0.08). Immunohistochemistry study showed caspase-3 protein was located in cytoplasm and nuclei of airway epithelial cells, alveolar epithelial cells and macrophage in hyperoxia mice. The expression of caspase-3 protein in airway epithelium significantly increased at 24 h of hyperoxia compared with their control group (41.62 +/- 3.46 verse 15.86 +/- 1.84), the expression level was highest at 72 h of hyperoxia (55.24 +/- 6.80). Both apoptosis and necrosis contribute to cell death during hyperoxia. Apoptosis plays an important role in alveolar damage and cell death from hyperoxia.

  12. Morphological correlates of fractionated radiation of the mouse lung: Early and late effects

    International Nuclear Information System (INIS)

    Penney, D.P.; Siemann, D.W.; Rubin, P.; Maltby, K.

    1994-01-01

    The definition and quantitation of radiation-induced morphologic alterations in murine lungs is presented. The extent of injury to the lung, which is the dose-limiting organ in the thorax, may be reduced by fractionating the total radiation exposure to permit partial repair of radiation-induced damage between fraction administration and also to permit a larger total exposure to be administered. The authors previously reported that, following fractionated radiation exposures, as the dose/fraction decreases, the total dose to reach an isoeffect increases, with an α/β ratio of 3.2 and 3.0 for breathing rates and lethality, respectively. In the present report, they provide comparative morphologic evaluation of the effects of weekly fractionated, daily fractionated, and hyperfractionated radiation exposures. The doses administered within each group were uniform. To determine morphologic alterations, LAF1 mice were irradiated with 3, 15, and 30 fractions delivered in 19 days overall treatment time. In the hyperfractionation schedule, the two fractions per day were separated by a 6-h time interval. Total doses were as follows: 15-21 Gy for weekly fractionation, 30-41.5 Gy for daily fractionation, and 30-49.5 Gy for hyperfractionated schedules. Lung tissue, recovered either 24 or 72 weeks following the final exposure, was evaluated by transmission and scanning electron microscopy and light microscopy. Morphological damage was not uniform throughout the exposed lung and tended to be concentrated in lobes or portions of lobes. In the three fractionation regimens studied, there is progressive sparing of the lung with increased fractionation during the pnuemonitic state (24 weeks postirradiation). Both daily and twice daily fractionations provide increased sparing over weekly fractionation during the fibrotic stages (72 weeks postirradiation), but were not markedly different from each other (i.e. weekly < daily = twice daily). 41 refs., 15 figs., 2 tabs

  13. Vitamin D Repletion Reduces the Progression of Premalignant Squamous Lesions in the NTCU Lung Squamous Cell Carcinoma Mouse Model

    Science.gov (United States)

    Mazzilli, Sarah A.; Hershberger, Pamela A.; Reid, Mary E.; Bogner, Paul N.; Atwood, Kristopher; Trump, Donald L.; Johnson, Candace S.

    2015-01-01

    The chemopreventive actions of vitamin D were examined in the N-nitroso-tris-chloroethylurea (NTCU) mouse model, a progressive model of lung squamous cell carcinoma (SCC). SWR/J mice were fed a deficient diet (D) containing no vitamin D3, a sufficient diet (S) containing 2000 IU/kg vitamin D3, or the same diets in combination with the active metabolite of vitamin D, calcitriol (C) (80 μg/kg, weekly). The percentage (%) of the mucosal surface of large airways occupied by dysplastic lesions was determined in mice after treatment with a total dose of 15 or 25 μmol NTCU (N). After treatment with 15 μmol NTCU, the % of the surface of large airways containing high-grade dysplastic (HGD) lesions were vitamin D-deficient +NTCU (DN), 22.7 % (p<0.05 compared to vitamin D-sufficient +NTCU (SN)); DN + C, 12.3%; SN, 8.7%; and SN + C, 6.6%. The extent of HGD increased with NTCU dose in the DN group. Proliferation, assessed by Ki-67 labeling, increased upon NTCU treatment. The highest Ki-67 labeling index was seen in the DN group. As compared to SN mice, DN mice exhibited a 3-fold increase (p <0.005) in circulating white blood cells (WBC), a 20% (p <0.05) increase in IL-6 levels, and a 4 -fold (p <0.005) increase in WBC in bronchial lavages. Thus, vitamin D repletion reduces the progression of premalignant lesions, proliferation, and inflammation, and may thereby suppress development of lung SCC. Further investigations of the chemopreventive effects of vitamin D in lung SCC are warranted. PMID:26276745

  14. Iron homeostasis and its disruption in mouse lung in iron deficiency and overload.

    Science.gov (United States)

    Giorgi, Gisela; D'Anna, María Cecilia; Roque, Marta Elena

    2015-10-01

    What is the central question of this study? The aim was to explore the role and hitherto unclear mechanisms of action of iron proteins in protecting the lung against the harmful effects of iron accumulation and the ability of pulmonary cells to mobilize iron in iron deficiency. What is the main finding and its importance? We show that pulmonary hepcidin appears not to modify cellular iron mobilization in the lung. We propose pathways for supplying iron to the lung in iron deficiency and for protecting the lung against iron excess in iron overload, mediated by the co-ordinated action of iron proteins, such as divalent metal transporter 1, ZRT-IRE-like-protein 14, transferrin receptor, ferritin, haemochromatosis-associated protein and ferroportin. Iron dyshomeostasis is associated with several forms of chronic lung disease, but its mechanisms of action remain to be elucidated. The aim of the present study was to determine the role of the lung in whole-animal models with iron deficiency and iron overload, studying the divalent metal transporter 1 (DMT1), ZRT-IRE-like protein 14 (ZIP14), transferrin receptor (TfR), haemochromatosis-associated protein (HFE), hepcidin, ferritin and ferroportin (FPN) expression. In each model, adult CF1 mice were divided into the following groups (six mice per group): (i) iron-overload model, iron saccharate i.p. and control group (iron adequate), 0.9% NaCl i.p.; and (ii) iron-deficiency model, induced by repeated bleeding, and control group (sham operated). Proteins were assessed by immunohistochemistry and Western blot. In control mice, DMT1 was localized in the cytoplasm of airway cells, and in iron deficiency and overload it was in the apical membrane. Divalent metal transporter 1 and TfR increased in iron deficiency, without changes in iron overload. ZRT-IRE-like protein 14 decreased in airway cells in iron deficiency and increased in iron overload. In iron deficiency, HFE and FPN were immunolocalized close to the apical membrane

  15. Ultrastructural alterations in the mouse lung caused by real-life ambient PM{sub 10} at urban traffic sites

    Energy Technology Data Exchange (ETDEWEB)

    Samara, Constantini, E-mail: csamara@chem.auth.gr [Environmental Pollution Control Laboratory, Department of Chemistry, Aristotle University of Thessaloniki, 541 24 Thesaloniki (Greece); Kouras, Athanasios; Kaidoglou, Katerina [Environmental Pollution Control Laboratory, Department of Chemistry, Aristotle University of Thessaloniki, 541 24 Thesaloniki (Greece); Emmanouil-Nikoloussi, Elpida-Niki; Simou, Chrysanthi; Bousnaki, Maria [Laboratory of Histology-Embryology and Anthropology, School of Medicine, Aristotle University of Thessaloniki, 541 24 Thesaloniki (Greece); Kelessis, Apostolos [Environmental Department, Municipality of Thessaloniki, Kleanthous 18, 54 642 Thessaloniki (Greece)

    2015-11-01

    Current levels of ambient air particulate matter (PM) are associated with mortality and morbidity in urban populations worldwide. Nevertheless, current knowledge does not allow precise quantification or definitive ranking of the health effects of individual PM components and indeed, associations may be the result of multiple components acting on different physiological mechanisms. In this paper, healthy Balb/c mice were exposed to ambient PM{sub 10} at a traffic site of a large city (Thessaloniki, northern Greece), in parallel to control mice that were exposed to filtered air. Structural damages were examined in ultrafine sections of lung tissues by Transmission Electronic Microscopy (TEM). Ambient PM{sub 10} samples were also collected during the exposure experiment and characterized with respect to chemical composition and oxidative potential. Severe ultrastructural alterations in the lung tissue after a 10-week exposure of mice at PM{sub 10} levels often exceeding the daily limit of Directive 2008/50/EC were revealed mainly implying PM-induced oxidative stress. The DTT-based redox activity of PM{sub 10} was found within the range of values reported for traffic sites being correlated with traffic-related constituents. Although linkage of the observed lung damage with specific chemical components or sources need further elucidation, the magnitude of biological responses highlight the necessity for national and local strategies for mitigation of particle emissions from combustion sources. - Highlights: • Animal exposure to PM10 was conducted at a traffic site of a large city. • Chemical and toxicological characterization of PM10 was carried out. • Severe degenerative alterations in alveolar cells were revealed. • PM induced oxidative stress from carbonaceous species was suggested.

  16. Ultrastructural alterations in the mouse lung caused by real-life ambient PM10 at urban traffic sites

    International Nuclear Information System (INIS)

    Samara, Constantini; Kouras, Athanasios; Kaidoglou, Katerina; Emmanouil-Nikoloussi, Elpida-Niki; Simou, Chrysanthi; Bousnaki, Maria; Kelessis, Apostolos

    2015-01-01

    Current levels of ambient air particulate matter (PM) are associated with mortality and morbidity in urban populations worldwide. Nevertheless, current knowledge does not allow precise quantification or definitive ranking of the health effects of individual PM components and indeed, associations may be the result of multiple components acting on different physiological mechanisms. In this paper, healthy Balb/c mice were exposed to ambient PM 10 at a traffic site of a large city (Thessaloniki, northern Greece), in parallel to control mice that were exposed to filtered air. Structural damages were examined in ultrafine sections of lung tissues by Transmission Electronic Microscopy (TEM). Ambient PM 10 samples were also collected during the exposure experiment and characterized with respect to chemical composition and oxidative potential. Severe ultrastructural alterations in the lung tissue after a 10-week exposure of mice at PM 10 levels often exceeding the daily limit of Directive 2008/50/EC were revealed mainly implying PM-induced oxidative stress. The DTT-based redox activity of PM 10 was found within the range of values reported for traffic sites being correlated with traffic-related constituents. Although linkage of the observed lung damage with specific chemical components or sources need further elucidation, the magnitude of biological responses highlight the necessity for national and local strategies for mitigation of particle emissions from combustion sources. - Highlights: • Animal exposure to PM10 was conducted at a traffic site of a large city. • Chemical and toxicological characterization of PM10 was carried out. • Severe degenerative alterations in alveolar cells were revealed. • PM induced oxidative stress from carbonaceous species was suggested

  17. Selective small-chemical inhibitors of protein arginine methyltransferase 5 with anti-lung cancer activity.

    Directory of Open Access Journals (Sweden)

    Gui-Mei Kong

    Full Text Available Protein arginine methyltransferase 5 (PRMT5 plays critical roles in a wide variety of biological processes, including tumorigenesis. By screening a library of small chemical compounds, we identified eight compounds that selectively inhibit the PRMT5 enzymatic activity, with IC50 values ranging from 0.1 to 6 μM. Molecular docking simulation and site-directed mutagenesis indicated that identified compounds target the substrate-binding site in PRMT5. Treatment of lung cancer cells with identified inhibitors led to inhibition of the symmetrical arginine methylation of SmD3 and histones and the cellular proliferation. Oral administration of the inhibitor demonstrated antitumor activity in a lung tumor xenograft model. Thus, identified PRMT5-specific small-molecule inhibitors would help elucidate the biological roles of PRMT5 and serve as lead compounds for future drug development.

  18. Detecting small lung tumors in mouse models by refractive-index microradiology

    Energy Technology Data Exchange (ETDEWEB)

    Chien, Chia-Chi; Hwu, Y. [Academia Sinica, Institute of Physics, Taipei (China); National Tsing Hua University, Department of Engineering and System Science, Hsinchu (China); Zhang, Guilin; Yue, Weisheng; Li, Yan; Xue, Hongjie [Chinese Academy of Sciences, Shanghai Institute of Applied Physics, Shanghai (China); Liu, Ping; Sun, Jianqi; Xu, Lisa X. [Shanghai Jiao Tong University, Shanghai (China); Wang, Chang Hai; Chen, Nanyow; Lu, Chien Hung; Lee, Ting-Kuo [Academia Sinica, Institute of Physics, Taipei (China); Yang, Yuh-Cheng; Lu, Yen-Ta [Mackay Memorial Hospital, Taipei City (China); Ching, Yu-Tai [National Chiao Tung University, Department of Computer Science, Hsinchu (China); Shih, T.F.; Yang, P.C. [National Taiwan University, College of Medicine, Taipei (China); Je, J.H. [Pohang University of Science and Technology Pohang, X-ray Imaging Center, Pohang CT, Kyungbuk (Korea, Republic of); Margaritondo, G. [Ecole Polytechnique Federale de Lausanne (EPFL), Lausanne (Switzerland)

    2011-08-15

    Refractive-index (phase-contrast) radiology was able to detect lung tumors less than 1 mm in live mice. Significant micromorphology differences were observed in the microradiographs between normal, inflamed, and lung cancer tissues. This was made possible by the high phase contrast and by the fast image taking that reduces the motion blur. The detection of cancer and inflammation areas by phase contrast microradiology and microtomography was validated by bioluminescence and histopathological analysis. The smallest tumor detected is less than 1 mm{sup 3} with accuracy better than 1 x 10{sup -3} mm{sup 3}. This level of performance is currently suitable for animal studies, while further developments are required for clinical application. (orig.)

  19. Detecting small lung tumors in mouse models by refractive-index microradiology

    International Nuclear Information System (INIS)

    Chien, Chia-Chi; Hwu, Y.; Zhang, Guilin; Yue, Weisheng; Li, Yan; Xue, Hongjie; Liu, Ping; Sun, Jianqi; Xu, Lisa X.; Wang, Chang Hai; Chen, Nanyow; Lu, Chien Hung; Lee, Ting-Kuo; Yang, Yuh-Cheng; Lu, Yen-Ta; Ching, Yu-Tai; Shih, T.F.; Yang, P.C.; Je, J.H.; Margaritondo, G.

    2011-01-01

    Refractive-index (phase-contrast) radiology was able to detect lung tumors less than 1 mm in live mice. Significant micromorphology differences were observed in the microradiographs between normal, inflamed, and lung cancer tissues. This was made possible by the high phase contrast and by the fast image taking that reduces the motion blur. The detection of cancer and inflammation areas by phase contrast microradiology and microtomography was validated by bioluminescence and histopathological analysis. The smallest tumor detected is less than 1 mm 3 with accuracy better than 1 x 10 -3 mm 3 . This level of performance is currently suitable for animal studies, while further developments are required for clinical application. (orig.)

  20. Genetic variation in HTR4 and lung function: GWAS follow-up in mouse.

    Science.gov (United States)

    House, John S; Li, Huiling; DeGraff, Laura M; Flake, Gordon; Zeldin, Darryl C; London, Stephanie J

    2015-01-01

    Human genome-wide association studies (GWASs) have identified numerous associations between single nucleotide polymorphisms (SNPs) and pulmonary function. Proving that there is a causal relationship between GWAS SNPs, many of which are noncoding and without known functional impact, and these traits has been elusive. Furthermore, noncoding GWAS-identified SNPs may exert trans-regulatory effects rather than impact the proximal gene. Noncoding variants in 5-hydroxytryptamine (serotonin) receptor 4 (HTR4) are associated with pulmonary function in human GWASs. To gain insight into whether this association is causal, we tested whether Htr4-null mice have altered pulmonary function. We found that HTR4-deficient mice have 12% higher baseline lung resistance and also increased methacholine-induced airway hyperresponsiveness (AHR) as measured by lung resistance (27%), tissue resistance (48%), and tissue elastance (30%). Furthermore, Htr4-null mice were more sensitive to serotonin-induced AHR. In models of exposure to bacterial lipopolysaccharide, bleomycin, and allergic airway inflammation induced by house dust mites, pulmonary function and cytokine profiles in Htr4-null mice differed little from their wild-type controls. The findings of altered baseline lung function and increased AHR in Htr4-null mice support a causal relationship between genetic variation in HTR4 and pulmonary function identified in human GWAS. © FASEB.

  1. Developing predictions of in vivo developmental toxicity of ToxCast chemicals using mouse embryonic stem cells.

    Science.gov (United States)

    Developing predictions of in vivo developmental toxicity of ToxCast chemicals using mouse embryonic stem cells S. Hunter, M. Rosen, M. Hoopes, H. Nichols, S. Jeffay, K. Chandler1, Integrated Systems Toxicology Division, National Health and Environmental Effects Research Labor...

  2. Gremlin-1 Overexpression in Mouse Lung Reduces Silica-Induced Lymphocyte Recruitment - A Link to Idiopathic Pulmonary Fibrosis through Negative Correlation with CXCL10 Chemokine.

    Directory of Open Access Journals (Sweden)

    Katri Koli

    Full Text Available Idiopathic pulmonary fibrosis (IPF is characterized by activation and injury of epithelial cells, the accumulation of connective tissue and changes in the inflammatory microenvironment. The bone morphogenetic protein (BMP inhibitor protein gremlin-1 is associated with the progression of fibrosis both in human and mouse lung. We generated a transgenic mouse model expressing gremlin-1 in type II lung epithelial cells using the surfactant protein C (SPC promoter and the Cre-LoxP system. Gremlin-1 protein expression was detected specifically in the lung after birth and did not result in any signs of respiratory insufficiency. Exposure to silicon dioxide resulted in reduced amounts of lymphocyte aggregates in transgenic lungs while no alteration in the fibrotic response was observed. Microarray gene expression profiling and analyses of bronchoalveolar lavage fluid cytokines indicated a reduced lymphocytic response and a downregulation of interferon-induced gene program. Consistent with reduced Th1 response, there was a downregulation of the mRNA and protein expression of the anti-fibrotic chemokine CXCL10, which has been linked to IPF. In human IPF patient samples we also established a strong negative correlation in the mRNA expression levels of gremlin-1 and CXCL10. Our results suggest that in addition to regulation of epithelial-mesenchymal crosstalk during tissue injury, gremlin-1 modulates inflammatory cell recruitment and anti-fibrotic chemokine production in the lung.

  3. Gremlin-1 Overexpression in Mouse Lung Reduces Silica-Induced Lymphocyte Recruitment - A Link to Idiopathic Pulmonary Fibrosis through Negative Correlation with CXCL10 Chemokine.

    Science.gov (United States)

    Koli, Katri; Sutinen, Eva; Rönty, Mikko; Rantakari, Pia; Fortino, Vittorio; Pulkkinen, Ville; Greco, Dario; Sipilä, Petra; Myllärniemi, Marjukka

    2016-01-01

    Idiopathic pulmonary fibrosis (IPF) is characterized by activation and injury of epithelial cells, the accumulation of connective tissue and changes in the inflammatory microenvironment. The bone morphogenetic protein (BMP) inhibitor protein gremlin-1 is associated with the progression of fibrosis both in human and mouse lung. We generated a transgenic mouse model expressing gremlin-1 in type II lung epithelial cells using the surfactant protein C (SPC) promoter and the Cre-LoxP system. Gremlin-1 protein expression was detected specifically in the lung after birth and did not result in any signs of respiratory insufficiency. Exposure to silicon dioxide resulted in reduced amounts of lymphocyte aggregates in transgenic lungs while no alteration in the fibrotic response was observed. Microarray gene expression profiling and analyses of bronchoalveolar lavage fluid cytokines indicated a reduced lymphocytic response and a downregulation of interferon-induced gene program. Consistent with reduced Th1 response, there was a downregulation of the mRNA and protein expression of the anti-fibrotic chemokine CXCL10, which has been linked to IPF. In human IPF patient samples we also established a strong negative correlation in the mRNA expression levels of gremlin-1 and CXCL10. Our results suggest that in addition to regulation of epithelial-mesenchymal crosstalk during tissue injury, gremlin-1 modulates inflammatory cell recruitment and anti-fibrotic chemokine production in the lung.

  4. Gremlin-1 Overexpression in Mouse Lung Reduces Silica-Induced Lymphocyte Recruitment – A Link to Idiopathic Pulmonary Fibrosis through Negative Correlation with CXCL10 Chemokine

    Science.gov (United States)

    Koli, Katri; Sutinen, Eva; Rönty, Mikko; Rantakari, Pia; Fortino, Vittorio; Pulkkinen, Ville; Greco, Dario; Sipilä, Petra; Myllärniemi, Marjukka

    2016-01-01

    Idiopathic pulmonary fibrosis (IPF) is characterized by activation and injury of epithelial cells, the accumulation of connective tissue and changes in the inflammatory microenvironment. The bone morphogenetic protein (BMP) inhibitor protein gremlin-1 is associated with the progression of fibrosis both in human and mouse lung. We generated a transgenic mouse model expressing gremlin-1 in type II lung epithelial cells using the surfactant protein C (SPC) promoter and the Cre-LoxP system. Gremlin-1 protein expression was detected specifically in the lung after birth and did not result in any signs of respiratory insufficiency. Exposure to silicon dioxide resulted in reduced amounts of lymphocyte aggregates in transgenic lungs while no alteration in the fibrotic response was observed. Microarray gene expression profiling and analyses of bronchoalveolar lavage fluid cytokines indicated a reduced lymphocytic response and a downregulation of interferon-induced gene program. Consistent with reduced Th1 response, there was a downregulation of the mRNA and protein expression of the anti-fibrotic chemokine CXCL10, which has been linked to IPF. In human IPF patient samples we also established a strong negative correlation in the mRNA expression levels of gremlin-1 and CXCL10. Our results suggest that in addition to regulation of epithelial-mesenchymal crosstalk during tissue injury, gremlin-1 modulates inflammatory cell recruitment and anti-fibrotic chemokine production in the lung. PMID:27428020

  5. Vascular and epithelial damage in the lung of the mouse after X rays or neutrons

    International Nuclear Information System (INIS)

    Law, M.P.; Ahier, R.G.

    1989-01-01

    The response of the lung was studied in CFLP mice after exposure of the whole thorax to X rays (250 kVp) or cyclotron neutrons (16 MeV deuterons on Be, mean energy 7.5 MeV). To measure blood volume and leakage of plasma proteins, 51Cr-labeled red blood cells and 125I-albumin were injected intravenously and 24 h later lungs were lavaged via the trachea. Radioactivities in lung tissue and lavage fluid were determined to estimate the accumulation of albumin in the interstitial and alveolar spaces indicating damage to blood vessels and alveolar epithelium respectively. Function of type II pneumonocytes was assessed by the amounts of surfactant (assayed as lipid phosphorous) released into the lavage fluid. During the first 6 weeks, lavage protein and surfactant were increased, the neutron relative biological effectiveness (RBE) being unity. During pneumonitis at 12-24 weeks, surfactant levels were normal, blood volume was decreased, and both interstitial and alveolar albumin were increased. Albumin levels then decreased. At late times after exposure (42-64 weeks) alveolar albumin returned to normal but interstitial albumin was still slightly elevated. Values of RBE for changes in blood volume and interstitial and alveolar albumin at 15 weeks and for changes in blood volume and interstitial albumin at 46 weeks were 1.4, comparable with that for animal survival at 180 days. The results indicate that surfactant production is not critical for animal survival. They suggest that changes in blood vessels and alveolar epithelium occur during acute pneumonitis; epithelial repair follows but some vascular damage may persist. The time course of the changes in albumin levels did not correlate with increases in collagen biosynthesis which have been observed as early as 1 month after exposure and persist for up to 1 year

  6. Tyrosine Mutation in AAV9 Capsid Improves Gene Transfer to the Mouse Lung.

    Science.gov (United States)

    Martini, Sabrina V; Silva, Adriana L; Ferreira, Debora; Rabelo, Rafael; Ornellas, Felipe M; Gomes, Karina; Rocco, Patricia R M; Petrs-Silva, Hilda; Morales, Marcelo M

    2016-01-01

    Adeno-associated virus (AAV) vectors are being increasingly used as the vector of choice for in vivo gene delivery and gene therapy for many pulmonary diseases. Recently, it was shown that phosphorylation of surface-exposed tyrosine residues from AAV capsid targets the viral particles for ubiquitination and proteasome-mediated degradation, and mutations of these tyrosine residues lead to highly efficient vector transduction in vitro and in vivo in different organs. In this study, we evaluated the pulmonary transgene expression efficacy of AAV9 vectors containing point mutations in surface-exposed capsid tyrosine residues. Eighteen C57BL/6 mice were randomly assigned into three groups: (1) a control group (CTRL) animals underwent intratracheal (i.t.) instillation of saline, (2) the wild-type AAV9 group (WT-AAV9, 1010 vg), and (3) the tyrosine-mutant Y731F AAV9 group (M-AAV9, 1010 vg), which received (i.t.) self-complementary AAV9 vectors containing the DNA sequence of enhanced green fluorescence protein (eGFP). Four weeks after instillation, lung mechanics, morphometry, tissue cellularity, gene expression, inflammatory cytokines, and growth factor expression were analyzed. No significant differences were observed in lung mechanics and morphometry among the experimental groups. However, the number of polymorphonuclear cells was higher in the WT-AAV9 group than in the CTRL and M-AAV9 groups, suggesting that the administration of tyrosine-mutant AAV9 vectors was better tolerated. Tyrosine-mutant AAV9 vectors significantly improved transgene delivery to the lung (30%) compared with their wild-type counterparts, without eliciting an inflammatory response. Our results provide the impetus for further studies to exploit the use of AAV9 vectors as a tool for pulmonary gene therapy. © 2016 The Author(s) Published by S. Karger AG, Basel.

  7. Gene and metabolite time-course response to cigarette smoking in mouse lung and plasma.

    Directory of Open Access Journals (Sweden)

    Mikaela A Miller

    Full Text Available Prolonged cigarette smoking (CS causes chronic obstructive pulmonary disease (COPD, a prevalent serious condition that may persist or progress after smoking cessation. To provide insight into how CS triggers COPD, we investigated temporal patterns of lung transcriptome expression and systemic metabolome changes induced by chronic CS exposure and smoking cessation. Whole lung RNA-seq data was analyzed at transcript and exon levels from C57Bl/6 mice exposed to CS for 1- or 7 days, for 3-, 6-, or 9 months, or for 6 months followed by 3 months of cessation using age-matched littermate controls. We identified previously unreported dysregulation of pyrimidine metabolism and phosphatidylinositol signaling pathways and confirmed alterations in glutathione metabolism and circadian gene pathways. Almost all dysregulated pathways demonstrated reversibility upon smoking cessation, except the lysosome pathway. Chronic CS exposure was significantly linked with alterations in pathways encoding for energy, phagocytosis, and DNA repair and triggered differential expression of genes or exons previously unreported to associate with CS or COPD, including Lox, involved in matrix remodeling, Gp2, linked to goblet cells, and Slc22a12 and Agpat3, involved in purine and glycerolipid metabolism, respectively. CS-induced lung metabolic pathways changes were validated using metabolomic profiles of matched plasma samples, indicating that dynamic metabolic gene regulation caused by CS is reflected in the plasma metabolome. Using advanced technologies, our study uncovered novel pathways and genes altered by chronic CS exposure, including those involved in pyrimidine metabolism, phosphatidylinositol signaling and lysosome function, highlighting their potential importance in the pathogenesis or diagnosis of CS-associated conditions.

  8. Radiotherapy and chemotherapy change vessel tree geometry and metastatic spread in a small cell lung cancer xenograft mouse tumor model.

    Directory of Open Access Journals (Sweden)

    Thorsten Frenzel

    Full Text Available Tumor vasculature is critical for tumor growth, formation of distant metastases and efficiency of radio- and chemotherapy treatments. However, how the vasculature itself is affected during cancer treatment regarding to the metastatic behavior has not been thoroughly investigated. Therefore, the aim of this study was to analyze the influence of hypofractionated radiotherapy and cisplatin chemotherapy on vessel tree geometry and metastasis formation in a small cell lung cancer xenograft mouse tumor model to investigate the spread of malignant cells during different treatments modalities.The biological data gained during these experiments were fed into our previously developed computer model "Cancer and Treatment Simulation Tool" (CaTSiT to model the growth of the primary tumor, its metastatic deposit and also the influence on different therapies. Furthermore, we performed quantitative histology analyses to verify our predictions in xenograft mouse tumor model.According to the computer simulation the number of cells engrafting must vary considerably to explain the different weights of the primary tumor at the end of the experiment. Once a primary tumor is established, the fractal dimension of its vasculature correlates with the tumor size. Furthermore, the fractal dimension of the tumor vasculature changes during treatment, indicating that the therapy affects the blood vessels' geometry. We corroborated these findings with a quantitative histological analysis showing that the blood vessel density is depleted during radiotherapy and cisplatin chemotherapy. The CaTSiT computer model reveals that chemotherapy influences the tumor's therapeutic susceptibility and its metastatic spreading behavior.Using a system biological approach in combination with xenograft models and computer simulations revealed that the usage of chemotherapy and radiation therapy determines the spreading behavior by changing the blood vessel geometry of the primary tumor.

  9. Changed Expression of Cytoskeleton Proteins During Lung Injury in a Mouse Model of Streptococcus pneumoniae Infection

    Directory of Open Access Journals (Sweden)

    Mario Ferrer-Navarro

    2018-05-01

    Full Text Available Infections by Streptococcus pneumoniae are a major cause of morbidity and mortality worldwide, often causing community-acquired pneumonia, otitis media and also bacteremia and meningitis. Studies on S. pneumoniae are mainly focused on its virulence or capacity to evade the host immune system, but little is known about the injury caused in lungs during a pneumococcal infection. Herein we investigated this issue comparing the proteome profile of lungs from S. pneumoniae-infected mice with control mice by means of difference gel electrophoresis (DIGE technology. In order to obtain reliable results three biological replicas were used, and four technical replicas were carried out in each biological replica. Proteomic comparison was performed at two time points: 24 and 48 h post infection. A total of 91 proteins were identified with different abundance. We found important changes in the protein profiles during pneumococcal infection mainly associated with regulation of vesicle-mediated transport, wound healing, and cytoskeleton organization. In conclusion, the results obtained show that the cytoskeleton of the host cell is modified in S. pneumoniae infection.

  10. Early alterations in extracellular matrix and transforming growth factor β gene expression in mouse lung indicative of late radiation fibrosis

    International Nuclear Information System (INIS)

    Finkelstein, J.N.; Johnston, C.J.; Baggs, R.; Rubin, P.

    1994-01-01

    Fibrosis, characterized by the accumulation of collagen, is a late result of thoracic irradiation. The expression of late radiation injury can be found immediately after irradiation by measuring messenger RNA (mRNA) abundance. To determine if extracellular matrix mRNA and transforming growth factor beta abundance was affected acutely after irradiation, the authors measured mRNA levels of collagen I (CI), collagen III (CIII), collagen IV (CIV), fibronectin (FN), and transforming growth factor β (TGFβ 1,2ampersand3 ) in mouse lungs on day 1 and day 14 after graded doses of radiation. C57BL/6 female mice were irradiated with a single dose to the thorax of 5 or 12.5 Gy. Total lung RNA was prepared and immobilized by Northern and slot blotting and hybridized with radiolabelled cDNA probes for CI, CIII, CIV, FN, TGFβ 1,2ampersand3 and a control probe encoding for glyceraldehyde-3-phosphate dehydrogenase (GAPDH). Autoradiographic data were quantified by video densitometry and results normalized to GAPDH. Changes in the expression of CI, CIII, CIV, FN and TGFβ 1,2ampersand3 were observed as early as 1 day after exposure. Through 14 days, changes in mRNA up to 5-fold were seen for any one dose. Dose related changes as high as 10-fold were also evident. The CI:CIII ratio increased gradually for the 5 Gy dose at 14 days postirradiation while the CI:CII ratio for the 12.5 Gy dose decreased by approximately 4-fold as compared to the control. These studies suggest that alterations in expression of extracellular matrix and TGFβ mRNA occur very early after radiation injury even at low doses and may play a role in the development of chronic fibrosis. 37 refs., 6 figs

  11. Platelet CLEC-2 protects against lung injury via effects of its ligand podoplanin on inflammatory alveolar macrophages in the mouse.

    Science.gov (United States)

    Lax, Siân; Rayes, Julie; Wichaiyo, Surasak; Haining, Elizabeth J; Lowe, Kate; Grygielska, Beata; Laloo, Ryan; Flodby, Per; Borok, Zea; Crandall, Edward D; Thickett, David R; Watson, Steve P

    2017-12-01

    There is no therapeutic intervention proven to prevent acute respiratory distress syndrome (ARDS). Novel mechanistic insights into the pathophysiology of ARDS are therefore required. Platelets are implicated in regulating many of the pathogenic processes that occur during ARDS; however, the mechanisms remain elusive. The platelet receptor CLEC-2 has been shown to regulate vascular integrity at sites of acute inflammation. Therefore the purpose of this study was to establish the role of CLEC-2 and its ligand podoplanin in a mouse model of ARDS. Platelet-specific CLEC-2-deficient, as well as alveolar epithelial type I cell (AECI)-specific or hematopoietic-specific podoplanin deficient, mice were established using cre-loxP strategies. Combining these with intratracheal (IT) instillations of lipopolysaccharide (LPS), we demonstrate that arterial oxygen saturation decline in response to IT-LPS in platelet-specific CLEC-2-deficient mice is significantly augmented. An increase in bronchoalveolar lavage (BAL) neutrophils and protein was also observed 48 h post-IT-LPS, with significant increases in pro-inflammatory chemokines detected in BAL of platelet-specific CLEC-2-deficient animals. Deletion of podoplanin from hematopoietic cells but not AECIs also reduces lung function and increases pro-inflammatory chemokine expression following IT-LPS. Furthermore, we demonstrate that following IT-LPS, platelets are present in BAL in aggregates with neutrophils, which allows for CLEC-2 interaction with podoplanin expressed on BAL inflammatory alveolar macrophages. Taken together, these data suggest that the platelet CLEC-2-podoplanin signaling axis regulates the severity of lung inflammation in mice and is a possible novel target for therapeutic intervention in patients at risk of developing ARDS. Copyright © 2017 the American Physiological Society.

  12. Intratumoral Immunization by p19Arf and Interferon-β Gene Transfer in a Heterotopic Mouse Model of Lung Carcinoma

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    João Paulo Portela Catani

    2016-12-01

    Full Text Available Therapeutic strategies that act by eliciting and enhancing antitumor immunity have been clinically validated as an effective treatment modality but may benefit from the induction of both cell death and immune activation as primary stimuli. Using our AdRGD-PG adenovector platform, we show here for the first time that in situ gene transfer of p19Arf and interferon-β (IFNβ in the LLC1 mouse model of lung carcinoma acts as an immunotherapy. Although p19Arf is sufficient to induce cell death, only its pairing with IFNβ significantly induced markers of immunogenic cell death. In situ gene therapy with IFNβ, either alone or in combination with p19Arf, could retard tumor progression, but only the combined treatment was associated with a protective immune response. Specifically in the case of combined intratumoral gene transfer, we identified 167 differentially expressed genes when using microarray to evaluate tumors that were treated in vivo and confirmed the activation of CCL3, CXCL3, IL1α, IL1β, CD274, and OSM, involved in immune response and chemotaxis. Histologic evaluation revealed significant tumor infiltration by neutrophils, whereas functional depletion of granulocytes ablated the antitumor effect of our approach. The association of in situ gene therapy with cisplatin resulted in synergistic elimination of tumor progression. In all, in situ gene transfer with p19Arf and IFNβ acts as an immunotherapy involving recruitment of neutrophils, a desirable but previously untested outcome, and this approach may be allied with chemotherapy, thus providing significant antitumor activity and warranting further development for the treatment of lung carcinoma.

  13. Chemical coding and chemosensory properties of cholinergic brush cells in the mouse gastrointestinal and biliary tract

    Directory of Open Access Journals (Sweden)

    Burkhard eSchütz

    2015-03-01

    Full Text Available The mouse gastro-intestinal and biliary tract mucosal epithelia harbor choline acetyltransferase (ChAT-positive brush cells with taste cell-like traits. With the aid of two transgenic mouse lines that express green fluorescent protein (EGFP under the control of the ChAT promoter (EGFPChAT and by using in situ hybridization and immunohistochemistry we found that EGFPChAT cells were clustered in the epithelium lining the gastric groove. EGFPChAT cells were numerous in the gall bladder and bile duct, and found scattered as solitary cells along the small and large intestine. While all EGFPChAT cells were also ChAT-positive, expression of the high-affinity choline transporter (ChT1 was never detected. Except for the proximal colon, EGFPChAT cells also lacked detectable expression of the vesicular acetylcholine transporter (VAChT. EGFPChAT cells were found to be separate from enteroendocrine cells, however they were all immunoreactive for cytokeratin 18 (CK18, transient receptor potential melastatin-like subtype 5 channel (TRPM5, and for cyclooxygenases 1 (COX1 and 2 (COX2. The ex vivo stimulation of colonic EGFPChAT cells with the bitter substance denatonium resulted in a strong increase in intracellular calcium, while in other epithelial cells such an increase was significantly weaker and also timely delayed. Subsequent stimulation with cycloheximide was ineffective in both cell populations. Given their chemical coding and chemosensory properties, EGFPChAT brush cells thus may have integrative functions and participate in induction of protective reflexes and inflammatory events by utilizing ACh and prostaglandins for paracrine signaling.

  14. Chemical coding and chemosensory properties of cholinergic brush cells in the mouse gastrointestinal and biliary tract.

    Science.gov (United States)

    Schütz, Burkhard; Jurastow, Innokentij; Bader, Sandra; Ringer, Cornelia; von Engelhardt, Jakob; Chubanov, Vladimir; Gudermann, Thomas; Diener, Martin; Kummer, Wolfgang; Krasteva-Christ, Gabriela; Weihe, Eberhard

    2015-01-01

    The mouse gastro-intestinal and biliary tract mucosal epithelia harbor choline acetyltransferase (ChAT)-positive brush cells with taste cell-like traits. With the aid of two transgenic mouse lines that express green fluorescent protein (EGFP) under the control of the ChAT promoter (EGFP (ChAT) ) and by using in situ hybridization and immunohistochemistry we found that EGFP (ChAT) cells were clustered in the epithelium lining the gastric groove. EGFP (ChAT) cells were numerous in the gall bladder and bile duct, and found scattered as solitary cells along the small and large intestine. While all EGFP (ChAT) cells were also ChAT-positive, expression of the high-affinity choline transporter (ChT1) was never detected. Except for the proximal colon, EGFP (ChAT) cells also lacked detectable expression of the vesicular acetylcholine transporter (VAChT). EGFP (ChAT) cells were found to be separate from enteroendocrine cells, however they were all immunoreactive for cytokeratin 18 (CK18), transient receptor potential melastatin-like subtype 5 channel (TRPM5), and for cyclooxygenases 1 (COX1) and 2 (COX2). The ex vivo stimulation of colonic EGFP (ChAT) cells with the bitter substance denatonium resulted in a strong increase in intracellular calcium, while in other epithelial cells such an increase was significantly weaker and also timely delayed. Subsequent stimulation with cycloheximide was ineffective in both cell populations. Given their chemical coding and chemosensory properties, EGFP (ChAT) brush cells thus may have integrative functions and participate in induction of protective reflexes and inflammatory events by utilizing ACh and prostaglandins for paracrine signaling.

  15. Delineating pathological pathways in a chemically induced mouse model of Gaucher disease.

    Science.gov (United States)

    Vardi, Ayelet; Zigdon, Hila; Meshcheriakova, Anna; Klein, Andrés D; Yaacobi, Chen; Eilam, Raya; Kenwood, Brandon M; Rahim, Ahad A; Massaro, Giulia; Merrill, Alfred H; Vitner, Einat B; Futerman, Anthony H

    2016-08-01

    Great interest has been shown in understanding the pathology of Gaucher disease (GD) due to the recently discovered genetic relationship with Parkinson's disease. For such studies, suitable animal models of GD are required. Chemical induction of GD by inhibition of acid β-glucosidase (GCase) using the irreversible inhibitor conduritol B-epoxide (CBE) is particularly attractive, although few systematic studies examining the effect of CBE on the development of symptoms associated with neurological forms of GD have been performed. We now demonstrate a correlation between the amount of CBE injected into mice and levels of accumulation of the GD substrates, glucosylceramide and glucosylsphingosine, and show that disease pathology, indicated by altered levels of pathological markers, depends on both the levels of accumulated lipids and the time at which their accumulation begins. Gene array analysis shows a remarkable similarity in the gene expression profiles of CBE-treated mice and a genetic GD mouse model, the Gba(flox/flox) ;nestin-Cre mouse, with 120 of the 144 genes up-regulated in CBE-treated mice also up-regulated in Gba(flox/flox) ;nestin-Cre mice. We also demonstrate that various aspects of neuropathology and some behavioural abnormalities can be arrested upon cessation of CBE treatment during a specific time window. Together, our data demonstrate that injection of mice with CBE provides a rapid and relatively easy way to induce symptoms typical of neuronal forms of GD. This is particularly useful when examining the role of specific biochemical pathways in GD pathology, since CBE can be injected into mice defective in components of putative pathological pathways, alleviating the need for time-consuming crossing of mice. Copyright © 2016 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd. Copyright © 2016 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

  16. Metabolism of styrene to styrene oxide and vinylphenols in cytochrome P450 2F2- and P450 2E1-knockout mouse liver and lung microsomes.

    Science.gov (United States)

    Shen, Shuijie; Li, Lei; Ding, Xinxin; Zheng, Jiang

    2014-01-21

    Pulmonary toxicity of styrene is initiated by cytochromes P450-dependent metabolic activation. P450 2E1 and P450 2F2 are considered to be two main cytochrome P450 enzymes responsible for styrene metabolism in mice. The objective of the current study was to determine the correlation between the formation of styrene metabolites (i.e., styrene oxide and 4-vinylphenol) and pulmonary toxicity of styrene, using Cyp2e1- and Cyp2f2-null mouse models. A dramatic decrease in the formation of styrene glycol and 4-vinylphenol was found in Cyp2f2-null mouse lung microsomes relative to that in the wild-type mouse lung microsomes; however, no significant difference in the production of the styrene metabolites was observed between lung microsomes obtained from Cyp2e1-null and the wild-type mice. The knockout and wild-type mice were treated with styrene (6.0 mmol/kg, ip), and cell counts and LDH activity in bronchoalveolar lavage fluids were monitored to evaluate the pulmonary toxicity induced by styrene. Cyp2e1-null mice displayed a susceptibility to lung toxicity of styrene similar to that of the wild-type animals; however, Cyp2f2-null mice were resistant to styrene-induced pulmonary toxicity. In conclusion, both P450 2E1 and P450 2F2 are responsible for the metabolic activation of styrene. The latter enzyme plays an important role in styrene-induced pulmonary toxicity. Both styrene oxide and 4-vinylphenol are suggested to participate in the development of lung injury induced by styrene.

  17. Identification of radiation response genes and proteins from mouse pulmonary tissues after high-dose per fraction irradiation of limited lung volumes.

    Science.gov (United States)

    Jin, Hee; Jeon, Seulgi; Kang, Ga-Young; Lee, Hae-June; Cho, Jaeho; Lee, Yun-Sil

    2017-02-01

    The molecular effects of focal exposure of limited lung volumes to high-dose per fraction irradiation (HDFR) such as stereotactic body radiotherapy (SBRT) have not been fully characterized. In this study, we used such an irradiation system and identified the genes and proteins after HDFR to mouse lung, similar to those associated with human therapy. High focal radiation (90 Gy) was applied to a 3-mm volume of the left lung of C57BL6 mice using a small-animal stereotactic irradiator. As well as histological examination for lungs, a cDNA micro array using irradiated lung tissues and a protein array of sera were performed until 4 weeks after irradiation, and radiation-responsive genes and proteins were identified. For comparison, the long-term effects (12 months) of 20 Gy radiation wide-field dose to the left lung were also investigated. The genes ermap, epb4.2, cd200r3 (up regulation) and krt15, hoxc4, gdf2, cst9, cidec, and bnc1 (down-regulation) and the proteins of AIF, laminin, bNOS, HSP27, β-amyloid (upregulation), and calponin (downregulation) were identified as being responsive to 90 Gy HDFR. The gdf2, cst9, and cidec genes also responded to 20 Gy, suggesting that they are universal responsive genes in irradiated lungs. No universal proteins were identified in both 90 Gy and 20 Gy. Calponin, which was downregulated in protein antibody array analysis, showed a similar pattern in microarray data, suggesting a possible HDFR responsive serum biomarker that reflects gene alteration of irradiated lung tissue. These genes and proteins also responded to the lower doses of 20 Gy and 50 Gy HDFR. These results suggest that identified candidate genes and proteins are HDFR-specifically expressed in lung damage induced by HDFR relevant to SBRT in humans.

  18. Modeling genome-wide dynamic regulatory network in mouse lungs with influenza infection using high-dimensional ordinary differential equations.

    Science.gov (United States)

    Wu, Shuang; Liu, Zhi-Ping; Qiu, Xing; Wu, Hulin

    2014-01-01

    The immune response to viral infection is regulated by an intricate network of many genes and their products. The reverse engineering of gene regulatory networks (GRNs) using mathematical models from time course gene expression data collected after influenza infection is key to our understanding of the mechanisms involved in controlling influenza infection within a host. A five-step pipeline: detection of temporally differentially expressed genes, clustering genes into co-expressed modules, identification of network structure, parameter estimate refinement, and functional enrichment analysis, is developed for reconstructing high-dimensional dynamic GRNs from genome-wide time course gene expression data. Applying the pipeline to the time course gene expression data from influenza-infected mouse lungs, we have identified 20 distinct temporal expression patterns in the differentially expressed genes and constructed a module-based dynamic network using a linear ODE model. Both intra-module and inter-module annotations and regulatory relationships of our inferred network show some interesting findings and are highly consistent with existing knowledge about the immune response in mice after influenza infection. The proposed method is a computationally efficient, data-driven pipeline bridging experimental data, mathematical modeling, and statistical analysis. The application to the influenza infection data elucidates the potentials of our pipeline in providing valuable insights into systematic modeling of complicated biological processes.

  19. In vivo Brain Delivery of v-myc Overproduced Human Neural Stem Cells via the Intranasal Pathway: Tumor Characteristics in the Lung of a Nude Mouse

    Directory of Open Access Journals (Sweden)

    Eun Seong Lee

    2015-01-01

    Full Text Available We aimed to monitor the successful brain delivery of stem cells via the intranasal route and to observe the long-term consequence of the immortalized human neural stem cells in the lungs of a nude mouse model. Stably immortalized HB1.F3 human neural stem cells with firefly luciferase gene (F3-effluc were intranasally delivered to BALB/c nude mice. Bioluminescence images were serially acquired until 41 days in vivo and at 4 hours and 41 days ex vivo after intranasal delivery. Lungs were evaluated by histopathology. After intranasal delivery of F3-effluc cells, the intense in vivo signals were detected in the nasal area, migrated toward the brain areas at 4 hours (4 of 13, 30.8%, and gradually decreased for 2 days. The brain signals were confirmed by ex vivo imaging (2 of 4, 50%. In the mice with initial lung signals (4 of 9, 44.4%, the lung signals disappeared for 5 days but reappeared 2 weeks later. The intense lung signals were confirmed to originate from the tumors in the lungs formed by F3-effluc cells by ex vivo imaging and histopathology. We propose that intranasal delivery of immortalized stem cells should be monitored for their successful delivery to the brain and their tumorigenicity longitudinally.

  20. Pseudomonas aeruginosa alginate is refractory to Th1 immune response and impedes host immune clearance in a mouse model of acute lung infection

    DEFF Research Database (Denmark)

    Song, Zhijun; Wu, Hong; Ciofu, Oana

    2003-01-01

    . The effect of alginate production on pathogenicity was investigated by using an acute lung infection mouse model that compared a non-mucoid P. aeruginosa strain, PAO1, to its constitutive alginate-overproducing derivative, Alg(+) PAOmucA22, and an alginate-defective strain, Alg(-) PAOalgD. Bacterial......Pseudomonas aeruginosa is an opportunistic respiratory pathogen that accounts for most of the morbidity and mortality in cystic fibrosis (CF) patients. In CF-affected lungs, the bacteria undergo conversion from a non-mucoid to a non-tractable mucoid phenotype, due to overproduction of alginate...... suspensions were instilled into the left bronchus and examined 24 and 48 h post-infection. The highest bacterial loads and the most severe lung pathology were observed with strain Alg(-) PAOalgD at 24 h post-infection, which may have been due to an increase in expression of bacterial elastase by the mutant...

  1. Protein anabolic effects of two chemically distinct relaxins in mouse uteri

    International Nuclear Information System (INIS)

    Bylander, J.E.; Adams, W.C.; Frieden, E.H.

    1986-01-01

    In addition to B-28 relaxin (relaxin B) and B-32 relaxin, acid-acetone extracts of porcine ovaries contain relaxin C, which differs both chemically and biologically from the others. Relaxin C contains one proline residue and a single tryptophane residue; it is about half as active as relaxin B in the guinea pig assay, is active in the motility inhibition assay, but is essentially completely inactive in the mouse pubic ligament assay. Relaxin B has been shown to exhibit protein anabolic properties in rat uteri. To compare the effects of relaxins B and C on uterine protein synthesis, ovariectomized, estrogen-primed mice were given relaxin B or C (10-100 μgm/100 gm b.w. in 1% benzopurpurine 4B) and the uptake of 3 H-proline into uterine protein measured in vitro and in vivo 3-12 hours later. Both relaxins induced significant (40-100%) increases in proline incorporation rates. Maximal stimulation of soluble protein synthesis occurred 3 hr after administration of either relaxin; in contrast, peak uptake of proline into uterine collagen occurred after 6 hr. Stimulation of collagen synthesis was more pronounced as well as more prolonged than the synthesis of soluble protein. Larger doses of relaxin C (as compared to B) were required for continued enhancement of collagen synthesis

  2. Repair in mouse lung of multifraction X rays and neutrons: extension to 40 fractions

    International Nuclear Information System (INIS)

    Parkins, C.S.; Fowler, J.F.

    1985-01-01

    Repair parameters were calculated from measurements of breathing rate and lethality at monthly intervals up to 17 months after irradiation with 1, 10, 20 or 40 equal fractions, down to 1.1 Gy of x-rays and 0.18 Gy of 3 MeV neutrons per fraction. Sparing of neutron damage was negligible when the neutron dose was divided into multiple fractions; progressively greater repair of lung damage was seen after increasing x-ray fractions. Significant increase in the iso-effect dose for 40 x-ray fractions was found compared with 20, even at two fractions per day at six hour intervals, as was the case in the 40 fraction experiment. Data were well fitted by the linear quadratic formula for response vs. dose per fraction and the ratio γ/β yielded values of approx. 3 Gy after x-rays and 30 to 40 Gy after neutron irradiation, not different from γ/β ratios found for up to 20 fractions. Single dose RBE was less than 2, increasing to about six at the lowest dose per fraction measured, agreeing with previous results. The ratio of the γ component for neutrons to that for x-rays was approx. 8, which is therefore the limiting RBE predicted for infinitely small fractional doses. (U.K.)

  3. Response of mouse lung to irradiation at different dose-rates

    International Nuclear Information System (INIS)

    Hill, R.P.

    1983-01-01

    Groups of LAF1 mice were given thoracic irradiation using 60 Co γ-rays at dose-rates of 0.05 Gy/min (LDR) or 1.1 Gy/min (HDR) and the death of the animals was monitored as a function of time. It was found that the time pattern of animal deaths was similar for the two different dose-rates. Dose response curves for animals dying at various times up to 500 days after irradiation were calculated and the LD 50 values determined. The curves for the LD 50 values, plotted as a function of the time at analysis for treatment at HDR or LDR, were essentially parallel to each other but separated by a factor (LDR/HDR) of about 1.8. This indicates that the sparing effect of LDR treatment is the same for deaths occurring during the early pneumonitis phase or during the late fibrotic phase of lung damage. The available information on the response of patients to whole thoracic irradiation, given for either palliation or piror to bone marrow transplantation, suggests that for similar dose-rates to those studied here the ratio (LDR/HDR) is only 1.2 to 1.3. This difference between the animal and human data may reflect the modifying effect of the large doses of cytotoxic drugs used in combination with the irradiation of bone marrow transplant patients

  4. GOLGA2 loss causes fibrosis with autophagy in the mouse lung and liver.

    Science.gov (United States)

    Park, Sungjin; Kim, Sanghwa; Kim, Min Jung; Hong, Youngeun; Lee, Ah Young; Lee, Hyunji; Tran, Quangdon; Kim, Minhee; Cho, Hyeonjeong; Park, Jisoo; Kim, Kwang Pyo; Park, Jongsun; Cho, Myung-Haing

    2018-01-01

    Autophagy is a biological recycling process via the self-digestion of organelles, proteins, and lipids for energy-consuming differentiation and homeostasis. The Golgi serves as a donor of the double-membraned phagophore for autophagosome assembly. In addition, recent studies have demonstrated that pulmonary and hepatic fibrosis is accompanied by autophagy. However, the relationships among Golgi function, autophagy, and fibrosis are unclear. Here, we show that the deletion of GOLGA2, encoding a cis-Golgi protein, induces autophagy with Golgi disruption. The induction of autophagy leads to fibrosis along with the reduction of subcellular lipid storage (lipid droplets and lamellar bodies) by autophagy in the lung and liver. GOLGA2 knockout mice clearly demonstrated fibrosis features such as autophagy-activated cells, densely packed hepatocytes, increase of alveolar macrophages, and decrease of alveolar surfactant lipids (dipalmitoylphosphatidylcholine). Therefore, we confirmed the associations among Golgi function, fibrosis, and autophagy. Moreover, GOLGA2 knockout mice may be a potentially valuable animal model for studying autophagy-induced fibrosis. Copyright © 2017 Elsevier Inc. All rights reserved.

  5. Role of Aquaporin-4 in Airspace-to-Capillary Water Permeability in Intact Mouse Lung Measured by a Novel Gravimetric Method

    Science.gov (United States)

    Song, Yuanlin; Ma, Tonghui; Matthay, Michael A.; Verkman, A.S.

    2000-01-01

    The mammalian peripheral lung contains at least three aquaporin (AQP) water channels: AQP1 in microvascular endothelia, AQP4 in airway epithelia, and AQP5 in alveolar epithelia. In this study, we determined the role of AQP4 in airspace-to-capillary water transport by comparing water permeability in wild-type mice and transgenic null mice lacking AQP1, AQP4, or AQP1/AQP4 together. An apparatus was constructed to measure lung weight continuously during pulmonary artery perfusion of isolated mouse lungs. Osmotically induced water flux (Jv) between the airspace and capillary compartments was measured from the kinetics of lung weight change in saline-filled lungs in response to changes in perfusate osmolality. Jv in wild-type mice varied linearly with osmotic gradient size (4.4 × 10−5 cm3 s−1 mOsm−1) and was symmetric, independent of perfusate osmolyte size, weakly temperature dependent, and decreased 11-fold by AQP1 deletion. Transcapillary osmotic water permeability was greatly reduced by AQP1 deletion, as measured by the same method except that the airspace saline was replaced by an inert perfluorocarbon. Hydrostatically induced lung edema was characterized by lung weight changes in response to changes in pulmonary arterial inflow or pulmonary venous outflow pressure. At 5 cm H2O outflow pressure, the filtration coefficient was 4.7 cm3 s−1 mOsm−1 and reduced 1.4-fold by AQP1 deletion. To study the role of AQP4 in lung water transport, AQP1/AQP4 double knockout mice were generated by crossbreeding of AQP1 and AQP4 null mice. Jv were (cm3 s−1 mOsm−1 × 10−5, SEM, n = 7–12 mice): 3.8 ± 0.4 (wild type), 0.35 ± 0.02 (AQP1 null), 3.7 ± 0.4 (AQP4 null), and 0.25 ± 0.01 (AQP1/AQP4 null). The significant reduction in P f in AQP1 vs. AQP1/AQP4 null mice was confirmed by an independent pleural surface fluorescence method showing a 1.6 ± 0.2-fold (SEM, five mice) reduced P f in the AQP1/AQP4 double knockout mice vs. AQP1 null mice. These results establish

  6. Dose-responsiveness and persistence of microRNA expression alterations induced by cigarette smoke in mouse lung

    International Nuclear Information System (INIS)

    Izzotti, Alberto; Larghero, Patrizia; Longobardi, Mariagrazia; Cartiglia, Cristina; Camoirano, Anna; Steele, Vernon E.; De Flora, Silvio

    2011-01-01

    Our previous studies demonstrated that exposure to cigarette smoke (CS), either mainstream or environmental, results in a remarkable downregulation of microRNA expression in the lung of both mice and rats. The goals of the present study were to evaluate the dose responsiveness to CS and the persistence of microRNA alterations after smoking cessation. ICR (CD-1) neonatal mice were exposed whole-body to mainstream CS, at the doses of 119, 292, 438, and 631 mg/m 3 of total particulate matter. Exposure started within 12 h after birth and continued daily for 4 weeks. The levels of bulky DNA adducts and 8-oxo-7,8-dihydro-2′-deoxyguanosine (8-oxodGuo) were measured by 32 P postlabeling procedures, and the expression of 697 mouse microRNAs was analyzed by microarray. The highest CS dose was lethal. Exposure to CS caused a dose-dependent increase of DNA alterations. DNA adducts and, even more sharply, 8-oxodGuo were reverted 1 and 4 weeks after smoking cessation. Exposure to CS resulted in an evident dysregulation of microRNA expression profiles, mainly in the sense of downregulation. The two lowest doses were not particularly effective, while the highest nonlethal dose produced extensive microRNA alterations. The expression of most downregulated microRNAs, including among others 7 members of the let-7 family, was restored one week after smoking cessation. However, the recovery was incomplete for a limited array of microRNAs, including mir-34b, mir-345, mir-421, mir-450b, mir-466, and mir-469. Thus, it appears that microRNAs mainly behave as biomarkers of effect and that exposure to high-dose, lasting for an adequate period of time, is needed to trigger the CS-related carcinogenesis process in the experimental animal model used.

  7. Response of the mouse lung transcriptome to welding fume: effects of stainless and mild steel fumes on lung gene expression in A/J and C57BL/6J mice

    Directory of Open Access Journals (Sweden)

    Antonini James M

    2010-06-01

    Full Text Available Abstract Background Debate exists as to whether welding fume is carcinogenic, but epidemiological evidence suggests that welders are an at risk population for the development of lung cancer. Recently, we found that exposure to welding fume caused an acutely greater and prolonged lung inflammatory response in lung tumor susceptible A/J versus resistant C57BL/6J (B6 mice and a trend for increased tumor incidence after stainless steel (SS fume exposure. Here, our objective was to examine potential strain-dependent differences in the regulation and resolution of the lung inflammatory response induced by carcinogenic (Cr and Ni abundant or non-carcinogenic (iron abundant metal-containing welding fumes at the transcriptome level. Methods Mice were exposed four times by pharyngeal aspiration to 5 mg/kg iron abundant gas metal arc-mild steel (GMA-MS, Cr and Ni abundant GMA-SS fume or vehicle and were euthanized 4 and 16 weeks after the last exposure. Whole lung microarray using Illumina Mouse Ref-8 expression beadchips was done. Results Overall, we found that tumor susceptibility was associated with a more marked transcriptional response to both GMA-MS and -SS welding fumes. Also, Ingenuity Pathway Analysis revealed that gene regulation and expression in the top molecular networks differed between the strains at both time points post-exposure. Interestingly, a common finding between the strains was that GMA-MS fume exposure altered behavioral gene networks. In contrast, GMA-SS fume exposure chronically upregulated chemotactic and immunomodulatory genes such as CCL3, CCL4, CXCL2, and MMP12 in the A/J strain. In the GMA-SS-exposed B6 mouse, genes that initially downregulated cellular movement, hematological system development/function and immune response were involved at both time points post-exposure. However, at 16 weeks, a transcriptional switch to an upregulation for neutrophil chemotactic genes was found and included genes such as S100A8, S100A9 and

  8. Assessment of immunotoxicity induced by chemicals in human precision-cut lung slices (PCLS).

    Science.gov (United States)

    Lauenstein, L; Switalla, S; Prenzler, F; Seehase, S; Pfennig, O; Förster, C; Fieguth, H; Braun, A; Sewald, K

    2014-06-01

    Occupational asthma can be induced by a number of chemicals at the workplace. Risk assessment of potential sensitizers is mostly performed in animal experiments. With increasing public demand for alternative methods, human precision-cut lung slices (PCLS) have been developed as an ex vivo model. Human PCLS were exposed to increasing concentrations of 20 industrial chemicals including 4 respiratory allergens, 11 contact allergens, and 5 non-sensitizing irritants. Local respiratory irritation was characterized and expressed as 75% (EC25) and 50% (EC50) cell viability with respect to controls. Dose-response curves of all chemicals except for phenol were generated. Local respiratory inflammation was quantified by measuring the production of cytokines and chemokines. TNF-α and IL-1α were increased significantly in human PCLS after exposure to the respiratory sensitizers trimellitic anhydride (TMA) and ammonium hexachloroplatinate (HClPt) at subtoxic concentrations, while contact sensitizers and non-sensitizing irritants failed to induce the release of these cytokines to the same extent. Interestingly, significant increases in T(H)1/T(H)2 cytokines could be detected only after exposure to HClPt at a subtoxic concentration. In conclusion, allergen-induced cytokines were observed but not considered as biomarkers for the differentiation between respiratory and contact sensitizers. Our preliminary results show an ex vivo model which might be used for prediction of chemical-induced toxicity, but is due to its complex three-dimensional structure not applicable for a simple screening of functional and behavior changes of certain cell populations such as dendritic cells and T-cells in response to allergens. Copyright © 2014 The Authors. Published by Elsevier Ltd.. All rights reserved.

  9. A dual role for the immune response in a mouse model of inflammation-associated lung cancer

    OpenAIRE

    Dougan, Michael; Li, Danan; Neuberg, Donna; Mihm, Martin; Googe, Paul; Wong, Kwok-Kin; Dranoff, Glenn

    2011-01-01

    Lung cancer is the leading cause of cancer death worldwide. Both principal factors known to cause lung cancer, cigarette smoke and asbestos, induce pulmonary inflammation, and pulmonary inflammation has recently been implicated in several murine models of lung cancer. To further investigate the role of inflammation in the development of lung cancer, we generated mice with combined loss of IFN-γ and the β-common cytokines GM-CSF and IL-3. These immunodeficient mice develop chronic pulmonary in...

  10. Seasonal variations in fine particle composition from Beijing prompt oxidative stress response in mouse lung and liver.

    Science.gov (United States)

    Pardo, Michal; Xu, Fanfan; Qiu, Xinghua; Zhu, Tong; Rudich, Yinon

    2018-06-01

    Exposure to air pollution can induce oxidative stress, inflammation and adverse health effects. To understand how seasonal and chemical variations drive health impacts, we investigated indications for oxidative stress and inflammation in mice exposed to water and organic extracts from urban fine particles/PM 2.5 (particles with aerodynamic diameter ≤ 2.5 μm) collected in Beijing, China. Higher levels of pollution components were detected in heating season (HS, winter and part of spring) PM 2.5 than in the non-heating season (NHS, summer and part of spring and autumn) PM 2.5 . HS samples were high in metals for the water extraction and high in polycyclic aromatic hydrocarbons (PAHs) for the organic extraction compared to their controls. An increased inflammatory response was detected in the lung and liver following exposure to the organic extracts compared to the water extracts, and mostly in the HS PM 2.5 . While reduced antioxidant response was observed in the lung, it was activated in the liver, again, more in the HS extracts. Nrf2 transcription factor, a master regulator of stress response that controls the basal oxidative capacity and induces the expression of antioxidant response, and its related genes were induced. In the liver, elevated levels of lipid peroxidation adducts were measured, correlated with histologic analysis that revealed morphologic features of cell damage and proliferation, indicating oxidative and toxic damage. In addition, expression of genes related to detoxification of PAHs was observed. Altogether, the study suggests that the acute effects of PM 2.5 can vary seasonally with stronger health effects in the HS than in the NHS in Beijing, China and that some secondary organs may be susceptible for the exposure damage. Specifically, the liver is a potential organ influenced by exposure to organic components such as PAHs from coal or biomass burning and heating. Copyright © 2018 Elsevier B.V. All rights reserved.

  11. Apoptotic role of natural isothiocyanate from broccoli (Brassica oleracea italica) in experimental chemical lung carcinogenesis.

    Science.gov (United States)

    Kalpana Deepa Priya, D; Gayathri, R; Gunassekaran, G R; Murugan, S; Sakthisekaran, D

    2013-05-01

    Sulforaphane (SFN) [1-isothiocyanato-4-(methylsulfinyl)butane] is a naturally occurring isothiocyanate found in cruciferous vegetables such as broccoli [Brassica oleracea L. var. italica Plenck. (Brassicaceae)]. Since it is among the most potent bioactive components with antioxidant and antitumor properties, it has received intense attention in the recent years for its chemopreventive properties. The present work determined the rehabilitating role in alleviating the oxidative damage caused by benzo(a)pyrene [B(a)P] to biomolecules and the apoptotic cascade mediated by orally administered isothiocyanate-SFN (9 µmol/mouse/day) against B(a)P (100 mg/kg body weight, i.p.) induced pulmonary carcinogenesis in Swiss albino mice. Oxidative damage was assessed by measuring lipid peroxidation, 8-hydroxydeoxyguanosine, hydrogen peroxide (H2O2) production, glycoprotein components, protein carbonyl levels and DNA-protein crosslinks. DNA fragmentation by agarose gel electrophoresis and caspase-3 activity by ELISA proved apoptotic induction by SFN along with the protein expression of Bcl-2, Bax and Cyt c. SFN treatment was found to decrease the H2O2 production (p < 0.001) in cancer induced animals, proving its antioxidant potential. Apoptosis was induced by increasing the release of Cyt c (p < 0.001) from mitochondria, decreasing and increasing the expression of Bcl-2 (p < 0.01) and Bax (p < 0.001), respectively. Caspase-3 activity was also enhanced (p < 0.001) which leads to DNA fragmentation in SFN treated groups. Our results reflect the rehabilitating role of SFN in B(a)P induced lung carcinogenesis.

  12. Expression of NR1I3 in mouse lung tumors induced by the tobacco-specific nitrosamine 4-(methylnitrosamino)-4-(3-pyridyl)-1-butanone

    Energy Technology Data Exchange (ETDEWEB)

    Fukumasu, H.; Cordeiro, Y.G.; Rochetti, A.L.; Barra, C.N.; Sámora, T.S.; Strefezzi, R.F. [Laboratório de Oncologia Comparada e Translacional, Departmento de Medicina Veterinária, Faculdade de Zootecnia e Engenharia de Alimentos, Universidade de São Paulo, Pirassununga, SP (Brazil); Dagli, M.L.Z. [Laboratório de Oncologia Experimental e Comparada, Departmento de Patologia, Faculdade de Medicina Veterinária e Zootecnia, Universidade de São Paulo, São Paulo, SP (Brazil)

    2015-02-13

    Nuclear receptor subfamily 1, group I, member 3 (NR1I3) is reported to be a possible novel therapeutic target for some cancers, including lung, brain and hematopoietic tumors. Here, we characterized expression of NR1I3 in a mouse model of lung carcinogenesis induced by 4-(methylnitrosamino)-4-(3-pyridyl)-1-butanone (NNK), the most potent tobacco carcinogen. Lung tumors were collected from mice treated with NNK (400 mg/kg) and euthanized after 52 weeks. Benign and malignant lesions were formalin-fixed and paraffin-embedded for histology and immunohistochemistry, with samples snap-frozen for mRNA analysis. Immunohistochemically, we found that most macrophages and type I and II pneumocytes expressed NR1I3, whereas fibroblasts and endothelial cells were NR1I3{sup −}. Compared with benign lesions, malignant lesions had less NR1I3{sup +} tumor cells. Gene expression analysis also showed an inverse correlation between NR1I3 mRNA expression and tumor size (P=0.0061), suggesting that bigger tumors expressed less NR1I3 transcripts, in accordance with our immunohistochemical NR1I3 tests. Our results indicate that NR1I3 expression decreased during progression of malignant lung tumors induced by NNK in mice.

  13. Expression of NR1I3 in mouse lung tumors induced by the tobacco-specific nitrosamine 4-(methylnitrosamino)-4-(3-pyridyl)-1-butanone

    International Nuclear Information System (INIS)

    Fukumasu, H.; Cordeiro, Y.G.; Rochetti, A.L.; Barra, C.N.; Sámora, T.S.; Strefezzi, R.F.; Dagli, M.L.Z.

    2015-01-01

    Nuclear receptor subfamily 1, group I, member 3 (NR1I3) is reported to be a possible novel therapeutic target for some cancers, including lung, brain and hematopoietic tumors. Here, we characterized expression of NR1I3 in a mouse model of lung carcinogenesis induced by 4-(methylnitrosamino)-4-(3-pyridyl)-1-butanone (NNK), the most potent tobacco carcinogen. Lung tumors were collected from mice treated with NNK (400 mg/kg) and euthanized after 52 weeks. Benign and malignant lesions were formalin-fixed and paraffin-embedded for histology and immunohistochemistry, with samples snap-frozen for mRNA analysis. Immunohistochemically, we found that most macrophages and type I and II pneumocytes expressed NR1I3, whereas fibroblasts and endothelial cells were NR1I3 − . Compared with benign lesions, malignant lesions had less NR1I3 + tumor cells. Gene expression analysis also showed an inverse correlation between NR1I3 mRNA expression and tumor size (P=0.0061), suggesting that bigger tumors expressed less NR1I3 transcripts, in accordance with our immunohistochemical NR1I3 tests. Our results indicate that NR1I3 expression decreased during progression of malignant lung tumors induced by NNK in mice

  14. Lung

    International Nuclear Information System (INIS)

    DeNardo, G.L.; Blankenship, W.J.; Burdine, J.A. Jr.; DeNardo, S.J.

    1975-01-01

    At present no simple statement can be made relative to the role of radionuclidic lung studies in the pediatric population. It is safe to assume that they will be used with increasing frequency for research and clinical applications because of their sensitivity and ready applicability to the pediatric patient. Methods comparable to those used in adults can be used in children older than 4 years. In younger children, however, a single injection of 133 Xe in solution provides an index of both regional perfusion and ventilation which is easier to accomplish. This method is particularly valuable in infants and neonates because it is rapid, requires no patient cooperation, results in a very low radiation dose, and can be repeated in serial studies. Radionuclidic studies of ventilation and perfusion can be performed in almost all children if the pediatrician and the nuclear medicine specialist have motivation and ingenuity. S []ontaneous pulmonary vascular occlusive disease which occurs in infants and pulmonary emboli in children are easily detected using radionuclides. The pathophysiologic defects of pulmonary agenesis, bronchopulmonary sequestration, and foreign body aspiration may be demonstrated by these techniques. These techniques also appear to be useful in following patients with bronchial asthma, cystic fibrosis, congenital emphysema, and postinfection pulmonary abnormalities. (auth)

  15. Deoxynivalenol (DON) is toxic to human colonic, lung and monocytic cell lines, but does not increase the IgE response in a mouse model for allergy

    International Nuclear Information System (INIS)

    Instanes, Christine; Hetland, Geir

    2004-01-01

    We examined whether the common crop mycotoxin deoxynivalenol (DON) from Fusarium species is toxic to human colonic (Caco-2), lung (A549) and monocytic (U937) cell lines. Moreover, since DON reportedly induces increased levels of Th2 cytokines and total IgE, and we have observed that mould extracts adjuvated allergy development in mice, possible adjuvant effect of DON on allergy was studied in a mouse model. For all the cells, exposure to DON for 24 h reduced cellular protein synthesis, proliferation and survival rate dose-dependently. In addition, production of IL-8 in the U937 cell line increased up to eight-fold at levels of DON just lower than the most toxic one, suggesting that IL-8 can be used as an additional index for cytotoxicity in mononuclear phagocytes. However, DON did not increase levels of allergen-specific IgE or IgG1 in the mouse model for allergy. These results suggest that DON, when inhaled or ingested, may have toxic effect on human alveolar macrophages and epithelial cells in lungs and colon, but does not increase the allergic response to allergens

  16. Assessment of a 42 metal salts chemical library in mouse embryonic stem cells

    Science.gov (United States)

    The developmental effects of xenobiotics on differentiation can be profiled using mouse embryonic stem cells (mESCs). The adherent cell differentiation and cytotoxicity (ACDC) technique was used to evaluate a library of 42 metal and metaloid salts. Jl mESCs were allowed to prolif...

  17. Protective effects of black rice bran against chemically-induced inflammation of mouse skin

    Science.gov (United States)

    We investigated the inhibitory effects of black rice (cv. LK1-3-6-12-1-1) bran against 12-O-tetradecanolylphorbol-13-acetate (TPA)-induced skin edema and 2,4-dinitroflurobenzene (DNFB)-induced allergic contact dermatitis (ACD) in inflammatory mouse models. We also determined the effects of the bran...

  18. Establishment of A Malignant Pleural Effusion Mouse Model with Lewis Lung 
Carcinoma Cell Lines Expressing Enhanced Green Fluorescent Protein

    Directory of Open Access Journals (Sweden)

    Xingqun MA

    2012-06-01

    Full Text Available Background and objective Malignant pleural effusion (MPE is a poor prognosis factor in patients with advanced lung cancer. The aim of this study is to establish a mouse model of MPE using Lewis lung carcinoma (LLC cell lines expressing enhanced green fluorescent protein (EGFP. Methods The mouse model was created by injecting LLC-EGFP cells directly into the pleural cavity of mice that were sacrificed periodically. The dynamic growth and metastasis of tumor cells were screened using in vivo fluorescence imaging. The remaining mice were subjected to transverse computed tomography (CT imaging periodically to analyze the formation rate of pleural effusion. The survival rate and tumor metastasis were also observed. Pleural fluid was gently aspirated using a 1 mL syringe and its volume was measured. When two or more mice bore pleural effusion at the same time, we calculated the average volume. The correlation of pleural effusion with the integrated optical density (IOD were analyzed. Results Four days after the inoculation of LLC-EGFP cells, green fluorescence was observed by opening the chest wall. The tumor formation rate was 100%, and the IOD gradually increased after inoculation. The metastasis sites were mediastinal, and the hilar lymph nodes were contralateral pleural as well as pericardial. The metastasis rates were 87%, 73% and 20%, respectively. The CT scan revealed that the formation rates of pleural effusion on days 7, 14 and 21 were 13%, 46% and 53%, respectively. The average volume of pleural effusion increased obviously on day 10 and peaked on day 16 with a value of 0.5 mL. The mean survival time of nude mice was 28.8 days. The volume of pleural effusion and IOD were significantly correlated (r=0.91, P<0.000,1. Conclusion A mouse model of lung cancer malignant pleural effusion was successfully established by injecting LLC lines expressing EGFP into the pleural cavity under a microscope. The model can enable dynamic observations of the

  19. Involvement of EZH2, SUV39H1, G9a and associated molecules in pathogenesis of urethane induced mouse lung tumors: Potential targets for cancer control

    International Nuclear Information System (INIS)

    Pandey, Manuraj; Sahay, Satya; Tiwari, Prakash; Upadhyay, Daya S.; Sultana, Sarwat; Gupta, Krishna P.

    2014-01-01

    In the present study, we showed the correlation of EZH2, SUV39H1 or G9a expression and histone modifications with the urethane induced mouse lung tumorigenesis in the presence or absence of antitumor agent, inositol hexaphosphate (IP6). Tumorigenesis and the molecular events involved therein were studied at 1, 4, 12 or 36 weeks after the exposure. There were no tumors at 1 or 4 weeks but tumors started appearing at 12 weeks and grew further till 36 weeks after urethane exposure. Among the molecular events, upregulation of EZH2 and SUV39H1 expressions appeared to be time dependent, but G9a expression was altered significantly only at later stages of 12 or 36 weeks. Alteration in miR-138 expression supports the upregulation of its target, EZH2. H3K9me2, H3K27me3 or H4K20me3 was found to be altered at 12 or 36 weeks. However, ChIP analysis of p16 and MLH1 promoters showed their binding with H3K9me2 and H3K27me3 which was maximum at 36 weeks. Thus, histone modification and their interactions with gene promoter resulted in the reduced expression of p16 and MLH1. IP6 prevented the incidence and the size of urethane induced lung tumors. IP6 also prevented the urethane induced alterations in EZH2, SUV39H1, G9a expressions and histone modifications. Our results suggest that the alterations in the histone modification pathways involving EZH2 and SUV39H1 expressions are among the early events in urethane induced mouse lung tumorigenesis and could be exploited for cancer control. - Highlights: • Urethane induces mouse lung tumor in a time dependent manner. • EZH2, SUV39H1, G9a induced by urethane and progress with time • Downregulation of miRNA-138 supports the EZH2 upregulation. • Methylation of histones showed a consequence of upregulated EZH2, SUV39H1 and G9a. • IP6 inhibits urethane induced changes and prevents tumor development

  20. Involvement of EZH2, SUV39H1, G9a and associated molecules in pathogenesis of urethane induced mouse lung tumors: Potential targets for cancer control

    Energy Technology Data Exchange (ETDEWEB)

    Pandey, Manuraj; Sahay, Satya; Tiwari, Prakash [Carcinogenesis Laboratory, CSIR-Indian Institute of Toxicology Research, Mahatma Gandhi Marg, Lucknow –226001 (India); Upadhyay, Daya S. [Laboratory Animals Services, CSIR-Central Drug Research Institute, Sitapur Road, Lucknow (India); Sultana, Sarwat [Dept. Medical Elementology and Toxicology, Jamia Hamdard, Hamdard Nagar, New Delhi (India); Gupta, Krishna P., E-mail: krishnag522@yahoo.co.in [Carcinogenesis Laboratory, CSIR-Indian Institute of Toxicology Research, Mahatma Gandhi Marg, Lucknow –226001 (India)

    2014-10-15

    In the present study, we showed the correlation of EZH2, SUV39H1 or G9a expression and histone modifications with the urethane induced mouse lung tumorigenesis in the presence or absence of antitumor agent, inositol hexaphosphate (IP6). Tumorigenesis and the molecular events involved therein were studied at 1, 4, 12 or 36 weeks after the exposure. There were no tumors at 1 or 4 weeks but tumors started appearing at 12 weeks and grew further till 36 weeks after urethane exposure. Among the molecular events, upregulation of EZH2 and SUV39H1 expressions appeared to be time dependent, but G9a expression was altered significantly only at later stages of 12 or 36 weeks. Alteration in miR-138 expression supports the upregulation of its target, EZH2. H3K9me2, H3K27me3 or H4K20me3 was found to be altered at 12 or 36 weeks. However, ChIP analysis of p16 and MLH1 promoters showed their binding with H3K9me2 and H3K27me3 which was maximum at 36 weeks. Thus, histone modification and their interactions with gene promoter resulted in the reduced expression of p16 and MLH1. IP6 prevented the incidence and the size of urethane induced lung tumors. IP6 also prevented the urethane induced alterations in EZH2, SUV39H1, G9a expressions and histone modifications. Our results suggest that the alterations in the histone modification pathways involving EZH2 and SUV39H1 expressions are among the early events in urethane induced mouse lung tumorigenesis and could be exploited for cancer control. - Highlights: • Urethane induces mouse lung tumor in a time dependent manner. • EZH2, SUV39H1, G9a induced by urethane and progress with time • Downregulation of miRNA-138 supports the EZH2 upregulation. • Methylation of histones showed a consequence of upregulated EZH2, SUV39H1 and G9a. • IP6 inhibits urethane induced changes and prevents tumor development.

  1. cAMP response element binding protein1 is essential for activation of steroyl co-enzyme a desaturase 1 (Scd1 in mouse lung type II epithelial cells.

    Directory of Open Access Journals (Sweden)

    Nisha Antony

    Full Text Available Cyclic AMP Response Element-Binding Protein 1 (Creb1 is a transcription factor that mediates cyclic adenosine 3', 5'-monophosphate (cAMP signalling in many tissues. Creb1(-/- mice die at birth due to respiratory failure and previous genome-wide microarray analysis of E17.5 Creb1(-/- fetal mouse lung identified important Creb1-regulated gene targets during lung development. The lipogenic enzymes stearoyl-CoA desaturase 1 (Scd1 and fatty acid synthase (Fasn showed highly reduced gene expression in Creb1(-/- lungs. We therefore hypothesized that Creb1 plays a crucial role in the transcriptional regulation of genes involved in pulmonary lipid biosynthetic pathways during lung development. In this study we confirmed that Scd1 and Fasn mRNA levels were down regulated in the E17.5 Creb1(-/- mouse lung while the lipogenic-associated transcription factors SrebpF1, C/ebpα and Pparγ were increased. In vivo studies using germline (Creb1(-/- and lung epithelial-specific (Creb1(EpiΔ/Δ Creb1 knockout mice showed strongly reduced Scd1, but not Fasn gene expression and protein levels in lung epithelial cells. In vitro studies using mouse MLE-15 epithelial cells showed that forskolin-mediated activation of Creb1 increased both Scd1 gene expression and protein synthesis. Additionally, MLE15 cells transfected with a dominant-negative ACreb vector blocked forskolin-mediated stimulation of Scd1 gene expression. Lipid profiling in MLE15 cells showed that dominant-negative ACreb suppressed forskolin-induced desaturation of ether linked lipids to produce plasmalogens, as well as levels of phosphatidylethanolamine, ceramide and lysophosphatidylcholine. Taken together these results demonstrate that Creb1 is essential for the induction and maintenance of Scd1 in developing fetal mouse lung epithelial cells.

  2. Evaluation of 309 environmental chemicals using a mouse embryonic stem cell adherent cell differentiation and cytotoxicity assay.

    Directory of Open Access Journals (Sweden)

    Kelly J Chandler

    Full Text Available The vast landscape of environmental chemicals has motivated the need for alternative methods to traditional whole-animal bioassays in toxicity testing. Embryonic stem (ES cells provide an in vitro model of embryonic development and an alternative method for assessing developmental toxicity. Here, we evaluated 309 environmental chemicals, mostly food-use pesticides, from the ToxCast™ chemical library using a mouse ES cell platform. ES cells were cultured in the absence of pluripotency factors to promote spontaneous differentiation and in the presence of DMSO-solubilized chemicals at different concentrations to test the effects of exposure on differentiation and cytotoxicity. Cardiomyocyte differentiation (α,β myosin heavy chain; MYH6/MYH7 and cytotoxicity (DRAQ5™/Sapphire700™ were measured by In-Cell Western™ analysis. Half-maximal activity concentration (AC₅₀ values for differentiation and cytotoxicity endpoints were determined, with 18% of the chemical library showing significant activity on either endpoint. Mining these effects against the ToxCast Phase I assays (∼500 revealed significant associations for a subset of chemicals (26 that perturbed transcription-based activities and impaired ES cell differentiation. Increased transcriptional activity of several critical developmental genes including BMPR2, PAX6 and OCT1 were strongly associated with decreased ES cell differentiation. Multiple genes involved in reactive oxygen species signaling pathways (NRF2, ABCG2, GSTA2, HIF1A were strongly associated with decreased ES cell differentiation as well. A multivariate model built from these data revealed alterations in ABCG2 transporter was a strong predictor of impaired ES cell differentiation. Taken together, these results provide an initial characterization of metabolic and regulatory pathways by which some environmental chemicals may act to disrupt ES cell growth and differentiation.

  3. Electroporation-mediated in vivo gene delivery of the Na+/K+-ATPase pump reduced lung injury in a mouse model of lung contusion.

    Science.gov (United States)

    Machado-Aranda, David A; Suresh, M V; Yu, Bi; Raghavendran, Krishnan

    2012-01-01

    Lung contusion (LC) is an independent risk factor for acute respiratory distress syndrome. The final common pathway in ARDS involves accumulation of fluid in the alveoli. In this study, we demonstrate the application of a potential gene therapy approach by delivering the Na+/K+-ATPase pump subunits in a murine model of LC. We hypothesized that restoring the activity of the pump will result in removal of excess alveolar fluid and additionally reduce inflammation. Under anesthesia, C57/BL6 mice were struck along the right posterior axillary line 1 cm above the costal margin with a cortical contusion impactor. Immediately afterward, 100 μg of plasmid DNA coding for the α,β of the Na+/K+-ATPase pump were instilled into the lungs (LC-electroporation-pump group). Contusion only (LC-only) and a sham saline instillation group after contusion were used as controls (LC-electroporation-sham). By using a BTX 830 electroporator, eight electrical pulses of 200 V/cm field strength were applied transthoracically. Mice were killed at 24 hours, 48 hours, and 72 hours after delivery. Bronchial alveolar lavage was recollected to measure albumin and cytokines by enzyme-linked immunosorbent assay. Pulmonary compliance was measured, and lungs were subject to histopathologic analysis. After the electroporation and delivery of genes coding for the α,β subunits of the Na+/K+-ATPase pump, there was a significant mitigation of acute lung injury as evidenced by reduction in bronchial alveolar lavage levels of albumin, improved pressure volume curves, and reduced inflammation seen on histology. Electroporation-mediated gene transfer of the subunits of the Na+/K+-ATPase pump enhanced recovery from acute inflammatory lung injury after LC.

  4. Lung disease phenotypes caused by overexpression of combinations of α-, β-, and γ-subunits of the epithelial sodium channel in mouse airways.

    Science.gov (United States)

    Livraghi-Butrico, Alessandra; Wilkinson, Kristen J; Volmer, Allison S; Gilmore, Rodney C; Rogers, Troy D; Caldwell, Ray A; Burns, Kimberlie A; Esther, Charles R; Mall, Marcus A; Boucher, Richard C; O'Neal, Wanda K; Grubb, Barbara R

    2018-02-01

    The epithelial Na + channel (ENaC) regulates airway surface hydration. In mouse airways, ENaC is composed of three subunits, α, β, and γ, which are differentially expressed (α > β > γ). Airway-targeted overexpression of the β subunit results in Na + hyperabsorption, causing airway surface dehydration, hyperconcentrated mucus with delayed clearance, lung inflammation, and perinatal mortality. Notably, mice overexpressing the α- or γ-subunit do not exhibit airway Na + hyperabsorption or lung pathology. To test whether overexpression of multiple ENaC subunits produced Na + transport and disease severity exceeding that of βENaC-Tg mice, we generated double (αβ, αγ, βγ) and triple (αβγ) transgenic mice and characterized their lung phenotypes. Double αγENaC-Tg mice were indistinguishable from WT littermates. In contrast, double βγENaC-Tg mice exhibited airway Na + absorption greater than that of βENaC-Tg mice, which was paralleled by worse survival, decreased mucociliary clearance, and more severe lung pathology. Double αβENaC-Tg mice exhibited Na + transport rates comparable to those of βENaC-Tg littermates. However, αβENaC-Tg mice had poorer survival and developed severe parenchymal consolidation. In situ hybridization (RNAscope) analysis revealed both alveolar and airway αENaC-Tg overexpression. Triple αβγENaC-Tg mice were born in Mendelian proportions but died within the first day of life, and the small sample size prevented analyses of cause(s) of death. Cumulatively, these results indicate that overexpression of βENaC is rate limiting for generation of pathological airway surface dehydration. Notably, airway co-overexpression of β- and γENaC had additive effects on Na + transport and disease severity, suggesting dose dependency of these two variables.

  5. Vapors produced by electronic cigarettes and e-juices with flavorings induce toxicity, oxidative stress, and inflammatory response in lung epithelial cells and in mouse lung.

    Directory of Open Access Journals (Sweden)

    Chad A Lerner

    Full Text Available Oxidative stress and inflammatory response are the key events in the pathogenesis of chronic airway diseases. The consumption of electronic cigarettes (e-cigs with a variety of e-liquids/e-juices is alarmingly increasing without the unrealized potential harmful health effects. We hypothesized that electronic nicotine delivery systems (ENDS/e-cigs pose health concerns due to oxidative toxicity and inflammatory response in lung cells exposed to their aerosols. The aerosols produced by vaporizing ENDS e-liquids exhibit oxidant reactivity suggesting oxidants or reactive oxygen species (OX/ROS may be inhaled directly into the lung during a "vaping" session. These OX/ROS are generated through activation of the heating element which is affected by heating element status (new versus used, and occurs during the process of e-liquid vaporization. Unvaporized e-liquids were oxidative in a manner dependent on flavor additives, while flavors containing sweet or fruit flavors were stronger oxidizers than tobacco flavors. In light of OX/ROS generated in ENDS e-liquids and aerosols, the effects of ENDS aerosols on tissues and cells of the lung were measured. Exposure of human airway epithelial cells (H292 in an air-liquid interface to ENDS aerosols from a popular device resulted in increased secretion of inflammatory cytokines, such as IL-6 and IL-8. Furthermore, human lung fibroblasts exhibited stress and morphological change in response to treatment with ENDS/e-liquids. These cells also secrete increased IL-8 in response to a cinnamon flavored e-liquid and are susceptible to loss of cell viability by ENDS e-liquids. Finally, exposure of wild type C57BL/6J mice to aerosols produced from a popular e-cig increase pro-inflammatory cytokines and diminished lung glutathione levels which are critical in maintaining cellular redox balance. Thus, exposure to e-cig aerosols/juices incurs measurable oxidative and inflammatory responses in lung cells and tissues that

  6. Variable flip angle 3D ultrashort echo time (UTE) T1 mapping of mouse lung: A repeatability assessment.

    Science.gov (United States)

    Alamidi, Daniel F; Smailagic, Amir; Bidar, Abdel W; Parker, Nicole S; Olsson, Marita; Hockings, Paul D; Lagerstrand, Kerstin M; Olsson, Lars E

    2018-03-08

    Lung T 1 is a potential translational biomarker of lung disease. The precision and repeatability of variable flip angle (VFA) T 1 mapping using modern 3D ultrashort echo time (UTE) imaging of the whole lung needs to be established before it can be used to assess response to disease and therapy. To evaluate the feasibility of regional lung T 1 quantification with VFA 3D-UTE and to investigate long- and short-term T 1 repeatability in the lungs of naive mice. Prospective preclinical animal study. Eight naive mice and phantoms. 3D free-breathing radial UTE (8 μs) at 4.7T. VFA 3D-UTE T 1 calculations were validated against T 1 values measured with inversion recovery (IR) in phantoms. Lung T 1 and proton density (S 0 ) measurements of whole lung and muscle were repeated five times over 1 month in free-breathing naive mice. Two consecutive T 1 measurements were performed during one of the imaging sessions. Agreement in T 1 between VFA 3D-UTE and IR in phantoms was assessed using Bland-Altman and Pearson 's correlation analysis. The T 1 repeatability in mice was evaluated using coefficient of variation (CV), repeated-measures analysis of variance (ANOVA), and paired t-test. Good T 1 agreement between the VFA 3D-UTE and IR methods was found in phantoms. T 1 in lung and muscle showed a 5% and 3% CV (1255 ± 63 msec and 1432 ± 42 msec, respectively, mean ± SD) with no changes in T 1 or S 0 over a month. Consecutive measurements resulted in an increase of 2% in both lung T 1 and S 0 . VFA 3D-UTE shows promise as a reliable T 1 mapping method that enables full lung coverage, high signal-to-noise ratio (∼25), and spatial resolution (300 μm) in freely breathing animals. The precision of the VFA 3D-UTE method will enable better design and powering of studies. 1 Technical Efficacy: Stage 2 J. Magn. Reson. Imaging 2018. © 2018 International Society for Magnetic Resonance in Medicine.

  7. The effect of CSF-1 administration on lung maturation in a mouse model of neonatal hyperoxia exposure.

    Science.gov (United States)

    Jones, Christina V; Alikhan, Maliha A; O'Reilly, Megan; Sozo, Foula; Williams, Timothy M; Harding, Richard; Jenkin, Graham; Ricardo, Sharon D

    2014-09-06

    Lung immaturity due to preterm birth is a significant complication affecting neonatal health. Despite the detrimental effects of supplemental oxygen on alveolar formation, it remains an important treatment for infants with respiratory distress. Macrophages are traditionally associated with the propagation of inflammatory insults, however increased appreciation of their diversity has revealed essential functions in development and regeneration. Macrophage regulatory cytokine Colony-Stimulating Factor-1 (CSF-1) was investigated in a model of neonatal hyperoxia exposure, with the aim of promoting macrophages associated with alveologenesis to protect/rescue lung development and function. Neonatal mice were exposed to normoxia (21% oxygen) or hyperoxia (Hyp; 65% oxygen); and administered CSF-1 (0.5 μg/g, daily × 5) or vehicle (PBS) in two treatment regimes; 1) after hyperoxia from postnatal day (P)7-11, or 2) concurrently with five days of hyperoxia from P1-5. Lung structure, function and macrophages were assessed using alveolar morphometry, barometric whole-body plethysmography and flow cytometry. Seven days of hyperoxia resulted in an 18% decrease in body weight and perturbation of lung structure and function. In regime 1, growth restriction persisted in the Hyp + PBS and Hyp + CSF-1 groups, although perturbations in respiratory function were resolved by P35. CSF-1 increased CSF-1R+/F4/80+ macrophage number by 34% at P11 compared to Hyp + PBS, but was not associated with growth or lung structural rescue. In regime 2, five days of hyperoxia did not cause initial growth restriction in the Hyp + PBS and Hyp + CSF-1 groups, although body weight was decreased at P35 with CSF-1. CSF-1 was not associated with increased macrophages, or with functional perturbation in the adult. Overall, CSF-1 did not rescue the growth and lung defects associated with hyperoxia in this model; however, an increase in CSF-1R+ macrophages was not associated with an

  8. Losartan Attenuates Degradation of Aorta and Lung Tissue Micromechanics in a Mouse Model of Severe Marfan Syndrome.

    Science.gov (United States)

    Lee, Jia-Jye; Galatioto, Josephine; Rao, Satish; Ramirez, Francesco; Costa, Kevin D

    2016-10-01

    Marfan syndrome (MFS) is an autosomal dominant disease of the connective tissue due to mutations in the fibrillin-1 gene (FBN1). This study aimed at characterizing microelastic properties of the ascending aortic wall and lung parenchyma tissues from wild type (WT) and age-matched Fbn1 hypomorphic mice (Fbn1(mgR/mgR) mice) to identify tissue-specific biomechanical effects of aging and disease in MFS. Atomic force microscopy was used to indent lung parenchyma and aortic wall tissues, using Hybrid Eshelby Decomposition analysis to extract layer-specific properties of the intima and media. The intima stiffened with age and was not different between WT and Fbn1(mgR/mgR) tissues, whereas the media layer of MFS aortas showed progressive structural and mechanical degradation with a modulus that was 50% softer than WT by 3.5 months of age. Similarly, MFS mice displayed progressive structural and mechanical deterioration of lung tissue, which was over 85% softer than WT by 3.5 months of age. Chronic treatment with the angiotensin type I receptor antagonist, losartan, attenuated the aorta and lung tissue degradation, resulting in structural and mechanical properties not significantly different from age-matched WT controls. By revealing micromechanical softening of elastin-rich aorta and lung tissues with disease progression in fibrillin-1 deficient mice, our findings support the use of losartan as a prophylactic treatment that may abrogate the life-threatening symptoms of MFS.

  9. Effective silencing of ENaC by siRNA delivered with epithelial-targeted nanocomplexes in human cystic fibrosis cells and in mouse lung.

    Science.gov (United States)

    Tagalakis, Aristides D; Munye, Mustafa M; Ivanova, Rositsa; Chen, Hanpeng; Smith, Claire M; Aldossary, Ahmad M; Rosa, Luca Z; Moulding, Dale; Barnes, Josephine L; Kafetzis, Konstantinos N; Jones, Stuart A; Baines, Deborah L; Moss, Guy W J; O'Callaghan, Christopher; McAnulty, Robin J; Hart, Stephen L

    2018-05-10

    Loss of the cystic fibrosis transmembrane conductance regulator in cystic fibrosis (CF) leads to hyperabsorption of sodium and fluid from the airway due to upregulation of the epithelial sodium channel (ENaC). Thickened mucus and depleted airway surface liquid (ASL) then lead to impaired mucociliary clearance. ENaC regulation is thus a promising target for CF therapy. Our aim was to develop siRNA nanocomplexes that mediate effective silencing of airway epithelial ENaC in vitro and in vivo with functional correction of epithelial ion and fluid transport. We investigated translocation of nanocomplexes through mucus and their transfection efficiency in primary CF epithelial cells grown at air-liquid interface (ALI).Short interfering RNA (SiRNA)-mediated silencing was examined by quantitative RT-PCR and western analysis of ENaC. Transepithelial potential (V t ), short circuit current (I sc ), ASL depth and ciliary beat frequency (CBF) were measured for functional analysis. Inflammation was analysed by histological analysis of normal mouse lung tissue sections. Nanocomplexes translocated more rapidly than siRNA alone through mucus. Transfections of primary CF epithelial cells with nanocomplexes targeting αENaC siRNA, reduced αENaC and βENaC mRNA by 30%. Transfections reduced V t , the amiloride-sensitive I sc and mucus protein concentration while increasing ASL depth and CBF to normal levels. A single dose of siRNA in mouse lung silenced ENaC by approximately 30%, which persisted for at least 7 days. Three doses of siRNA increased silencing to approximately 50%. Nanoparticle-mediated delivery of ENaCsiRNA to ALI cultures corrected aspects of the mucociliary defect in human CF cells and offers effective delivery and silencing in vivo. © Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2018. All rights reserved. No commercial use is permitted unless otherwise expressly granted.

  10. Vascularization of the dorsal root ganglia and peripheral nerve of the mouse: Implications for chemical-induced peripheral sensory neuropathies

    Directory of Open Access Journals (Sweden)

    Melemedjian Ohannes K

    2008-03-01

    Full Text Available Abstract Although a variety of industrial chemicals, as well as several chemotherapeutic agents used to treat cancer or HIV, preferentially induce a peripheral sensory neuropathy what remains unclear is why these agents induce a sensory vs. a motor or mixed neuropathy. Previous studies have shown that the endothelial cells that vascularize the dorsal root ganglion (DRG, which houses the primary afferent sensory neurons, are unique in that they have large fenestrations and are permeable to a variety of low and high molecular weight agents. In the present report we used whole-mount preparations, immunohistochemistry, and confocal laser scanning microscopy to show that the cell body-rich area of the L4 mouse DRG has a 7 fold higher density of CD31+ capillaries than cell fiber rich area of the DRG or the distal or proximal aspect of the sciatic nerve. This dense vascularization, coupled with the high permeability of these capillaries, may synergistically contribute, and in part explain, why many potentially neurotoxic agents preferentially accumulate and injure cells within the DRG. Currently, cancer survivors and HIV patients constitute the largest and most rapidly expanding groups that have chemically induced peripheral sensory neuropathy. Understanding the unique aspects of the vascularization of the DRG and closing the endothelial fenestrations of the rich vascular bed of capillaries that vascularize the DRG before intravenous administration of anti-neoplastic or anti-HIV therapies, may offer a mechanism based approach to attenuate these chemically induced peripheral neuropathies in these patients.

  11. Mouse lipocalins (MUP, OBP, LCN) are co-expressed in tissues involved in chemical communication

    Czech Academy of Sciences Publication Activity Database

    Stopková, R.; Vinkler, D.; Kuntová, B.; Šedo, O.; Albrecht, T.; Suchan, J.; Dvořáková-Hortová, Kateřina; Zdráhal, Z.; Stopka, P.

    2016-01-01

    Roč. 47, č. 4 (2016), s. 1-11 ISSN 2296-701X Institutional support: RVO:86652036 Keywords : lipocalin * odorant * chemical communication * Mus musculus * olfaction Subject RIV: EB - Genetics ; Molecular Biology OBOR OECD: Biochemistry and molecular biology

  12. C-glycosylflavones from the aerial parts of Eleusine indica inhibit LPS-induced mouse lung inflammation.

    Science.gov (United States)

    De Melo, Giany O; Muzitano, Michelle F; Legora-Machado, Alexandre; Almeida, Thais A; De Oliveira, Daniela B; Kaiser, Carlos R; Koatz, Vera Lucia G; Costa, Sônia S

    2005-04-01

    The infusion of aerial parts (EI) of Eleusine indica Gaertn (Poaceae) is used in Brazil against airway inflammatory processes like influenza and pneumonia. Pre-treatment with 400 mg/kg of crude extract inhibited 98% of lung neutrophil recruitment in mice exposed to aerosols of lipopolysaccharide (LPS) from Gram-negative bacteria, in a dose-dependent manner. At 400 microg/kg, schaftoside (6-C-beta-glucopyranosyl-8-C-alpha-arabinopyranosylapigenin) and vitexin (8-C-beta-glucopyranosylapigenin), isolated from EI, inhibited 62% and 80% of lung neutrophil influx, respectively. These results may justify the popular use of E. indica against airway inflammatory processes.

  13. Overexpression and amplification of the c-myc gene in mouse tumors induced by chemical and radiations

    Energy Technology Data Exchange (ETDEWEB)

    Niwa, Ohtsura; Enoki, Yoshitaka; Yokoro, Kenjiro

    1989-03-01

    We examined expression of the c-myc gene by the dot blot hybridization of total cellular RNA from mouse primary tumors induced by chemicals and radiations. Expression of the c-myc gene was found to be elevated in 69 cases among 177 independently induced tumors of 12 different types. DNA from tumors overexpressing the myc gene was analyzed by Southern blotting. No case of rearrangement was detected. However, amplification of the c-myc gene was found in 7 cases of primary sarcomas. These included 4 cases out of 24 methylcholanthrene-induced sarcomas and 3 cases out of 7 /alpha/-tocopherol-induced sacromas. We also analyzed 8 cases of sarcomas induced by radiations, but could not find changes in the gene structure of the c-myc gene. Thus, our data indicate tumor type specificity and agent specificity of c-myc gene amplification. (author).

  14. Quantitative evaluation of a single-distance phase-retrieval method applied on in-line phase-contrast images of a mouse lung

    International Nuclear Information System (INIS)

    Mohammadi, Sara; Larsson, Emanuel; Alves, Frauke; Dal Monego, Simeone; Biffi, Stefania; Garrovo, Chiara; Lorenzon, Andrea; Tromba, Giuliana; Dullin, Christian

    2014-01-01

    Quantitative analysis concerning the application of a single-distance phase-retrieval algorithm on in-line phase-contrast images of a mouse lung at different sample-to-detector distances is presented. Propagation-based X-ray phase-contrast computed tomography (PBI) has already proven its potential in a great variety of soft-tissue-related applications including lung imaging. However, the strong edge enhancement, caused by the phase effects, often hampers image segmentation and therefore the quantitative analysis of data sets. Here, the benefits of applying single-distance phase retrieval prior to the three-dimensional reconstruction (PhR) are discussed and quantified compared with three-dimensional reconstructions of conventional PBI data sets in terms of contrast-to-noise ratio (CNR) and preservation of image features. The PhR data sets show more than a tenfold higher CNR and only minor blurring of the edges when compared with PBI in a predominately absorption-based set-up. Accordingly, phase retrieval increases the sensitivity and provides more functionality in computed tomography imaging

  15. Biodiesel versus diesel exposure: Enhanced pulmonary inflammation, oxidative stress, and differential morphological changes in the mouse lung

    International Nuclear Information System (INIS)

    Yanamala, Naveena; Hatfield, Meghan K.; Farcas, Mariana T.; Schwegler-Berry, Diane; Hummer, Jon A.; Shurin, Michael R.; Birch, M. Eileen; Gutkin, Dmitriy W.; Kisin, Elena; Kagan, Valerian E.; Bugarski, Aleksandar D.; Shvedova, Anna A.

    2013-01-01

    The use of biodiesel (BD) or its blends with petroleum diesel (D) is considered to be a viable approach to reduce occupational and environmental exposures to particulate matter (PM). Due to its lower particulate mass emissions compared to D, use of BD is thought to alleviate adverse health effects. Considering BD fuel is mainly composed of unsaturated fatty acids, we hypothesize that BD exhaust particles could induce pronounced adverse outcomes, due to their ability to readily oxidize. The main objective of this study was to compare the effects of particles generated by engine fueled with neat BD and neat petroleum-based D. Biomarkers of tissue damage and inflammation were significantly elevated in lungs of mice exposed to BD particulates. Additionally, BD particulates caused a significant accumulation of oxidatively modified proteins and an increase in 4-hydroxynonenal. The up-regulation of inflammatory cytokines/chemokines/growth factors was higher in lungs upon BD particulate exposure. Histological evaluation of lung sections indicated presence of lymphocytic infiltrate and impaired clearance with prolonged retention of BD particulate in pigment laden macrophages. Taken together, these results clearly indicate that BD exhaust particles could exert more toxic effects compared to D. - Highlights: • Exposure of mice to BDPM caused higher pulmonary toxicity compared to DPM. • Oxidative stress and inflammation were higher in BD vs to D exposed mice. • Inflammatory lymphocyte infiltrates were seen only in lungs of mice exposed to BD. • Ineffective clearance, prolonged PM retention was present only after BD exposure

  16. Biodiesel versus diesel exposure: Enhanced pulmonary inflammation, oxidative stress, and differential morphological changes in the mouse lung

    Energy Technology Data Exchange (ETDEWEB)

    Yanamala, Naveena, E-mail: wqu1@cdc.gov [Pathology and Physiology Research Branch/NIOSH/CDC, Morgantown, WV 26505 (United States); Hatfield, Meghan K., E-mail: wla4@cdc.gov [Pathology and Physiology Research Branch/NIOSH/CDC, Morgantown, WV 26505 (United States); Farcas, Mariana T., E-mail: woe7@cdc.gov [Pathology and Physiology Research Branch/NIOSH/CDC, Morgantown, WV 26505 (United States); Schwegler-Berry, Diane [Pathology and Physiology Research Branch/NIOSH/CDC, Morgantown, WV 26505 (United States); Hummer, Jon A., E-mail: qzh3@cdc.gov [Office of Mine Safety and Health Research/NIOSH/CDC, Pittsburgh, PA 15236 (United States); Shurin, Michael R., E-mail: shurinmr@upmc.edu [Department of Pathology, University of Pittsburgh Medical Center, Pittsburgh, PA (United States); Birch, M. Eileen, E-mail: mib2@cdc.gov [NIOSH/CDC, 4676 Columbia Parkway, Cincinnati, OH 45226 (United States); Gutkin, Dmitriy W., E-mail: dwgutkin@hotmail.com [Department of Pathology, University of Pittsburgh Medical Center, Pittsburgh, PA (United States); Kisin, Elena, E-mail: edk8@cdc.gov [Pathology and Physiology Research Branch/NIOSH/CDC, Morgantown, WV 26505 (United States); Kagan, Valerian E., E-mail: kagan@pitt.edu [Department of Environmental and Occupational Health, University of Pittsburgh, PA (United States); Bugarski, Aleksandar D., E-mail: zjl1@cdc.gov [Office of Mine Safety and Health Research/NIOSH/CDC, Pittsburgh, PA 15236 (United States); Shvedova, Anna A., E-mail: ats1@cdc.gov [Pathology and Physiology Research Branch/NIOSH/CDC, Morgantown, WV 26505 (United States); Department Physiology and Pharmacology, WVU, Morgantown, WV 26505 (United States)

    2013-10-15

    The use of biodiesel (BD) or its blends with petroleum diesel (D) is considered to be a viable approach to reduce occupational and environmental exposures to particulate matter (PM). Due to its lower particulate mass emissions compared to D, use of BD is thought to alleviate adverse health effects. Considering BD fuel is mainly composed of unsaturated fatty acids, we hypothesize that BD exhaust particles could induce pronounced adverse outcomes, due to their ability to readily oxidize. The main objective of this study was to compare the effects of particles generated by engine fueled with neat BD and neat petroleum-based D. Biomarkers of tissue damage and inflammation were significantly elevated in lungs of mice exposed to BD particulates. Additionally, BD particulates caused a significant accumulation of oxidatively modified proteins and an increase in 4-hydroxynonenal. The up-regulation of inflammatory cytokines/chemokines/growth factors was higher in lungs upon BD particulate exposure. Histological evaluation of lung sections indicated presence of lymphocytic infiltrate and impaired clearance with prolonged retention of BD particulate in pigment laden macrophages. Taken together, these results clearly indicate that BD exhaust particles could exert more toxic effects compared to D. - Highlights: • Exposure of mice to BDPM caused higher pulmonary toxicity compared to DPM. • Oxidative stress and inflammation were higher in BD vs to D exposed mice. • Inflammatory lymphocyte infiltrates were seen only in lungs of mice exposed to BD. • Ineffective clearance, prolonged PM retention was present only after BD exposure.

  17. Effects of Gui Zhi Ma Huang Ge Ban Tang on the TLR7 Pathway in Influenza Virus Infected Mouse Lungs in a Cold Environment.

    Science.gov (United States)

    Qin, Hong-Qiong; Shi, Shan-Shan; Fu, Ying-Jie; Yan, Yu-Qi; Wu, Sha; Tang, Xiao-Long; Chen, Xiao-Yin; Hou, Guang-Hui; Jiang, Zhen-You

    2018-01-01

    We wished to investigate the effects of the traditional Chinese medicine Gui Zhi Ma Huang Ge Ban Tang on controlling influenza A virus (IAV) infection and improving inflammation in mouse lungs. Mice were maintained in normal and cold environments and infected with IAV by intranasal application, respectively. Real-time quantitative polymerase chain reaction was used to measure mRNA expression of TLR7, myeloid differentiation primary response 88 (MyD88), and nuclear factor-kappa B (NF- κ B)p65 in the TLR7 signaling pathway and virus replication in lungs. Western blotting was used to measure expression levels of TLR7, MyD88, and NF- κ B p65 proteins. Flow cytometry was used to detect the proportion of T-helper (Th)1/Th2 and Th17/T-regulatory (Treg) cells. Application of Gui Zhi Ma Huang Ge Ban Tang in influenza-infected mice in a cold environment showed (i) downregulation of TLR7, MyD88, and NF- κ Bp65; (ii) inhibition of transcriptional activities of promoters coding for TLR7, MyD88, and NF- κ Bp65; (iii) reduction in the proportion of Th1/Th2 and Th17/Treg cells. Gui Zhi Ma Huang Ge Ban Tang had a good therapeutic effect on mice infected with IAV, especially in the cold environment. It could reduce lung inflammation in mice significantly and elicit an anti-influenza effect by downregulating expression of the key factors in TLR7 signaling pathway.

  18. Relative Efficacy of Uptake and Presentation of Mycobacterium bovis BCG Antigens by Type I Mouse Lung Epithelial Cells and Peritoneal Macrophages ▿

    Science.gov (United States)

    Kumari, Mandavi; Saxena, Rajiv K.

    2011-01-01

    Flow cytometric studies indicated that both peritoneal macrophages (PMs) and primary lung epithelial (PLE) cells isolated from mouse lungs could take up fluorescence-tagged Mycobacterium bovis BCG. BCG uptake in both cases was significantly inhibited by cytochalasin D, indicating active internalization of BCG by these cells. Confocal microscopy data further confirmed that BCG was internalized by PLE cells. BCG sonicate antigen (sBCG) had marked toxicity toward PMs but was relatively nontoxic to PLE cells. Accordingly, BCG sonicate antigen induced a significantly higher apoptotic and necrotic response in PMs compared to that in PLE cells. Both PMs and PLE cells exposed to BCG antigens and fixed thereafter could efficiently present antigens to purified BCG-sensitized T helper cells, as assessed by the release of interleukin-2 (IL-2) and gamma interferon (IFN-γ). If, however, PLE cells were fixed before exposure to BCG, antigen presentation was abrogated, indicating that the PLE cells may in some way process the BCG antigen. A comparison of efficacies of BCG-pulsed PLE cells and PMs to present antigen at various antigen-presenting cell (APC)/T cell ratios indicated that PMs had only marginally greater APC function than that of PLE cells. Staining with specific monoclonal antibodies indicated that the cultured PLE cells used for antigen presentation essentially comprised type I epithelial cells. Our results suggest that type I lung epithelial cells may present BCG antigens to sensitized T helper cells and that their performance as APCs is comparable with that of PMs. PMID:21646448

  19. Network model of chemical-sensing system inspired by mouse taste buds.

    Science.gov (United States)

    Tateno, Katsumi; Igarashi, Jun; Ohtubo, Yoshitaka; Nakada, Kazuki; Miki, Tsutomu; Yoshii, Kiyonori

    2011-07-01

    Taste buds endure extreme changes in temperature, pH, osmolarity, so on. Even though taste bud cells are replaced in a short span, they contribute to consistent taste reception. Each taste bud consists of about 50 cells whose networks are assumed to process taste information, at least preliminarily. In this article, we describe a neural network model inspired by the taste bud cells of mice. It consists of two layers. In the first layer, the chemical stimulus is transduced into an irregular spike train. The synchronization of the output impulses is induced by the irregular spike train at the second layer. These results show that the intensity of the chemical stimulus is encoded as the degree of the synchronization of output impulses. The present algorithms for signal processing result in a robust chemical-sensing system.

  20. Effects of chemically modified nanostructured PLGA on functioning of lung and breast cancer cells

    Directory of Open Access Journals (Sweden)

    Zhang L

    2013-05-01

    Full Text Available Lijuan Zhang,1 Thomas J Webster21Department of Chemistry, 2School of Engineering, Brown University, Providence, RI, USABackground: The aim of this study was to investigate the effects of poly-lactic-co-glycolic acid (PLGA nanotopographies with alginate or chitosan protein preadsorption on the functioning of healthy and cancerous lung and breast cells, including adhesion, proliferation, apoptosis, and release of vascular endothelial growth factor (VEGF, which promotes tumor angiogenesis and secretion.Methods: We used a well established cast-mold technique to create nanoscale surface features on PLGA. Some of the nanomodified PLGA films were then exposed to alginate and chitosan. Surface roughness and the presence of protein was confirmed by atomic force microscopy. Surface energy was quantified by contact angle measurement.Results: Nanostructured PLGA surfaces with 23 nm features decreased synthesis of VEGF in both lung and breast cancer cells compared with conventional PLGA. Preadsorbing alginate further decreased cancer cell function, with nanostructured PLGA preadsorbed with alginate achieving the greatest decrease in synthesis of VEGF in both lung and breast cancer cells. In contrast, compared with nonmodified smooth PLGA, healthy cell functions were either not altered (ie, breast or were enhanced (ie, lung by use of nanostructured features and alginate or chitosan protein preadsorption.Conclusion: Using this technique, we developed surface nanometric roughness and modification of surface chemistry that could selectively decrease breast and lung cancer cell functioning without the need for chemotherapeutics. This technique requires further study in a wide range of anticancer and regenerative medicine applications.Keywords: breast, lung, cancer, nanotechnology, alginate, chitosan

  1. Essential Oils from Thyme (Thymus vulgaris): Chemical Composition and Biological Effects in Mouse Model.

    Science.gov (United States)

    Vetvicka, Vaclav; Vetvickova, Jana

    2016-12-01

    Thymus species are popular spices and contain volatile oils as main chemical constituents. Recently, plant-derived essential oils are gaining significant attention due to their significant biological activities. Seven different thymus-derived essential oils were compared in our study. First, we focused on their chemical composition, which was followed up by testing their effects on phagocytosis, cytokine production, chemotaxis, edema inhibition, and liver protection. We found limited biological activities among tested oils, with no correlation between composition and biological effects. Similarly, no oils were effective in every reaction. Based on our data, the tested biological use of these essential oils is questionable.

  2. MWCNTs of different physicochemical properties cause similar inflammatory responses, but differences in transcriptional and histological markers of fibrosis in mouse lungs

    International Nuclear Information System (INIS)

    Poulsen, Sarah S.; Saber, Anne T.; Williams, Andrew; Andersen, Ole; Købler, Carsten; Atluri, Rambabu; Pozzebon, Maria E.; Mucelli, Stefano P.; Simion, Monica; Rickerby, David; Mortensen, Alicja; Jackson, Petra; Kyjovska, Zdenka O.

    2015-01-01

    Multi-walled carbon nanotubes (MWCNTs) are an inhomogeneous group of nanomaterials that vary in lengths, shapes and types of metal contamination, which makes hazard evaluation difficult. Here we present a toxicogenomic analysis of female C57BL/6 mouse lungs following a single intratracheal instillation of 0, 18, 54 or 162 μg/mouse of a small, curled (CNT Small , 0.8 ± 0.1 μm in length) or large, thick MWCNT (CNT Large , 4 ± 0.4 μm in length). The two MWCNTs were extensively characterized by SEM and TEM imaging, thermogravimetric analysis, and Brunauer–Emmett–Teller surface area analysis. Lung tissues were harvested 24 h, 3 days and 28 days post-exposure. DNA microarrays were used to analyze gene expression, in parallel with analysis of bronchoalveolar lavage fluid, lung histology, DNA damage (comet assay) and the presence of reactive oxygen species (dichlorodihydrofluorescein assay), to profile and characterize related pulmonary endpoints. Overall changes in global transcription following exposure to CNT Small or CNT Large were similar. Both MWCNTs elicited strong acute phase and inflammatory responses that peaked at day 3, persisted up to 28 days, and were characterized by increased cellular influx in bronchoalveolar lavage fluid, interstitial pneumonia and gene expression changes. However, CNT Large elicited an earlier onset of inflammation and DNA damage, and induced more fibrosis and a unique fibrotic gene expression signature at day 28, compared to CNT Small . The results indicate that the extent of change at the molecular level during early response phases following an acute exposure is greater in mice exposed to CNT Large , which may eventually lead to the different responses observed at day 28. - Highlights: • We evaluate the toxicogenomic response in mice following MWCNT instillation. • Two MWCNTs of different properties were examined and thoroughly characterized. • MWCNT exposure leads to increased pulmonary inflammation and acute phase

  3. MWCNTs of different physicochemical properties cause similar inflammatory responses, but differences in transcriptional and histological markers of fibrosis in mouse lungs

    Energy Technology Data Exchange (ETDEWEB)

    Poulsen, Sarah S., E-mail: spo@nrcwe.dk [National Research Centre for the Working Environment, Copenhagen DK-2100 (Denmark); Department of Science, Systems and Models, Roskilde University, DK-4000 Roskilde (Denmark); Saber, Anne T., E-mail: ats@nrcwe.dk [National Research Centre for the Working Environment, Copenhagen DK-2100 (Denmark); Williams, Andrew, E-mail: Andrew.williams@hc-sc.gc.ca [Environmental and Radiation Health Sciences Directorate, Health Canada, Ottawa, Ontario K1A 0K9 (Canada); Andersen, Ole, E-mail: oa@ruc.dk [Department of Science, Systems and Models, Roskilde University, DK-4000 Roskilde (Denmark); Købler, Carsten, E-mail: carko@nanotech.dtu.dk [Department of Micro- and Nanotechnology, Technical University of Denmark, DK-2800 Kgs. Lyngby (Denmark); Atluri, Rambabu, E-mail: rba@nrcwe.dk [Nanologica AB, SE-114 28 Stockholm (Sweden); Pozzebon, Maria E., E-mail: mariaelena.pozzebon@yahoo.it [Veneto Nanotech SCpA, ECSIN — European Centre for the Sustainable Impact of Nanotechnology, I-45100 Rovigo (Italy); Mucelli, Stefano P., E-mail: stefano.pozzimucelli@venetonanotech.it [Veneto Nanotech SCpA, ECSIN — European Centre for the Sustainable Impact of Nanotechnology, I-45100 Rovigo (Italy); Simion, Monica, E-mail: moni304ro@gmail.com [Laboratory of Nanobiotechnology, National Institute for Research and Development in Microtechnologies, 077190 Bucharest (Romania); Rickerby, David, E-mail: david.rickerby@jrc.ec.europa.eu [European Commission Joint Research Centre Institute for Environment and Sustainability, I-21027 Ispra, VA (Italy); Mortensen, Alicja, E-mail: almo@food.dtu.dk [National Food Institute, Technical University of Denmark, Søborg (Denmark); Jackson, Petra, E-mail: pja@nrcwe.dk [National Research Centre for the Working Environment, Copenhagen DK-2100 (Denmark); Kyjovska, Zdenka O., E-mail: zky@nrcwe.dk [National Research Centre for the Working Environment, Copenhagen DK-2100 (Denmark); and others

    2015-04-01

    Multi-walled carbon nanotubes (MWCNTs) are an inhomogeneous group of nanomaterials that vary in lengths, shapes and types of metal contamination, which makes hazard evaluation difficult. Here we present a toxicogenomic analysis of female C57BL/6 mouse lungs following a single intratracheal instillation of 0, 18, 54 or 162 μg/mouse of a small, curled (CNT{sub Small}, 0.8 ± 0.1 μm in length) or large, thick MWCNT (CNT{sub Large}, 4 ± 0.4 μm in length). The two MWCNTs were extensively characterized by SEM and TEM imaging, thermogravimetric analysis, and Brunauer–Emmett–Teller surface area analysis. Lung tissues were harvested 24 h, 3 days and 28 days post-exposure. DNA microarrays were used to analyze gene expression, in parallel with analysis of bronchoalveolar lavage fluid, lung histology, DNA damage (comet assay) and the presence of reactive oxygen species (dichlorodihydrofluorescein assay), to profile and characterize related pulmonary endpoints. Overall changes in global transcription following exposure to CNT{sub Small} or CNT{sub Large} were similar. Both MWCNTs elicited strong acute phase and inflammatory responses that peaked at day 3, persisted up to 28 days, and were characterized by increased cellular influx in bronchoalveolar lavage fluid, interstitial pneumonia and gene expression changes. However, CNT{sub Large} elicited an earlier onset of inflammation and DNA damage, and induced more fibrosis and a unique fibrotic gene expression signature at day 28, compared to CNT{sub Small}. The results indicate that the extent of change at the molecular level during early response phases following an acute exposure is greater in mice exposed to CNT{sub Large}, which may eventually lead to the different responses observed at day 28. - Highlights: • We evaluate the toxicogenomic response in mice following MWCNT instillation. • Two MWCNTs of different properties were examined and thoroughly characterized. • MWCNT exposure leads to increased pulmonary

  4. COMPARISON OF CHEMICAL-INDUCED CHANGES IN PROLIFERATION AND APOPTOSIS IN HUMAN AND MOUSE NEUROPROGENITOR CELLS.

    Science.gov (United States)

    There is a need to develop rapid and efficient models for screening chemicals for their potential to cause developmental neurotoxicity. Use of in vitro neuronal models, including human cells, is one approach that allows for timely, cost-effective toxicity screening. The present s...

  5. Comparison of Chemical-induced Changes in Proliferation and Apoptosis in Human and Mouse Neuroprogenitor Cells.***

    Science.gov (United States)

    There is a need to develop rapid and efficient models to screen chemicals for their potential to cause developmental neurotoxicity. Use of in vitro neuronal models, including human cells, is one approach that allows for timely, cost-effective toxicity screening. The present study...

  6. Effect of mouse strain in a model of chemical-induced respiratory allergy.

    Science.gov (United States)

    Nishino, Risako; Fukuyama, Tomoki; Watanabe, Yuko; Kurosawa, Yoshimi; Ueda, Hideo; Kosaka, Tadashi

    2014-01-01

    The inhalation of many types of chemicals is a leading cause of allergic respiratory diseases, and effective protocols are needed for the detection of environmental chemical-related respiratory allergies. In our previous studies, we developed a method for detecting environmental chemical-related respiratory allergens by using a long-term sensitization-challenge protocol involving BALB/c mice. In the current study, we sought to improve our model by characterizing strain-associated differences in respiratory allergic reactions to the well-known chemical respiratory allergen glutaraldehyde (GA). According to our protocol, BALB/c, NC/Nga, C3H/HeN, C57BL/6N, and CBA/J mice were sensitized dermally with GA for 3 weeks and then challenged with intratracheal or inhaled GA at 2 weeks after the last sensitization. The day after the final challenge, all mice were euthanized, and total serum IgE levels were assayed. In addition, immunocyte counts, cytokine production, and chemokine levels in the hilar lymph nodes (LNs) and bronchoalveolar lavage fluids (BALF) were also assessed. In conclusion, BALB/c and NC/Nga mice demonstrated markedly increased IgE reactions. Inflammatory cell counts in BALF were increased in the treated groups of all strains, especially BALB/c, NC/Nga, and CBA/J strains. Cytokine levels in LNs were increased in all treated groups except for C3H/HeN and were particularly high in BALB/c and NC/Nga mice. According to our results, we suggest that BALB/c and NC/Nga are highly susceptible to respiratory allergic responses and therefore are good candidates for use in our model for detecting environmental chemical respiratory allergens.

  7. Focal exposure of limited lung volumes to high-dose irradiation down-regulated organ development-related functions and up-regulated the immune response in mouse pulmonary tissues.

    Science.gov (United States)

    Kim, Bu-Yeo; Jin, Hee; Lee, Yoon-Jin; Kang, Ga-Young; Cho, Jaeho; Lee, Yun-Sil

    2016-01-27

    Despite the emergence of stereotactic body radiotherapy (SBRT) for treatment of medically inoperable early-stage non-small-cell lung cancer patients, the molecular effects of focal exposure of limited lung volumes to high-dose radiation have not been fully characterized. This study was designed to identify molecular changes induced by focal high-dose irradiation using a mouse model of SBRT. Central areas of the mouse left lung were focally-irradiated (3 mm in diameter) with a single high-dose of radiation (90 Gy). Temporal changes in gene expression in the irradiated and non-irradiated neighboring lung regions were analyzed by microarray. For comparison, the long-term effect (12 months) of 20 Gy radiation on a diffuse region of lung was also measured. The majority of genes were down-regulated in the focally-irradiated lung areas at 2 to 3 weeks after irradiation. This pattern of gene expression was clearly different than gene expression in the diffuse region of lungs exposed to low-dose radiation. Ontological and pathway analyses indicated these down-regulated genes were mainly associated with organ development. Although the number was small, genes that were up-regulated after focal irradiation were associated with immune-related functions. The temporal patterns of gene expression and the associated biological functions were also similar in non-irradiated neighboring lung regions, although statistical significance was greatly reduced when compared with those from focally-irradiated areas of the lung. From network analysis of temporally regulated genes, we identified inter-related modules associated with diverse functions, including organ development and the immune response, in both the focally-irradiated regions and non-irradiated neighboring lung regions. Focal exposure of lung tissue to high-dose radiation induced expression of genes associated with organ development and the immune response. This pattern of gene expression was also observed in non

  8. Developing Novel Therapeutic Approaches in Small Cell Lung Carcinoma Using Genetically Engineered Mouse Models and Human Circulating Tumor Cells

    Science.gov (United States)

    2016-12-01

    ABT-263 (Fig. 2I and SI Appendix, Fig. S6A). We therefore sought to identify pharmacological strategies that could suppress MCL-1 levels and increase...resonance imaging ( MRI ) of the thorax was performed 1 day before starting treatment and on day 21 of treatment, and lung tumor volumes pre- and...spread on MRI were included in the analysis. Tumors progressed in all untreated animals (n = 7), although we observed significant variability in the

  9. Morphologic changes reflecting early and late effects of irradiation of the distal lung of the mouse: a review

    International Nuclear Information System (INIS)

    Penney, D.P.; Siemann, D.W.; Rubin, P.; Shapiro, D.L.; Finkelstein, J.; Cooper, R.A. Jr.

    1982-01-01

    In radiation of the thorax, the lung has been shown to be a major dose-limiting organ. The early and late responses of the lung to radiation has been reviewed, with primary emphasis on the following cell types: type II pneumocyte, type I pneumocyte, pulmonary endothelial cell and macrophage. The earliest observable and quantifiable cellular response to radiation is exhibited by the type II pneumocytes as a decrease in lamellar bodies and a corresponding increase in surfactant content of the alveolar lavage. By 18-63 weeks following exposure, several type II cells, restored in their lamellar body population, undergo degeneration and sloughing into alveolar spaces. Type I pneumocytes generally exhibit little change, although some investigators describe alveolar denudation due to degenerating type I cells. Macrophages decrease in numbers following irradiation, returning to normal populations by 4 weeks. These changes correspond closely to the changes in alveolar lavage phospholipid phosphorus. Descriptions of radiation-induced damage to endothelial cells are variable. However, blebbing and vacuolation appear to be late developing responses, although altered permeability may be earlier in its expression. Radiation pneumonitis and fibrosis are the two major clinical and experimental responses of the lung to radiation following exposures of greater than 12 Gy. The former appears to involve type II cells, macrophages and pulmonary endothelial cells, and for the latter macrophages, fibroblasts, type II pneumocytes and the pulmonary endothelial cells are involved. The two events are not interdependent, and may not necessarily be interrelated

  10. Identification of nuclear phosphoproteins as novel tobacco markers in mouse lung tissue following short-term exposure to tobacco smoke

    Directory of Open Access Journals (Sweden)

    Kanako Niimori-Kita

    2014-01-01

    Full Text Available Smoking is a risk factor for lung diseases, including chronic obstructive pulmonary disease and lung cancer. However, the molecular mechanisms mediating the progression of these diseases remain unclear. Therefore, we sought to identify signaling pathways activated by tobacco-smoke exposure, by analyzing nuclear phosphoprotein expression using phosphoproteomic analysis of lung tissue from mice exposed to tobacco smoke. Sixteen mice were exposed to tobacco smoke for 1 or 7 days, and the expression of phosphorylated peptides was analyzed by mass spectrometry. A total of 253 phosphoproteins were identified, including FACT complex subunit SPT16 in the 1-day exposure group, keratin type 1 cytoskeletal 18 (K18, and adipocyte fatty acid-binding protein, in the 7-day exposure group, and peroxiredoxin-1 (OSF3 and spectrin β chain brain 1 (SPTBN1, in both groups. Semi-quantitative analysis of the identified phosphoproteins revealed that 33 proteins were significantly differentially expressed between the control and exposed groups. The identified phosphoproteins were classified according to their biological functions. We found that the identified proteins were related to inflammation, regeneration, repair, proliferation, differentiation, morphogenesis, and response to stress and nicotine. In conclusion, we identified proteins, including OSF3 and SPTBN1, as candidate tobacco smoke-exposure markers; our results provide insights into the mechanisms of tobacco smoke-induced diseases.

  11. Transcriptome Analysis of Individual Stromal Cell Populations Identifies Stroma-Tumor Crosstalk in Mouse Lung Cancer Model

    Directory of Open Access Journals (Sweden)

    Hyejin Choi

    2015-02-01

    Full Text Available Emerging studies have begun to demonstrate that reprogrammed stromal cells play pivotal roles in tumor growth, metastasis, and resistance to therapy. However, the contribution of stromal cells to non-small-cell lung cancer (NSCLC has remained underexplored. We used an orthotopic model of Kras-driven NSCLC to systematically dissect the contribution of specific hematopoietic stromal cells in lung cancer. RNA deep-sequencing analysis of individually sorted myeloid lineage and tumor epithelial cells revealed cell-type-specific differentially regulated genes, indicative of activated stroma. We developed a computational model for crosstalk signaling discovery based on ligand-receptor interactions and downstream signaling networks and identified known and novel tumor-stroma paracrine and tumor autocrine crosstalk-signaling pathways in NSCLC. We provide cellular and molecular insights into components of the lung cancer microenvironment that contribute to carcinogenesis. This study has the potential for development of therapeutic strategies that target tumor-stroma interactions and may complement conventional anti-cancer treatments.

  12. Consecutive native chemical ligation-route to synthetic mouse prion protein

    Czech Academy of Sciences Publication Activity Database

    Zawada, Zbigniew; Šebestík, Jaroslav; Šafařík, Martin; Březinová, Anna; Bouř, Petr; Hlaváček, Jan; Stibor, Ivan

    2009-01-01

    Roč. 103, č. 11 (2009), s. 1001-1001 ISSN 0009-2770. [Pokroky v organické, bioorganické a farmaceutické chemii /44./. 27.11.2009-29.11.2009, Liblice] R&D Projects: GA ČR GA203/07/1517 Institutional research plan: CEZ:AV0Z40550506 Keywords : prion * chemical ligation Subject RIV: CC - Organic Chemistry

  13. Effect of Mouse Strain in a Model of Chemical-induced Respiratory Allergy

    OpenAIRE

    Nishino, Risako; Fukuyama, Tomoki; Watanabe, Yuko; Kurosawa, Yoshimi; Ueda, Hideo; Kosaka, Tadashi

    2014-01-01

    The inhalation of many types of chemicals is a leading cause of allergic respiratory diseases, and effective protocols are needed for the detection of environmental chemical–related respiratory allergies. In our previous studies, we developed a method for detecting environmental chemical–related respiratory allergens by using a long-term sensitization–challenge protocol involving BALB/c mice. In the current study, we sought to improve our model by characterizing strain-associated differences ...

  14. Hypoxia inducible factor 3α plays a critical role in alveolarization and distal epithelial cell differentiation during mouse lung development.

    Directory of Open Access Journals (Sweden)

    Yadi Huang

    Full Text Available Lung development occurs under relative hypoxia and the most important oxygen-sensitive response pathway is driven by Hypoxia Inducible Factors (HIF. HIFs are heterodimeric transcription factors of an oxygen-sensitive subunit, HIFα, and a constitutively expressed subunit, HIF1β. HIF1α and HIF2α, encoded by two separate genes, contribute to the activation of hypoxia inducible genes. A third HIFα gene, HIF3α, is subject to alternative promoter usage and splicing, leading to three major isoforms, HIF3α, NEPAS and IPAS. HIF3α gene products add to the complexity of the hypoxia response as they function as dominant negative inhibitors (IPAS or weak transcriptional activators (HIF3α/NEPAS. Previously, we and others have shown the importance of the Hif1α and Hif2α factors in lung development, and here we investigated the role of Hif3α during pulmonary development. Therefore, HIF3α was conditionally expressed in airway epithelial cells during gestation and although HIF3α transgenic mice were born alive and appeared normal, their lungs showed clear abnormalities, including a post-pseudoglandular branching defect and a decreased number of alveoli. The HIF3α expressing lungs displayed reduced numbers of Clara cells, alveolar epithelial type I and type II cells. As a result of HIF3α expression, the level of Hif2α was reduced, but that of Hif1α was not affected. Two regulatory genes, Rarβ, involved in alveologenesis, and Foxp2, a transcriptional repressor of the Clara cell specific Ccsp gene, were significantly upregulated in the HIF3α expressing lungs. In addition, aberrant basal cells were observed distally as determined by the expression of Sox2 and p63. We show that Hif3α binds a conserved HRE site in the Sox2 promoter and weakly transactivated a reporter construct containing the Sox2 promoter region. Moreover, Hif3α affected the expression of genes not typically involved in the hypoxia response, providing evidence for a novel

  15. Cellular uptake and cytotoxic potential of respirable bentonite particles with different quartz contents and chemical modifications in human lung fibroblasts

    Energy Technology Data Exchange (ETDEWEB)

    Geh, Stefan; Rettenmeier, Albert W.; Dopp, Elke [University Hospital, Institute of Hygiene and Occupational Medicine, Essen (Germany); Yuecel, Raif [University Hospital, Institute of Cell Biology (Cancer Research), Essen (Germany); Duffin, Rodger [Institute of Environmental Health Research (IUF), Duesseldorf (Germany); University of Edinburgh, ELEGI COLT Lab, Scotland (United Kingdom); Albrecht, Catrin; Borm, Paul J.A. [Institute of Environmental Health Research (IUF), Duesseldorf (Germany); Armbruster, Lorenz [Verein fuer Technische Sicherheit und Umweltschutz e.V., Gotha (Germany); Raulf-Heimsoth, Monika; Bruening, Thomas [Research Institute for Occupational Medicine of the Institutions for Statutory Accident Insurance and Prevention (BGFA), Bochum (Germany); Hoffmann, Eik [University of Rostock, Institute of Biology, Department of Cell Biology and Biosystems Technology, Rostock (Germany)

    2006-02-01

    Considering the biological reactivity of pure quartz in lung cells, there is a strong interest to clarify the cellular effects of respirable siliceous dusts, like bentonites. In the present study, we investigated the cellular uptake and the cytotoxic potential of bentonite particles (Oe< 10 {mu}m) with an {alpha}-quartz content of up to 6% and different chemical modifications (activation: alkaline, acidic, organic) in human lung fibroblasts (IMR90). Additionally, the ability of the particles to induce apoptosis in IMR90-cells and the hemolytic activity was tested. All bentonite samples were tested for endotoxins with the in vitro-Pyrogen test and were found to be negative. Cellular uptake of particles by IMR90-cells was studied by transmission electron microscopy (TEM). Cytotoxicity was analyzed in IMR90-cells by determination of viable cells using flow cytometry and by measuring of the cell respiratory activity. Induced apoptotic cells were detected by AnnexinV/Propidiumiodide-staining and gel electrophoresis. Our results demonstrate that activated bentonite particles are better taken up by IMR90-cells than untreated (native) bentonite particles. Also, activated bentonite particles with a quartz content of 5-6% were more cytotoxic than untreated bentonites or bentonites with a quartz content lower than 4%. The bentonite samples induced necrotic as well as apoptotic cell death. In general, bentonites showed a high membrane-damaging potential shown as hemolytic activity in human erythrocytes. We conclude that cellular effects of bentonite particles in human lung cells are enhanced after chemical treatment of the particles. The cytotoxic potential of the different bentonites is primarily characterized by a strong lysis of the cell membrane. (orig.)

  16. Adoptively transferred human lung tumor specific cytotoxic T cells can control autologous tumor growth and shape tumor phenotype in a SCID mouse xenograft model

    Directory of Open Access Journals (Sweden)

    Ferrone Soldano

    2007-06-01

    Full Text Available Abstract Background The anti-tumor efficacy of human immune effector cells, such as cytolytic T lymphocytes (CTLs, has been difficult to study in lung cancer patients in the clinical setting. Improved experimental models for the study of lung tumor-immune cell interaction as well as for evaluating the efficacy of adoptive transfer of immune effector cells are needed. Methods To address questions related to the in vivo interaction of human lung tumor cells and immune effector cells, we obtained an HLA class I + lung tumor cell line from a fresh surgical specimen, and using the infiltrating immune cells, isolated and characterized tumor antigen-specific, CD8+ CTLs. We then established a SCID mouse-human tumor xenograft model with the tumor cell line and used it to study the function of the autologous CTLs provided via adoptive transfer. Results The tumor antigen specific CTLs isolated from the tumor were found to have an activated memory phenotype and able to kill tumor cells in an antigen specific manner in vitro. Additionally, the tumor antigen-specific CTLs were fully capable of homing to and killing autologous tumors in vivo, and expressing IFN-γ, each in an antigen-dependent manner. A single injection of these CTLs was able to provide significant but temporary control of the growth of autologous tumors in vivo without the need for IL-2. The timing of injection of CTLs played an essential role in the outcome of tumor growth control. Moreover, immunohistochemical analysis of surviving tumor cells following CTL treatment indicated that the surviving tumor cells expressed reduced MHC class I antigens on their surface. Conclusion These studies confirm and extend previous studies and provide additional information regarding the characteristics of CTLs which can be found within a patient's tumor. Moreover, the in vivo model described here provides a unique window for observing events that may also occur in patients undergoing adoptive cellular

  17. Anti-respiratory syncytial virus (RSV) G monoclonal antibodies reduce lung inflammation and viral lung titers when delivered therapeutically in a BALB/c mouse model.

    Science.gov (United States)

    Caidi, Hayat; Miao, Congrong; Thornburg, Natalie J; Tripp, Ralph A; Anderson, Larry J; Haynes, Lia M

    2018-06-01

    RSV continues to be a high priority for vaccine and antiviral drug development. Unfortunately, no safe and effective RSV vaccine is available and treatment options are limited. Over the past decade, several studies have focused on the role of RSV G protein on viral entry, viral neutralization, and RSV-mediated pathology. Anti-G murine monoclonal antibody (mAb) 131-2G treatment has been previously shown to reduce weight loss, bronchoalveolar lavage (BAL) cell number, airway reactivity, and Th2-type cytokine production in RSV-infected mice more rapidly than a commercial humanized monoclonal antibody (mAb) against RSV F protein (Palivizumab). In this study, we have tested two human anti-RSV G mAbs, 2B11 and 3D3, by both prophylactic and therapeutic treatment for RSV in the BALB/c mouse model. Both anti-G mAbs reduced viral load, leukocyte infiltration and IFN-γ and IL-4 expression in cell-free BAL supernatants emphasizing the potential of anti-G mAbs as anti-inflammatory and antiviral strategies. Published by Elsevier B.V.

  18. Ultrastructural demonstration of chemical modification of melanogenesis in hairless mouse skin

    International Nuclear Information System (INIS)

    Nishimura, M.; Gellin, G.A.; Hoshino, S.; Epstein, J.H.; Epstein, W.L.; Fukuyama, K.

    1982-01-01

    We investigated chemical and physical modifications of the genetically determined ultrastructure of melanosomes. The flank skin of hairless mice was treated with ultraviolet energy (UV) shorter than 320 nm or with a combination of a photosensitizer and UV (PUVA treatment). All melanosomes in the induced melanocytes and those in resident melanocytes in the ear skin showed eumelanogenesis, although the degree of melanin deposition differed considerably according to the induction process. Eumelanogenesis was most advanced in the resident melanocytes while PUVA-induced melanocytes showed more immature premelanosomes. We then topically applied 4-tertiary butyl catechol on the skin. The depigmenting agent caused an appearance of pheomelanosomes. The alteration in melanogenesis was seen most distinctly in premelanosomes of the PUVA-induced cells. Altered ultrastructure was also observed in matured melanosomes; this change was most apparent in the resident melanocytes. These findings indicate that cells with eumelanogenesis may undergo pheomelanogenesis. The present study demonstrated effects of chemicals on genetically determined function of melanocytes by quantitative analysis of melanosome ultrastructure

  19. Magnetic Resonance Tracking of Endothelial Progenitor Cells Labeled with Alkyl-Polyethylenimine 2 kDa/Superparamagnetic Iron Oxide in a Mouse Lung Carcinoma Xenograft Model

    Directory of Open Access Journals (Sweden)

    Cong Chen

    2014-11-01

    Full Text Available The potential of using endothelial progenitor cells (EPCs in novel anticancer therapy and the repair of vascular injury has been increasingly recognized. In the present study, EPCs were labeled with N-alkyl-polyethylenimine 2 kDa (PEI2k-stabilized superparamagnetic iron oxide (SPIO to facilitate magnetic resonance imaging (MRI of EPCs in a mouse lung carcinoma xenograft model. EPCs derived from human peripheral blood were labeled with alkyl-PEI2k/SPIO. The viability and activity of labeled cells were evaluated using proliferation, migration, and tubulogenesis assays. Alkyl-PEI2k/SPIO-labeled EPCs were injected intravenously (group 1 or mixed and injected together with A549 cells subcutaneously (group 2 into groups of six mice with severe combined immunodeficiency. The labeling efficiency with alkyl-PEI2k/SPIO at 7 mg Fe/mL concentration was approximately 100%. Quantitative analysis of cellular iron was 6.062 ± 0.050 pg/cell. No significant effects on EPC proliferation, migration, or tubulogenesis were seen after labeling. Seventesla micro-MRI showed the presence of schistic or linear hypointense regions at the tumor margins starting from days 7 to 8 after EPC administration. This gradually extended into the inner tumor layers in group 1. In group 2, tumor growth was accompanied by dispersion of low-signal intensity regions inside the tumor. Iron-positive cells identified by Prussian blue dye were seen at the sites identified using MRI. Human CD31-positive cells and mouse CD31-positive cells were present in both groups. Labeling EPCs with alkyl-PEI2k/SPIO allows noninvasive magnetic resonance investigation of EPC involvement in tumor neovasculature and is associated with excellent biocompatibility and MRI sensitivity.

  20. Lung cancer

    Science.gov (United States)

    ... causing chemicals such as uranium, beryllium, vinyl chloride, nickel chromates, coal products, mustard gas, chloromethyl ethers, gasoline, and diesel exhaust Exposure to radon gas Family history of lung cancer ...

  1. TCDD and a putative endogenous AhR ligand, ITE, elicit the same immediate changes in gene expression in mouse lung fibroblasts.

    Science.gov (United States)

    Henry, Ellen C; Welle, Stephen L; Gasiewicz, Thomas A

    2010-03-01

    The aryl hydrocarbon receptor (AhR), a ligand-dependent transcription factor, mediates toxicity of several classes of xenobiotics and also has important physiological roles in differentiation, reproduction, and immunity, although the endogenous ligand(s) mediating these functions is/are as yet unidentified. One candidate endogenous ligand, 2-(1'H-indolo-3'-carbonyl)-thiazole-4-carboxylic acid methyl ester (ITE), is a potent AhR agonist in vitro, activates the murine AhR in vivo, but does not induce toxicity. We hypothesized that ITE and the toxic ligand, 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), may modify transcription of different sets of genes to account for their different toxicity. To test this hypothesis, primary mouse lung fibroblasts were exposed to 0.5muM ITE, 0.2nM TCDD, or vehicle for 4 h, and total gene expression was evaluated using microarrays. After this short-term and low-dose treatment, several hundred genes were changed significantly, and the response to ITE and TCDD was remarkably similar, both qualitatively and quantitatively. Induced gene sets included the expected battery of AhR-dependent xenobiotic-metabolizing enzymes, as well as several sets that reflect the inflammatory role of lung fibroblasts. Real time quantitative RT-qPCR assay of several selected genes confirmed these microarray data and further suggested that there may be kinetic differences in expression between ligands. These data suggest that ITE and TCDD elicit an analogous change in AhR conformation such that the initial transcription response is the same. Furthermore, if the difference in toxicity between TCDD and ITE is mediated by differences in gene expression, then it is likely that secondary changes enabled by the persistent TCDD, but not by the shorter lived ITE, are responsible.

  2. A study on relation between nitroxyl radical reduction potency and X-ray irradiation on mouse lung using L-band electron spin resonance

    International Nuclear Information System (INIS)

    Taneike, Makoto; Sho, Keizen; Morita, Rikushi

    1999-01-01

    Changes in nitroxy radical reduction potency (''reduction potency''), caused by different doses and different number of fractions of X-ray irradiation were studied using a L-band electron spin resonance system on mouse lungs into which 4-hydroxy-2,2,6,6-tetramethylpiperidine-N-oxyl (hydroxy-TEMPO) was introduced through the trachea. The ''reduction potency'' lineally decreased as the irradiation dose increased from 1.0 to 5.0 Gy, but no further decrease was observed at higher doses of 7.5 and 10 Gy. The reduction potency'' dropped at 20 min after each irradiation, but it recovered to the control levels after 1 week in all 3 groups of single dose of 10 Gy, 3 fractions and 5 fractions in a similar manner. Although the levels of the ''reduction potency'' were kept high in the groups of fractionated irradiation through 1-4 weeks after irradiation, the levels dropped again in the single dose group at 1 week and the levels were kept significantly low until 4 weeks after irradiation. suggesting that the fractionation of X-ray irradiation would also be effective to prevent the deterioration of the ''reduction potency''. Pre-treatment with sufficient ascorbic acid inhibited the lowering effects of radiation on the ''reduction potency'' in a dose dependent manner. Furthermore the levels of the reduction potency'' ever elevated higher than those of controls with the large amount of ascorbic acid of 750 mg/kg or more, suggesting that the large amounts of ascorbic acid could prevent the adverse effects associated with radiation therapy for the lung malignancy. (author)

  3. Anti-tumor activity of high-dose EGFR tyrosine kinase inhibitor and sequential docetaxel in wild type EGFR non-small cell lung cancer cell nude mouse xenografts

    OpenAIRE

    Tang, Ning; Zhang, Qianqian; Fang, Shu; Han, Xiao; Wang, Zhehai

    2016-01-01

    Treatment of non-small-cell lung cancer (NSCLC) with wild-type epidermal growth factor receptor (EGFR) is still a challenge. This study explored antitumor activity of high-dose icotinib (an EGFR tyrosine kinase inhibitor) plus sequential docetaxel against wild-type EGFR NSCLC cells-generated nude mouse xenografts. Nude mice were subcutaneously injected with wild-type EGFR NSCLC A549 cells and divided into different groups for 3-week treatment. Tumor xenograft volumes were monitored and record...

  4. Regional quantification of lung function in cystic fibrosis using hyperpolarized xenon-129 and chemical shift imaging

    OpenAIRE

    Fernandes, Carolina Campanha

    2012-01-01

    Tese de mestrado em Engenharia Biomédica e Biofísica (Radiações em Diagnóstico e Terapia), apresentada à Universidade de Lisboa, através da Faculdade de Ciências, 2012 Cystic fibrosis (CF) is a genetic disorder in which the defective gene causes the production of unusually thick and viscous mucus that builds-up in the airways, leading to impaired ventilation and infection of lung structures. Currently, there is a lack of methods capable of routinely assessing, in a regional manner, basic p...

  5. Subchronic inhalation of soluble manganese induces expression of hypoxia-associated angiogenic genes in adult mouse lungs

    International Nuclear Information System (INIS)

    Bredow, Sebastian; Falgout, Melanie M.; March, Thomas H.; Yingling, Christin M.; Malkoski, Stephen P.; Aden, James; Bedrick, Edward J.; Lewis, Johnnye L.; Divine, Kevin K.

    2007-01-01

    Although the lung constitutes the major exposure route for airborne manganese (Mn), little is known about the potential pulmonary effects and the underlying molecular mechanisms. Transition metals can mimic a hypoxia-like response, activating the hypoxia inducible factor-1 (HIF-1) transcription factor family. Through binding to the hypoxia-response element (HRE), these factors regulate expression of many genes, including vascular endothelial growth factor (VEGF). Increases in VEGF, an important biomarker of angiogenesis, have been linked to respiratory diseases, including pulmonary hypertension. The objective of this study was to evaluate pulmonary hypoxia-associated angiogenic gene expression in response to exposure of soluble Mn(II) and to assess the genes' role as intermediaries of potential pulmonary Mn toxicity. In vitro, 0.25 mM Mn(II) altered morphology and slowed the growth of human pulmonary epithelial cell lines. Acute doses between 0.05 and 1 mM stimulated VEGF promoter activity up to 3.7-fold in transient transfection assays. Deletion of the HRE within the promoter had no effect on Mn(II)-induced VEGF expression but decreased cobalt [Co(II)]-induced activity 2-fold, suggesting that HIF-1 may not be involved in Mn(II)-induced VEGF gene transcription. Nose-only inhalation to 2 mg Mn(II)/m 3 for 5 days at 6 h/day produced no significant pulmonary inflammation but induced a 2-fold increase in pulmonary VEGF mRNA levels in adult mice and significantly altered expression of genes associated with murine angiogenesis. These findings suggest that even short-term exposures to soluble, occupationally relevant Mn(II) concentrations may alter pulmonary gene expression in pathways that ultimately could affect the lungs' susceptibility to respiratory disease

  6. CRP-ductin, the mouse homologue of gp-340/deleted in malignant brain tumors 1 (DMBT1), binds gram-positive and gram-negative bacteria and interacts with lung surfactant protein D

    DEFF Research Database (Denmark)

    Madsen, Jens; Tornøe, Ida; Nielsen, Ole

    2003-01-01

    CRP-ductin is a protein expressed mainly by mucosal epithelial cells in the mouse. Sequence homologies indicate that CRP-ductin is the mouse homologue of human gp-340, a glycoprotein that agglutinates microorganisms and binds the lung mucosal collectin surfactant protein-D (SP-D). Here we report...... that purified CRP-ductin binds human SP-D in a calcium-dependent manner and that the binding is not inhibited by maltose. The same properties have previously been observed for gp-340 binding of SP-D. CRP-ductin also showed calcium-dependent binding to both gram-positive and -negative bacteria. A polyclonal...... antibody raised against gp-340 reacted specifically with CRP-ductin in Western blots. Immunoreactivity to CRP-ductin was found in the exocrine pancreas, in epithelial cells throughout the gastrointestinal tract and in the parotid ducts. A panel of RNA preparations from mouse tissues was screened for CRP...

  7. Application of BALB/c mouse in the local lymph node assay:BrdU-ELISA for the prediction of the skin sensitizing potential of chemicals.

    Science.gov (United States)

    Hou, Fenxia; Xing, Caihong; Li, Bin; Cheng, Juan; Chen, Wei; Zhang, Man

    2015-01-01

    Allergic contact dermatitis (ACD) is a skin disease characterized by eczema and itching. A considerable proportion of chemicals induce ACD in humans. More than 10,000 substances should be tested for skin sensitization potential under the Registration, Evaluation, Authorization and Restriction of Chemical substances (REACH) regulation. The Local Lymph Node Assay (LLNA) has been designated as the first-choice in vivo assay for sensitization testing by REACH. The LLNA:BrdU-ELISA is a validated non-radioactive modification to the LLNA. For both the LLNA and the LLNA:BrdU-ELISA, CBA/JN mouse is the preferred mouse strain recommended in the regulatory guidelines. However, the availability of CBA/JN mouse in China is only limited to a few animal suppliers, which makes the mouse difficult to obtain. BALB/c mouse, which is widely commercially available, is considered for alternative use but it can only be used in the assay after it has been evaluated by formal validation study. Thus, a validation study was conducted in our laboratory to determine if BALB/c mouse could also be used in the LLNA:BrdU-ELISA. Forty-three test substances including 32 LLNA sensitizers and 11 LLNA non-sensitizers, their vehicles and each concentration used were the same as that used in the formal validation study for the LLNA:BrdU-ELISA using CBA/JN mouse. Female BALB/c mice of 8-10 weeks old were randomly allocated to groups (four mice per group). The test substance (25 μl) or the vehicle alone was applied to the dorsum of both ears daily for 3 consecutive days. A single intraperitoneal injection of 0.5 ml of BrdU (10mg/ml) solution was given on day 5. On day 6, a pair of auricular lymph nodes from each mouse was excised, weighed and stored at -20°C until BrdU-ELISA was conducted. This validation study for the LLNA:BrdU-ELISA using BALB/c mouse correctly identified 30 of 31 sensitizers and 8 of 11 non-sensitizers. The accuracy, sensitivity, specificity, false positive rate, false negative rate

  8. Comparative proteome analysis of three mouse lung adenocarcinoma CMT cell lines with different metastatic potential by two-dimensional gel electrophoresis and mass spectrometry.

    Science.gov (United States)

    Zhang, Kelan; Wrzesinski, Krzysztof; Stephen, J Fey; Larsen, Peter Mose; Zhang, Xumin; Roepstorff, Peter

    2008-12-01

    Metastasis is a lethal attribute of a cancer and presents a continuing therapeutic challenge. Metastasis is a highly complex process and more knowledge about the mechanisms behind metastasis is highly desirable. Isogenic CMT cell lines were selected from a spontaneous mouse lung adenocarcinoma and characterized in vivo to have different metastatic potential. In this study, the comprehensive protein expression profiles of three of these CMT cell lines at passage 5, 15 and 35 were analyzed by 2-DE separation followed by MS identification. As a result, 82 and 40 unique proteins were found to be significantly up- or down-regulated between cell lines with different metastatic potential at passages 5 and 15, respectively. These proteins were identified by MS and most of them have previously been reported to be related to cancer development and/or metastasis. Bioinformatics analysis indicated that several of the proteins were involved in proteasome, cell-cycle and cell-communication pathways. Among them, some keratins, 14-3-3 proteins and 26S proteasome proteins were identified and their aberrant expression may be directly or indirectly involved in cancer development and metastasis. In conclusion, our comprehensive 2-DE-based proteomics studies revealed some candidate proteins, protein families and signaling pathways, which might be important in cancer development and metastasis.

  9. Functionalized synchrotron in-line phase-contrast computed tomography: a novel approach for simultaneous quantification of structural alterations and localization of barium-labelled alveolar macrophages within mouse lung samples

    Energy Technology Data Exchange (ETDEWEB)

    Dullin, Christian, E-mail: christian.dullin@med.uni-goettingen.de [University Medical Center Göttingen, Robert Koch Strasse 40, 37075 Göttingen (Germany); Monego, Simeone dal [Cluster in Biomedicine, AREA Science Park Basovizza, Trieste (Italy); Larsson, Emanuel [Elettra Sincrotrone Trieste, Strada Statale 14, km 163.5 in AREA Science Park, 34149 Basovizza (Trieste) (Italy); University of Trieste, Trieste (Italy); Linköping University, SE-581 83 Linkoeping (Sweden); Mohammadi, Sara [Elettra Sincrotrone Trieste, Strada Statale 14, km 163.5 in AREA Science Park, 34149 Basovizza (Trieste) (Italy); Krenkel, Martin [University of Göttingen, Göttingen (Germany); Garrovo, Chiara; Biffi, Stefania [IRCCS Burlo Garofolo, Trieste (Italy); Lorenzon, Andrea [Cluster in Biomedicine, AREA Science Park Basovizza, Trieste (Italy); Markus, Andrea [University Medical Center Göttingen, Robert Koch Strasse 40, 37075 Göttingen (Germany); Napp, Joanna [University Medical Center Göttingen, Robert Koch Strasse 40, 37075 Göttingen (Germany); Max Planck Institute for Experimental Medicine, Hermann-Rein-Strasse 3, 37075 Göttingen (Germany); University Medical Center Göttingen, Robert Koch Strasse 40, 37075 Göttingen (Germany); Salditt, Tim [University of Göttingen, Göttingen (Germany); Accardo, Agostino [University of Trieste, Trieste (Italy); Alves, Frauke [University Medical Center Göttingen, Robert Koch Strasse 40, 37075 Göttingen (Germany); Max Planck Institute for Experimental Medicine, Hermann-Rein-Strasse 3, 37075 Göttingen (Germany); University Medical Center Göttingen, Robert Koch Strasse 40, 37075 Göttingen (Germany); Tromba, Giuliana [Elettra Sincrotrone Trieste, Strada Statale 14, km 163.5 in AREA Science Park, 34149 Basovizza (Trieste) (Italy)

    2015-01-01

    This study presents an approach to increase the sensitivity of lung computed tomography (CT) imaging by utilizing in-line phase contrast CT in combination with single-distance phase-retrieval algorithms and a dedicated image-processing regime. As demonstrated here, functional CT imaging can be achieved for the assessment of both structural alterations in asthmatic mouse lung tissue and the accumulation pattern of instilled barium-sulfate-labelled macrophages in comparison with healthy controls. Functionalized computed tomography (CT) in combination with labelled cells is virtually non-existent due to the limited sensitivity of X-ray-absorption-based imaging, but would be highly desirable to realise cell tracking studies in entire organisms. In this study we applied in-line free propagation X-ray phase-contrast CT (XPCT) in an allergic asthma mouse model to assess structural changes as well as the biodistribution of barium-labelled macrophages in lung tissue. Alveolar macrophages that were barium-sulfate-loaded and fluorescent-labelled were instilled intratracheally into asthmatic and control mice. Mice were sacrificed after 24 h, lungs were kept in situ, inflated with air and scanned utilizing XPCT at the SYRMEP beamline (Elettra Synchrotron Light Source, Italy). Single-distance phase retrieval was used to generate data sets with ten times greater contrast-to-noise ratio than absorption-based CT (in our setup), thus allowing to depict and quantify structural hallmarks of asthmatic lungs such as reduced air volume, obstruction of airways and increased soft-tissue content. Furthermore, we found a higher concentration as well as a specific accumulation of the barium-labelled macrophages in asthmatic lung tissue. It is believe that XPCT will be beneficial in preclinical asthma research for both the assessment of therapeutic response as well as the analysis of the role of the recruitment of macrophages to inflammatory sites.

  10. Simvastatin Inhibits Goblet Cell Hyperplasia and Lung Arginase in a Mouse Model of Allergic Asthma: A Novel Treatment for Airway Remodeling?

    Science.gov (United States)

    Zeki, Amir A.; Bratt, Jennifer M.; Rabowsky, Michelle; Last, Jerold A.; Kenyon, Nicholas J.

    2010-01-01

    Airway remodeling in asthma contributes to airway hyperreactivity, loss of lung function, and persistent symptoms. Current therapies do not adequately treat the structural airway changes associated with asthma. The statins are cholesterol-lowering drugs that inhibit the enzyme 3-hydroxy-3-methyl-glutaryl-CoA reductase, the rate-limiting step of cholesterol biosynthesis in the mevalonate pathway. These drugs have been associated with improved respiratory health and ongoing clinical trials are testing their therapeutic potential in asthma. We hypothesized that simvastatin treatment of ovalbumin-exposed mice would attenuate early features of airway remodeling, by a mevalonate-dependent mechanism. BALB/c mice were initially sensitized to ovalbumin, and then exposed to 1% ovalbumin aerosol for 2 weeks after sensitization for a total of six exposures. Simvastatin (40 mg/kg) or simvastatin plus mevalonate (20 mg/kg) were injected intraperitoneally before each ovalbumin exposure. Treatment with simvastatin attenuated goblet cell hyperplasia, arginase-1 protein expression, and total arginase enzyme activity, but did not alter airway hydroxyproline content or transforming growth factor-β1. Inhibition of goblet cell hyperplasia by simvastatin was mevalonate-dependent. No appreciable changes to airway smooth muscle cells were observed in any of the control or treatment groups. In conclusion, in an acute mouse model of allergic asthma, simvastatin inhibited early hallmarks of airway remodeling, indicators that can lead to airway thickening and fibrosis. Statins are potentially novel treatments for airway remodeling in asthma. Further studies utilizing sub-chronic or chronic allergen exposure models are needed to extend these initial findings. PMID:21078495

  11. Translation of Angiotensin-Converting Enzyme 2 upon Liver- and Lung-Targeted Delivery of Optimized Chemically Modified mRNA

    Directory of Open Access Journals (Sweden)

    Eva Schrom

    2017-06-01

    Full Text Available Changes in lifestyle and environmental conditions give rise to an increasing prevalence of liver and lung fibrosis, and both have a poor prognosis. Promising results have been reported for recombinant angiotensin-converting enzyme 2 (ACE2 protein administration in experimental liver and lung fibrosis. However, the full potential of ACE2 may be achieved by localized translation of a membrane-anchored form. For this purpose, we advanced the latest RNA technology for liver- and lung-targeted ACE2 translation. We demonstrated in vitro that transfection with ACE2 chemically modified messenger RNA (cmRNA leads to robust translation of fully matured, membrane-anchored ACE2 protein. In a second step, we designed eight modified ACE2 cmRNA sequences and identified a lead sequence for in vivo application. Finally, formulation of this ACE2 cmRNA in tailor-made lipidoid nanoparticles and in lipid nanoparticles led to liver- and lung-targeted translation of significant amounts of ACE2 protein, respectively. In summary, we provide evidence that RNA transcript therapy (RTT is a promising approach for ACE2-based treatment of liver and lung fibrosis to be tested in fibrotic disease models.

  12. Functionalized synchrotron in-line phase-contrast computed tomography: a novel approach for simultaneous quantification of structural alterations and localization of barium-labelled alveolar macrophages within mouse lung samples.

    Science.gov (United States)

    Dullin, Christian; dal Monego, Simeone; Larsson, Emanuel; Mohammadi, Sara; Krenkel, Martin; Garrovo, Chiara; Biffi, Stefania; Lorenzon, Andrea; Markus, Andrea; Napp, Joanna; Salditt, Tim; Accardo, Agostino; Alves, Frauke; Tromba, Giuliana

    2015-01-01

    Functionalized computed tomography (CT) in combination with labelled cells is virtually non-existent due to the limited sensitivity of X-ray-absorption-based imaging, but would be highly desirable to realise cell tracking studies in entire organisms. In this study we applied in-line free propagation X-ray phase-contrast CT (XPCT) in an allergic asthma mouse model to assess structural changes as well as the biodistribution of barium-labelled macrophages in lung tissue. Alveolar macrophages that were barium-sulfate-loaded and fluorescent-labelled were instilled intratracheally into asthmatic and control mice. Mice were sacrificed after 24 h, lungs were kept in situ, inflated with air and scanned utilizing XPCT at the SYRMEP beamline (Elettra Synchrotron Light Source, Italy). Single-distance phase retrieval was used to generate data sets with ten times greater contrast-to-noise ratio than absorption-based CT (in our setup), thus allowing to depict and quantify structural hallmarks of asthmatic lungs such as reduced air volume, obstruction of airways and increased soft-tissue content. Furthermore, we found a higher concentration as well as a specific accumulation of the barium-labelled macrophages in asthmatic lung tissue. It is believe that XPCT will be beneficial in preclinical asthma research for both the assessment of therapeutic response as well as the analysis of the role of the recruitment of macrophages to inflammatory sites.

  13. Diffusing capacity for lung carbon monoxide (dlco) in chemical lung injuries due to the use of mustard gas in the poisoned soldiers of Iran-Iraq war 2006

    International Nuclear Information System (INIS)

    Rouhi, H.; Ganji, F.

    2010-01-01

    To assess the Mustard gas exposure effects on pulmonary system, particularly on diffusing capacity for lung carbon monoxide (DLCO) and simple spirometry. Sixty-five sulfur mustard- poisoned soldiers from Mostazafan and Janbazan organization were referred to our center in 2005. Complete history, physical examination, chest X ray, Echocardiography, Arterial blood gas, high - resolution computerized tomography, diffusion capacity for lung carbon monoxide and spirometry of these were performed and compared this result with normal value. The mean value of indices in studied injured subjects was: Spirometry: forced expiratory volume in one second (FEV1) = 70.4, Forced vital capacity (FVC) = 66.5, EFE 25-75=81.1, FEV1/FVC=101.9, Flow 25% = 28.7, Flow 50%= 72.9, Flow 75%= 100.1, Sample volume: Functional residual capacity of lungs (FRC) = 131.5, residual volume (RV) = 157.3, RV/TLC= 169.1, Total lung capacity (TLC) = 91.3, KCO= 131.6, TLCO= 116.3. No significant correlation was observed between TLCO values with HRCT, echocardiography, ABG and spirometry values (P>0.05). We recommend TLCO and RV/TLV tests to assess severity of Injuries as there is no a suitable criterion to measure the real consequences of mustard gas on affected combatants. and Biological markers are also needed to determine cause effect relations. (author)

  14. Subchronic Arsenic Exposure Induces Anxiety-Like Behaviors in Normal Mice and Enhances Depression-Like Behaviors in the Chemically Induced Mouse Model of Depression

    Directory of Open Access Journals (Sweden)

    Chia-Yu Chang

    2015-01-01

    Full Text Available Accumulating evidence implicates that subchronic arsenic exposure causes cerebral neurodegeneration leading to behavioral disturbances relevant to psychiatric disorders. However, there is still little information regarding the influence of subchronic exposure to arsenic-contaminated drinking water on mood disorders and its underlying mechanisms in the cerebral prefrontal cortex. The aim of this study is to assess the effects of subchronic arsenic exposure (10 mg/LAs2O3 in drinking water on the anxiety- and depression-like behaviors in normal mice and in the chemically induced mouse model of depression by reserpine pretreatment. Our findings demonstrated that 4 weeks of arsenic exposure enhance anxiety-like behaviors on elevated plus maze (EPM and open field test (OFT in normal mice, and 8 weeks of arsenic exposure augment depression-like behaviors on tail suspension test (TST and forced swimming test (FST in the reserpine pretreated mice. In summary, in this present study, we demonstrated that subchronic arsenic exposure induces only the anxiety-like behaviors in normal mice and enhances the depression-like behaviors in the reserpine induced mouse model of depression, in which the cerebral prefrontal cortex BDNF-TrkB signaling pathway is involved. We also found that eight weeks of subchronic arsenic exposure are needed to enhance the depression-like behaviors in the mouse model of depression. These findings imply that arsenic could be an enhancer of depressive symptoms for those patients who already had the attribute of depression.

  15. Intersections of lung progenitor cells, lung disease and lung cancer.

    Science.gov (United States)

    Kim, Carla F

    2017-06-30

    The use of stem cell biology approaches to study adult lung progenitor cells and lung cancer has brought a variety of new techniques to the field of lung biology and has elucidated new pathways that may be therapeutic targets in lung cancer. Recent results have begun to identify the ways in which different cell populations interact to regulate progenitor activity, and this has implications for the interventions that are possible in cancer and in a variety of lung diseases. Today's better understanding of the mechanisms that regulate lung progenitor cell self-renewal and differentiation, including understanding how multiple epigenetic factors affect lung injury repair, holds the promise for future better treatments for lung cancer and for optimising the response to therapy in lung cancer. Working between platforms in sophisticated organoid culture techniques, genetically engineered mouse models of injury and cancer, and human cell lines and specimens, lung progenitor cell studies can begin with basic biology, progress to translational research and finally lead to the beginnings of clinical trials. Copyright ©ERS 2017.

  16. Intersections of lung progenitor cells, lung disease and lung cancer

    Directory of Open Access Journals (Sweden)

    Carla F. Kim

    2017-06-01

    Full Text Available The use of stem cell biology approaches to study adult lung progenitor cells and lung cancer has brought a variety of new techniques to the field of lung biology and has elucidated new pathways that may be therapeutic targets in lung cancer. Recent results have begun to identify the ways in which different cell populations interact to regulate progenitor activity, and this has implications for the interventions that are possible in cancer and in a variety of lung diseases. Today's better understanding of the mechanisms that regulate lung progenitor cell self-renewal and differentiation, including understanding how multiple epigenetic factors affect lung injury repair, holds the promise for future better treatments for lung cancer and for optimising the response to therapy in lung cancer. Working between platforms in sophisticated organoid culture techniques, genetically engineered mouse models of injury and cancer, and human cell lines and specimens, lung progenitor cell studies can begin with basic biology, progress to translational research and finally lead to the beginnings of clinical trials.

  17. Expression of biomarker genes of differentiation in D3 mouse embryonic stem cells after exposure to different embryotoxicant and non-embryotoxicant model chemicals

    Directory of Open Access Journals (Sweden)

    Andrea C. Romero

    2015-12-01

    Full Text Available There is a necessity to develop in vitro methods for testing embryotoxicity (Romero et al., 2015 [1]. We studied the progress of D3 mouse embryonic stem cells differentiation exposed to model embryotoxicants and non-embryotoxicants chemicals through the expression of biomarker genes. We studied a set of 16 different genes biomarkers of general cellular processes (Cdk1, Myc, Jun, Mixl, Cer and Wnt3, ectoderm formation (Nrcam, Nes, Shh and Pnpla6, mesoderm formation (Mesp1, Vegfa, Myo1e and Hdac7 and endoderm formation (Flk1 and Afp. We offer dose response in order to derive the concentration causing either 50% or 200% of expression of the biomarker gene. These records revealed to be a valuable end-point to predict in vitro the embryotoxicity of chemicals (Romero et al., 2015 [1].

  18. Chemically-induced photoreceptor degeneration and protection in mouse iPSC-derived three-dimensional retinal organoids

    Directory of Open Access Journals (Sweden)

    Shin-ichiro Ito

    2017-10-01

    Full Text Available Induced pluripotent stem cells (iPSCs, which can be differentiated into various tissues and cell types, have been used for clinical research and disease modeling. Self-organizing three-dimensional (3D tissue engineering has been established within the past decade and enables researchers to obtain tissues and cells that almost mimic in vivo development. However, there are no reports of practical experimental procedures that reproduce photoreceptor degeneration. In this study, we induced photoreceptor cell death in mouse iPSC-derived 3D retinal organoids (3D-retinas by 4-hydroxytamoxifen (4-OHT, which induces photoreceptor degeneration in mouse retinal explants, and then established a live-cell imaging system to measure degeneration-related properties. Furthermore, we quantified the protective effects of representative ophthalmic supplements for treating the photoreceptor degeneration. This drug evaluation system enables us to monitor drug effects in photoreceptor cells and could be useful for drug screening.

  19. An orally active Cannabis extract with high content in cannabidiol attenuates chemical induced intestinal inflammation and hypermotility in the mouse

    OpenAIRE

    Ester Pagano; Raffaele Capasso; Fabiana Piscitelli; Barbara Romano; Olga Alessandra Parisi; Stefania Finizio; Anna Lauritano; Vincenzo Di Marzo; Angelo A Izzo; Francesca Borrelli

    2016-01-01

    Anecdotal and scientific evidence suggests that Cannabis use may be beneficial in inflammatory bowel disease (IBD) patients. Here, we have investigated the effect of a standardized Cannabis sativa extract with high content of cannabidiol (CBD), here named CBD BDS for CBD botanical drug substance, on mucosal inflammation and hypermotility in mouse models of intestinal inflammation. Colitis was induced in mice by intracolonic administration of dinitrobenzenesulfonic acid (DNBS). Motility was ev...

  20. An optimized, fast-to-perform mouse lung infection model with the human pathogen Chlamydia trachomatis for in vivo screening of antibiotics, vaccine candidates and modified host-pathogen interactions.

    Science.gov (United States)

    Dutow, Pavel; Wask, Lea; Bothe, Miriam; Fehlhaber, Beate; Laudeley, Robert; Rheinheimer, Claudia; Yang, Zhangsheng; Zhong, Guangming; Glage, Silke; Klos, Andreas

    2016-03-01

    Chlamydia trachomatis causes sexually transmitted diseases with infertility, pelvic inflammatory disease and neonatal pneumonia as complications. The duration of urogenital mouse models with the strict mouse pathogen C. muridarum addressing vaginal shedding, pathological changes of the upper genital tract or infertility is rather long. Moreover, vaginal C. trachomatis application usually does not lead to the complications feared in women. A fast-to-perform mouse model is urgently needed to analyze new antibiotics, vaccine candidates, immune responses (in gene knockout animals) or mutants of C. trachomatis. To complement the valuable urogenital model with a much faster and quantifiable screening method, we established an optimized lung infection model for the human intracellular bacterium C. trachomatis serovar D (and L2) in immunocompetent C57BL/6J mice. We demonstrated its usefulness by sensitive determination of antibiotic effects characterizing advantages and limitations achievable by early or delayed short tetracycline treatment and single-dose azithromycin application. Moreover, we achieved partial acquired protection in reinfection with serovar D indicating usability for vaccine studies, and showed a different course of disease in absence of complement factor C3. Sensitive monitoring parameters were survival rate, body weight, clinical score, bacterial load, histological score, the granulocyte marker myeloperoxidase, IFN-γ, TNF-α, MCP-1 and IL-6. © FEMS 2015. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

  1. A cross-sectional study of lung function and respiratory symptoms among chemical workers producing diacetyl for food flavourings.

    NARCIS (Netherlands)

    van Rooy, F.G.; Smit, L.A.; Houba, R.; Zaat, V.A.; Rooijackers, J.M.; Heederik, D.J.J.

    2009-01-01

    OBJECTIVES: Four diacetyl workers were found to have bronchiolitis obliterans syndrome. Exposures, respiratory symptoms, lung function and exposure-response relationships were investigated. METHODS: 175 workers from a plant producing diacetyl between 1960 and 2003 were investigated. Exposure data

  2. Interleukin-33 from Monocytes Recruited to the Lung Contributes to House Dust Mite-Induced Airway Inflammation in a Mouse Model.

    Directory of Open Access Journals (Sweden)

    Hiroki Tashiro

    Full Text Available Interleukin-33 (IL-33 activates group 2 innate lymphoid cells (ILC2, resulting in T-helper-2 inflammation in bronchial asthma. Airway epithelial cells were reported as sources of IL-33 during apoptosis and necrosis. However, IL-33 is known to be from sources other than airway epithelial cells such as leukocytes, and the mechanisms of IL-33 production and release are not fully understood. The aim of this study was to clarify the role of IL-33 production by monocytes in airway inflammation.BALB/c mice were sensitized and challenged with a house dust mite (HDM preparation. Airway inflammation was assessed by quantifying inflammatory cells in bronchoalveolar lavage (BAL fluid, and IL-25, IL-33, and thymic stromal lymphopoietin (TSLP levels in lung. Immunohistochemistry for IL-33 in lung sections was also performed. Ly6c, CD11b, and CD11c expression was examined by flow cytometry. Clodronate liposomes were used in the HDM-airway inflammation model to deplete circulating monocytes.The IL-33, but not IL-25 or TSLP, level in lung homogenates was markedly increased in HDM mice compared to control mice. IL-33-positive cells in the lungs were identified using immunohistochemistry and were increased in areas surrounding bronchi and vasculature. Furthermore, IL-33 levels were increased in mononuclear cells derived from lungs of HDM mice compared to controls. The expression of Ly6c in mononuclear cells was significantly higher in HDM mice than in controls. Treatment with clodronate liposomes led to inhibition of not only inflammatory cells in BAL fluid, airway hyper reactivity and Th2 cytokines in lung, but also IL-33 in lung.IL-33 from monocytes recruited to the lung may contribute to the pathogenesis of HDM-induced airway inflammation.

  3. Silica-induced Chronic Inflammation Promotes Lung Carcinogenesis in the Context of an Immunosuppressive Microenvironment

    Directory of Open Access Journals (Sweden)

    Javier Freire

    2013-08-01

    Full Text Available The association between inflammation and lung tumor development has been clearly demonstrated. However, little is known concerning the molecular events preceding the development of lung cancer. In this study, we characterize a chemically induced lung cancer mouse model in which lung cancer developed in the presence of silicotic chronic inflammation. Silica-induced lung inflammation increased the incidence and multiplicity of lung cancer in mice treated with N-nitrosodimethylamine, a carcinogen found in tobacco smoke. Histologic and molecular analysis revealed that concomitant chronic inflammation contributed to lung tumorigenesis through induction of preneoplastic changes in lung epithelial cells. In addition, silica-mediated inflammation generated an immunosuppressive microenvironment in which we observed increased expression of programmed cell death protein 1 (PD-1, transforming growth factor-β1, monocyte chemotactic protein 1 (MCP-1, lymphocyte-activation gene 3 (LAG3, and forkhead box P3 (FOXP3, as well as the presence of regulatory T cells. Finally, the K-RAS mutational profile of the tumors changed from Q61R to G12D mutations in the inflammatory milieu. In summary, we describe some of the early molecular changes associated to lung carcinogenesis in a chronic inflammatory microenvironment and provide novel information concerning the mechanisms underlying the formation and the fate of preneoplastic lesions in the silicotic lung.

  4. LungMAP: The Molecular Atlas of Lung Development Program.

    Science.gov (United States)

    Ardini-Poleske, Maryanne E; Clark, Robert F; Ansong, Charles; Carson, James P; Corley, Richard A; Deutsch, Gail H; Hagood, James S; Kaminski, Naftali; Mariani, Thomas J; Potter, Steven S; Pryhuber, Gloria S; Warburton, David; Whitsett, Jeffrey A; Palmer, Scott M; Ambalavanan, Namasivayam

    2017-11-01

    The National Heart, Lung, and Blood Institute is funding an effort to create a molecular atlas of the developing lung (LungMAP) to serve as a research resource and public education tool. The lung is a complex organ with lengthy development time driven by interactive gene networks and dynamic cross talk among multiple cell types to control and coordinate lineage specification, cell proliferation, differentiation, migration, morphogenesis, and injury repair. A better understanding of the processes that regulate lung development, particularly alveologenesis, will have a significant impact on survival rates for premature infants born with incomplete lung development and will facilitate lung injury repair and regeneration in adults. A consortium of four research centers, a data coordinating center, and a human tissue repository provides high-quality molecular data of developing human and mouse lungs. LungMAP includes mouse and human data for cross correlation of developmental processes across species. LungMAP is generating foundational data and analysis, creating a web portal for presentation of results and public sharing of data sets, establishing a repository of young human lung tissues obtained through organ donor organizations, and developing a comprehensive lung ontology that incorporates the latest findings of the consortium. The LungMAP website (www.lungmap.net) currently contains more than 6,000 high-resolution lung images and transcriptomic, proteomic, and lipidomic human and mouse data and provides scientific information to stimulate interest in research careers for young audiences. This paper presents a brief description of research conducted by the consortium, database, and portal development and upcoming features that will enhance the LungMAP experience for a community of users. Copyright © 2017 the American Physiological Society.

  5. Cigarette smoke alters the secretome of lung epithelial cells.

    Science.gov (United States)

    Mossina, Alessandra; Lukas, Christina; Merl-Pham, Juliane; Uhl, Franziska E; Mutze, Kathrin; Schamberger, Andrea; Staab-Weijnitz, Claudia; Jia, Jie; Yildirim, Ali Ö; Königshoff, Melanie; Hauck, Stefanie M; Eickelberg, Oliver; Meiners, Silke

    2017-01-01

    Cigarette smoke is the most relevant risk factor for the development of lung cancer and chronic obstructive pulmonary disease. Many of its more than 4500 chemicals are highly reactive, thereby altering protein structure and function. Here, we used subcellular fractionation coupled to label-free quantitative MS to globally assess alterations in the proteome of different compartments of lung epithelial cells upon exposure to cigarette smoke extract. Proteomic profiling of the human alveolar derived cell line A549 revealed the most pronounced changes within the cellular secretome with preferential downregulation of proteins involved in wound healing and extracellular matrix organization. In particular, secretion of secreted protein acidic and rich in cysteine, a matricellular protein that functions in tissue response to injury, was consistently diminished by cigarette smoke extract in various pulmonary epithelial cell lines and primary cells of human and mouse origin as well as in mouse ex vivo lung tissue cultures. Our study reveals a previously unrecognized acute response of lung epithelial cells to cigarette smoke that includes altered secretion of proteins involved in extracellular matrix organization and wound healing. This may contribute to sustained alterations in tissue remodeling as observed in lung cancer and chronic obstructive pulmonary disease. © 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  6. Inflammation-associated gene transcription and expression in mouse lungs induced by low molecular weight compounds from fungi from the built environment.

    Science.gov (United States)

    Miller, J D; Sun, M; Gilyan, A; Roy, J; Rand, T G

    2010-01-05

    Few metabolites from fungi found indoors have been tested for inflammatory mediators endpoints in primary cultures of alveolar macrophages or in vivo. In this study, mice were intratracheally instilled with a single dose comprising 4x10(-5)moletoxin/kg lung wt dose of either atranone C, brevianamide, cladosporin, mycophenolic acid, neoechinulin A & B, sterigmatocystin or TMC-120A. These toxins are from fungi common on damp building materials. The dose used was comparable to the estimated doses of possible human exposure. Hematoxylin and eosin (H&E) histology and Alcian Blue/Periodic Acid Schiff (AB/PAS) histochemistry were used to evaluate lungs for time course (4h and 12h post-exposure (PE)) inflammatory and toxic changes. Reverse-transcription (RT)-PCR based arrays were also employed to evaluate time course inflammation-associated gene transcription in lung tissues of the different toxins. Immunohistochemistry (IHC) was used to probe MIP-2 and Tnf-alpha protein expression in treatment lungs to determine whether responses correspond with gene transcription data. Both histology and histochemistry revealed that toxin exposed lungs at 12h PE showed evidence of inflammation. H&E revealed that bronchioli were lined with irregularly thickened and sometimes sloughing epithelium and bronchiolar spaces supported infiltration of leukocytes, cellular and mucus-like debris while alveolar spaces supported swollen macrophages and modest amorphous debris accumulations. All toxin-instilled lungs exhibited copious mucus production and alveolar macrophages with red stained cytoplasm on bronchiolar surfaces, especially at 12h PE. Array analysis of 83 inflammation-associated genes extracted from lung tissue demonstrated a number of patterns, compared to controls. 82 genes assayed at 4h PE and 75 genes at 12h PE were significantly altered (por =1.5-fold or cladosporin, atranone C and TMC-120. The results further confirm the inflammatory nature of metabolites/toxins from such fungi can

  7. Chemical composition of PM10 and its in vitro toxicological impacts on lung cells during the Middle Eastern Dust (MED) storms in Ahvaz, Iran.

    Science.gov (United States)

    Naimabadi, Abolfazl; Ghadiri, Ata; Idani, Esmaeil; Babaei, Ali Akbar; Alavi, Nadali; Shirmardi, Mohammad; Khodadadi, Ali; Marzouni, Mohammad Bagherian; Ankali, Kambiz Ahmadi; Rouhizadeh, Ahmad; Goudarzi, Gholamreza

    2016-04-01

    Reports on the effects of PM10 from dust storm on lung cells are limited. The main purpose of this study was to investigate the chemical composition and in vitro toxicological impacts of PM10 suspensions, its water-soluble fraction, and the solvent-extractable organics extracted from Middle Eastern Dust storms on the human lung epithelial cell (A549). Samples of dust storms and normal days (PM10 0.05). These results led to the conclusions that dust storm PM10 as well as normal day PM10 could lead to cytotoxicity, and the organic compounds (PAHs) and the insoluble particle-core might be the main contributors to cytotoxicity. Our results showed that cytotoxicity and the risk of PM10 to human lung may be more severe during dust storm than normal days due to inhalation of a higher mass concentration of airborne particles. Further research on PM dangerous fractions and the most responsible components to make cytotoxicity in exposed cells is recommended. Copyright © 2016 Elsevier Ltd. All rights reserved.

  8. Responses of the L51781Y tk/sup +//tk/sup -/ mouse lymphoma cell forward mutation assay: III. 72 coded chemicals

    Energy Technology Data Exchange (ETDEWEB)

    McGregor, D.B.; Brown, A.; Cattanach, P.; Edwards, I.; McBride, D.; Riach, C.; Caspary, W.J.

    1988-01-01

    Seventy-two chemicals were tested for their mutagenic potential in the L51781Y tk/sup +///sup -/ mouse lymphoma cell forward mutation assay, using procedures based upon those described previously. Cultures were exposed to the chemicals for 4 hr, then cultured for 2 days before planting in soft agar with or without trifluorothymidine (TFT), 3 ..mu..g/ml. The chemicals were tested at least twice. Significant responses were obtained with allyl isothiocyanate, p-benzoquinone dioxime, benzyl acetate, 2-biphenylamine HCl, bis(2-chloro-1-methylethyl)ether, cadmium chloride, chlordane, chlorobenzene, chlorobenzilate, 2-chloroethanol, chlorothalonil, cytarabine x HCl, p,p'-DDE, diazinon, 2,6-dichloro-p-phenylenediamine, N,N-diethylthiourea, diglycidylresorcinol ether, 2,4-dimethoxy aniline x HCl, disperse yellow 3, endosulfan, 1,2-epoxyhexadecane, ethyl acrylate, ethyl benzene, ethylene thiourea, F D and C yellow Number 6, furan, heptachlor, isophorone, mercuric chloride, 4,4'-methylenedianiline x 2 HCl, methyl viologen, nickel sulfate x 6H/sub 2/O, 4,4'-oxydianiline, pentachloroethane, piperonyl butoxide, propyl gallate, quinoline, rotenone, 2,4,5,6-tetrachloro-4-nitro-anisole, 1,1,1,2-tetrachloroethane, trichlorfon, 2,4,6-trichlorophenol, 2,4,5-trimethoxybenzaldehyde, 1,1,3-trimethyl-2-thiourea, 1-vinyl-3-cyclopetene dioxide, vinyl toluene, and ziram. The assay was incapable of providing a clear indication of whether some chemicals were mutagens; these benzyl alcohol, 1,4-dichlorobenzene, phenol, succinic acid-2,2-dimethyl hydrazide, and toluene.

  9. Toxicity of silver nanoparticles in mouse embryonic stem cells and chemical based reprogramming of somatic cells to sphere cells

    Science.gov (United States)

    Rajanahalli Krishnamurthy, Pavan

    Abstract 1: Silver nanoparticles (Ag Np's) have an interesting surface chemistry and unique plasmonic properties. They are used in a wide variety of applications ranging from consumer products like socks, medical dressing, computer chips and it is also shown to have antimicrobial, anti bacterial activity and wound healing. Ag Np toxicity studies have been limited to date which needs to be critically addressed due to its wide applications. Mouse embryonic stem (MES) cells represent a unique cell population with the ability to undergo both self renewal and differentiation. They exhibit very stringent and tightly regulated mechanisms to circumvent DNA damage and stress response. We used 10 nm coated (polysaccharide) and uncoated Ag Np's to test its toxic effects on MES cells. MES cells and embryoid bodies (EB's) were treated with two concentrations of Ag Np's: 5 microg/ml and 50 ug/ml and exposed for 24, 48 and 72 hours. Increased cell death, ROS production and loss of mitochondrial membrane potential and alkaline phosphatase (AP) occur in a time and a concentration dependant manner. Due to increased cell death, there is a progressive increase in Annexin V (apoptosis) and Propidium Iodide (PI) staining (necrosis). Oct4 and Nanog undergo ubiquitination and dephosphorylation post-translational modifications in MES cells thereby altering gene expression of pluripotency factors and differentiation of EB's into all the three embryonic germ layers with specific growth factors were also inhibited after Ag Np exposure. Flow cytometry analysis revealed Ag Np's treated cells had altered cell cycle phases correlating with altered self renewal capacity. Our results suggest that Ag Np's effect MES cell self renewal, pluripotency and differentiation and serves as a perfect model system for studying toxicity induced by engineered Ag Np's. Abstract 2: The reprogramming of fibroblasts to pluripotent stem cells and the direct conversion of fibroblasts to functional neurons has been

  10. Chemical composition of PM_1_0 and its in vitro toxicological impacts on lung cells during the Middle Eastern Dust (MED) storms in Ahvaz, Iran

    International Nuclear Information System (INIS)

    Naimabadi, Abolfazl; Ghadiri, Ata; Idani, Esmaeil; Babaei, Ali Akbar; Alavi, Nadali; Shirmardi, Mohammad; Khodadadi, Ali

    2016-01-01

    Reports on the effects of PM_1_0 from dust storm on lung cells are limited. The main purpose of this study was to investigate the chemical composition and in vitro toxicological impacts of PM_1_0 suspensions, its water-soluble fraction, and the solvent-extractable organics extracted from Middle Eastern Dust storms on the human lung epithelial cell (A549). Samples of dust storms and normal days (PM_1_0   0.05). These results led to the conclusions that dust storm PM_1_0 as well as normal day PM_1_0 could lead to cytotoxicity, and the organic compounds (PAH_s) and the insoluble particle-core might be the main contributors to cytotoxicity. Our results showed that cytotoxicity and the risk of PM_1_0 to human lung may be more severe during dust storm than normal days due to inhalation of a higher mass concentration of airborne particles. Further research on PM dangerous fractions and the most responsible components to make cytotoxicity in exposed cells is recommended. - Highlights: • Chemical compositions of PM_1_0 during normal and dust event days were obtained. • Heavy metal concentrations in dusty conditions were higher than normal days. • PM_1_0 caused a decrease in the cell viability and an increase in LDH in supernatant. • Water-soluble fraction had severe cytotoxicity than solvent extractable organics. • Higher mass concentrations of PM_1_0 may contribute to more severe cytotoxicity. - Inhalation of higher mass concentration of PM during the MED storms may contribute to more severe cytotoxicity than normal days.

  11. Anti-tumor activity of high-dose EGFR tyrosine kinase inhibitor and sequential docetaxel in wild type EGFR non-small cell lung cancer cell nude mouse xenografts

    Science.gov (United States)

    Tang, Ning; Zhang, Qianqian; Fang, Shu; Han, Xiao; Wang, Zhehai

    2017-01-01

    Treatment of non-small-cell lung cancer (NSCLC) with wild-type epidermal growth factor receptor (EGFR) is still a challenge. This study explored antitumor activity of high-dose icotinib (an EGFR tyrosine kinase inhibitor) plus sequential docetaxel against wild-type EGFR NSCLC cells-generated nude mouse xenografts. Nude mice were subcutaneously injected with wild-type EGFR NSCLC A549 cells and divided into different groups for 3-week treatment. Tumor xenograft volumes were monitored and recorded, and at the end of experiments, tumor xenografts were removed for Western blot and immunohistochemical analyses. Compared to control groups (negative control, regular-dose icotinib [IcoR], high-dose icotinib [IcoH], and docetaxel [DTX]) and regular icotinib dose (60 mg/kg) with docetaxel, treatment of mice with a high-dose (1200 mg/kg) of icotinib plus sequential docetaxel for 3 weeks (IcoH-DTX) had an additive effect on suppression of tumor xenograft size and volume (P Icotinib-containing treatments markedly reduced phosphorylation of EGFR, mitogen activated protein kinase (MAPK), and protein kinase B (Akt), but only the high-dose icotinib-containing treatments showed an additive effect on CD34 inhibition (P icotinib plus docetaxel had a similar effect on mouse weight loss (a common way to measure adverse reactions in mice), compared to the other treatment combinations. The study indicate that the high dose of icotinib plus sequential docetaxel (IcoH-DTX) have an additive effect on suppressing the growth of wild-type EGFR NSCLC cell nude mouse xenografts, possibly through microvessel density reduction. Future clinical trials are needed to confirm the findings of this study. PMID:27852073

  12. MicroRNA-31 functions as an oncogenic microRNA in mouse and human lung cancer cells by repressing specific tumor suppressors

    DEFF Research Database (Denmark)

    Liu, Xi; Sempere, Lorenzo F; Ouyang, Haoxu

    2010-01-01

    MicroRNAs (miRNAs) regulate gene expression. It has been suggested that obtaining miRNA expression profiles can improve classification, diagnostic, and prognostic information in oncology. Here, we sought to comprehensively identify the miRNAs that are overexpressed in lung cancer by conducting mi...

  13. March1 E3 Ubiquitin Ligase Modulates Features of Allergic Asthma in an Ovalbumin-Induced Mouse Model of Lung Inflammation

    Directory of Open Access Journals (Sweden)

    Osama A. Kishta

    2018-01-01

    Full Text Available Membrane-associated RING-CH-1 (March1 is a member of the March family of E3 ubiquitin ligases. March1 downregulates cell surface expression of MHC II and CD86 by targeting them to lysosomal degradation. Given the key roles of MHC class II and CD86 in T cell activation and to get further insights into the development of allergic inflammation, we asked whether March1 deficiency exacerbates or attenuates features of allergic asthma in mice. Herein, we used an acute model of allergy to compare the asthmatic phenotype of March1-deficient and -sufficient mice immunized with ovalbumin (OVA and later challenged by intranasal instillation of OVA in the lungs. We found that eosinophilic inflammation in airways and lung tissue was similar between WT and March1−/− allergic mice, whereas neutrophilic inflammation was significant only in March1−/− mice. Airway hyperresponsiveness as well as levels of IFN-γ, IL-13, IL-6, and IL-10 was lower in the lungs of asthmatic March1−/− mice compared to WT, whereas lung levels of TNF-α, IL-4, and IL-5 were not significantly different. Interestingly, in the serum, levels of total and ova-specific IgE were reduced in March1-deficient mice as compared to WT mice. Taken together, our results demonstrate a role of March1 E3 ubiquitin ligase in modulating allergic responses.

  14. An orally active Cannabis extract with high content in cannabidiol attenuates chemical induced intestinal inflammation and hypermotility in the mouse

    Directory of Open Access Journals (Sweden)

    Ester Pagano

    2016-10-01

    Full Text Available Anecdotal and scientific evidence suggests that Cannabis use may be beneficial in inflammatory bowel disease (IBD patients. Here, we have investigated the effect of a standardized Cannabis sativa extract with high content of cannabidiol (CBD, here named CBD BDS for CBD botanical drug substance, on mucosal inflammation and hypermotility in mouse models of intestinal inflammation. Colitis was induced in mice by intracolonic administration of dinitrobenzenesulfonic acid (DNBS. Motility was evaluated in the experimental model of intestinal hypermotility induced by irritant croton oil. CBD BDS or pure CBD were given - either intraperitoneally or by oral gavage - after the inflammatory insult (curative protocol. The amounts of CBD in the colon, brain and liver after the oral treatments were measured by HPLC coupled to ion trap-time of flight mass spectrometry. CBD BDS, both when given intraperitoneally and by oral gavage, decreased the extent of the damage (as revealed by the decrease in the colon weight/length ratio and myeloperoxidase activity in the DNBS model of colitis. It also reduced intestinal hypermotility (at doses lower than those required to affect transit in healthy mice in the croton oil model of intestinal hypermotility. Under the same experimental conditions, pure CBD did not ameliorate colitis while it normalized croton oil-induced hypermotility when given intraperitoneally (in a dose-related fashion or orally (only at one dose. In conclusion, CBD BDS, given after the inflammatory insult, attenuates injury and motility in intestinal models of inflammation. These findings sustain the rationale of combining CBD with other minor Cannabis constituents and support the clinical development of CBD BDS for IBD treatment.

  15. CHEMICALS

    CERN Multimedia

    Medical Service

    2002-01-01

    It is reminded that all persons who use chemicals must inform CERN's Chemistry Service (TIS-GS-GC) and the CERN Medical Service (TIS-ME). Information concerning their toxicity or other hazards as well as the necessary individual and collective protection measures will be provided by these two services. Users must be in possession of a material safety data sheet (MSDS) for each chemical used. These can be obtained by one of several means : the manufacturer of the chemical (legally obliged to supply an MSDS for each chemical delivered) ; CERN's Chemistry Service of the General Safety Group of TIS ; for chemicals and gases available in the CERN Stores the MSDS has been made available via EDH either in pdf format or else via a link to the supplier's web site. Training courses in chemical safety are available for registration via HR-TD. CERN Medical Service : TIS-ME :73186 or service.medical@cern.ch Chemistry Service : TIS-GS-GC : 78546

  16. Chemical chaperones reduce ER stress and adipose tissue inflammation in high fat diet-induced mouse model of obesity.

    Science.gov (United States)

    Chen, Yaqin; Wu, Zhihong; Zhao, Shuiping; Xiang, Rong

    2016-06-08

    Obesity, which is characteristic by chronic inflammation, is defined as abnormal or excessive fat accumulation in adipose tissues. Endoplasmic reticulum (ER) stress is increased in adipose tissue of obese state and is known to be strongly associated with chronic inflammation. The aim of this study was to investigate the effect of ER stress on adipokine secretion in obese mice and explore the potential mechanisms. In this study, we found high-fat diet induced-obesity contributed to strengthened ER stress and triggered chronic inflammation in adipose tissue. Chemical chaperones, 4-PBA and TUDCA, modified metabolic disorders and decreased the levels of inflammatory cytokines in obese mice fed a high-fat diet. The alleviation of ER stress is in accordance with the decrease of free cholesterol in adipose tissue. Furthermore chemical chaperones suppress NF-κB activity in adipose tissue of obese mice in vivo. In vitro studies showed IKK/NF-κB may be involved in the signal transduction of adipokine secretion dysfunction induced by ER stress. The present study revealed the possibility that inhibition of ER stress may be a novel drug target for metabolic abnormalities associated with obesity. Further studies are now needed to characterize the initial incentive of sustained ER stress in obese.

  17. In vitro culture and characterization of human lung cancer circulating tumor cells isolated by size exclusion from an orthotopic nude-mouse model expressing fluorescent protein.

    Science.gov (United States)

    Kolostova, Katarina; Zhang, Yong; Hoffman, Robert M; Bobek, Vladimir

    2014-09-01

    In the present study, we demonstrate an animal model and recently introduced size-based exclusion method for circulating tumor cells (CTCs) isolation. The methodology enables subsequent in vitro CTC-culture and characterization. Human lung cancer cell line H460, expressing red fluorescent protein (H460-RFP), was orthotopically implanted in nude mice. CTCs were isolated by a size-based filtration method and successfully cultured in vitro on the separating membrane (MetaCell®), analyzed by means of time-lapse imaging. The cultured CTCs were heterogeneous in size and morphology even though they originated from a single tumor. The outer CTC-membranes were blebbing in general. Abnormal mitosis resulting in three daughter cells was frequently observed. The expression of RFP ensured that the CTCs originated from lung tumor. These readily isolatable, identifiable and cultivable CTCs can be used to characterize individual patient cancers and for screening of more effective treatment.

  18. Combined exposure to protons and 56Fe leads to overexpression of Il13 and reactivation of repetitive elements in the mouse lung

    Science.gov (United States)

    Nzabarushimana, Etienne; Prior, Sara; Miousse, Isabelle R.; Pathak, Rupak; Allen, Antiño R.; Latendresse, John; Olsen, Reid H. J.; Raber, Jacob; Hauer-Jensen, Martin; Nelson, Gregory A.; Koturbash, Igor

    2015-11-01

    Interest in deep space exploration underlines the needs to investigate the effects of exposure to combined sources of space radiation. The lung is a target organ for radiation, and exposure to protons and heavy ions as radiation sources may lead to the development of degenerative disease and cancer. In this study, we evaluated the pro-fibrotic and epigenetic effects of exposure to protons (150 MeV/nucleon, 0.1 Gy) and heavy iron ions (56Fe, 600 MeV/nucleon, 0.5 Gy) alone or in combination (protons on Day 1 and 56Fe on Day 2) in C57BL/6 male mice 4 weeks after irradiation. Exposure to 56Fe, proton or in combination, did not result in histopathological changes in the murine lung. At the same time, combined exposure to protons and 56Fe resulted in pronounced molecular alterations in comparison with either source of radiation alone. Specifically, we observed a substantial increase in the expression of cytokine Il13, loss of expression of DNA methyltransferase Dnmt1, and reactivation of LINE-1, SINE B1 retrotransposons, and major and minor satellites. Given the deleterious potential of the observed effects that may lead to development of chronic lung injury, pulmonary fibrosis, and cancer, future studies devoted to the investigation of the long-term effects of combined exposures to proton and heavy ions are clearly needed.

  19. Dynamic FDG-PET Imaging to Differentiate Malignancies from Inflammation in Subcutaneous and In Situ Mouse Model for Non-Small Cell Lung Carcinoma (NSCLC).

    Science.gov (United States)

    Yang, Zhen; Zan, Yunlong; Zheng, Xiujuan; Hai, Wangxi; Chen, Kewei; Huang, Qiu; Xu, Yuhong; Peng, Jinliang

    2015-01-01

    [18F]fluoro-2-deoxy-D-glucose positron emission tomography (FDG-PET) has been widely used in oncologic procedures such as tumor diagnosis and staging. However, false-positive rates have been high, unacceptable and mainly caused by inflammatory lesions. Misinterpretations take place especially when non-subcutaneous inflammations appear at the tumor site, for instance in the lung. The aim of the current study is to evaluate the use of dynamic PET imaging procedure to differentiate in situ and subcutaneous non-small cell lung carcinoma (NSCLC) from inflammation, and estimate the kinetics of inflammations in various locations. Dynamic FDG-PET was performed on 33 female mice inoculated with tumor and/or inflammation subcutaneously or inside the lung. Standardized Uptake Values (SUVs) from static imaging (SUVmax) as well as values of influx rate constant (Ki) of compartmental modeling from dynamic imaging were obtained. Static and kinetic data from different lesions (tumor and inflammations) or different locations (subcutaneous, in situ and spontaneous group) were compared. Values of SUVmax showed significant difference in subcutaneous tumor and inflammation (pPET based SUVmax, both subcutaneous and in situ inflammations and malignancies can be differentiated via dynamic FDG-PET based Ki. Moreover, Values of influx rate constant Ki from compartmental modeling can offer an assessment for inflammations at different locations of the body, which also implies further validation is necessary before the replacement of in situ inflammation with its subcutaneous counterpart in animal experiments.

  20. Medical countermeasure against respiratory toxicity and acute lung injury following inhalation exposure to chemical warfare nerve agent VX

    International Nuclear Information System (INIS)

    Nambiar, Madhusoodana P.; Gordon, Richard K.; Rezk, Peter E.; Katos, Alexander M.; Wajda, Nikolai A.; Moran, Theodore S.; Steele, Keith E.; Doctor, Bhupendra P.; Sciuto, Alfred M.

    2007-01-01

    To develop therapeutics against lung injury and respiratory toxicity following nerve agent VX exposure, we evaluated the protective efficacy of a number of potential pulmonary therapeutics. Guinea pigs were exposed to 27.03 mg/m 3 of VX or saline using a microinstillation inhalation exposure technique for 4 min and then the toxicity was assessed. Exposure to this dose of VX resulted in a 24-h survival rate of 52%. There was a significant increase in bronchoalveolar lavage (BAL) protein, total cell number, and cell death. Surprisingly, direct pulmonary treatment with surfactant, liquivent, N-acetylcysteine, dexamethasone, or anti-sense syk oligonucleotides 2 min post-exposure did not significantly increase the survival rate of VX-exposed guinea pigs. Further blocking the nostrils, airway, and bronchioles, VX-induced viscous mucous secretions were exacerbated by these aerosolized treatments. To overcome these events, we developed a strategy to protect the animals by treatment with atropine. Atropine inhibits muscarinic stimulation and markedly reduces the copious airway secretion following nerve agent exposure. Indeed, post-exposure treatment with atropine methyl bromide, which does not cross the blood-brain barrier, resulted in 100% survival of VX-exposed animals. Bronchoalveolar lavage from VX-exposed and atropine-treated animals exhibited lower protein levels, cell number, and cell death compared to VX-exposed controls, indicating less lung injury. When pulmonary therapeutics were combined with atropine, significant protection to VX-exposure was observed. These results indicate that combinations of pulmonary therapeutics with atropine or drugs that inhibit mucous secretion are important for the treatment of respiratory toxicity and lung injury following VX exposure

  1. DNA damage induced in mouse peritoneal exudate cells after in vivo administration of chemical and physical agents as determined by alkaline elution

    International Nuclear Information System (INIS)

    Nishi, Yoshisuke; Miyanaga, Kumiko; Sato, Sei-ichi; Inui, Naomichi

    1990-01-01

    The alkaline elution technique for detecting DNA strand breaks has been applied to the study of DNA damage in mouse peritoneal exudate cells resulting from the in vivo administration of chemical and physical agents. The direct methylating agents methyl methanesulphonate and N-methyl-N-nitrosourea induced extensive breakage in samples taken 2 h after administration. The direct ethylating agents ethyl methanesulphonate and N-ethyl-N-nitrosourea also induced DNA strand breaks, but to a lesser extent than the methylating agents. The indirect methylating agent dimethylnitrosamine showed hardly any effect in this system. A weak but positive response was observed upon treatment with the anti-neoplastic alkylating agent procarbazine hydrochloride. The whole-body irradiation of mice with 60 Co γ-rays also induced DNA strand breaks. The elution profiles for γ-ray irradiation were different from those of alkylating agents, and indicate that alkylating agents produce many more secondary lesions leading to DNA strand breaks than γ-rays. N-methyl-N-nitrosourea produced slightly more DNA strand breaks in mutagen-sensitive mice, which are derived from the CD-1 strain, than in ICR mice. (Author)

  2. DNA damage induced in mouse peritoneal exudate cells after in vivo administration of chemical and physical agents as determined by alkaline elution

    Energy Technology Data Exchange (ETDEWEB)

    Nishi, Yoshisuke (Japan Tobacco Inc., Yokohama (Japan). Central Research Inst.); Miyanaga, Kumiko; Sato, Sei-ichi (Japan Tobacco Inc., Hatano, Kanagawa (Japan). Toxicology Research Lab.); Inui, Naomichi (Japan Tobacco Inc., Yokohama, Kanagawa (Japan). Pharmaceutical Research Labs.)

    1990-01-01

    The alkaline elution technique for detecting DNA strand breaks has been applied to the study of DNA damage in mouse peritoneal exudate cells resulting from the in vivo administration of chemical and physical agents. The direct methylating agents methyl methanesulphonate and N-methyl-N-nitrosourea induced extensive breakage in samples taken 2 h after administration. The direct ethylating agents ethyl methanesulphonate and N-ethyl-N-nitrosourea also induced DNA strand breaks, but to a lesser extent than the methylating agents. The indirect methylating agent dimethylnitrosamine showed hardly any effect in this system. A weak but positive response was observed upon treatment with the anti-neoplastic alkylating agent procarbazine hydrochloride. The whole-body irradiation of mice with {sup 60}Co {gamma}-rays also induced DNA strand breaks. The elution profiles for {gamma}-ray irradiation were different from those of alkylating agents, and indicate that alkylating agents produce many more secondary lesions leading to DNA strand breaks than {gamma}-rays. N-methyl-N-nitrosourea produced slightly more DNA strand breaks in mutagen-sensitive mice, which are derived from the CD-1 strain, than in ICR mice. (Author).

  3. Immunity against mouse thymus-leukemia antigen (TL) protects against development of lymphomas induced by a chemical carcinogen, N-butyl-N-nitrosourea.

    Science.gov (United States)

    Tsujimura, Kunio; Obata, Yuichi; Matsudaira, Yasue; Ozeki, Satoshi; Taguchi, Osamu; Nishida, Keiko; Okanami, Yuko; Akatsuka, Yoshiki; Kuzushima, Kiyotaka; Takahashi, Toshitada

    2004-11-01

    Mouse thymus-leukemia antigens (TL) are aberrantly expressed on T lymphomas in C57BL/6 (B6) and C3H/He (C3H) mice, while they are not expressed on normal T lymphocytes in these strains. When N-butyl-N-nitrosourea (NBU), a chemical carcinogen, was administered orally to B6 and C3H strains, lymphoma development was slower than in T3(b)-TL gene-transduced counterpart strains expressing TL ubiquitously as self-antigens, suggesting that anti-TL immunity may play a protective role. In addition, the development of lymphomas was slightly slower in C3H than in B6, which seems to be in accordance with the results of skin graft experiments indicating that both cellular and humoral immunities against TL were stronger in C3H than B6 mice. The interesting finding that B lymphomas derived from a T3(b)-TL transgenic strain (C3H background) expressing a very high level of TL were rejected in C3H, but not in H-2K(b) transgenic mice (C3H background), raises the possibility that TL-specific effector T cell populations are eliminated and/or energized to a certain extent by interacting with H-2K(b) molecules.

  4. Cutaneous challenge with chemical warfare agents in the SKH-1 hairless mouse. (I) Development of a model for screening studies in skin decontamination and protection.

    Science.gov (United States)

    Dorandeu, F; Taysse, L; Boudry, I; Foquin, A; Hérodin, F; Mathieu, J; Daulon, S; Cruz, C; Lallement, G

    2011-06-01

    Exposure to lethal chemical warfare agents (CWAs) is no longer only a military issue due to the terrorist threat. Among the CWAs of concern are the organophosphorus nerve agent O-ethyl-S-(2[di-isopropylamino]ethyl)methyl-phosphonothioate (VX) and the vesicant sulfur mustard (SM). Although efficient means of decontamination are available, most of them lose their efficacy when decontamination is delayed after exposure of the bare skin. Alternatively, CWA skin penetration can be prevented by topical skin protectants. Active research in skin protection and decontamination is thus paramount. In vivo screening of decontaminants or skin protectants is usually time consuming and may be expensive depending on the animal species used. We were thus looking for a suitable, scientifically sound and cost-effective model, which is easy to handle. The euthymic hairless mouse Crl: SKH-1 (hr/hr) BR is widely used in some skin studies and has previously been described to be suitable for some experiments involving SM or SM analogs. To evaluate the response of this species, we studied the consequences of exposing male anaesthetized SKH-1 mice to either liquid VX or to SM, the latter being used in liquid form or as saturated vapours. Long-term effects of SM burn were also evaluated. The model was then used in the companion paper (Taysse et al.(1)).

  5. Combined effects of a chemical mutagen and radiation sterilized diet in mutagenicity and reproduction studies in the same mouse

    International Nuclear Information System (INIS)

    Renner, H.W.

    1975-01-01

    The possible intensification of the mutagenic effect of cyclophosphamide (Endoxan) by the feeding of a radiation-sterilized diet (dose, 4.5 Mrad) was studied in 2000 NMRI/Han mice. In a dominant lethal test, males were pretreated with 100 mg Endoxan/kg body weight. The greatest sensitivity towards Endoxan was observed during the late-spermatid stage. No significant differences were detected between the control group (Endoxan plus non-irradiated diet) and the experimental group (Endoxan plus radiation-sterilized diet). In this test, radiation-sterilized feed showed no co-mutagenic effect when combined with Endoxan treatment. In a reproduction study of 7 months duration (continuous mating without lactation periods), the females were treated every 2 wk with 20 mg Endoxan/kg body weight. The decline in litter size with increasing number of litters (i.e. with advancing age of the females) was more pronounced after treatment with the chemical mutagen than in the untreated group. Increases in the frequency of abortions and in premature sterility resulted from Endoxan treatment. During the entire observation period, no effects from the intake of radiation-sterilized food were detected. (author)

  6. Solubility of reactor fuels in the mouse lung with respect to their U/Pu and 238Pu/239Pu ratios

    International Nuclear Information System (INIS)

    Talbot, R.J.; Baker, S.T.

    1989-01-01

    The studies reported were designed to assess the comparative in vivo solubilities of a range of plutonium containing reactor fuels. To simulate these fuels, mixed U/Pu oxides were prepared and calcined at 1600 0 C. A plutonium content of 3% w/w was chosen as typical of water-cooled reactor fuel. Higher concentrations of plutonium (10, 20 and 30%) were included to simulate fast reactor fuel. As it is known that 238 PuO 2 , with high specific activity, is translocated more rapidly from lung than 239 PuO 2 , the effect of isotopic composition of plutonium in simulated reactor fuels was also investigated. For this purpose, both the water-cooled and fast-reactor fuels were prepared with plutonium containing 2% of 238 Pu by weight. The resulting oxides had about 6 times the specific activity of those prepared with 239 Pu. Groups of mice were killed at 1, 3, 6, 12 and 18 months after inhaling aerosols of the simulated reactor fuels. After 3 months, measurements of Pu retention in the lung showed no marked differences between materials. After 6 months, measurements of plutonium deposited in the liver and skeleton showed that mixed U/Pu oxides were more soluble in vivo than 239 PuO 2 . Their solubility was inversely related to their plutonium content. The addition of 238 Pu to the plutonium resulted in enhanced translocation of plutonium from the lung, in the cases of water-cooled reactor fuel by a factor of two. (author)

  7. Perinatal exposure to environmental tobacco smoke is associated with changes in DNA methylation that precede the adult onset of lung disease in a mouse model.

    Science.gov (United States)

    Cole, Elizabeth; Brown, Traci A; Pinkerton, Kent E; Postma, Britten; Malany, Keegan; Yang, Mihi; Kim, Yang Jee; Hamilton, Raymond F; Holian, Andrij; Cho, Yoon Hee

    2017-08-01

    Prenatal and early-life environmental tobacco smoke (ETS) exposure can induce epigenetic alterations associated with inflammation and respiratory disease. The objective of this study was to address the long-term epigenetic consequences of perinatal ETS exposure on latent respiratory disease risk, which are still largely unknown. C57BL/6 mice were exposed to prenatal and early-life ETS; offspring lung pathology, global DNA, and gene-specific methylation were measured at two adult ages. Significant alterations in global DNA methylation and promoter methylation of IFN-γ and Thy-1 were found in ETS-exposed offspring at 10-12 and 20 weeks of age. These sustained epigenetic alterations preceded the onset of significant pulmonary pathologies observed at 20 weeks of age. This study suggests that perinatal ETS exposure induces persistent epigenetic alterations in global DNA, as well as IFN-γ and Thy-1 promoter methylation that precede the adult onset of fibrotic lung pathology. These epigenetic findings could represent potential biomarkers of latent respiratory disease risk.

  8. Fluorescence background subtraction technique for hybrid fluorescence molecular tomography/x-ray computed tomography imaging of a mouse model of early stage lung cancer.

    Science.gov (United States)

    Ale, Angelique; Ermolayev, Vladimir; Deliolanis, Nikolaos C; Ntziachristos, Vasilis

    2013-05-01

    The ability to visualize early stage lung cancer is important in the study of biomarkers and targeting agents that could lead to earlier diagnosis. The recent development of hybrid free-space 360-deg fluorescence molecular tomography (FMT) and x-ray computed tomography (XCT) imaging yields a superior optical imaging modality for three-dimensional small animal fluorescence imaging over stand-alone optical systems. Imaging accuracy was improved by using XCT information in the fluorescence reconstruction method. Despite this progress, the detection sensitivity of targeted fluorescence agents remains limited by nonspecific background accumulation of the fluorochrome employed, which complicates early detection of murine cancers. Therefore we examine whether x-ray CT information and bulk fluorescence detection can be combined to increase detection sensitivity. Correspondingly, we research the performance of a data-driven fluorescence background estimator employed for subtraction of background fluorescence from acquisition data. Using mice containing known fluorochromes ex vivo, we demonstrate the reduction of background signals from reconstructed images and sensitivity improvements. Finally, by applying the method to in vivo data from K-ras transgenic mice developing lung cancer, we find small tumors at an early stage compared with reconstructions performed using raw data. We conclude with the benefits of employing fluorescence subtraction in hybrid FMT-XCT for early detection studies.

  9. Assessing molecular initiating events (MIEs), key events (KEs) and modulating factors (MFs) for styrene responses in mouse lungs using whole genome gene expression profiling following 1-day and multi-week exposures.

    Science.gov (United States)

    Andersen, Melvin E; Cruzan, George; Black, Michael B; Pendse, Salil N; Dodd, Darol; Bus, James S; Sarang, Satinder S; Banton, Marcy I; Waites, Robbie; McMullen, Patrick D

    2017-11-15

    Styrene increased lung tumors in mice at chronic inhalation exposures of 20ppm and greater. MIEs, KEs and MFs were examined using gene expression in three strains of male mice (the parental C57BL/6 strain, a CYP2F2(-/-) knock out and a CYP2F2(-/-) transgenic containing human CYP2F1, 2A13 and 2B6). Exposures were for 1-day and 1, 4 and 26weeks. After 1-day exposures at 1, 5, 10, 20, 40 and 120ppm significant increases in differentially expressed genes (DEGs) occurred only in parental strain lungs where there was already an increase in DEGs at 5ppm and then many thousands of DEGs by 120ppm. Enrichment for 1-day and 1-week exposures included cell cycle, mitotic M-M/G1 phases, DNA-synthesis and metabolism of lipids and lipoproteins pathways. The numbers of DEGs decreased steadily over time with no DEGs meeting both statistical significance and fold-change criteria at 26weeks. At 4 and 26weeks, some key transcription factors (TFs) - Nr1d1, Nr1d2, Dbp, Tef, Hlf, Per3, Per2 and Bhlhe40 - were upregulated (|FC|>1.5), while others - Npas, Arntl, Nfil3, Nr4a1, Nr4a2, and Nr4a3 - were down-regulated. At all times, consistent changes in gene expression only occurred in the parental strain. Our results support a MIE for styrene of direct mitogenicity from mouse-specific CYP2F2-mediated metabolites activating Nr4a signaling. Longer-term MFs include down-regulation of Nr4a genes and shifts in both circadian clock TFs and other TFs, linking circadian clock to cellular metabolism. We found no gene expression changes indicative of cytotoxicity or activation of p53-mediated DNA-damage pathways. Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.

  10. Lung cancer

    International Nuclear Information System (INIS)

    Aisner, J.

    1985-01-01

    This book contains 13 chapters. Some of the chapter titles are: The Pathology of Lung Cancer; Radiotherapy for Non-Small-Cell Cancer of the Lung; Chemotherapy for Non-Small-Cell Lung Cancer; Immunotherapy in the Management of Lung Cancer; Preoperative Staging and Surgery for Non-Small-Cell Lung Cancer; and Prognostic Factors in Lung Cancer

  11. Short-Course Treatment With Gefitinib Enhances Curative Potential of Radiation Therapy in a Mouse Model of Human Non-Small Cell Lung Cancer

    International Nuclear Information System (INIS)

    Bokobza, Sivan M.; Jiang, Yanyan; Weber, Anika M.; Devery, Aoife M.; Ryan, Anderson J.

    2014-01-01

    Purpose: To evaluate the combination of radiation and an epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) in preclinical models of human non-small cell lung cancer. Methods and Materials: Sensitivity to an EGFR TKI (gefitinib) or radiation was assessed using proliferation assays and clonogenic survival assays. Effects on receptor signal transduction pathways (pEGFR, pAKT, pMAPK) and apoptosis (percentage of cleaved PARP Poly (ADP-ribose) polymerase (PARP)) were assessed by Western blotting. Radiation-induced DNA damage was assessed by γH2AX immunofluorescence. Established (≥100 mm 3 ) EGFR-mutated (HCC287) or EGFR wild-type (A549) subcutaneous xenografts were treated with radiation (10 Gy, day 1) or gefitinib (50 mg/kg, orally, on days 1-3) or both. Results: In non-small cell lung cancer (NSCLC) cell lines with activating EGFR mutations (PC9 or HCC827), gefitinib treatment markedly reduced pEGFR, pAKT, and pMAPK levels and was associated with an increase in cleaved PARP but not in γH2AX foci. Radiation treatment increased the mean number of γH2AX foci per cell but did not significantly affect EGFR signaling. In contrast, NSCLC cell lines with EGFR T790M (H1975) or wild-type EGFR (A549) were insensitive to gefitinib treatment. The combination of gefitinib and radiation treatment in cell culture produced additive cell killing with no evidence of synergy. In xenograft models, a short course of gefitinib (3 days) did not significantly increase the activity of radiation treatment in wild-type EGFR (A549) tumors (P=.27), whereas this combination markedly increased the activity of radiation (P<.001) or gefitinib alone (P=.002) in EGFR-mutated HCC827 tumors, producing sustained tumor regressions. Conclusions: Gefitinib treatment increases clonogenic cell killing by radiation but only in cell lines sensitive to gefitinib alone. Our data suggest additive rather than synergistic interactions between gefitinib and radiation and that a

  12. Age-dependent oxidation of extracellular cysteine/cystine redox state (Eh(Cys/CySS)) in mouse lung fibroblasts is mediated by a decline in Slc7a11 expression.

    Science.gov (United States)

    Zheng, Yuxuan; Ritzenthaler, Jeffrey D; Burke, Tom J; Otero, Javier; Roman, Jesse; Watson, Walter H

    2018-04-01

    reveals Slc7a11 is the key regulator of age-dependent changes in extracellular E h (Cys/CySS) in primary mouse lung fibroblasts, and its effects are not dependent on GSH synthesis. Copyright © 2018 Elsevier Inc. All rights reserved.

  13. Inhibition of metastatic tumor growth in mouse lung by repeated administration of polyethylene glycol-conjugated catalase: quantitative analysis with firefly luciferase-expressing melanoma cells.

    Science.gov (United States)

    Hyoudou, Kenji; Nishikawa, Makiya; Umeyama, Yukari; Kobayashi, Yuki; Yamashita, Fumiyoshi; Hashida, Mitsuru

    2004-11-15

    To develop a novel and effective approach to inhibit tumor metastasis based on controlled delivery of catalase, we first evaluated the characteristics of the disposition and proliferation of tumor cells. Then, we examined the effects of polyethylene glycol-conjugated catalase (PEG-catalase) on tumor metastasis. On the basis of the results obtained, PEG-catalase was repetitively administered to completely suppress the growth of tumor cells. Murine melanoma B16-BL6 cells were stably transfected with firefly luciferase gene to obtain B16-BL6/Luc cells. These cells were injected intravenously into syngeneic C57BL/6 mice. PEG-catalase was injected intravenously, and the effect was evaluated by measuring the luciferase activity as the indicator of the number of tumor cells. At 1 hour after injection of B16-BL6/Luc cells, 60 to 90% of the injected cells were recovered in the lung. The numbers decreased to 2 to 4% at 24 hours, then increased. An injection of PEG-catalase just before inoculation significantly reduced the number of tumor cells at 24 hours. Injection of PEG-catalase at 1 or 3 days after inoculation was also effective in reducing the cell numbers. Daily dosing of PEG-catalase greatly inhibited the proliferation and the number assayed at 14 days after inoculation was not significantly different from the minimal number observed at 1 day, suggesting that the growth had been markedly suppressed by the treatment. These findings indicate that sustained catalase activity in the blood circulation can prevent the multiple processes of tumor metastasis in the lung, which could lead to a state of tumor dormancy.

  14. Immunological circumvention of multiple organ metastases of multidrug resistant human small cell lung cancer cells by mouse-human chimeric anti-ganglioside GM2 antibody KM966.

    Science.gov (United States)

    Hanibuchi, M; Yano, S; Nishioka, Y; Yanagawa, H; Miki, T; Sone, S

    2000-01-01

    serum against SBC-3/DOX cells to a similar extent compared with parental SBC-3 cells. Pretreatment of human effector cells with various cytokines induced further enhancement of the KM966-dependent ADCC against SBC-3/DOX cells. Intravenous injection of SBC-3 or SBC-3/DOX cells into natural killer (NK) cell-depleted severe combined immunodeficient (SCID) mice developed metastases in multiple organs (liver, kidneys and lymph nodes). Interestingly, SBC-3/DOX cells produced metastases more rapidly than SBC-3 cells, suggesting more aggressive phenotype of SBC-3/DOX cells than their parental cells in vivo. Systemic treatment with KM966, given on days 2 and 7, drastically inhibited the formation of multiple-organ metastases produced by both SBC-3 and SBC-3/DOX cells, indicating that KM966 can eradicate metastasis by SCLC cells irrespective of MDR phenotype. These findings suggest that the mouse-human chimeric KM966 targets the GM2 antigen, and might be useful for the immunological circumvention of multiple-organ metastases of refractory SCLC.

  15. Responses of genes involved in cell cycle control to diverse DNA damaging chemicals in human lung adenocarcinoma A549 cells

    Directory of Open Access Journals (Sweden)

    Gooderham Nigel J

    2005-08-01

    Full Text Available Abstract Background Many anticancer agents and carcinogens are DNA damaging chemicals and exposure to such chemicals results in the deregulation of cell cycle progression. The molecular mechanisms of DNA damage-induced cell cycle alteration are not well understood. We have studied the effects of etoposide (an anticancer agent, cryptolepine (CLP, a cytotoxic alkaloid, benzo [a]pyrene (BaP, a carcinogenic polycyclic aromatic hydrocarbon and 2-amino-1-methyl-6-phenylimidazo [4,5-b]pyridine (PhIP, a cooked-meat derived carcinogen on the expression of cell cycle regulatory genes to understand the molecular mechanisms of the cell cycle disturbance. Results A549 cells were treated with DMSO or chemicals for up to 72 h and periodically sampled for cell cycle analysis, mRNA and protein expression. DMSO treated cells showed a dominant G1 peak in cell cycle at all times examined. Etoposide and CLP both induced G2/M phase arrest yet the former altered the expression of genes functioning at multiple phases, whilst the latter was more effective in inhibiting the expression of genes in G2-M transition. Both etoposide and CLP induced an accumulation of p53 protein and upregulation of p53 transcriptional target genes. Neither BaP nor PhIP had substantial phase-specific cell cycle effect, however, they induced distinctive changes in gene expression. BaP upregulated the expression of CYP1B1 at 6–24 h and downregulated many cell cycle regulatory genes at 48–72 h. By contrast, PhIP increased the expression of many cell cycle regulatory genes. Changes in the expression of key mRNAs were confirmed at protein level. Conclusion Our experiments show that DNA damaging agents with different mechanisms of action induced distinctive changes in the expression pattern of a panel of cell cycle regulatory genes. We suggest that examining the genomic response to chemical exposure provides an exceptional opportunity to understand the molecular mechanism involved in cellular

  16. Inflammatory Response and Barrier Dysfunction by Different e-Cigarette Flavoring Chemicals Identified by Gas Chromatography-Mass Spectrometry in e-Liquids and e-Vapors on Human Lung Epithelial Cells and Fibroblasts.

    Science.gov (United States)

    Gerloff, Janice; Sundar, Isaac K; Freter, Robert; Sekera, Emily R; Friedman, Alan E; Robinson, Risa; Pagano, Todd; Rahman, Irfan

    2017-03-01

    Recent studies suggest that electronic cigarette (e-cig) flavors can be harmful to lung tissue by imposing oxidative stress and inflammatory responses. The potential inflammatory response by lung epithelial cells and fibroblasts exposed to e-cig flavoring chemicals in addition to other risk-anticipated flavor enhancers inhaled by e-cig users is not known. The goal of this study was to evaluate the release of the proinflammatory cytokine (interleukin-8 [IL-8]) and epithelial barrier function in response to different e-cig flavoring chemicals identified in various e-cig e-liquid flavorings and vapors by chemical characterization using gas chromatography-mass spectrometry analysis. Flavorings, such as acetoin (butter), diacetyl, pentanedione, maltol (malt), ortho-vanillin (vanilla), coumarin, and cinnamaldehyde in comparison with tumor necrosis factor alpha (TNFα), were used in this study. Human bronchial epithelial cells (Beas2B), human mucoepidermoid carcinoma epithelial cells (H292), and human lung fibroblasts (HFL-1) were treated with each flavoring chemical for 24 hours. The cells and conditioned media were then collected and analyzed for toxicity (viability %), lung epithelial barrier function, and proinflammatory cytokine IL-8 release. Cell viability was not significantly affected by any of the flavoring chemicals tested at a concentration of 10 μM to 1 mM. Acetoin and diacetyl treatment induced IL-8 release in Beas2B cells. Acetoin- and pentanedione-treated HFL-1 cells produced a differential, but significant response for IL-8 release compared to controls and TNFα. Flavorings, such as ortho-vanillin and maltol, induced IL-8 release in Beas2B cells, but not in H292 cells. Of all the flavoring chemicals tested, acetoin and maltol were more potent inducers of IL-8 release than TNFα in Beas2B and HFL-1 cells. Flavoring chemicals rapidly impaired epithelial barrier function in human bronchial epithelial cells (16-HBE) as measured by electric cell surface

  17. Lung Emergencies

    Science.gov (United States)

    ... The Marfan Foundation Marfan & Related Disorders What is Marfan Syndrome? What are Related Disorders? What are the Signs? ... Emergencies Lung Emergencies Surgeries Lung Emergencies People with Marfan syndrome can be at increased risk of sudden lung ...

  18. The novel mouse mutant, chuzhoi, has disruption of Ptk7 protein and exhibits defects in neural tube, heart and lung development and abnormal planar cell polarity in the ear

    Directory of Open Access Journals (Sweden)

    Paudyal Anju

    2010-08-01

    Full Text Available Abstract Background The planar cell polarity (PCP signalling pathway is fundamental to a number of key developmental events, including initiation of neural tube closure. Disruption of the PCP pathway causes the severe neural tube defect of craniorachischisis, in which almost the entire brain and spinal cord fails to close. Identification of mouse mutants with craniorachischisis has proven a powerful way of identifying molecules that are components or regulators of the PCP pathway. In addition, identification of an allelic series of mutants, including hypomorphs and neomorphs in addition to complete nulls, can provide novel genetic tools to help elucidate the function of the PCP proteins. Results We report the identification of a new N-ethyl-N-nitrosourea (ENU-induced mutant with craniorachischisis, which we have named chuzhoi (chz. We demonstrate that chuzhoi mutant embryos fail to undergo initiation of neural tube closure, and have characteristics consistent with defective convergent extension. These characteristics include a broadened midline and reduced rate of increase of their length-to-width ratio. In addition, we demonstrate disruption in the orientation of outer hair cells in the inner ear, and defects in heart and lung development in chuzhoi mutants. We demonstrate a genetic interaction between chuzhoi mutants and both Vangl2Lp and Celsr1Crsh mutants, strengthening the hypothesis that chuzhoi is involved in regulating the PCP pathway. We demonstrate that chuzhoi maps to Chromosome 17 and carries a splice site mutation in Ptk7. This mutation results in the insertion of three amino acids into the Ptk7 protein and causes disruption of Ptk7 protein expression in chuzhoi mutants. Conclusions The chuzhoi mutant provides an additional genetic resource to help investigate the developmental basis of several congenital abnormalities including neural tube, heart and lung defects and their relationship to disruption of PCP. The chuzhoi mutation

  19. Nutrition for Lung Cancer

    Science.gov (United States)

    ... Become An Advocate Volunteer Ways To Give Lung Cancer www.lung.org > Lung Health and Diseases > Lung Disease Lookup > ... Cancer Learn About Lung Cancer What Is Lung Cancer Lung Cancer Basics Causes & Risk Factors Lung Cancer Staging ...

  20. Radiation equivalence of genotoxic chemicals - Validation in cultered mammalian cell lines

    International Nuclear Information System (INIS)

    Murthy, M.S.S.

    1982-01-01

    Published data on mutations induced by ionizing radiation and 6 monofunctional alkylating agents, namely EMS, MMS, ENNG, MNNG, ENU and MNU, in different cell lines (Chinese hamster ovary, Chinese hamster lung V79, mouse lymphoma L5178 and human cells) were analysed so that radiation-equivalent chemical (REC) values could be calculated. REC values thus obtained for a given alkylating agent with different cell lines fall within a narrow range suggesting its validation in cultured mammalian cell systems including human. (orig.)

  1. Testing lung cancer drugs and therapies in mice

    Science.gov (United States)

    National Cancer Institute (NCI) investigators have designed a genetically engineered mouse for use in the study of human lung squamous cell carcinoma (SCC). SCC is a type of non-small cell lung carcinoma, one of the most common types of lung cancer, with

  2. Mouse adhalin

    DEFF Research Database (Denmark)

    Liu, L; Vachon, P H; Kuang, W

    1997-01-01

    . To analyze the biological roles of adhalin, we cloned the mouse adhalin cDNA, raised peptide-specific antibodies to its cytoplasmic domain, and examined its expression and localization in vivo and in vitro. The mouse adhalin sequence was 80% identical to that of human, rabbit, and hamster. Adhalin...... was specifically expressed in striated muscle cells and their immediate precursors, and absent in many other cell types. Adhalin expression in embryonic mouse muscle was coincident with primary myogenesis. Its expression was found to be up-regulated at mRNA and protein levels during myogenic differentiation...

  3. Chemical composition of the essential oil from basil (Ocimum basilicum Linn.) and its in vitro cytotoxicity against HeLa and HEp-2 human cancer cell lines and NIH 3T3 mouse embryonic fibroblasts.

    Science.gov (United States)

    Kathirvel, Poonkodi; Ravi, Subban

    2012-01-01

    This study examines the chemical composition and in vitro anticancer activity of the essential oil from Ocimum basilicum Linn. (Lamiaceae), cultivated in the Western Ghats of South India. The chemical compositions of basil fresh leaves were identified by GC-MS: 11 components were identified. The major constituents were found to be methyl cinnamate (70.1%), linalool (17.5%), β-elemene (2.6%) and camphor (1.52%). The results revealed that this plant may belong to the methyl cinnamate and linalool chemotype. A methyl thiazol tetrazolium assay was used for in vitro cytotoxicity screening against the human cervical cancer cell line (HeLa), human laryngeal epithelial carcinoma cell line (HEp-2) and NIH 3T3 mouse embryonic fibroblasts. The IC(50) values obtained were 90.5 and 96.3 µg mL(-1), respectively, and the results revealed that basil oil has potent cytotoxicity.

  4. An Orally Active Cannabis Extract with High Content in Cannabidiol attenuates Chemically-induced Intestinal Inflammation and Hypermotility in the Mouse

    OpenAIRE

    Pagano, Ester; Capasso, Raffaele; Piscitelli, Fabiana; Romano, Barbara; Parisi, Olga A.; Finizio, Stefania; Lauritano, Anna; Marzo, Vincenzo Di; Izzo, Angelo A.; Borrelli, Francesca

    2016-01-01

    Anecdotal and scientific evidence suggests that Cannabis use may be beneficial in inflammatory bowel disease (IBD) patients. Here, we have investigated the effect of a standardized Cannabis sativa extract with high content of cannabidiol (CBD), here named CBD BDS for “CBD botanical drug substance,” on mucosal inflammation and hypermotility in mouse models of intestinal inflammation. Colitis was induced in mice by intracolonic administration of dinitrobenzenesulfonic acid (DNBS). Motility was ...

  5. Lung scintigraphy

    International Nuclear Information System (INIS)

    Dalenz, Roberto.

    1994-01-01

    A review of lung scintigraphy, perfusion scintigraphy with SPECT, lung ventilation SPECT, blood pool SPECT. The procedure of lung perfusion studies, radiopharmaceutical, administration and clinical applications, imaging processing .Results encountered and evaluation criteria after Biello and Pioped. Recommendations and general considerations have been studied about relation of this radiopharmaceutical with other pathologies

  6. Differential tumor biology effects of double-initiation in a mouse skin chemical carcinogenesis model comparing wild type versus protein kinase Cepsilon overexpression mice.

    Science.gov (United States)

    Li, Yafan; Wheeler, Deric L; Ananthaswamy, Honnavara N; Verma, Ajit K; Oberley, Terry D

    2007-12-01

    Our previous studies showed that protein kinase Cepsilon (PKCepsilon) verexpression in mouse skin resulted in metastatic squamous cell carcinoma (SCC) elicited by single 7,12-dimethylbenz(a)anthracene (DMBA)-initiation and 12-O-tetradecanoylphorbol-13-acetate (TPA)-promotion in the absence of preceding papilloma formation as is typically observed in wild type mice. The present study demonstrates that double-DMBA initiation modulates tumor incidence, multiplicity, and latency period in both wild type and PKCepsilon overexpression transgenic (PKCepsilon-Tg) mice. After 17 weeks (wks) of tumor promotion, a reduction in papilloma multiplicity was observed in double- versus single-DMBA initiated wild type mice. Papilloma multiplicity was inversely correlated with cell death indices of interfollicular keratinocytes, indicating decreased papilloma formation was caused by increased cell death and suggesting the origin of papillomas is in interfollicular epidermis. Double-initiated PKCepsilon-Tg mice had accelerated carcinoma formation and cancer incidence in comparison to single-initiated PKCepsilon-Tg mice. Morphologic analysis of mouse skin following double initiation and tumor promotion showed a similar if not identical series of events to those previously observed following single initiation and tumor promotion: putative preneoplastic cells were observed arising from hyperplastic hair follicles (HFs) with subsequent cancer cell infiltration into the dermis. Single-initiated PKCepsilon-Tg mice exhibited increased mitosis in epidermal cells of HFs during tumor promotion.

  7. Lung density

    DEFF Research Database (Denmark)

    Garnett, E S; Webber, C E; Coates, G

    1977-01-01

    The density of a defined volume of the human lung can be measured in vivo by a new noninvasive technique. A beam of gamma-rays is directed at the lung and, by measuring the scattered gamma-rays, lung density is calculated. The density in the lower lobe of the right lung in normal man during quiet...... breathing in the sitting position ranged from 0.25 to 0.37 g.cm-3. Subnormal values were found in patients with emphsema. In patients with pulmonary congestion and edema, lung density values ranged from 0.33 to 0.93 g.cm-3. The lung density measurement correlated well with the findings in chest radiographs...... but the lung density values were more sensitive indices. This was particularly evident in serial observations of individual patients....

  8. What Is Lung Cancer?

    Science.gov (United States)

    ... Shareable Graphics Infographics “African-American Men and Lung Cancer” “Lung Cancer Is the Biggest Cancer Killer in Both ... starts in the lungs, it is called lung cancer. Lung cancer begins in the lungs and may spread ...

  9. Abscess in the Lungs

    Science.gov (United States)

    ... Home Lung and Airway Disorders Abscess in the Lungs Abscess in the Lungs Causes Symptoms Diagnosis Treatment Resources ... here for the Professional Version Abscess in the Lungs Abscess in the Lungs A lung abscess is a ...

  10. RANK rewires energy homeostasis in lung cancer cells and drives primary lung cancer.

    Science.gov (United States)

    Rao, Shuan; Sigl, Verena; Wimmer, Reiner Alois; Novatchkova, Maria; Jais, Alexander; Wagner, Gabriel; Handschuh, Stephan; Uribesalgo, Iris; Hagelkruys, Astrid; Kozieradzki, Ivona; Tortola, Luigi; Nitsch, Roberto; Cronin, Shane J; Orthofer, Michael; Branstetter, Daniel; Canon, Jude; Rossi, John; D'Arcangelo, Manolo; Botling, Johan; Micke, Patrick; Fleur, Linnea La; Edlund, Karolina; Bergqvist, Michael; Ekman, Simon; Lendl, Thomas; Popper, Helmut; Takayanagi, Hiroshi; Kenner, Lukas; Hirsch, Fred R; Dougall, William; Penninger, Josef M

    2017-10-15

    Lung cancer is the leading cause of cancer deaths. Besides smoking, epidemiological studies have linked female sex hormones to lung cancer in women; however, the underlying mechanisms remain unclear. Here we report that the receptor activator of nuclear factor-kB (RANK), the key regulator of osteoclastogenesis, is frequently expressed in primary lung tumors, an active RANK pathway correlates with decreased survival, and pharmacologic RANK inhibition reduces tumor growth in patient-derived lung cancer xenografts. Clonal genetic inactivation of KRas G12D in mouse lung epithelial cells markedly impairs the progression of KRas G12D -driven lung cancer, resulting in a significant survival advantage. Mechanistically, RANK rewires energy homeostasis in human and murine lung cancer cells and promotes expansion of lung cancer stem-like cells, which is blocked by inhibiting mitochondrial respiration. Our data also indicate survival differences in KRas G12D -driven lung cancer between male and female mice, and we show that female sex hormones can promote lung cancer progression via the RANK pathway. These data uncover a direct role for RANK in lung cancer and may explain why female sex hormones accelerate lung cancer development. Inhibition of RANK using the approved drug denosumab may be a therapeutic drug candidate for primary lung cancer. © 2017 Rao et al.; Published by Cold Spring Harbor Laboratory Press.

  11. Lung Cancer

    International Nuclear Information System (INIS)

    Maghfoor, Irfan; Perry, M.C.

    2005-01-01

    Lung cancer is the leading cause of cancer-related mortality. Since tobacco smoking is the cause in vast majority of cases, the incidence of lung cancer is expected to rise in those countries with high or rising incidence of tobacco smoking. Even though population at a risk of developing lung cancer are easily identified, mass screening for lung cancer is not supported by currently available evidence. In case of non-small cell lung cancer, a cure may be possible with surgical resection followed by post-operative chemotherapy in those diagnosed at an early stage. A small minority of patients who present with locally advanced disease may also benefit from preoperative chemotherapy and/or radiation therapy to down stage the tumor to render it potentially operable. In a vast majority of patients, however, lung cancer presents at an advanced stage and a cure is not possible with currently available therapeutic strategies. Similarly small cell lung cancer confined to one hemi-thorax may be curable with a combination of chemotherapy and thoracic irradiation followed by prophylactic cranial irradiation, if complete remission is achieved at the primary site. Small cell lung cancer that is spread beyond the confines of one hemi-thorax is however, considered incurable. In this era of molecular targeted therapies, new agents are constantly undergoing pre-clinical and clinical testing with the aim of targeting the molecular pathways thought to involved in etiology and pathogenesis of lung cancer. (author)

  12. Cell surface response of chemically transformed, malignant mouse embryonal fibroblasts and human colon cancer cells to the maturation-promoting agent, N,N-dimethylformamide

    International Nuclear Information System (INIS)

    Marks, M.E.

    1985-01-01

    The lactoperoxidase/ 125 I radioiodination procedure was used to probe the cell surface of normal, nontransformed AKR-2B mouse embryo fibroblasts and malignant, permanently methylcholanthrene-transformed AKR-2B (AKR-MCA) cells to establish the relationship between cell surface changes and transformation/differentiation in this call system. AKR-MCA cells displayed surface alterations secondary to N,N-dimethylformamide (DFM)-promoted differentiation. Growth of AKR-MCA cells in DMF virtually eliminated the 85,000 and 63,000 molecular weight surface proteins susceptible to radioiodination and increased surface material of ∼200,000 molecular weight. Thus, surface profiles of DFM-treated AKR-MCA cells were essentially identical to those of nontransformed AKR-2B cells. Experimentation was extended to a cultured human colon cancer cell line (HCT MOSER). HCT MOSER cells exposed to DMF manifested marked, reversible morphological and surface changes which occurred as a function of time of growth in DMF and DMF concentration. Interestingly, material reactive with anti-fibronectin was found on the surfaces and in the culture medium of DFM-treated HCT MOSER cells

  13. A mammalian spot test: induction of genetic alterations in pigment cells or mouse embryos with X-rays and chemical mutagens

    International Nuclear Information System (INIS)

    Fahrig, R.

    1975-01-01

    Embryos heterozygous for five recessive coat-color genes from the cross C57 BL/6 J Han x T-stock were X-irradiated with 100 r or treated in utero with 50 mg/kg methyl methanesulfonate (MMS) and ethyl methanesulfonate (EMS), respectively. Controls consisted of irradiated embryos of C57 BL x C57 BL matings homozygous wild-type for the genes under study, and non-treated offspring of both types of mating. The colors of the spots observed in the adult fur were either due to expression of the recessive coat genes or were white. 1) Irradiated and mutagen-treated offspring of C57 BL x T-stock matings had almost exclusively nonwhite spots, distributed randomly over the mouse surface. 2) Irradiated offspring of C57 BL x C57 BL matings had only white spots which were always midventral. 3) In non-treated offspring of both types of mating no spot could be observed. It is discussed that the white midventral spots are preferentially the result of pigment cell killing, while the nonwhite spots are preferentially the result of gene mutations or recombinational processes like mitotic crossing over and mitotic gene conversion. (orig./BSC) [de

  14. Preclinical evaluation of racotumomab, an anti-idiotype monoclonal antibody to N-glycolyl-containing gangliosides, with or without chemotherapy in a mouse model of non-small cell lung cancer

    International Nuclear Information System (INIS)

    Segatori, Valeria I.; Vazquez, Ana M.; Gomez, Daniel E.; Gabri, Mariano R.; Alonso, Daniel F.

    2012-01-01

    N-glycolylneuraminic acid (NeuGc) is a sialic acid molecule usually found in mammalian cells as terminal constituents of different membrane glycoconjugates such as gangliosides. The NeuGcGM3 ganglioside has been described as a tumor antigen for non-small cell lung cancer (NSCLC) in humans. Racotumomab is an anti-NeuGc-containing gangliosides anti-idiotype monoclonal antibody (mAb) (formerly known as 1E10) that has received attention as a potential active immunotherapy for advanced lung cancer in clinical trials. In this work, we have examined the antitumor activity of racotumomab in combination or not with chemotherapy, using the 3LL Lewis lung carcinoma as a preclinical model of NSCLC in C57BL/6 mice. Vaccination with biweekly doses of racotumomab at 50–200 μg/dose formulated in aluminum hydroxide (racotumomab-alum vaccine) demonstrated a significant antitumor effect against the progression of lung tumor nodules. Racotumomab-alum vaccination exerted a comparable effect on lung disease to that of pemetrexed-based chemotherapy (100 mg/kg weekly). Interestingly, chemo-immunotherapy was highly effective against lung nodules and well-tolerated, although no significant synergistic effect was observed as compared to each treatment alone in the present model. We also obtained evidence on the role of the exogenous incorporation of NeuGc in the metastatic potential of 3LL cells. Our preclinical data provide support for the combination of chemotherapy with the anti-idiotype mAb racotumomab, and also reinforce the biological significance of NeuGc in lung cancer.

  15. Preclinical evaluation of racotumomab, an anti-idiotype monoclonal antibody to N-glycolyl-containing gangliosides, with or without chemotherapy in a mouse model of non-small cell lung cancer

    Energy Technology Data Exchange (ETDEWEB)

    Segatori, Valeria I. [Laboratory of Molecular Oncology, Department of Science and Technology, Quilmes National University, Buenos Aires (Argentina); Vazquez, Ana M. [Center of Molecular Immunology, Innovation Managing Direction, La Habana (Cuba); Gomez, Daniel E.; Gabri, Mariano R.; Alonso, Daniel F., E-mail: dfalonso@unq.edu.ar [Laboratory of Molecular Oncology, Department of Science and Technology, Quilmes National University, Buenos Aires (Argentina)

    2012-11-08

    N-glycolylneuraminic acid (NeuGc) is a sialic acid molecule usually found in mammalian cells as terminal constituents of different membrane glycoconjugates such as gangliosides. The NeuGcGM3 ganglioside has been described as a tumor antigen for non-small cell lung cancer (NSCLC) in humans. Racotumomab is an anti-NeuGc-containing gangliosides anti-idiotype monoclonal antibody (mAb) (formerly known as 1E10) that has received attention as a potential active immunotherapy for advanced lung cancer in clinical trials. In this work, we have examined the antitumor activity of racotumomab in combination or not with chemotherapy, using the 3LL Lewis lung carcinoma as a preclinical model of NSCLC in C57BL/6 mice. Vaccination with biweekly doses of racotumomab at 50–200 μg/dose formulated in aluminum hydroxide (racotumomab-alum vaccine) demonstrated a significant antitumor effect against the progression of lung tumor nodules. Racotumomab-alum vaccination exerted a comparable effect on lung disease to that of pemetrexed-based chemotherapy (100 mg/kg weekly). Interestingly, chemo-immunotherapy was highly effective against lung nodules and well-tolerated, although no significant synergistic effect was observed as compared to each treatment alone in the present model. We also obtained evidence on the role of the exogenous incorporation of NeuGc in the metastatic potential of 3LL cells. Our preclinical data provide support for the combination of chemotherapy with the anti-idiotype mAb racotumomab, and also reinforce the biological significance of NeuGc in lung cancer.

  16. Lung Cancer

    Science.gov (United States)

    Lung cancer is one of the most common cancers in the world. It is a leading cause of cancer death in men and women in the United States. Cigarette smoking causes most lung cancers. The more cigarettes you smoke per day and ...

  17. Pathogenic mechanism in lung fibrosis

    International Nuclear Information System (INIS)

    Witschi, H.; Haschek, W.M.; Meyer, K.R.; Ullrich, R.L.; Dalbey, W.E.

    1979-01-01

    The purpose of the study was to examine whether an interaction between two agents causing alveolar epithelial damage would produce lung fibrosis. In mouse lung, intraperitoneal injection of the antioxidant butylated hydroxytoluene causes diffuse alveolar type I cell necrosis, followed by proliferation of type II alveolar cells. In animals exposed to 70% O 2 or 100-200 rad x rays during the phase of type II cell proliferation following BHT, diffuse interstitial lung fibrosis developed within 2 weeks. Quantitative analysis of the lungs for hydroxyproline showed that the interaction between BHT and O 2 or x rays was synergistic. If exposure to O 2 or x rays was delayed until epithelial recovery was complete, no fibrosis was seen. Abnormally high levels of lung collagen persisted up to 6 months after one single treatment with BHT and 100 rad x rays. A commonly seen form of chronic lung damage may thus be caused by an acute interaction between a bloodborne agent which damages the alveolar cell and a toxic inhalant or x rays, provided a critically ordered sequence of exposure is observed

  18. Lung Cancer Screening

    Science.gov (United States)

    ... factors increase or decrease the risk of lung cancer. Lung cancer is a disease in which malignant (cancer) ... following PDQ summaries for more information about lung cancer: Lung Cancer Prevention Non-Small Cell Lung Cancer Treatment ...

  19. Enhancement of mouse germ cell-associated genes expression by injection of human umbilical cord mesenchymal stem cells into the testis of chemical-induced azoospermic mice

    Directory of Open Access Journals (Sweden)

    Rui-Feng Yang

    2014-10-01

    Full Text Available Various methods are currently under investigation to preserve fertility in males treated with high-dose chemotherapy and radiation for malignant and nonmalignant disorders. Human umbilical cord mesenchymal stem cells (HUC-MSCs, which possess potent immunosuppressive function and secrete various cytokines and growth factors, have the potential clinical applications. As a potential alternative, we investigate whether injection of HUC-MSCs into the interstitial compartment of the testes to promote spermatogenic regeneration efficiently. HUC-MSCs were isolated from different sources of umbilical cords and injected into the interstitial space of one testis from 10 busulfan-treated mice (saline and HEK293 cells injections were performed in a separate set of mice and the other testis remained uninjected. Three weeks after MSCs injection, Relative quantitative reverse transcription polymerase chain reaction was used to identify the expression of 10 of germ cell associated, which are all related to meiosis, demonstrated higher levels of spermatogenic gene expression (2-8 fold in HUC-MSCs injected testes compared to the contralateral uninjected testes (five mice. Protein levels for germ cell-specific genes, miwi, vasa and synaptonemal complex protein (Scp3 were also higher in MSC-treated testes compared to injected controls 3 weeks after treatment. However, no different expression was detected in saline water and HEK293 cells injection control group. We have demonstrated HUC-MSCs could affect mouse germ cell-specific genes expression. The results also provide a possibility that the transplanted HUC-MSCs may promote the recovery of spermatogenesis. This study provides further evidence for preclinical therapeutic effects of HUC-MSCs, and explores a new approach to the treatment of azoospermia.

  20. Chemical and serologic definition of two unique D region-encoded molecules in the wild-derived mouse strain B10.GAA37.

    Science.gov (United States)

    Lillehoj, E P; Walsh, W D; Potter, T; Lee, D R; Coligan, J E; Hansen, T H

    1984-12-01

    Detailed serologic and biochemical characterization of D region products of the wild-derived mouse strain B10.GAA37 (Dw16) were performed and compared with previous studies of the D region products of the H-2d,b, and q haplotypes. Serologic analysis revealed that the antigens encoded by the Dw16 region express a unique combination of specificities defined by monoclonal antibodies (mAb) with established activity for the Ld and Dd molecules. Two out of five anti-Ld-reactive mAb reacted with B10.GAA37 cells, whereas one of three anti-Dd mAb showed B10.GAA37 reactivity. Sequential immunoprecipitation of B10.GAA37 antigens demonstrated the existence of at least two antigenically distinct molecules (designated Dw16 and Lw16) encoded by genes associated with the Dw16 region. Peptide map comparisons of the Dw16 and Lw16 molecules defined multiple differences in their primary protein structure, suggesting they are products of separate genes. Structural comparisons of the Lw16 and Dw16 molecules with the Ld and Dd molecules implied a) that the Dw16 and Dd regions did not result from a recent evolutionary divergence of a common primordial haplotype, and b) that the Lw16 and Dw16 molecules are more structurally homologous to each other than the Ld and Dd molecules are. Comparison of these findings with our previous studies of antigens encoded by the D regions suggest that each of these haplotypes has unique properties in terms of the number of gene products expressed and/or the structural relatedness of products of the same region.

  1. An Orally Active Cannabis Extract with High Content in Cannabidiol attenuates Chemically-induced Intestinal Inflammation and Hypermotility in the Mouse.

    Science.gov (United States)

    Pagano, Ester; Capasso, Raffaele; Piscitelli, Fabiana; Romano, Barbara; Parisi, Olga A; Finizio, Stefania; Lauritano, Anna; Marzo, Vincenzo Di; Izzo, Angelo A; Borrelli, Francesca

    2016-01-01

    Anecdotal and scientific evidence suggests that Cannabis use may be beneficial in inflammatory bowel disease (IBD) patients. Here, we have investigated the effect of a standardized Cannabis sativa extract with high content of cannabidiol (CBD), here named CBD BDS for "CBD botanical drug substance," on mucosal inflammation and hypermotility in mouse models of intestinal inflammation. Colitis was induced in mice by intracolonic administration of dinitrobenzenesulfonic acid (DNBS). Motility was evaluated in the experimental model of intestinal hypermotility induced by irritant croton oil. CBD BDS or pure CBD were given - either intraperitoneally or by oral gavage - after the inflammatory insult (curative protocol). The amounts of CBD in the colon, brain, and liver after the oral treatments were measured by high-performance liquid chromatography coupled to ion trap-time of flight mass spectrometry. CBD BDS, both when given intraperitoneally and by oral gavage, decreased the extent of the damage (as revealed by the decrease in the colon weight/length ratio and myeloperoxidase activity) in the DNBS model of colitis. It also reduced intestinal hypermotility (at doses lower than those required to affect transit in healthy mice) in the croton oil model of intestinal hypermotility. Under the same experimental conditions, pure CBD did not ameliorate colitis while it normalized croton oil-induced hypermotility when given intraperitoneally (in a dose-related fashion) or orally (only at one dose). In conclusion, CBD BDS, given after the inflammatory insult, attenuates injury and motility in intestinal models of inflammation. These findings sustain the rationale of combining CBD with other minor Cannabis constituents and support the clinical development of CBD BDS for IBD treatment.

  2. N-Hydroxylation of 4-Aminobiphenyl by CYP2E1 Produces Oxidative Stress in a Mouse Model of Chemically Induced Liver Cancer

    Science.gov (United States)

    Wang, Shuang; Sugamori, Kim S.; Tung, Aveline; McPherson, J. Peter; Grant, Denis M.

    2015-01-01

    4-Aminobiphenyl (ABP) is a trace component of cigarette smoke and hair dyes, a suspected human carcinogen and a potent rodent liver carcinogen. Postnatal exposure of mice to ABP results in a higher incidence of liver tumors in males than in females, paralleling the sex difference in human liver cancer incidence. A traditional model of ABP tumorigenesis involves initial CYP1A2-mediated N-hydroxylation, which eventually leads to production of mutagenic ABP-DNA adducts that initiate tumor growth. However, several studies have found no correlation between sex or CYP1A2 function and the DNA-damaging, mutagenic, or tumorigenic effects of ABP. Oxidative stress may be an important etiological factor for liver cancer, and it has also been linked to ABP exposure. The goals of this study were to identify novel enzyme(s) that contribute to ABP N-oxidation, and to investigate a potential role for oxidative stress in ABP liver tumorigenicity. Isozyme-selective inhibition experiments using liver microsomes from wild-type and genetically modified mice identified CYP2E1 as a major ABP N-hydroxylating enzyme. The N-hydroxylation of ABP by transiently expressed CYP2E1 produced oxidative stress in cultured mouse hepatoma cells. In vivo postnatal exposure of mice to a tumorigenic dose of ABP also produced oxidative stress in male wild-type mice, but not in male Cyp2e1(−/−) mice or in female mice. However, a stronger NRF2-associated antioxidant response was observed in females. Our results identify CYP2E1 as a novel ABP-N-oxidizing enzyme, and suggest that sex differences in CYP2E1-dependent oxidative stress and antioxidant responses to ABP may contribute to the observed sex difference in tumor incidence. PMID:25601990

  3. Formation of DNA adducts in mouse tissues after 1-nitropyrene administration

    International Nuclear Information System (INIS)

    Mitchell, C.E.

    1986-01-01

    DNA adducts were isolated and characterized in mouse lung, liver and kidney after intratracheal instillation of [ 3 H]-1-nitropyrene (1-NP). HPLC analysis of the enzymatically digested DNA indicated the presence of multiple DNA adducts in mouse lung, liver and kidney. These results indicate that DNA adducts of 1-NP are formed in mouse lung, liver and kidney after intratracheal instillation of 1-NP; the HPLC profiles of the multiple adducts suggests that adducts may be formed via metabolic pathways that involve both nitroreduction and ring-oxidation. 6 references, 1 figure

  4. Activation of an immune-regulatory macrophage response and inhibition of lung inflammation in a mouse model of COPD using heat-shock protein alpha B-crystallin-loaded PLGA microparticles

    NARCIS (Netherlands)

    van Noort, J.M.; Bsibsi, M.; Nacken, P.J.; Gerritsen, W.H.; Amor, S.; Holtman, I.R.; Boddeke, E.; van Ark, I.; Leusink-Muis, T.; Folkerts, G.; Hennink, W.E.; Amidi, M.

    2013-01-01

    As an extracellular protein, the small heat-shock protein alpha B-crystallin (HSPB5) has anti-inflammatory effects in several mouse models of inflammation. Here, we show that these effects are associated with the ability of HSPB5 to activate an immune-regulatory response in macrophages via

  5. Activation of an immune-regulatory macrophage response and inhibition of lung inflammation in a mouse model of COPD using heat-shock protein alpha B-crystallin-loaded PLGA microparticles

    NARCIS (Netherlands)

    van Noort, Johannes M.; Bsibsi, Malika; Nacken, Peter J.; Gerritsen, Wouter H.; Amor, Sandra; Holtman, Inge R.; Boddeke, Erik; van Ark, Ingrid; Leusink-Muis, Thea; Folkerts, Gert; Hennink, Wim E.; Amidi, Maryam

    As an extracellular protein, the small heat-shock protein alpha B-crystallin (HSPB5) has anti-inflammatory effects in several mouse models of inflammation. Here, we show that these effects are associated with the ability of HSPB5 to activate an immune-regulatory response in macrophages via

  6. Lung abscess

    International Nuclear Information System (INIS)

    Ha, H.K.; Kang, M.W.; Park, J.M.; Yang, W.J.; Shinn, K.S.; Bahk, Y.W.

    1993-01-01

    Lung abscess was successfully treated with percutaneous drainage in 5 of 6 patients. Complete abscess resolution occurred in 4 patients, partial resolution in one, and no response in one. The duration of drainage ranged from 7 to 18 days (mean 15.5 days) in successful cases. The failure of drainage in one neurologicall impaired patient was attributed to persistent aspiration. In 2 patients, concurrent pleural empyema was also cured. CT provided the anatomic details necessary for choosing the puncture site and avoiding puncture of the lung parenchyma. Percutaneous catheter drainage is a safe and effective method for treating lung abscess. (orig.)

  7. Teratology studies in the mouse.

    Science.gov (United States)

    Marsden, Edward; Leroy, Mariline

    2013-01-01

    The rat is the routine species of choice as the rodent model for regulatory safety testing of xenobiotics such as medicinal products, food additives, and other chemicals. However, the rat is not always suitable for pharmacological, toxicological, immunogenic, pharmacokinetic, or even practical reasons. Under such circumstances, the mouse offers an alternative for finding a suitable rodent model acceptable to the regulatory authorities. Since all essential routes of administration are possible, the short reproductive cycle and large litter size of the mouse make it a species well adapted for use in teratology studies. Given that good quality animals, including virgin mated females, can be acquired relatively easily and inexpensively, the mouse has been used in reproductive toxicity studies for decades and study protocols are well established.

  8. Hyperoxia decreases glycolytic capacity, glycolytic reserve and oxidative phosphorylation in MLE-12 cells and inhibits complex I and II function, but not complex IV in isolated mouse lung mitochondria.

    Directory of Open Access Journals (Sweden)

    Kumuda C Das

    Full Text Available High levels of oxygen (hyperoxia are frequently used in critical care units and in conditions of respiratory insufficiencies in adults, as well as in infants. However, hyperoxia has been implicated in a number of pulmonary disorders including bronchopulmonary dysplasia (BPD and adult respiratory distress syndrome (ARDS. Hyperoxia increases the generation of reactive oxygen species (ROS in the mitochondria that could impair the function of the mitochondrial electron transport chain. We analyzed lung mitochondrial function in hyperoxia using the XF24 analyzer (extracellular flux and optimized the assay for lung epithelial cells and mitochondria isolated from lungs of mice. Our data show that hyperoxia decreases basal oxygen consumption rate (OCR, spare respiratory capacity, maximal respiration and ATP turnover in MLE-12 cells. There was significant decrease in glycolytic capacity and glycolytic reserve in MLE-12 cells exposed to hyperoxia. Using mitochondria isolated from lungs of mice exposed to hyperoxia or normoxia we have shown that hyperoxia decreased the basal, state 3 and state3 μ (respiration in an uncoupled state respirations. Further, using substrate or inhibitor of a specific complex we show that the OCR via complex I and II, but not complex IV was decreased, demonstrating that complexes I and II are specific targets of hyperoxia. Further, the activities of complex I (NADH dehydrogenase, NADH-DH and complex II (succinate dehydrogenase, SDH were decreased in hyperoxia, but the activity of complex IV (cytochrome oxidase, COX remains unchanged. Taken together, our study show that hyperoxia impairs glycolytic and mitochondrial energy metabolism in in tact cells, as well as in lungs of mice by selectively inactivating components of electron transport system.

  9. Lung surgery

    Science.gov (United States)

    ... are thoracotomy and video-assisted thoracoscopic surgery (VATS). Robotic surgery may also be used. Lung surgery using ... Center-Shreveport, Shreveport, LA. Review provided by VeriMed Healthcare Network. Also reviewed by David Zieve, MD, MHA, ...

  10. Editor's Highlight: Complete Attenuation of Mouse Lung Cell Proliferation and Tumorigenicity in CYP2F2 Knockout and CYP2F1 Humanized Mice Exposed to Inhaled Styrene for up to 2 Years Supports a Lack of Human Relevance.

    Science.gov (United States)

    Cruzan, George; Bus, James S; Banton, Marcy I; Sarang, Satinder S; Waites, Robbie; Layko, Debra B; Raymond, James; Dodd, Darol; Andersen, Melvin E

    2017-10-01

    Styrene is a mouse-specific lung carcinogen, and short-term mode of action studies have demonstrated that cytotoxicity and/or cell proliferation, and genomic changes are dependent on CYP2F2 metabolism. The current study examined histopathology, cell proliferation, and genomic changes in CD-1, C57BL/6 (WT), CYP2F2(-/-) (KO), and CYP2F2(-/-) (CYP2F1, 2B6, 2A13-transgene) (TG; humanized) mice following exposure for up to 104 weeks to 0- or 120-ppm styrene vapor. Five mice per treatment group were sacrificed at 1, 26, 52, and 78 weeks. Additional 50 mice per treatment group were followed until death or 104 weeks of exposure. Cytotoxicity was present in the terminal bronchioles of some CD-1 and WT mice exposed to styrene, but not in KO or TG mice. Hyperplasia in the terminal bronchioles was present in CD-1 and WT mice exposed to styrene, but not in KO or TG mice. Increased cell proliferation, measured by KI-67 staining, occurred in CD-1 and WT mice exposed to styrene for 1 week, but not after 26, 52, or 78 weeks, nor in KO or TG mice. Styrene increased the incidence of bronchioloalveolar adenomas and carcinomas in CD-1 mice. No increase in lung tumors was found in WT despite clear evidence of lung toxicity, or, KO or TG mice. The absence of preneoplastic lesions and tumorigenicity in KO and TG mice indicates that mouse-specific CYP2F2 metabolism is responsible for both the short-term and chronic toxicity and tumorigenicity of styrene, and activation of styrene by CYP2F2 is a rodent MOA that is neither quantitatively or qualitatively relevant to humans. © The Author 2017. Published by Oxford University Press on behalf of the Society of Toxicology. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.

  11. Unexpandable lung.

    Science.gov (United States)

    Pereyra, Marco F; Ferreiro, Lucía; Valdés, Luis

    2013-02-01

    Unexpandable lung is a mechanical complication by which the lung does not expand to the chest wall, impeding a normal apposition between the two pleural layers. The main mechanism involved is the restriction of the visceral pleura due to the formation of a fibrous layer along this pleural membrane. This happens because of the presence of an active pleural disease (lung entrapment), which can be resolved if proper therapeutic measures are taken, or a remote disease (trapped lung), in which an irreversible fibrous pleural layer has been formed. The clinical suspicion arises with the presence of post-thoracocentesis hydropneumothorax or a pleural effusion that cannot be drained due to the appearance of thoracic pain. The diagnosis is based on the analysis of the pleural liquid, the determination of pleural pressures as we drain the effusion and on air-contrast chest CT. As both represent the continuity of one same process, the results will depend on the time at which these procedures are done. If, when given a lung that is becoming entrapped, the necessary therapeutic measures are not taken, the final result will be a trapped lung. In this instance, most patients are asymptomatic or have mild exertional dyspnea and therefore they do not require treatment. Nevertheless, in cases of incapacitating dyspnea, it may be necessary to use pleural decortication in order to resolve the symptoms. Copyright © 2012 SEPAR. Published by Elsevier Espana. All rights reserved.

  12. Cutaneous challenge with chemical warfare agents in the SKH-1 hairless mouse (II): effects of some currently used skin decontaminants (RSDL and Fuller's earth) against liquid sulphur mustard and VX exposure.

    Science.gov (United States)

    Taysse, L; Dorandeu, F; Daulon, S; Foquin, A; Perrier, N; Lallement, G; Breton, P

    2011-06-01

    Using the hairless mouse screening model presented in the companion paper(1) the aim of this study was to assess two skin decontaminating systems: Fuller's earth (FE) and Reactive Skin Decontamination Lotion (RSDL) against two extremely toxic chemical warfare agents that represent a special percutaneous hazard, sulphur mustard (SM) and O-ethyl-S-(2[di-isopropylamino]ethyl)methyl-phosphonothioate (VX). Five minutes after being exposed on the back to either 2 µL of neat sulphur mustard or 50 µg.kg(-1) of diluted VX, mice were decontaminated. Both systems were able to reduce blisters 3 days after SM exposure. However, RSDL was found to be more efficient than FE in reducing the necrosis of the epidermis and erosion. In the case of VX exposure, RSDL, whatever the ratio of decontaminant to toxicant used (RSDL 10, 20, 50), was not able to sufficiently prevent the inhibition of plasma cholinesterases taken as a surrogate marker of exposure and toxicity. Only FE reduced significantly the ChE inhibition. Some of these observations are different from our previous results obtained in domestic swine and these changes are thus discussed in the perspective of using SKH-1 hairless mice for the initial in vivo screening of decontaminants.

  13. Estrogen, Estrogen Receptor and Lung Cancer

    Directory of Open Access Journals (Sweden)

    Li-Han Hsu

    2017-08-01

    Full Text Available Estrogen has been postulated as a contributor for lung cancer development and progression. We reviewed the current knowledge about the expression and prognostic implications of the estrogen receptors (ER in lung cancer, the effect and signaling pathway of estrogen on lung cancer, the hormone replacement therapy and lung cancer risk and survival, the mechanistic relationship between the ER and the epidermal growth factor receptor (EGFR, and the relevant clinical trials combining the ER antagonist and the EGFR antagonist, to investigate the role of estrogen in lung cancer. Estrogen and its receptor have the potential to become a prognosticator and a therapeutic target in lung cancer. On the other hand, tobacco smoking aggravates the effect of estrogen and endocrine disruptive chemicals from the environment targeting ER may well contribute to the lung carcinogenesis. They have gradually become important issues in the course of preventive medicine.

  14. COMPARATIVE GENOTOXIC RESPONSES TO ARSENITE IN GUINEA PIG, MOUSE, RAT AND HUMAN LYMPHOCYTES

    Science.gov (United States)

    Comparative genotoxic responses to arsenite in guinea pig, mouse, rat and human lymphocytes.Inorganic arsenic is a known human carcinogen causing skin, lung, and bladder cancer following chronic exposures. Yet, long-term laboratory animal carcinogenicity studies have ...

  15. Lung function

    International Nuclear Information System (INIS)

    Sorichter, S.

    2009-01-01

    The term lung function is often restricted to the assessment of volume time curves measured at the mouth. Spirometry includes the assessment of lung volumes which can be mobilised with the corresponding flow-volume curves. In addition, lung volumes that can not be mobilised, such as the residual volume, or only partially as FRC and TLC can be measured by body plethysmography combined with the determination of the airway resistance. Body plethysmography allows the correct positioning of forced breathing manoeuvres on the volume-axis, e.g. before and after pharmacotherapy. Adding the CO single breath transfer factor (T LCO ), which includes the measurement of the ventilated lung volume using He, enables a clear diagnosis of different obstructive, restrictive or mixed ventilatory defects with and without trapped air. Tests of reversibility and provocation, as well as the assessment of inspiratory mouth pressures (PI max , P 0.1 ) help to classify the underlying disorder and to clarify treatment strategies. For further information and to complete the diagnostic of disturbances of the ventilation, diffusion and/or perfusion (capillar-)arterial bloodgases at rest and under physical strain sometimes amended by ergospirometry are recommended. Ideally, lung function measurements are amended by radiological and nuclear medicine techniques. (orig.) [de

  16. Open lung biopsy

    Science.gov (United States)

    Biopsy - open lung ... An open lung biopsy is done in the hospital using general anesthesia . This means you will be asleep and ... The open lung biopsy is done to evaluate lung problems seen on x-ray or CT scan .

  17. Lung Cancer: Glossary

    Science.gov (United States)

    ... professional support team today. Learn More . Find more lung cancer resources. Learn More Donate Today! What is Lung ... to Give How Your Support Helps Events Lung Cancer Awareness © Lung Cancer Alliance. The information presented in this website ...

  18. Lung Cancer Prevention

    Science.gov (United States)

    ... Colorectal Cancer Kidney (Renal Cell) Cancer Leukemia Liver Cancer Lung Cancer Lymphoma Pancreatic Cancer Prostate Cancer Skin Cancer ... following PDQ summaries for more information about lung cancer: Lung Cancer Screening Non-Small Cell Lung Cancer Treatment ...

  19. Lung cancer - small cell

    Science.gov (United States)

    Cancer - lung - small cell; Small cell lung cancer; SCLC ... About 15% of all lung cancer cases are SCLC. Small cell lung cancer is slightly more common in men than women. Almost all cases of SCLC are ...

  20. [Lung scintigraphy].

    Science.gov (United States)

    Schümichen, Carl; Schmidt, Matthias; Krause, Thomas

    2018-06-01

    The S1 guideline for lung scintigraphy has been updated and extended in order to emphasize the advantages oft the method in detecting acute pulmonary embolism (PE) in the periphery oft the lung (subsegmental PE), in underlying subacute and chronic pulmonary disorders, as well as in detecting chronic LE (CTEPH). Method of choice is ventilation / perfusion (V/P) SPECT or V/P SPECT/CT with even higher specificity. Because of its high sensitivity, a threshold (V/P mismatch in at least one segment or two subsegments) is introduced to avoid overtreatment. In case of a change in the therapeutic approach (observation only instead of anticoaculation) the threshold can be omitted. New data concerning the clinical and therapeutical impact of subsegmental PE are included, the chapters open questions have been extented. Other indications for V/P SPECT (secondary diagnoses, abnormalities in pulmonary perfusion, prediction of postoperative lung function) are presented with new data. Schattauer GmbH.

  1. Protective effects of total alkaloids from Dendrobium crepidatum against LPS-induced acute lung injury in mice and its chemical components.

    Science.gov (United States)

    Hu, Yang; Ren, Jie; Wang, Lei; Zhao, Xin; Zhang, Mian; Shimizu, Kuniyoshi; Zhang, Chaofeng

    2018-05-01

    Dendrobium crepidatum was one of the sources of Herba Dendrobii, a famous and precious traditional Chinese medicine. Indolizine-type alkaloids are the main characteristic ingredients of D. crepidatum, which possesses a variety of changeable skeletons. In the present study, we found that the total alkaloids of D. crepidatum (TAD) can inhibit the production of nitric oxide (NO) in lipopolysaccharide (LPS)-activated macrophages and showed protective effects against LPS-induced acute lung injury (ALI) in mice through downregulating the TLR4-mediated MyD88/MAPK signaling pathway. Further phytochemical study showed that six previously undescribed indolizine-type compounds, including a racemic mixture (dendrocrepidine A-E) were isolated from TAD. Meanwhile, dendrocrepidine F was separated into a pair of enantiomers by a chiral chromatography, and their absolute configurations were assigned by single-crystal X-ray diffraction analysis. The isomer (-)-dendrocrepidine F showed higher anti-inflammatory effects by inhibiting NO production in LPS-treated macrophages with an IC 50 value of 13.3 μM. Taken together, indolizine-type alkaloids are the active components of D. crepidatum through downregulating the TLR4-mediated pathway, indicating some kind of therapy of TAD for ALI treatment. Copyright © 2018 Elsevier Ltd. All rights reserved.

  2. Lung radiopharmaceuticals

    International Nuclear Information System (INIS)

    Gonzalez, B.M.

    1994-01-01

    Indication or main clinical use of Lung radiopharmaceuticals is presented and clasification of radiopharmaceuticals as ventilation and perfusion studies. Perfusion radiopharmaceuticals, main controls for administration quality acceptance. Clearence after blood administration and main clinical applications. Ventilation radiopharmaceuticals, gases and aerosols, characteristics of a ideal radioaerosol, techniques of good inhalation procedure, clinical applications. Comparison of several radiopharmaceuticals reflering to retention time as 50% administered dose, percent administered dose at 6 hours post inhalation, blood activity at 30 and 60 minutes post inhalation, initial lung absorbed dose, cumulated activity.Kinetic description of two radiopharmaceuticals, 99mTcDTPA and 99mTc-PYP

  3. Flow cytometric analysis of mitotic cycle perturbation by chemical carcinogens in cultured epithelial cells. [Effects of benzo(a)pyrene-diol-epoxide on mitotic cycle of cultural mouse liver epithelial cells

    Energy Technology Data Exchange (ETDEWEB)

    Pearlman, Andrew Leonard [Univ. of California, Berkeley, CA (United States)

    1978-08-01

    A system for kinetic analysis of mitotic cycle perturbation by various agents was developed and applied to the study of the mitotic cycle effects and dependency of the chemical carcinogen benzo(a)pyrene-diolepoxide, DE, upon a mouse lever epithelial cell line, NMuLi. The study suggests that the targets of DE action are not confined to DNA alone but may include cytoplasmic structures as well. DE was found to affect cells located in virtually every phase of the mitotic cycle, with cells that were actively synthesizing DNA showing the strongest response. However, the resulting perturbations were not confined to S-phase alone. DE slowed traversal through S-phase by about 40% regardless of the cycle phase of the cells exposed to it, and slowed traversal through G2M by about 50%. When added to G1 cells, DE delayed recruitment of apparently quiescent (G0) cells by 2 hours, and reduced the synchrony of the cohort of cells recruited into active proliferation. The kinetic analysis system consists of four elements: tissue culture methods for propagating and harvesting cell populations; an elutriation centrifugation system for bulk synchronization of cells in various phases of the mitotic cycle; a flow cytometer (FCM), coupled with appropriate staining protocols, to enable rapid analysis of the DNA distribution of any given cell population; and data reduction and analysis methods for extracting information from the DNA histograms produced by the FCM. The elements of the system are discussed. A mathematical analysis of DNA histograms obtained by FCM is presented. The analysis leads to the detailed implementation of a new modeling approach. The new modeling approach is applied to the estimation of cell cycle kinetic parameters from time series of DNA histograms, and methods for the reduction and interpretation of such series are suggested.

  4. A simple method for accurate endotracheal placement of an intubation tube in Guinea pigs to assess lung injury following chemical exposure.

    Science.gov (United States)

    Nambiar, M P; Gordon, R K; Moran, T S; Richards, S M; Sciuto, A M

    2007-01-01

    ABSTRACT Guinea pigs are considered as the animal model of choice for toxicology and medical countermeasure studies against chemical warfare agents (CWAs) and toxic organophosphate pesticides because of the low levels of carboxylesterase compared to rats and mice. However, it is difficult to intubate guinea pigs without damaging the larynx to perform CWA inhalation experiments. We describe an easy technique of intubation of guinea pigs for accurate endotracheal placement of the intubation tube. The technique involves a speculum made by cutting the medium-size ear speculum in the midline leaving behind the intact circular connector to the otoscope. Guinea pigs were anesthetized with Telazol/meditomidine, the tongue was pulled using blunt forceps, and an otoscope attached with the specially prepared speculum was inserted gently. Insertion of the speculum raises the epiglottis and restrains the movements of vocal cord, which allows smooth insertion of the metal stylet-reinforced intubation tube. Accurate endotracheal placement of the intubation tube was achieved by measuring the length from the tracheal bifurcation to vocal cord and vocal cord to the upper front teeth. The average length of the trachea in guinea pigs (275 +/- 25 g) was 5.5 +/- 0.2 cm and the distance from the vocal cord to the front teeth was typically 3 cm. Coinciding an intubation tube marked at 6 cm with the upper front teeth accurately places the intubation tube 2.5 cm above the tracheal bifurcation. This simple method of intubation does not disturb the natural flora of the mouth and causes minimum laryngeal damage. It is rapid and reliable, and will be very valuable in inhalation exposure to chemical/biological warfare agents or toxic chemicals to assess respiratory toxicity and develop medical countermeasures.

  5. Lung Transplant

    Science.gov (United States)

    ... Severity of the recipient's lung disease Recipient's overall health Likelihood that the transplant will be successful Immediately before ... will begin within days of your surgery. Your health care team will likely work with you to design an exercise program that's right for you. Your doctor may ...

  6. Lung cancer

    DEFF Research Database (Denmark)

    Hansen, H H; Rørth, M

    1999-01-01

    The results of the many clinical trials published in 1997 had only modest impact on the treatment results using either cytostatic agents alone or combined with radiotherapy in lung cancer. In SCLC, combination chemotherapy including platin-compounds (cisplatin, carboplatin) and the podophyllotoxins...

  7. Centralized mouse repositories.

    Science.gov (United States)

    Donahue, Leah Rae; Hrabe de Angelis, Martin; Hagn, Michael; Franklin, Craig; Lloyd, K C Kent; Magnuson, Terry; McKerlie, Colin; Nakagata, Naomi; Obata, Yuichi; Read, Stuart; Wurst, Wolfgang; Hörlein, Andreas; Davisson, Muriel T

    2012-10-01

    Because the mouse is used so widely for biomedical research and the number of mouse models being generated is increasing rapidly, centralized repositories are essential if the valuable mouse strains and models that have been developed are to be securely preserved and fully exploited. Ensuring the ongoing availability of these mouse strains preserves the investment made in creating and characterizing them and creates a global resource of enormous value. The establishment of centralized mouse repositories around the world for distributing and archiving these resources has provided critical access to and preservation of these strains. This article describes the common and specialized activities provided by major mouse repositories around the world.

  8. Localization and stretch-dependence of lung elastase activity in development and compensatory growth.

    Science.gov (United States)

    Young, Sarah Marie; Liu, Sheng; Joshi, Rashika; Batie, Matthew R; Kofron, Matthew; Guo, Jinbang; Woods, Jason C; Varisco, Brian Michael

    2015-04-01

    Synthesis and remodeling of the lung matrix is necessary for primary and compensatory lung growth. Because cyclic negative force is applied to developing lung tissue during the respiratory cycle, we hypothesized that stretch is a critical regulator of lung matrix remodeling. By using quantitative image analysis of whole-lung and whole-lobe elastin in situ zymography images, we demonstrated that elastase activity increased twofold during the alveolar stage of postnatal lung morphogenesis in the mouse. Remodeling was restricted to alveolar walls and ducts and was nearly absent in dense elastin band structures. In the mouse pneumonectomy model of compensatory lung growth, elastase activity increased threefold, peaking at 14 days postpneumonectomy and was higher in the accessory lobe compared with other lobes. Remodeling during normal development and during compensatory lung growth was different with increased major airway and pulmonary arterial remodeling during development but not regeneration, and with homogenous remodeling throughout the parenchyma during development, but increased remodeling only in subpleural regions during compensatory lung growth. Left lung wax plombage prevented increased lung elastin during compensatory lung growth. To test whether the adult lung retains an innate capacity to remodel elastin, we developed a confocal microscope-compatible stretching device. In ex vivo adult mouse lung sections, lung elastase activity increased exponentially with strain and in peripheral regions of lung more than in central regions. Our study demonstrates that lung elastase activity is stretch-dependent and supports a model in which externally applied forces influence the composition, structure, and function of the matrix during periods of alveolar septation. Copyright © 2015 the American Physiological Society.

  9. Homologous Recombination Repair Signaling in Chemical Carcinogenesis: Prolonged Particulate Hexavalent Chromium Exposure Suppresses the Rad51 Response in Human Lung Cells

    Science.gov (United States)

    Qin, Qin; Xie, Hong; Wise, Sandra S.; Browning, Cynthia L.; Thompson, Kelsey N.; Holmes, Amie L.; Wise, John Pierce

    2014-01-01

    The aim of this study was to focus on hexavalent chromium, [Cr(VI)], a chemical carcinogen and major public health concern, and consider its ability to impact DNA double strand break repair. We further focused on particulate Cr(VI), because it is the more potent carcinogenic form of Cr(VI). DNA double strand break repair serves to protect cells against the detrimental effects of DNA double strand breaks. For particulate Cr(VI), data show DNA double strand break repair must be overcome for neoplastic transformation to occur. Acute Cr(VI) exposures reveal a robust DNA double strand break repair response, however, longer exposures have not been considered. Using the comet assay, we found longer exposures to particulate zinc chromate induced concentration-dependent increases in DNA double strand breaks indicating breaks were occurring throughout the exposure time. Acute (24 h) exposure induced DNA double strand break repair signaling by inducing Mre11 foci formation, ATM phosphorylation and phosphorylated ATM foci formation, Rad51 protein levels and Rad51 foci formation. However, longer exposures reduced the Rad51 response. These data indicate a major chemical carcinogen can simultaneously induce DNA double strand breaks and alter their repair and describe a new and important aspect of the carcinogenic mechanism for Cr(VI). PMID:25173789

  10. Role of skeletal muscle in lung development.

    Science.gov (United States)

    Baguma-Nibasheka, Mark; Gugic, Dijana; Saraga-Babic, Mirna; Kablar, Boris

    2012-07-01

    Skeletal (striated) muscle is one of the four basic tissue types, together with the epithelium, connective and nervous tissues. Lungs, on the other hand, develop from the foregut and among various cell types contain smooth, but not skeletal muscle. Therefore, during earlier stages of development, it is unlikely that skeletal muscle and lung depend on each other. However, during the later stages of development, respiratory muscle, primarily the diaphragm and the intercostal muscles, execute so called fetal breathing-like movements (FBMs), that are essential for lung growth and cell differentiation. In fact, the absence of FBMs results in pulmonary hypoplasia, the most common cause of death in the first week of human neonatal life. Most knowledge on this topic arises from in vivo experiments on larger animals and from various in vitro experiments. In the current era of mouse mutagenesis and functional genomics, it was our goal to develop a mouse model for pulmonary hypoplasia. We employed various genetically engineered mice lacking different groups of respiratory muscles or lacking all the skeletal muscle and established the criteria for pulmonary hypoplasia in mice, and therefore established a mouse model for this disease. We followed up this discovery with systematic subtractive microarray analysis approach and revealed novel functions in lung development and disease for several molecules. We believe that our approach combines elements of both in vivo and in vitro approaches and allows us to study the function of a series of molecules in the context of lung development and disease and, simultaneously, in the context of lung's dependence on skeletal muscle-executed FBMs.

  11. Inhibition of B16-BL6 melanoma lung colonies by semisynthetic sulfaminoheparosan sulfates from E. coli K5 polysaccharide.

    Science.gov (United States)

    Poggi, Andreina; Rossi, Cosmo; Casella, Nicola; Bruno, Cristiana; Sturiale, Luisella; Dossi, Carla; Naggi, Annamaria

    2002-08-01

    Heparin (H), heparan sulfate (HS), and related glycosaminoglycans can inhibit cancer cell invasion, possibly due to their ability to interact with vascular growth factors, adhesion molecules, endoglycosidases, and signaling proteins, in addition to the well-known effects on the clotting system. We evaluated the antitumor activity of a series of semisynthetic sulfaminoheparosan sulfates (SAHSs) with different degree and distribution of sulfates, obtained by chemical modifications of the E. coli K5 polysaccharide, namely type A, B, and C compounds. B16-BL6 melanoma cells (10 5 cells/mouse) were injected intravenously (i.v.) in a lateral tail vein of C57BL6 mice at a dose of 0.5 mg/ mouse together with test compounds. Tumor lung nodules were significantly reduced as compared with controls only by H (95.5 +/- 1.0% inhibition), SAHS-2 (84.2 +/- 5.0% inhibition), and SAHS-4 (91.1 +/- 4.2% inhibition), among compounds tested. SAHS-2 and SAHS-4 are type B compounds, with a sulfate/carboxylate ratio similar to that of H. A typical mammalian HS showed only 54.8% inhibition. Supersulfated low-molecular-weight heparin and heparan sulfate (ssLMWH and ssLMWHS) showed an activity similar to that of unfractionated compounds. H and SAHS-4 inhibited dose dependently B16-BL6 lung colonies, with IC-50 values of 0.05 and 0.1 mg/mouse, respectively. The relationship with ex vivo anticoagulant potency was evaluated by activated partial thromboplastin time (aPTT) on mouse plasma at different time intervals after i.v. injection (0.1 to 0.5 mg/mouse) of the compound. H showed a dose-dependent anticoagulant activity lasting up to 2 hours, whereas SAHS-4 showed a potent anticoagulant effect only at a dose of 0.5 mg/mouse. Accordingly, H but not SAHS-4 consistently inhibited B16-BL6 lung colonies when given 1 hour before tumor cells. SAHS-4 derivatives, with different size and/or affinity depleted of AT binding sites, showed an inhibitory effect on B16-BL6 melanoma similar to that of SAHS-4

  12. ZNF 197L is dispensable in mouse development

    African Journals Online (AJOL)

    Jane

    2011-07-27

    protein interactions (Kim et al., 1996; Friedman et .... A fragment of pU17 vector was used as a probe to detect the trapping ... RNA was isolated from adult mouse brain, heart, lung, .... Zinc finger peptides for the regulation of gene.

  13. The lungs

    International Nuclear Information System (INIS)

    Macey, D.J.; Marshall, R.

    1982-01-01

    Currently emission tomography of the lungs is only practical for perfusion images with sup(99m)Tc microaggregates and ventilation images with sup(81m)Kr. The following topics are touched on: the rotating gamma camera single photon ECT system, spatial resolution and linearity, resolution in phantom studies, area and volume studies, quantitation studies, with particular reference to the authors' experience of perfusion and ventilation in investigations of pulmonary embolism. (U.K.)

  14. Hyperlucent lung

    International Nuclear Information System (INIS)

    Jimenez-Gutierrez, Florana; Soto-Quiros, Manuel E.

    2007-01-01

    Unilateral hyperlucent lung is also known as Swyer-James Syndrome, Macleod Syndrome or lobular or unilateral emphysema. It is an uncommon disease characterized by lung or unilateral lobe hiperlucency associated to an air trapping upon expiration. As regards to etiology, this syndrome is considered to be an acquired disease that appears secondary to respiratory infections during the early years of life, probably bronchiolitis and/ or viral pneumonia. The clinical presentation varies among patients. Some of them are asymptomatic, others present a history of recurrent episodes of pulmonary infections from early years of life or present effort dyspnea. The diagnosis is usually made accidentally by a chest radiograph in a child with history of respiratory infections or in an adult during a routine chest x- ray in an asymptomatic person. It is important to differentiate this syndrome from other causes of unilateral pulmonary hiperlucency on conventional chest x-rays. Few cases of Swyer-James Syndrome in children have been reported, it is presented the clinical case of a patient who had a parainfluenza 3 bronchopneumonia when he was a month and eighteen days of age. The differential diagnosis of this syndrome should be done with other thoracic entities that diminish the radiological pulmonary unilateral density. A case of a child who is the bearer of hyperlucent lung is described. (author) [es

  15. Metastatic tumors of lungs

    International Nuclear Information System (INIS)

    Rozenshtraukh, L.C.; Rybakova, N.I.; Vinner, M.G.

    1987-01-01

    Roentgenologic semiotics of lung metastases and their complications, as well as peculiarities of lung metastases of separate localization tumours are presented. Definition table for primary tumour by roentgenologic aspect of lung metastases is given

  16. How Lungs Work

    Science.gov (United States)

    ... Diseases > How Lungs Work How Lungs Work The Respiratory System Your lungs are part of the respiratory system, ... your sense of smell. The Parts of the Respiratory System and How They Work Airways SINUSES are hollow ...

  17. Protecting Your Lungs

    Science.gov (United States)

    ... lung capacity. Specific breathing exercises can also help improve your lung function if you have certain lung diseases, like COPD. Exercise and breathing techniques are also great for improving your mood and helping you relax. Public Health and Your ...

  18. Mitochondrial biogenesis in the pulmonary vasculature during inhalation lung injury and fibrosis

    Science.gov (United States)

    Cell survival and injury repair is facilitated by mitochondrial biogenesis; however, the role of this process in lung repair is unknown. We evaluated mitochondrial biogenesis in the mouse lung in two injuries that cause acute inflammation and in two that cause chronic inflammatio...

  19. Lung PET scan

    Science.gov (United States)

    ... Chest PET scan; Lung positron emission tomography; PET - chest; PET - lung; PET - tumor imaging; ... Grainger & Allison's Diagnostic Radiology: A Textbook of Medical Imaging . 6th ed. Philadelphia, ...

  20. Extravascular Lung Water and Acute Lung Injury

    Directory of Open Access Journals (Sweden)

    Ritesh Maharaj

    2012-01-01

    Full Text Available Acute lung injury carries a high burden of morbidity and mortality and is characterised by nonhydrostatic pulmonary oedema. The aim of this paper is to highlight the role of accurate quantification of extravascular lung water in diagnosis, management, and prognosis in “acute lung injury” and “acute respiratory distress syndrome”. Several studies have verified the accuracy of both the single and the double transpulmonary thermal indicator techniques. Both experimental and clinical studies were searched in PUBMED using the term “extravascular lung water” and “acute lung injury”. Extravascular lung water measurement offers information not otherwise available by other methods such as chest radiography, arterial blood gas, and chest auscultation at the bedside. Recent data have highlighted the role of extravascular lung water in response to treatment to guide fluid therapy and ventilator strategies. The quantification of extravascular lung water may predict mortality and multiorgan dysfunction. The limitations of the dilution method are also discussed.

  1. Prediction of acute inhalation toxicity using in vitro lung surfactant inhibition

    DEFF Research Database (Denmark)

    Sørli, Jorid Birkelund; Huang, Yishi; Da Silva, Emilie

    2018-01-01

    impregnation products using the constant flow through set-up of the constrained drop surfactometer to determine if they inhibited LS function or not. The same products were tested in a mouse inhalation bioassay to determine their toxicity in vivo. The sensitivity was 100%, i.e. the in vitro method predicted...... the chemical composition of the products and induction of toxicity. The currently accepted method for determination of acute inhalation toxicity is based on experiments on animals; it is time-consuming, expensive and causes stress for the animals. Impregnation products are present on the market in large...... numbers and amounts and exhibit great variety. Therefore, an alternative method to screen for acute inhalation toxicity is needed. The aim of our study was to determine if inhibition of lung surfactant by impregnation products in vitro could accurately predict toxicity in vivo in mice. We tested 21...

  2. Inverse relationship of tumors and mononuclear cell leukemia infiltration in the lungs of F344 rats

    Energy Technology Data Exchange (ETDEWEB)

    Lundgren, D.L.; Griffith, W.C.; Hahn, F.F.

    1995-12-01

    In 1970 and F344 rat, along with the B6C3F{sub 1} mouse, were selected as the standard rodents for the National Cancer Institute Carcinogenic Bioassay program for studies of potentially carcinogenic chemicals. The F344 rat has also been used in a variety of other carcinogenesis studies, including numerous studies at ITRI. A major concern to be considered in evaluating carcinogenic bioassay studies using the F344 rat is the relatively high background incidence of mononuclear cell leukemia (MCL) (also referred to as large granular lymphocytic leukemia, Fischer rat leukemia, or monocytic leukemia). Incidences of MCL ranging from 10 to 72% in male F344 rats to 6 to 31% in female F344 rats have been reported. Gaining the understanding of the mechanisms involved in the negative correlations noted should enhance our understanding of the mechanisms involved in the development of lung cancer.

  3. Precision cut lung slices as an efficient tool for in vitro lung physio-pharmacotoxicology studies.

    Science.gov (United States)

    Morin, Jean-Paul; Baste, Jean-Marc; Gay, Arnaud; Crochemore, Clément; Corbière, Cécile; Monteil, Christelle

    2013-01-01

    1.We review the specific approaches for lung tissue slices preparation and incubation systems and the research application fields in which lung slices proved to be a very efficient alternative to animal experimentation for biomechanical, physiological, pharmacological and toxicological approaches. 2.Focus is made on air-liquid interface dynamic organ culture systems that allow direct tissue exposure to complex aerosol and that best mimic in vivo lung tissue physiology. 3.A compilation of research applications in the fields of vascular and airway reactivity, mucociliary transport, polyamine transport, xenobiotic biotransformation, chemicals toxicology and complex aerosols supports the concept that precision cut lung slices are a very efficient tool maintaining highly differentiated functions similar to in vivo lung organ when kept under dynamic organ culture. They also have been successfully used for lung gene transfer efficiency assessment, for lung viral infection efficiency assessment, for studies of tissue preservation media and tissue post-conditioning to optimize lung tissue viability before grafting. 4.Taken all together, the reviewed studies point to a great interest for precision cut lung slices as an efficient and valuable alternative to in vivo lung organ experimentation.

  4. ErbB2 Pathway Activation upon Smad4 Loss Promotes Lung Tumor Growth and Metastasis

    OpenAIRE

    Liu, Jian; Cho, Sung-Nam; Akkanti, Bindu; Jin, Nili; Mao, Jianqiang; Long, Weiwen; Chen, Tenghui; Zhang, Yiqun; Tang, Ximing; Wistub, Ignacio I.; Creighton, Chad J.; Kheradmand, Farrah; DeMayo, Francesco J.

    2015-01-01

    Lung cancer remains the leading cause of cancer death. Genome sequencing of lung tumors from patients with squamous cell carcinoma has identified SMAD4 to be frequently mutated. Here, we use a mouse model to determine the molecular mechanisms by which Smad4 loss leads to lung cancer progression. Mice with ablation of Pten and Smad4 in airway epithelium develop metastatic adenosquamous tumors. Comparative transcriptomic and in vivo cistromic analyses determine that loss of PTEN and SMAD4 resul...

  5. Chemical Characterization and Toxicologic Evaluation of Airborne Mixtures. Tumorigenicity Studies of Diesel Fuel-2, Red Smoke Dye and Violet Smoke Dyes in the SENCAR Mouse Skin Tumorigenesis Bioassay System

    Science.gov (United States)

    1985-09-01

    methyl nitrosourea on mouse skin in the drop test. Acta Biol. Med. Ger. 16: KI-K3. Hennings, H., and R. K. Boutwel’.. 1969. Inhibition of DNA synthesis ...J., G. T. Bowden, B. G. Shapas, and R. K. Boutwell. 1973. "Macromolecular synthesis following a single application of alkylating agents used as

  6. Mouse cell culture - Methods and protocols

    Directory of Open Access Journals (Sweden)

    CarloAlberto Redi

    2010-12-01

    Full Text Available The mouse is, out of any doubt, the experimental animal par excellence for many many colleagues within the scientific community, notably for those working in mammalian biology (in a broad sense, from basic genetic to modeling human diseases, starting at least from 1664 Robert Hooke experiments on air’s propertyn. Not surprising then that mouse cell cultures is a well established field of research itself and that there are several handbooks devoted to this discipline. Here, Andrew Ward and David Tosh provide a necessary update of the protocols currently needed. In fact, nearly half of the book is devoted to stem cells culture protocols, mainly embryonic, from a list of several organs (kidney, lung, oesophagus and intestine, pancreas and liver to mention some........

  7. Development of mPMab-1, a Mouse-Rat Chimeric Antibody Against Mouse Podoplanin.

    Science.gov (United States)

    Yamada, Shinji; Kaneko, Mika K; Nakamura, Takuro; Ichii, Osamu; Konnai, Satoru; Kato, Yukinari

    2017-04-01

    Podoplanin (PDPN), the ligand of C-type lectin-like receptor-2, is used as a lymphatic endothelial marker. We previously established clone PMab-1 of rat IgG 2a as a specific monoclonal antibody (mAb) against mouse PDPN. PMab-1 is also very sensitive in immunohistochemical analysis; however, rat mAbs seem to be unfavorable for pathologists because anti-mouse IgG and anti-rabbit IgG are usually used as secondary antibodies in commercially available kits for immunohistochemical analysis. In this study, we develop a mouse-rat chimeric antibody, mPMab-1 of mouse IgG 2a , which was derived from rat PMab-1 mAb. Immunohistochemical analysis shows that mPMab-1 detects podocytes of the kidney, lymphatic endothelial cells of the colon, and type I alveolar cells of the lung. Importantly, mPMab-1 is more sensitive than PMab-1. This conversion strategy from rat mAb to mouse mAb could be applicable to other mAbs.

  8. Lung cancer

    International Nuclear Information System (INIS)

    Kato, Toshio

    1982-01-01

    Based on the own experience and world literatures, contribution of radiation in the treatment of lung cancer was reviewed and discussed. Although the patients with advanced cancer were referred to radiation usually, the results of radiotherapy were superior to those by chemotherapy. Of course the radiotherapy was a local one, radiation combined with chemotherapy was highly recommended, besides systemic administration of chemotherapeutics, special methods such as bronchial arterial infusion (BAI) and chemoembolization would be more favourable in selected patients. Treatment of undifferentiated small cell carcinoma was becoming more dependent on chemotherapy, radiation showed as excellent local control as ever. To treat locally extended cancer patients with involvement of the thoracic wall and Pancoast's syndrome, external radiation alone were not successful, interstitial radiation or a single exposure with a large dose during the thoracotomy would be promising. Finally, data indicated that aged and poor risk patients in early stage of cancer might be treated by radiation instead of unjustifiable operation. (author)

  9. Staging of Lung Cancer

    Science.gov (United States)

    ... LUNG CANCER MINI-SERIES #2 Staging of Lung Cancer Once your lung cancer is diagnosed, staging tells you and your health care provider about ... at it under a microscope. The stages of lung cancer are listed as I, II, III, and IV ...

  10. Lung needle biopsy

    Science.gov (United States)

    ... if you have certain lung diseases such as emphysema. Usually, a collapsed lung after a biopsy does not need treatment. But ... any type Bullae (enlarged alveoli that occur with emphysema) Cor pulmonale (condition ... of the lung High blood pressure in the lung arteries Severe ...

  11. Migration Of Ancylostoma caninum Larvae Into Lungs Of Mice Fed ...

    African Journals Online (AJOL)

    Two randomly selected groups of Swiss Albino Wistar mice were therefore infected with 1000 infective larvae of Ancylostoma caninum/mouse. Test mice received 250mg Allium sativum/kg body weight daily ... KEY WORDS: Allium sativum, lungs, Ancylostoma caninum. Global Journal of Pure and Applied Sciences Vol.11(2) ...

  12. Gaze beats mouse

    DEFF Research Database (Denmark)

    Mateo, Julio C.; San Agustin, Javier; Hansen, John Paulin

    2008-01-01

    Facial EMG for selection is fast, easy and, combined with gaze pointing, it can provide completely hands-free interaction. In this pilot study, 5 participants performed a simple point-and-select task using mouse or gaze for pointing and a mouse button or a facial-EMG switch for selection. Gaze...

  13. Bacterial lung abscess

    International Nuclear Information System (INIS)

    Groskin, S.A.; Panicek, D.M.; Ewing, D.K.; Rivera, F.; Math, K.; Teixeira, J.; Heitzman, E.R.

    1987-01-01

    A retrospective review of patients with bacterial lung abscess was carried out. Demographic, clinical, and radiographical features of this patient group are compared with similar data from patients with empyema and/or cavitated lung carcinoma; differential diagnostic points are stressed. The entity of radiographically occult lung abscess is discussed. Complications associated with bacterial lung abscess are discussed. Current therapeutic options and treatment philosophy for patients with bacterial lung abscess are noted

  14. In Vivo Inflammatory Effects of Ceria Nanoparticles on CD-1 Mouse: Evaluation by Hematological, Histological, and TEM Analysis

    Directory of Open Access Journals (Sweden)

    Anna Poma

    2014-01-01

    Full Text Available The attention on CeO2-NPs environmental and in vivo effects is due to their presence in diesel exhaust and in diesel filters that release a more water-soluble form of ceria NPs, as well as to their use for medical applications. In this work, acute and subacute in vivo toxicity assays demonstrate no lethal effect of these NPs. Anyhow, performing in vivo evaluations on CD-1 mouse systems, we demonstrate that it is even not correct to assert that ceria NPs are harmless for living systems as they can induce status of inflammation, revealed by hematological-chemical-clinical assays as well as histological and TEM microscope observations. TEM analysis showed the presence of NPs in alveolar macrophages. Histological evaluation demonstrated the NPs presence in lungs tissues and this can be explained by assuming their ability to go into the blood stream and lately into the organs (generating inflammation.

  15. In vitro cytotoxicity effect and antibacterial performance of human lung epithelial cells A549 activity of Zinc oxide doped TiO{sub 2} nanocrystals: Investigation of bio-medical application by chemical method

    Energy Technology Data Exchange (ETDEWEB)

    Kaviyarasu, K., E-mail: kaviyarasuloyolacollege@gmail.com [UNESCO-UNISA Africa Chair in Nanosciences/Nanotechnology Laboratories, College of Graduate Studies, University of South Africa (UNISA), Muckleneuk Ridge, PO Box 392, Pretoria (South Africa); Nanosciences African Network (NANOAFNET), Materials Research Group (MRG), i Themba LABS-National Research Foundation - NRF, 1 Old Faure Road, 7129, PO Box 722, Somerset West, Western Cape Province (South Africa); Geetha, N. [Research and Development Center, Bharathiyar University, Coimbatore 641046 (India); Kanimozhi, K. [PG Research & Department of Chemistry, Auxilium College (Autonomous), Vellore (India); Maria Magdalane, C. [Department of Chemistry, St. Xavier’s College (Autonomous), Tirunelveli 627002 (India); LIFE, Department of Chemistry, Loyola College (Autonomous), Chennai 600034 (India); Sivaranjani, S. [Research and Development Center, Bharathiyar University, Coimbatore 641046 (India); Department of Physics, SBM College of Engineering and Technology, Dindigul -624 005 (India); Ayeshamariam, A. [Research and Development Center, Bharathiyar University, Coimbatore 641046 (India); Department of Physics, Khadir Mohideen College, Adirampattinam 614601 (India); Kennedy, J. [UNESCO-UNISA Africa Chair in Nanosciences/Nanotechnology Laboratories, College of Graduate Studies, University of South Africa (UNISA), Muckleneuk Ridge, PO Box 392, Pretoria (South Africa); National Isotope Centre, GNS Science, PO Box 31312, Lower Hutt 5010 (New Zealand); Maaza, M. [UNESCO-UNISA Africa Chair in Nanosciences/Nanotechnology Laboratories, College of Graduate Studies, University of South Africa (UNISA), Muckleneuk Ridge, PO Box 392, Pretoria (South Africa); Nanosciences African Network (NANOAFNET), Materials Research Group (MRG), i Themba LABS-National Research Foundation - NRF, 1 Old Faure Road, 7129, PO Box 722, Somerset West, Western Cape Province (South Africa)

    2017-05-01

    We report the synthesis of high quality ZnO doped TiO{sub 2} nanocrystals by chemical method at room temperature (RT), it can cause serious oxidative stress and DNA damage to human lung epithelial cells (A549) lines. Our aim in this study, to reduce the cytotoxicity effect of ZnO doped TiO{sub 2} nanocrystals are widely in biological fields. Several studies have been performed to understand the influence of ZnO doped titanium dioxide (TiO{sub 2}-NPs) on cell function; however the effects of nanoparticle against to exposure on the cell membrane have been duly addressed fascinatingly so far. However, In this interaction, which may alter cell metabolism and integrity, it is one of the importance to understand the modifications of the cell membrane, mechanisms of pulmonary A549 cell lines nanoparticles were uptake and the molecular pathway during the initial cell responses are still unclear and much more investigative efforts are need to properly characterize the ZnO doped titanium dioxide nanoparticles were reported successfully. In particular of the epithelial cells, upon particles are exposed human pulmonary epithelial cells (A549) to various concentrations of composition, structure and morphology of the nanocrystals were analyzed by X-ray diffraction (XRD) and high resolution transmission electron microscopy (HRTEM). XRD assessed the crystal structure of the nanocrystals which identified peaks associated with (002), (100) and (101) planes of hexagonal wurtzite-type ZnO with lattice constants of a = b = 3.249 Å and c = 5.219 Å. The IR results showed high purity of products and indicated that the nanocrystals are made up of Ti−O and Zn−O bonds. The Photoluminescence (PL) spectra are dominated by a strong narrow band edge emission tunable in the blue region of the visible spectra indicating a narrow size distribution of ZnO/TiO{sub 2} nanocrystals which exhibits antibacterial activity over a broad range of bacterial species and in particular against Stre. Mut

  16. In vitro cytotoxicity effect and antibacterial performance of human lung epithelial cells A549 activity of Zinc oxide doped TiO2 nanocrystals: Investigation of bio-medical application by chemical method

    International Nuclear Information System (INIS)

    Kaviyarasu, K.; Geetha, N.; Kanimozhi, K.; Maria Magdalane, C.; Sivaranjani, S.; Ayeshamariam, A.; Kennedy, J.; Maaza, M.

    2017-01-01

    We report the synthesis of high quality ZnO doped TiO 2 nanocrystals by chemical method at room temperature (RT), it can cause serious oxidative stress and DNA damage to human lung epithelial cells (A549) lines. Our aim in this study, to reduce the cytotoxicity effect of ZnO doped TiO 2 nanocrystals are widely in biological fields. Several studies have been performed to understand the influence of ZnO doped titanium dioxide (TiO 2 -NPs) on cell function; however the effects of nanoparticle against to exposure on the cell membrane have been duly addressed fascinatingly so far. However, In this interaction, which may alter cell metabolism and integrity, it is one of the importance to understand the modifications of the cell membrane, mechanisms of pulmonary A549 cell lines nanoparticles were uptake and the molecular pathway during the initial cell responses are still unclear and much more investigative efforts are need to properly characterize the ZnO doped titanium dioxide nanoparticles were reported successfully. In particular of the epithelial cells, upon particles are exposed human pulmonary epithelial cells (A549) to various concentrations of composition, structure and morphology of the nanocrystals were analyzed by X-ray diffraction (XRD) and high resolution transmission electron microscopy (HRTEM). XRD assessed the crystal structure of the nanocrystals which identified peaks associated with (002), (100) and (101) planes of hexagonal wurtzite-type ZnO with lattice constants of a = b = 3.249 Å and c = 5.219 Å. The IR results showed high purity of products and indicated that the nanocrystals are made up of Ti−O and Zn−O bonds. The Photoluminescence (PL) spectra are dominated by a strong narrow band edge emission tunable in the blue region of the visible spectra indicating a narrow size distribution of ZnO/TiO 2 nanocrystals which exhibits antibacterial activity over a broad range of bacterial species and in particular against Stre. Mut where it out competes

  17. Lung Cancer—Patient Version

    Science.gov (United States)

    The two main types of lung cancer are non-small cell lung cancer and small cell lung cancer. Smoking causes most lung cancers, but nonsmokers can also develop lung cancer. Start here to find information on lung cancer treatment, causes and prevention, screening, research, and statistics on lung cancer.

  18. Verification of photon attenuation characteristics for 3D printer based small animal lung model

    International Nuclear Information System (INIS)

    Lee, Se Ho; Lee, Seung Wook; Han, Su Chul; Park, Seung Woo

    2016-01-01

    Since it is difficult to measure absorbed dose to mice in vivo, replica mice are mostly used as alternative. In this study, realistic mouse phantom was fabricated by using 3D printer (object500 connex3, Stratasys, USA). Elemental inks as material of 3D printer were selected corresponding to mouse tissue. To represent lung, selected material was partially used with air layer. In order to verify material equivalent, super-flex bolus was simply compared to verify photon attenuation characteristics. In the case of lung, Hounsfield unit (HU) of the phantom were compared with a live mouse. In this study, we fabricated mouse phantom by using 3D printer, and practically verified photon attenuation characteristics. The fabricated phantom shows tissue equivalence as well as similar geometry with live mouse. As more and more growing of 3D printer technique, 3D printer based small preclinical animal phantom would increase reliability of verification of absorbed dose in small animal for preclinical study

  19. Verification of photon attenuation characteristics for 3D printer based small animal lung model

    Energy Technology Data Exchange (ETDEWEB)

    Lee, Se Ho; Lee, Seung Wook [Pusan National University, Busan (Korea, Republic of); Han, Su Chul; Park, Seung Woo [Korea Institute of Radiological and Medical Sciences, Seoul (Korea, Republic of)

    2016-05-15

    Since it is difficult to measure absorbed dose to mice in vivo, replica mice are mostly used as alternative. In this study, realistic mouse phantom was fabricated by using 3D printer (object500 connex3, Stratasys, USA). Elemental inks as material of 3D printer were selected corresponding to mouse tissue. To represent lung, selected material was partially used with air layer. In order to verify material equivalent, super-flex bolus was simply compared to verify photon attenuation characteristics. In the case of lung, Hounsfield unit (HU) of the phantom were compared with a live mouse. In this study, we fabricated mouse phantom by using 3D printer, and practically verified photon attenuation characteristics. The fabricated phantom shows tissue equivalence as well as similar geometry with live mouse. As more and more growing of 3D printer technique, 3D printer based small preclinical animal phantom would increase reliability of verification of absorbed dose in small animal for preclinical study.

  20. DNA topoisomerase II enzyme activity appears in mouse sperm ...

    African Journals Online (AJOL)

    Jane

    2011-08-22

    Aug 22, 2011 ... 4 mg/ml bovine serum albumin (BSA; Sigma, Chemical Co., U.S.A) and at time of use, it was ..... Differential growth of mouse preimplantation embryos in chemically ... I. In vitro fertilization of eggs by fresh epididymal sperms.

  1. Host lung immunity is severely compromised during tropical pulmonary eosinophilia: role of lung eosinophils and macrophages.

    Science.gov (United States)

    Sharma, Pankaj; Sharma, Aditi; Vishwakarma, Achchhe Lal; Agnihotri, Promod Kumar; Sharma, Sharad; Srivastava, Mrigank

    2016-04-01

    Eosinophils play a central role in the pathogenesis of tropical pulmonary eosinophilia, a rare, but fatal, manifestation of filariasis. However, no exhaustive study has been done to identify the genes and proteins of eosinophils involved in the pathogenesis of tropical pulmonary eosinophilia. In the present study, we established a mouse model of tropical pulmonary eosinophilia that mimicked filarial manifestations of human tropical pulmonary eosinophilia pathogenesis and used flow cytometry-assisted cell sorting and real-time RT-PCR to study the gene expression profile of flow-sorted, lung eosinophils and lung macrophages during tropical pulmonary eosinophilia pathogenesis. Our results show that tropical pulmonary eosinophilia mice exhibited increased levels of IL-4, IL-5, CCL5, and CCL11 in the bronchoalveolar lavage fluid and lung parenchyma along with elevated titers of IgE and IgG subtypes in the serum. Alveolar macrophages from tropical pulmonary eosinophilia mice displayed decreased phagocytosis, attenuated nitric oxide production, and reduced T-cell proliferation capacity, and FACS-sorted lung eosinophils from tropical pulmonary eosinophilia mice upregulated transcript levels of ficolin A and anti-apoptotic gene Bcl2,but proapoptotic genes Bim and Bax were downregulated. Similarly, flow-sorted lung macrophages upregulated transcript levels of TLR-2, TLR-6, arginase-1, Ym-1, and FIZZ-1 but downregulated nitric oxide synthase-2 levels, signifying their alternative activation. Taken together, we show that the pathogenesis of tropical pulmonary eosinophilia is marked by functional impairment of alveolar macrophages, alternative activation of lung macrophages, and upregulation of anti-apoptotic genes by eosinophils. These events combine together to cause severe lung inflammation and compromised lung immunity. Therapeutic interventions that can boost host immune response in the lungs might thus provide relief to patients with tropical pulmonary eosinophilia.

  2. Lung growth and development.

    Science.gov (United States)

    Joshi, Suchita; Kotecha, Sailesh

    2007-12-01

    Human lung growth starts as a primitive lung bud in early embryonic life and undergoes several morphological stages which continue into postnatal life. Each stage of lung growth is a result of complex and tightly regulated events governed by physical, environmental, hormonal and genetic factors. Fetal lung liquid and fetal breathing movements are by far the most important determinants of lung growth. Although timing of the stages of lung growth in animals do not mimic that of human, numerous animal studies, mainly on sheep and rat, have given us a better understanding of the regulators of lung growth. Insight into the genetic basis of lung growth has helped us understand and improve management of complex life threatening congenital abnormalities such as congenital diaphragmatic hernia and pulmonary hypoplasia. Although advances in perinatal medicine have improved survival of preterm infants, premature birth is perhaps still the most important factor for adverse lung growth.

  3. Epidemiology of Lung Cancer

    Science.gov (United States)

    Brock, Malcolm V.; Ford, Jean G.; Samet, Jonathan M.; Spivack, Simon D.

    2013-01-01

    Background: Ever since a lung cancer epidemic emerged in the mid-1900s, the epidemiology of lung cancer has been intensively investigated to characterize its causes and patterns of occurrence. This report summarizes the key findings of this research. Methods: A detailed literature search provided the basis for a narrative review, identifying and summarizing key reports on population patterns and factors that affect lung cancer risk. Results: Established environmental risk factors for lung cancer include smoking cigarettes and other tobacco products and exposure to secondhand tobacco smoke, occupational lung carcinogens, radiation, and indoor and outdoor air pollution. Cigarette smoking is the predominant cause of lung cancer and the leading worldwide cause of cancer death. Smoking prevalence in developing nations has increased, starting new lung cancer epidemics in these nations. A positive family history and acquired lung disease are examples of host factors that are clinically useful risk indicators. Risk prediction models based on lung cancer risk factors have been developed, but further refinement is needed to provide clinically useful risk stratification. Promising biomarkers of lung cancer risk and early detection have been identified, but none are ready for broad clinical application. Conclusions: Almost all lung cancer deaths are caused by cigarette smoking, underscoring the need for ongoing efforts at tobacco control throughout the world. Further research is needed into the reasons underlying lung cancer disparities, the causes of lung cancer in never smokers, the potential role of HIV in lung carcinogenesis, and the development of biomarkers. PMID:23649439

  4. Genetics Home Reference: lung cancer

    Science.gov (United States)

    ... Share: Email Facebook Twitter Home Health Conditions Lung cancer Lung cancer Printable PDF Open All Close All Enable Javascript ... cancer, childhood Additional NIH Resources (3 links) National Cancer Institute: Lung Cancer Overview National Cancer Institute: Lung Cancer Prevention ...

  5. Radiation Therapy for Lung Cancer

    Science.gov (United States)

    ... is almost always due to smoking. TREATING LUNG CANCER Lung cancer treatment depends on several factors, including the ... org TARGETING CANCER CARE Radiation Therapy for Lung Cancer Lung cancer is the second most common cancer in ...

  6. Single-mass mutations associated with mouse lymphomas

    International Nuclear Information System (INIS)

    Guerrero, I.; Berman, J.W.; Diamond, L.E.; Newcomb, E.W.; Villasante, A.

    1986-01-01

    The authors study the induction of mouse lymphomas after treatment with a chemical carcinogen, nitrosomethyl urea (NMU), or with gamma irradiation. The koplan fractionated gamma radiation scheme and an established protocol for NMU tumor formation were chosen as protocols for induction of mouse lymphomas. In both cases, the mice developed thymic lymphomas with up to 90% incidence. In NMU induction, the latency period is shorter than irradiation

  7. Mouse Genome Informatics (MGI)

    Data.gov (United States)

    U.S. Department of Health & Human Services — MGI is the international database resource for the laboratory mouse, providing integrated genetic, genomic, and biological data to facilitate the study of human...

  8. Mouse Phenome Database (MPD)

    Data.gov (United States)

    U.S. Department of Health & Human Services — The Mouse Phenome Database (MPD) has characterizations of hundreds of strains of laboratory mice to facilitate translational discoveries and to assist in selection...

  9. Lungs and Respiratory System

    Science.gov (United States)

    ... Videos for Educators Search English Español Lungs and Respiratory System KidsHealth / For Parents / Lungs and Respiratory System ... ll have taken at least 600 million breaths. Respiratory System Basics All of this breathing couldn't ...

  10. Childhood Interstitial Lung Disease

    Science.gov (United States)

    ... rule out conditions such as asthma , cystic fibrosis , acid reflux, heart disease, neuromuscular disease, and immune deficiency. Various ... a lung infection. Acid-blocking medicines can prevent acid reflux, which can lead to aspiration. Lung Transplant A ...

  11. Interstitial Lung Disease

    Science.gov (United States)

    ... propranolol (Inderal, Innopran), may harm lung tissue. Some antibiotics. Nitrofurantoin (Macrobid, Macrodantin, others) and ethambutol (Myambutol) can cause lung damage. Anti-inflammatory drugs. Certain anti-inflammatory drugs, such as rituximab ( ...

  12. Eosinophilic Lung Disorders

    Science.gov (United States)

    ... problems characterized by having an increased number of eosinophils (white blood cells) in the lungs. These white ... category of pneumonias that feature increased numbers of eosinophils in the lung tissue. Pneumonia is an inflammatory ...

  13. Lung nodules after whole lung radiation

    International Nuclear Information System (INIS)

    Cohen, M.D.; Mirkin, D.L.; Provisor, A.; Hornback, N.B.; Smith, J.A.; Slabaugh, R.D.

    1983-01-01

    It is essential to recognize radiation pneumonitis after whole lung irradiation, or nodular changes in response to chemotherapy, so that such conditions are not mistaken for tumor metastases, causing grave error in patient management and the possibility of further lung damage

  14. Characterization and biological effect of Buenos Aires urban air particles on mice lungs

    International Nuclear Information System (INIS)

    Martin, Susana; Dawidowski, Laura; Mandalunis, Patricia; Cereceda-Balic, Francisco; Tasat, Deborah Ruth

    2007-01-01

    Exposure to increased levels of ambient air particulate matter (PM) is associated with increased cardiopulmonary morbidity and mortality. Its association with adverse health effects and the still unclear mechanisms of action are of concern worldwide. Our objective was to analyze air PM from downtown Buenos Aires (UAP-BA), and evaluate its biological impact on normal airways. We studied the inflammatory response to intranasal instillation of UAP-BA in a short-term-exposure mouse model. We analyzed UAP-BA morphology by scanning electron microscopy and characterized particle chemical composition by energy dispersive X-ray analysis and capillary gas chromatography. We evaluated lung changes by histomorphometry and histochemical methods. Regarding size, surface area and distribution, UAP-BA proved to be small spherical ultrafine particles: free, in clusters and associated to a matrix. The particles contained polycyclic aromatic hydrocarbons, polychlorinated biphenyls and almost no metal traces. Histologically, UAP-BA induced the recruitment of phagocytes, a reduction in air spaces, an increase in mucous PAS positive cells and weak incomplete elastic fiber network. Our results demonstrate that UAP-BA causes adverse biological effects on the respiratory tract generating inflammation that, in turn, may cause tissue injury or organ dysfunction and may contribute to the pathogenesis of lung diseases

  15. Anesthetic drugs accelerate the progression of postoperative metastases of mouse tumors.

    OpenAIRE

    Shapiro, J; Jersky, J; Katzav, S; Feldman, M; Segal, S

    1981-01-01

    Experiments were made to investigate the effect of four anesthetic drugs that are commonly used in surgical practice on the postoperative growth of mouse tumors in syngeneic recipients. These experiments revealed that some of the anesthetics when applied for surgical excision of the local tumor, strongly accelerated postoperative progression of spontaneous lung metastases produced by the 3LL Lewis lung carcinoma and by the B16 melanoma. Some of the drugs caused the appearance of metastases in...

  16. Radiosensitivity of mouse germ cells

    International Nuclear Information System (INIS)

    Matsuda, Yoichi; Takeuchi, Toyoko; Maemori, Mamiko; Seki, Naohiko; Tobari, Izuo

    1991-01-01

    To estimate radiosensitivity of mouse germ cells the analysis of chromosome aberrations was performed at diakinesis-metaphase I of spermatocytes and first-cleavage metaphase of one-cell embryos after exposure to radiations at various stages of primary spermatocytes and spermatids. The result provided evidence that there are two major types of DNA damage in X-irradiated sperm : (1) short-lived DNA lesions ; the lesions are subject to repair inhibition by agents added in G 1 , and are converted into chromosome-type aberrations during G 1 , and (2) long-lived DNA lesions ; the lesions persist until S phase and repair of the lesions is inhibited by caffeine, hydroxyurea and arabinofuranosyl cytosine in G 2 . The characteristic of X-ray damage induced in spermiogenic stage and repair mechanism for the damage in the fertilized egg were discussed comparing with the results with two chemicals, methyl methanesulfonate (MMS) and mitomycin C (MMC). (J.P.N.)

  17. Mouse models for understanding human developmental anomalies

    International Nuclear Information System (INIS)

    Generoso, W.M.

    1989-01-01

    The mouse experimental system presents an opportunity for studying the nature of the underlying mutagenic damage and the molecular pathogenesis of this class of anomalies by virtue of the accessibility of the zygote and its descendant blastomeres. Such studies could contribute to the understanding of the etiology of certain sporadic but common human malformations. The vulnerability of the zygotes to mutagens as demonstrated in the studies described in this report should be a major consideration in chemical safety evaluation. It raises questions regarding the danger to human zygotes when the mother is exposed to drugs and environmental chemicals

  18. Lung scintigraphy; Centellograma pulmonar

    Energy Technology Data Exchange (ETDEWEB)

    Dalenz, Roberto

    1994-12-31

    A review of lung scintigraphy, perfusion scintigraphy with SPECT, lung ventilation SPECT, blood pool SPECT. The procedure of lung perfusion studies, radiopharmaceutical, administration and clinical applications, imaging processing .Results encountered and evaluation criteria after Biello and Pioped. Recommendations and general considerations have been studied about relation of this radiopharmaceutical with other pathologies.

  19. American Lung Association

    Science.gov (United States)

    ... see if you should get screened. Learn more EDUCATION ADVOCACY RESEARCH Our vision is a world free of lung disease The American Lung Association is ... by lung disease. Help us continue to deliver education, advocacy and research to those who need it. $250 $100 $50 Your best gift Donate now Learn More ... nonprofit software

  20. SARS – Lung Pathology

    Indian Academy of Sciences (India)

    Dry nonproductive cough – may show minimal lung infiltration. Recovery; * Lungs get fluid in bronchi- droplets infective and +ve for virus in culture and PCR. May also have co-infection with chlamydia/metapneumoviruses. Recovery; * Lung tissue destroyed due to ? immunological/cytokine mediated damage-Recovery ...

  1. Muc1 deficiency exacerbates pulmonary fibrosis in a mouse model of silicosis.

    Science.gov (United States)

    Kato, Kosuke; Zemskova, Marina A; Hanss, Alec D; Kim, Marianne M; Summer, Ross; Kim, Kwang Chul

    2017-11-25

    MUC1 (MUC in human and Muc in animals) is a membrane-tethered mucin expressed on the apical surface of lung epithelial cells. However, in the lungs of patients with interstitial lung disease, MUC1 is aberrantly expressed in hyperplastic alveolar type II epithelial (ATII) cells and alveolar macrophages (AM), and elevated levels of extracellular MUC1 are found in bronchoalveolar lavage (BAL) fluid and the serum of these patients. While pro-fibrotic effects of extracellular MUC1 have recently been described in cultured fibroblasts, the contribution of MUC1 to the pathobiology of pulmonary fibrosis is unknown. In this study, we hypothesized that MUC1 deficiency would reduce susceptibility to pulmonary fibrosis in a mouse model of silicosis. We employed human MUC1 transgenic mice, Muc1 deficient mice and wild-type mice on C57BL/6 background in these studies. Some mice received a one-time dose of crystalline silica instilled into their oropharynx in order to induce pulmonary fibrosis and assess the effects of Muc1 deficiency on fibrotic and inflammatory responses in the lung. As previously described in other mouse models of pulmonary fibrosis, we found that extracellular MUC1 levels were markedly increased in whole lung tissues, BALF and serum of human MUC1 transgenic mice after silica. We also detected an increase in total MUC1 levels in the lungs of these mice, indicating that production as well as release contributed to elevated levels after lung injury. Immunohistochemical staining revealed that increased MUC1 expression was mostly confined to ATII cells and AMs in areas of fibrotic remodeling, illustrating a pattern similar to the expression of MUC1 in human fibrotic lung tissues. However, contrary to our hypothesis, we found that Muc1 deficiency resulted in a worsening of fibrotic remodeling in the mouse lung as judged by an increase in number of silicotic nodules, an increase in lung collagen deposition and an increase in the severity of pulmonary inflammation

  2. Quantification of Lung Metastases from In Vivo Mouse Models

    DEFF Research Database (Denmark)

    Chang, Joan; Erler, Janine T

    2016-01-01

    Cancer research has made significant progress in terms of understanding and targeting primary tumors; however, the challenge remains for the successful treatment of metastatic cancers. This highlights the importance to use in vivo models to study the metastatic process, as well as for preclinical...

  3. A Redox Sensitive Pathway in the Mouse ES Cell Assay Modeled From ToxCast HTS Data

    Science.gov (United States)

    The broad chemical landscape coupled with the lack of developmental toxicity information across most environmental chemicals has motivated the need for high- throughput screening methods and predictive models of developmental toxicity. Towards this end, we used the mouse embryoni...

  4. Aerosolized 3-bromopyruvate inhibits lung tumorigenesis without causing liver toxicity.

    Science.gov (United States)

    Zhang, Qi; Pan, Jing; North, Paula E; Yang, Shoua; Lubet, Ronald A; Wang, Yian; You, Ming

    2012-05-01

    3-Bromopyruvate, an alkylating agent and a well-known inhibitor of energy metabolism, has been proposed as a specific anticancer agent. However, the chemopreventive effect of 3-bromopyruvate in lung tumorigenesis has not been tested. In this study, we investigated the chemopreventive activity of 3-bromopyruvate in a mouse lung tumor model. Benzo(a)pyrene was used to induce lung tumors, and 3-bromopyruvate was administered by oral gavage to female A/J mice. We found that 3-bromopyruvate significantly decreased tumor multiplicity and tumor load by 58% and 83%, respectively, at a dose of 20 mg/kg body weight by gavage. Due to the known liver toxicity of 3-bromopyruvate in animal models given large doses of 3-bromopyruvate, confirmed in this study, we decided to test the chemopreventive activity of aerosolized 3-bromopyruvate in the same lung tumor model. As expected, aerosolized 3-bromopyruvate similarly significantly decreased tumor multiplicity and tumor load by 49% and 80%, respectively, at a dose of 10 mg/mL by inhalation. Interestingly, the efficacy of aerosolized 3-bromopyruvate did not accompany any liver toxicity indicating that it is a safer route of administering this compound. Treatment with 3-bromopyruvate increased immunohistochemical staining for cleaved caspase-3, suggesting that the lung tumor inhibitory effects of 3-bromopyruvate were through induction of apoptosis. 3-Bromopyruvate also dissociated hexokinase II from mitochondria, reduced hexokinase activity, and blocked energy metabolism in cancer cells, finally triggered cancer cell death and induced apoptosis through caspase-3, and PARP in human lung cancer cell line. The ability of 3-bromopyruvate to inhibit mouse lung tumorigenesis, in part through induction of apoptosis, merits further investigation of this compound as a chemopreventive agent for human lung cancer.

  5. 67Ga lung scan

    International Nuclear Information System (INIS)

    Niden, A.H.; Mishkin, F.S.; Khurana, M.M.L.; Pick, R.

    1977-01-01

    Twenty-three patients with clinical signs of pulmonary embolic disease and lung infiltrates were studied to determine the value of gallium citrate 67 Ga lung scan in differentiating embolic from inflammatory lung disease. In 11 patients without angiographically proved embolism, only seven had corresponding ventilation-perfusion defects compatible with inflammatory disease. In seven of these 11 patients, the 67 Ga concentration indicated inflammatory disease. In the 12 patients with angiographically proved embolic disease, six had corresponding ventilation-perfusion defects compatible with inflammatory disease. None had an accumulation of 67 Ga in the area of pulmonary infiltrate. Thus, ventilation-perfusion lung scans are of limited value when lung infiltrates are present. In contrast, the accumulation of 67 Ga in the lung indicates an inflammatory process. Gallium imaging can help select those patients with lung infiltrates who need angiography

  6. Imaging of Occupational Lung Disease.

    Science.gov (United States)

    Champlin, Jay; Edwards, Rachael; Pipavath, Sudhakar

    2016-11-01

    Occupational lung diseases span a variety of pulmonary disorders caused by inhalation of dusts or chemical antigens in a vocational setting. Included in these are the classic mineral pneumoconioses of silicosis, coal worker's pneumoconiosis, and asbestos-related diseases as well as many immune-mediated and airway-centric diseases, and new and emerging disorders. Although some of these have characteristic imaging appearances, a multidisciplinary approach with focus on occupational exposure history is essential to proper diagnosis. Copyright © 2016 Elsevier Inc. All rights reserved.

  7. Circadian Rhythm Disruption Promotes Lung Tumorigenesis.

    Science.gov (United States)

    Papagiannakopoulos, Thales; Bauer, Matthew R; Davidson, Shawn M; Heimann, Megan; Subbaraj, Lakshmipriya; Bhutkar, Arjun; Bartlebaugh, Jordan; Vander Heiden, Matthew G; Jacks, Tyler

    2016-08-09

    Circadian rhythms are 24-hr oscillations that control a variety of biological processes in living systems, including two hallmarks of cancer, cell division and metabolism. Circadian rhythm disruption by shift work is associated with greater risk for cancer development and poor prognosis, suggesting a putative tumor-suppressive role for circadian rhythm homeostasis. Using a genetically engineered mouse model of lung adenocarcinoma, we have characterized the effects of circadian rhythm disruption on lung tumorigenesis. We demonstrate that both physiologic perturbation (jet lag) and genetic mutation of the central circadian clock components decreased survival and promoted lung tumor growth and progression. The core circadian genes Per2 and Bmal1 were shown to have cell-autonomous tumor-suppressive roles in transformation and lung tumor progression. Loss of the central clock components led to increased c-Myc expression, enhanced proliferation, and metabolic dysregulation. Our findings demonstrate that both systemic and somatic disruption of circadian rhythms contribute to cancer progression. Copyright © 2016 Elsevier Inc. All rights reserved.

  8. Protective mechanical ventilation does not exacerbate lung function impairment or lung inflammation following influenza A infection.

    Science.gov (United States)

    Zosky, Graeme R; Cannizzaro, Vincenzo; Hantos, Zoltan; Sly, Peter D

    2009-11-01

    The degree to which mechanical ventilation induces ventilator-associated lung injury is dependent on the initial acute lung injury (ALI). Viral-induced ALI is poorly studied, and this study aimed to determine whether ALI induced by a clinically relevant infection is exacerbated by protective mechanical ventilation. Adult female BALB/c mice were inoculated with 10(4.5) plaque-forming units of influenza A/Mem/1/71 in 50 microl of medium or medium alone. This study used a protective ventilation strategy, whereby mice were anesthetized, tracheostomized, and mechanically ventilated for 2 h. Lung mechanics were measured periodically throughout the ventilation period using a modification of the forced oscillation technique to obtain measures of airway resistance and coefficients of tissue damping and tissue elastance. Thoracic gas volume was measured and used to obtain specific airway resistance, tissue damping, and tissue elastance. At the end of the ventilation period, a bronchoalveolar lavage sample was collected to measure inflammatory cells, macrophage inflammatory protein-2, IL-6, TNF-alpha, and protein leak. Influenza infection caused significant increases in inflammatory cells, protein leak, and deterioration in lung mechanics that were not exacerbated by mechanical ventilation, in contrast to previous studies using bacterial and mouse-specific viral infection. This study highlighted the importance of type and severity of lung injury in determining outcome following mechanical ventilation.

  9. Punica granatum L. Leaf Extract Attenuates Lung Inflammation in Mice with Acute Lung Injury

    Science.gov (United States)

    Pinheiro, Aruanã Joaquim Matheus Costa Rodrigues; Gonçalves, Jaciara Sá; Dourado, Ádylla Wilenna Alves; de Sousa, Eduardo Martins; Brito, Natilene Mesquita; Silva, Lanna Karinny; Batista, Marisa Cristina Aranha; de Sá, Joicy Cortez; Monteiro, Cinara Regina Aragão Vieira; Fernandes, Elizabeth Soares; Campbell, Lee Ann; Zago, Patrícia Maria Wiziack

    2018-01-01

    The hydroalcoholic extract of Punica granatum (pomegranate) leaves was previously demonstrated to be anti-inflammatory in a rat model of lipopolysaccharide- (LPS-) induced acute peritonitis. Here, we investigated the anti-inflammatory effects of the ethyl acetate fraction obtained from the pomegranate leaf hydroalcoholic extract (EAFPg) on the LPS-induced acute lung injury (ALI) mouse model. Male Swiss mice received either EAFPg at different doses or dexamethasone (per os) prior to LPS intranasal instillation. Vehicle-treated mice were used as controls. Animals were culled at 4 h after LPS challenge, and the bronchoalveolar lavage fluid (BALF) and lung samples were collected for analysis. EAFPg and kaempferol effects on NO and cytokine production by LPS-stimulated RAW 264.7 macrophages were also investigated. Pretreatment with EAFPg (100–300 mg/kg) markedly reduced cell accumulation (specially neutrophils) and collagen deposition in the lungs of ALI mice. The same animals presented with reduced lung and BALF TNF-α and IL-1β expression in comparison with vehicle controls (p < 0.05). Additionally, incubation with either EAFPg or kaempferol (100 μg/ml) reduced NO production and cytokine gene expression in cultured LPS-treated RAW 264.7 macrophages. Overall, these results demonstrate that the prophylactic treatment with EAFPg attenuates acute lung inflammation. We suggest this fraction may be useful in treating ALI. PMID:29675437

  10. Punica granatum L. Leaf Extract Attenuates Lung Inflammation in Mice with Acute Lung Injury.

    Science.gov (United States)

    Pinheiro, Aruanã Joaquim Matheus Costa Rodrigues; Gonçalves, Jaciara Sá; Dourado, Ádylla Wilenna Alves; de Sousa, Eduardo Martins; Brito, Natilene Mesquita; Silva, Lanna Karinny; Batista, Marisa Cristina Aranha; de Sá, Joicy Cortez; Monteiro, Cinara Regina Aragão Vieira; Fernandes, Elizabeth Soares; Monteiro-Neto, Valério; Campbell, Lee Ann; Zago, Patrícia Maria Wiziack; Lima-Neto, Lidio Gonçalves

    2018-01-01

    The hydroalcoholic extract of Punica granatum (pomegranate) leaves was previously demonstrated to be anti-inflammatory in a rat model of lipopolysaccharide- (LPS-) induced acute peritonitis. Here, we investigated the anti-inflammatory effects of the ethyl acetate fraction obtained from the pomegranate leaf hydroalcoholic extract (EAFPg) on the LPS-induced acute lung injury (ALI) mouse model. Male Swiss mice received either EAFPg at different doses or dexamethasone (per os) prior to LPS intranasal instillation. Vehicle-treated mice were used as controls. Animals were culled at 4 h after LPS challenge, and the bronchoalveolar lavage fluid (BALF) and lung samples were collected for analysis. EAFPg and kaempferol effects on NO and cytokine production by LPS-stimulated RAW 264.7 macrophages were also investigated. Pretreatment with EAFPg (100-300 mg/kg) markedly reduced cell accumulation (specially neutrophils) and collagen deposition in the lungs of ALI mice. The same animals presented with reduced lung and BALF TNF- α and IL-1 β expression in comparison with vehicle controls ( p < 0.05). Additionally, incubation with either EAFPg or kaempferol (100  μ g/ml) reduced NO production and cytokine gene expression in cultured LPS-treated RAW 264.7 macrophages. Overall, these results demonstrate that the prophylactic treatment with EAFPg attenuates acute lung inflammation. We suggest this fraction may be useful in treating ALI.

  11. Obesity-Induced Endoplasmic Reticulum Stress Causes Lung Endothelial Dysfunction and Promotes Acute Lung Injury.

    Science.gov (United States)

    Shah, Dilip; Romero, Freddy; Guo, Zhi; Sun, Jianxin; Li, Jonathan; Kallen, Caleb B; Naik, Ulhas P; Summer, Ross

    2017-08-01

    Obesity is a significant risk factor for acute respiratory distress syndrome. The mechanisms underlying this association are unknown. We recently showed that diet-induced obese mice exhibit pulmonary vascular endothelial dysfunction, which is associated with enhanced susceptibility to LPS-induced acute lung injury. Here, we demonstrate that lung endothelial dysfunction in diet-induced obese mice coincides with increased endoplasmic reticulum (ER) stress. Specifically, we observed enhanced expression of the major sensors of misfolded proteins, including protein kinase R-like ER kinase, inositol-requiring enzyme α, and activating transcription factor 6, in whole lung and in primary lung endothelial cells isolated from diet-induced obese mice. Furthermore, we found that primary lung endothelial cells exposed to serum from obese mice, or to saturated fatty acids that mimic obese serum, resulted in enhanced expression of markers of ER stress and the induction of other biological responses that typify the lung endothelium of diet-induced obese mice, including an increase in expression of endothelial adhesion molecules and a decrease in expression of endothelial cell-cell junctional proteins. Similar changes were observed in lung endothelial cells and in whole-lung tissue after exposure to tunicamycin, a compound that causes ER stress by blocking N-linked glycosylation, indicating that ER stress causes endothelial dysfunction in the lung. Treatment with 4-phenylbutyric acid, a chemical protein chaperone that reduces ER stress, restored vascular endothelial cell expression of adhesion molecules and protected against LPS-induced acute lung injury in diet-induced obese mice. Our work indicates that fatty acids in obese serum induce ER stress in the pulmonary endothelium, leading to pulmonary endothelial cell dysfunction. Our work suggests that reducing protein load in the ER of pulmonary endothelial cells might protect against acute respiratory distress syndrome in obese

  12. Immunostimulatory mouse granuloma protein.

    Science.gov (United States)

    Fontan, E; Fauve, R M; Hevin, B; Jusforgues, H

    1983-10-01

    Earlier studies have shown that from subcutaneous talc-induced granuloma in mice, a fraction could be extracted that fully protected mice against Listeria monocytogenes. Using standard biochemical procedures--i.e., ammonium sulfate fractionation, preparative electrophoresis, gel filtration chromatography, isoelectric focusing, and preparative polyacrylamide gel electrophoresis--we have now purified an active factor to homogeneity. A single band was obtained in NaDodSO4/polyacrylamide gel with an apparent Mr of 55,000. It migrated with alpha 1-globulins and the isoelectric point was 5 +/- 0.1. The biological activity was destroyed with Pronase but not with trypsin and a monospecific polyclonal rabbit antiserum was obtained. The intravenous injection of 5 micrograms of this "mouse granuloma protein" fully protects mice against a lethal inoculum of L. monocytogenes. Moreover, after their incubation with 10 nM mouse granuloma protein, mouse peritoneal cells became cytostatic against Lewis carcinoma cells.

  13. Burn mouse models

    DEFF Research Database (Denmark)

    Calum, Henrik; Høiby, Niels; Moser, Claus

    2014-01-01

    Severe thermal injury induces immunosuppression, involving all parts of the immune system, especially when large fractions of the total body surface area are affected. An animal model was established to characterize the burn-induced immunosuppression. In our novel mouse model a 6 % third-degree b......Severe thermal injury induces immunosuppression, involving all parts of the immune system, especially when large fractions of the total body surface area are affected. An animal model was established to characterize the burn-induced immunosuppression. In our novel mouse model a 6 % third...... with infected burn wound compared with the burn wound only group. The burn mouse model resembles the clinical situation and provides an opportunity to examine or develop new strategies like new antibiotics and immune therapy, in handling burn wound victims much....

  14. Chemical Peels

    Science.gov (United States)

    ... care Kids’ zone Video library Find a dermatologist Chemical peels Overview Chemical peels: Overview Also called chemexfoliation , derma peeling Do ... Overview Chemical peels: FAQs Chemical peels: Preparation FAQs Chemical peels: FAQs To help you decide whether this ...

  15. Absence of respiratory inflammatory reaction of elemental sulfur using the California Pesticide Illness Database and a mouse model.

    Science.gov (United States)

    Lee, Kiyoung; Smith, Jodi L; Last, Jerold A

    2005-01-01

    Elemental sulfur, a natural substance, is used as a fungicide. Elemental sulfur is the most heavily used agricultural chemical in California. In 2003, annual sulfur usage in California was about 34% of the total weight of pesticide active ingredient used in production agriculture. Even though sulfur is mostly used in dust form, the respiratory health effects of elemental sulfur are not well documented. The purpose of this paper is to address the possible respiratory effect of elemental sulfur using the California Pesticide Illness Database and laboratory experiments with mice. We analyzed the California Pesticide Illness Database between 1991 and 2001. Among 127 reports of definite, probable, and possible illness involving sulfur, 21 cases (16%) were identified as respiratory related. A mouse model was used to examine whether there was an inflammatory or fibrotic response to elemental sulfur. Dust solutions were injected intratracheally into ovalbumin sensitized mice and lung damage was evaluated. Lung inflammatory response was analyzed via total lavage cell counts and differentials, and airway collagen content was analyzed histologically and biochemically. No significant differences from controls were seen in animals exposed to sulfur particles. The findings suggest that acute exposure of elemental sulfur itself may not cause an inflammatory reaction. However, further studies are needed to understand the possible health effects of chronic sulfur exposure and environmental weathering of sulfur dust.

  16. Imaging Primary Lung Cancers in Mice to Study Radiation Biology

    International Nuclear Information System (INIS)

    Kirsch, David G.; Grimm, Jan; Guimaraes, Alexander R.; Wojtkiewicz, Gregory R.; Perez, Bradford A.; Santiago, Philip M.; Anthony, Nikolas K.; Forbes, Thomas; Doppke, Karen

    2010-01-01

    Purpose: To image a genetically engineered mouse model of non-small-cell lung cancer with micro-computed tomography (micro-CT) to measure tumor response to radiation therapy. Methods and Materials: The Cre-loxP system was used to generate primary lung cancers in mice with mutation in K-ras alone or in combination with p53 mutation. Mice were serially imaged by micro-CT, and tumor volumes were determined. A comparison of tumor volume by micro-CT and tumor histology was performed. Tumor response to radiation therapy (15.5 Gy) was assessed with micro-CT. Results: The tumor volume measured with free-breathing micro-CT scans was greater than the volume calculated by histology. Nevertheless, this imaging approach demonstrated that lung cancers with mutant p53 grew more rapidly than lung tumors with wild-type p53 and also showed that radiation therapy increased the doubling time of p53 mutant lung cancers fivefold. Conclusions: Micro-CT is an effective tool to noninvasively measure the growth of primary lung cancers in genetically engineered mice and assess tumor response to radiation therapy. This imaging approach will be useful to study the radiation biology of lung cancer.

  17. Uncertainties on lung doses from inhaled plutonium.

    Science.gov (United States)

    Puncher, Matthew; Birchall, Alan; Bull, Richard K

    2011-10-01

    In a recent epidemiological study, Bayesian uncertainties on lung doses have been calculated to determine lung cancer risk from occupational exposures to plutonium. These calculations used a revised version of the Human Respiratory Tract Model (HRTM) published by the ICRP. In addition to the Bayesian analyses, which give probability distributions of doses, point estimates of doses (single estimates without uncertainty) were also provided for that study using the existing HRTM as it is described in ICRP Publication 66; these are to be used in a preliminary analysis of risk. To infer the differences between the point estimates and Bayesian uncertainty analyses, this paper applies the methodology to former workers of the United Kingdom Atomic Energy Authority (UKAEA), who constituted a subset of the study cohort. The resulting probability distributions of lung doses are compared with the point estimates obtained for each worker. It is shown that mean posterior lung doses are around two- to fourfold higher than point estimates and that uncertainties on doses vary over a wide range, greater than two orders of magnitude for some lung tissues. In addition, we demonstrate that uncertainties on the parameter values, rather than the model structure, are largely responsible for these effects. Of these it appears to be the parameters describing absorption from the lungs to blood that have the greatest impact on estimates of lung doses from urine bioassay. Therefore, accurate determination of the chemical form of inhaled plutonium and the absorption parameter values for these materials is important for obtaining reliable estimates of lung doses and hence risk from occupational exposures to plutonium.

  18. Role for Cela1 in Postnatal Lung Remodeling and AAT-deficient Emphysema

    DEFF Research Database (Denmark)

    Joshi, Rashika; Heinz, Andrea; Fan, Qiang

    2018-01-01

    RATIONALE: α1-antitrypsin (AAT) deficiency-related emphysema is the fourth leading indication for lung transplantation. Chymotrypsin-like elastase 1 (Cela1) is a digestive protease that is expressed during lung development in association with regions of elastin remodeling, exhibits stretch...... elastin similarly to pancreatic elastase. Cela1 promoter and protein sequences were phylogenetically distinct in the placental mammal lineage suggesting an adaptive role for lung-expressed Cela1 in this clade. A six-week antisense oligo mouse model of AAT deficiency resulted in emphysema with increased......-dependent expression during lung regeneration, and binds lung elastin in a stretch-dependent manner. AAT covalently neutralizes Cela1 in vitro. OBJECTIVES: We sought to determine the role of Cela1 in postnatal lung physiology, whether it interacted with AAT in vivo, and any effects it may have in the context of AAT...

  19. Polymorphonuclear leukocytes restrict growth of Pseudomonas aeruginosa in the lungs of cystic fibrosis patients

    DEFF Research Database (Denmark)

    Kragh, Kasper Nørskov; Alhede, Morten; Jensen, Peter Østrup

    2014-01-01

    Cystic fibrosis (CF) patients have increased susceptibility to chronic lung infections by Pseudomonas aeruginosa, but the ecophysiology within the CF lung during infections is poorly understood. The aim of this study was to elucidate the in vivo growth physiology of P. aeruginosa within lungs...... of chronically infected CF patients. A novel, quantitative peptide nucleic acid (PNA) fluorescence in situ hybridization (PNA-FISH)-based method was used to estimate the in vivo growth rates of P. aeruginosa directly in lung tissue samples from CF patients and the growth rates of P. aeruginosa in infected lungs...... in a mouse model. The growth rate of P. aeruginosa within CF lungs did not correlate with the dimensions of bacterial aggregates but showed an inverse correlation to the concentration of polymorphonuclear leukocytes (PMNs) surrounding the bacteria. A growth-limiting effect on P. aeruginosa by PMNs was also...

  20. Chemical warfare agents.

    Science.gov (United States)

    Kuca, Kamil; Pohanka, Miroslav

    2010-01-01

    Chemical warfare agents are compounds of different chemical structures. Simple molecules such as chlorine as well as complex structures such as ricin belong to this group. Nerve agents, vesicants, incapacitating agents, blood agents, lung-damaging agents, riot-control agents and several toxins are among chemical warfare agents. Although the use of these compounds is strictly prohibited, the possible misuse by terrorist groups is a reality nowadays. Owing to this fact, knowledge of the basic properties of these substances is of a high importance. This chapter briefly introduces the separate groups of chemical warfare agents together with their members and the potential therapy that should be applied in case someone is intoxicated by these agents.

  1. Lung cancer in elderly

    International Nuclear Information System (INIS)

    Wagnerova, M.

    2007-01-01

    Lung cancer is the leading cause of cancer deaths in Europe and USA. The median age of diagnosis is currently 69 years, however this is gradually increasing with the aging population. Patients over age of 70 represent 40 % of all patients with non-small cell lung cancer. Age alone has not been found to be a significant prognostic factor in many malignancies, including lung cancer with performance status and stage being of greater importance. In lung cancer it is also evident that older patients gain equivalent benefit from cancer therapies as their younger counterparts. Elderly patients are under-treated in all aspects of their disease course from histological diagnosis to active therapy with surgical resection, radiotherapy or chemotherapy, irrespective of performance status or co-morbidities. Elderly patients are also underrepresented in lung cancer clinical trials. In this review is presented knowledge about lung cancer in elderly. (author)

  2. Diet and lung cancer

    DEFF Research Database (Denmark)

    Fabricius, P; Lange, Peter

    2003-01-01

    Lung cancer is the leading cause of cancer-related deaths worldwide. While cigarette smoking is of key importance, factors such as diet also play a role in the development of lung cancer. MedLine and Embase were searched with diet and lung cancer as the key words. Recently published reviews...... and large well designed original articles were preferred to form the basis for the present article. A diet rich in fruit and vegetables reduces the incidence of lung cancer by approximately 25%. The reduction is of the same magnitude in current smokers, ex-smokers and never smokers. Supplementation...... with vitamins A, C and E and beta-carotene offers no protection against the development of lung cancer. On the contrary, beta-carotene supplementation has, in two major randomised intervention trials, resulted in an increased mortality. Smoking remains the leading cause of lung cancer. The adverse effects...

  3. The toxicity of silver and silica nanoparticles in comparable human and mouse cell lines

    DEFF Research Database (Denmark)

    Foldbjerg, Rasmus; Beer, Christiane; Sutherland, Duncan S

    The toxicity of silica (SiO2) and PVP-coated silver (Ag) nanoparticles (NPs) was investigated in two pairs of human or mouse cell lines originating from lung epithelium (A549 and ASB-XIV) and macrophages (THP-1 and J744A.1). Both NPs were characterized in H2O and cell media and demonstrated to be...

  4. Colonization, mouse-style

    Directory of Open Access Journals (Sweden)

    Searle Jeremy B

    2010-10-01

    Full Text Available Abstract Several recent papers, including one in BMC Evolutionary Biology, examine the colonization history of house mice. As well as background for the analysis of mouse adaptation, such studies offer a perspective on the history of movements of the humans that accidentally transported the mice. See research article: http://www.biomedcentral.com/1471-2148/10/325

  5. Multi-scale X-ray computed tomography to detect and localize metal-based nanomaterials in lung tissues of in vivo exposed mice.

    Science.gov (United States)

    Chaurand, Perrine; Liu, Wei; Borschneck, Daniel; Levard, Clément; Auffan, Mélanie; Paul, Emmanuel; Collin, Blanche; Kieffer, Isabelle; Lanone, Sophie; Rose, Jérôme; Perrin, Jeanne

    2018-03-13

    In this methodological study, we demonstrated the relevance of 3D imaging performed at various scales for the ex vivo detection and location of cerium oxide nanomaterials (CeO 2 -NMs) in mouse lung. X-ray micro-computed tomography (micro-CT) with a voxel size from 14 µm to 1 µm (micro-CT) was combined with X-ray nano-computed tomography with a voxel size of 63 nm (nano-CT). An optimized protocol was proposed to facilitate the sample preparation, to minimize the experimental artifacts and to optimize the contrast of soft tissues exposed to metal-based nanomaterials (NMs). 3D imaging of the NMs biodistribution in lung tissues was consolidated by combining a vast variety of techniques in a correlative approach: histological observations, 2D chemical mapping and speciation analysis were performed for an unambiguous detection of NMs. This original methodological approach was developed following a worst-case scenario of exposure, i.e. high dose of exposure with administration via intra-tracheal instillation. Results highlighted both (i) the non-uniform distribution of CeO 2 -NMs within the entire lung lobe (using large field-of-view micro-CT) and (ii) the detection of CeO 2 -NMs down to the individual cell scale, e.g. macrophage scale (using nano-CT with a voxel size of 63 nm).

  6. Epidemiology of Lung Cancer.

    Science.gov (United States)

    Schwartz, Ann G; Cote, Michele L

    2016-01-01

    Lung cancer continues to be one of the most common causes of cancer death despite understanding the major cause of the disease: cigarette smoking. Smoking increases lung cancer risk 5- to 10-fold with a clear dose-response relationship. Exposure to environmental tobacco smoke among nonsmokers increases lung cancer risk about 20%. Risks for marijuana and hookah use, and the new e-cigarettes, are yet to be consistently defined and will be important areas for continued research as use of these products increases. Other known environmental risk factors include exposures to radon, asbestos, diesel, and ionizing radiation. Host factors have also been associated with lung cancer risk, including family history of lung cancer, history of chronic obstructive pulmonary disease and infections. Studies to identify genes associated with lung cancer susceptibility have consistently identified chromosomal regions on 15q25, 6p21 and 5p15 associated with lung cancer risk. Risk prediction models for lung cancer typically include age, sex, cigarette smoking intensity and/or duration, medical history, and occupational exposures, however there is not yet a risk prediction model currently recommended for general use. As lung cancer screening becomes more widespread, a validated model will be needed to better define risk groups to inform screening guidelines.

  7. Nonrespiratory lung function

    International Nuclear Information System (INIS)

    Isawa, Toyoharu

    1994-01-01

    The function of the lungs is primarily the function as a gas exchanger: the venous blood returning to the lungs is arterialized with oxygen in the lungs and the arterialized blood is sent back again to the peripheral tissues of the whole body to be utilized for metabolic oxygenation. Besides the gas exchanging function which we call ''respiratory lung function'' the lungs have functions that have little to do with gas exchange itself. We categorically call the latter function of the lungs as ''nonrespiratory lung function''. The lungs consist of the conductive airways, the gas exchanging units like the alveoli, and the interstitial space that surrounds the former two compartments. The interstitial space contains the blood and lymphatic capillaries, collagen and elastic fibers and cement substances. The conductive airways and the gas exchanging units are directly exposed to the atmosphere that contains various toxic and nontoxic gases, fume and biological or nonbiological particles. Because the conductive airways are equipped with defense mechanisms like mucociliary clearance or coughs to get rid of these toxic gases, particles or locally produced biological debris, we are usually free from being succumbed to ill effects of inhaled materials. By use of nuclear medicine techniques, we can now evaluate mucociliary clearance function, and other nonrespiratory lung functions as well in vivo

  8. Cervical lung hernia

    Science.gov (United States)

    Lightwood, Robin G.; Cleland, W. P.

    1974-01-01

    Lightwood, R. G., and Cleland, W. P. (1974).Thorax, 29, 349-351. Cervical lung hernia. Lung hernias occur in the cervical position in about one third of cases. The remainder appear through the chest wall. Some lung hernias are congenital, but trauma is the most common cause. The indications for surgery depend upon the severity of symptoms. Repair by direct suture can be used for small tears in Sibson's (costovertebral) fascia while larger defects have been closed using prosthetic materials. Four patients with cervical lung hernia are described together with an account of their operations. PMID:4850946

  9. Nonrespiratory lung function

    Energy Technology Data Exchange (ETDEWEB)

    Isawa, Toyoharu [Tohoku University Research Institute for Chest Disease and Cancer, Sendai (Japan)

    1994-07-01

    The function of the lungs is primarily the function as a gas exchanger: the venous blood returning to the lungs is arterialized with oxygen in the lungs and the arterialized blood is sent back again to the peripheral tissues of the whole body to be utilized for metabolic oxygenation. Besides the gas exchanging function which we call ''respiratory lung function'' the lungs have functions that have little to do with gas exchange itself. We categorically call the latter function of the lungs as ''nonrespiratory lung function''. The lungs consist of the conductive airways, the gas exchanging units like the alveoli, and the interstitial space that surrounds the former two compartments. The interstitial space contains the blood and lymphatic capillaries, collagen and elastic fibers and cement substances. The conductive airways and the gas exchanging units are directly exposed to the atmosphere that contains various toxic and nontoxic gases, fume and biological or nonbiological particles. Because the conductive airways are equipped with defense mechanisms like mucociliary clearance or coughs to get rid of these toxic gases, particles or locally produced biological debris, we are usually free from being succumbed to ill effects of inhaled materials. By use of nuclear medicine techniques, we can now evaluate mucociliary clearance function, and other nonrespiratory lung functions as well in vivo.

  10. Parasitic diseases of lungs

    International Nuclear Information System (INIS)

    Rozenshtraukh, L.C.; Rybakova, N.I.; Vinner, M.G.

    1987-01-01

    Roentgenologic semiotics of the main parasitic diseases of lungs is described: echinococcosis, paragonimiasis, cysticercosis, toxoplasmosis, ascariasis, amebiosis and some rarely met parasitic diseases

  11. Radiofrequency Ablation of Lung Tumors

    Science.gov (United States)

    ... News Physician Resources Professions Site Index A-Z Radiofrequency Ablation (RFA) / Microwave Ablation (MWA) of Lung Tumors ... and Microwave Ablation of Lung Tumors? What are Radiofrequency and Microwave Ablation of Lung Tumors? Radiofrequency ablation, ...

  12. 6 Common Cancers - Lung Cancer

    Science.gov (United States)

    ... Bar Home Current Issue Past Issues 6 Common Cancers - Lung Cancer Past Issues / Spring 2007 Table of Contents ... Desperate Housewives. (Photo ©2005 Kathy Hutchins / Hutchins) Lung Cancer Lung cancer causes more deaths than the next three ...

  13. Characterization of 7A7, an anti-mouse EGFR monoclonal antibody proposed to be the mouse equivalent of cetuximab.

    Science.gov (United States)

    He, Xuzhi; Cruz, Jazmina L; Joseph, Shannon; Pett, Nicola; Chew, Hui Yi; Tuong, Zewen K; Okano, Satomi; Kelly, Gabrielle; Veitch, Margaret; Simpson, Fiona; Wells, James W

    2018-02-23

    The Epidermal Growth Factor Receptor (EGFR) is selectively expressed on the surface of numerous tumours, such as non-small cell lung, ovarian, colorectal and head and neck carcinomas. EGFR has therefore become a target for cancer therapy. Cetuximab is a chimeric human/mouse monoclonal antibody (mAb) that binds to EGFR, where it both inhibits signaling and induces cell death by antibody-dependent cell mediated cytotoxicity (ADCC). Cetuximab has been approved for clinical use in patients with head and neck squamous cell carcinoma (HNSCC) and colorectal cancer. However, only 15-20% patients benefit from this drug, thus new strategies to improve cetuximab efficiency are required. We aimed to develop a reliable and easy preclinical mouse model to evaluate the efficacy of EGFR-targeted antibodies and examine the immune mechanisms involved in tumour regression. We selected an anti-mouse EGFR mAb, 7A7, which has been reported to be "mouse cetuximab" and to exhibit similar properties to its human counterpart. Unfortunately, we were unable to reproduce previous results obtained with the 7A7 mAb. In our hands, 7A7 failed to recognize mouse EGFR, both in native and reducing conditions. Moreover, in vivo administration of 7A7 in an EGFR-expressing HPV38 tumour model did not have any impact on tumour regression or animal survival. We conclude that 7A7 does not recognize mouse EGFR and therefore cannot be used as the mouse equivalent of cetuximab use in humans. As a number of groups have spent effort and resources with similar issues we feel that publication is a responsible approach.

  14. Chemical Emergencies

    Science.gov (United States)

    When a hazardous chemical has been released, it may harm people's health. Chemical releases can be unintentional, as in the case of an ... the case of a terrorist attack with a chemical weapon. Some hazardous chemicals have been developed by ...

  15. In vitro differentiation of mouse embryonic stem cells into functional ...

    African Journals Online (AJOL)

    Studies have shown that embryonic stem (ES) cells can be successfully differentiated into liver cells, which offer the potential unlimited cell source for a variety of end-stage liver disease. In our study, in order to induce mouse ES cells to differentiate into hepatocyte-like cells under chemically defined conditions, ES cells ...

  16. The Mouse That Soared

    Science.gov (United States)

    2004-09-01

    Astronomers have used an X-ray image to make the first detailed study of the behavior of high-energy particles around a fast moving pulsar. The image, from NASA's Chandra X-ray Observatory, shows the shock wave created as a pulsar plows supersonically through interstellar space. These results will provide insight into theories for the production of powerful winds of matter and antimatter by pulsars. Chandra's image of the glowing cloud, known as the Mouse, shows a stubby bright column of high-energy particles, about four light years in length, swept back by the pulsar's interaction with interstellar gas. The intense source at the head of the X-ray column is the pulsar, estimated to be moving through space at about 1.3 million miles per hour. VLA Radio Image of the Mouse, Full Field VLA Radio Image of the Mouse, Full Field A cone-shaped cloud of radio-wave-emitting particles envelopes the X-ray column. The Mouse, a.k.a. G359.23-0.82, was discovered in 1987 by radio astronomers using the National Science Foundation's Very Large Array in New Mexico. It gets its name from its appearance in radio images that show a compact snout, a bulbous body, and a remarkable long, narrow, tail that extends for about 55 light years. "A few dozen pulsar wind nebulae are known, including the spectacular Crab Nebula, but none have the Mouse's combination of relatively young age and incredibly rapid motion through interstellar space," said Bryan Gaensler of the Harvard-Smithsonian Center for Astrophysics and lead author of a paper on the Mouse that will appear in an upcoming issue of The Astrophysical Journal. "We effectively are seeing a supersonic cosmic wind tunnel, in which we can study the effects of a pulsar's motion on its pulsar wind nebula, and test current theories." Illustration of the Mouse System Illustration of the Mouse System Pulsars are known to be rapidly spinning, highly magnetized neutron stars -- objects so dense that a mass equal to that of the Sun is packed into a

  17. Grape seed extract ameliorates bleomycin-induced mouse pulmonary fibrosis.

    Science.gov (United States)

    Liu, Qi; Jiang, Jun-Xia; Liu, Ya-Nan; Ge, Ling-Tian; Guan, Yan; Zhao, Wei; Jia, Yong-Liang; Dong, Xin-Wei; Sun, Yun; Xie, Qiang-Min

    2017-05-05

    Pulmonary fibrosis is common in a variety of inflammatory lung diseases, such as interstitial pneumonia, chronic obstructive pulmonary disease, and silicosis. There is currently no effective clinical drug treatment. It has been reported that grape seed extracts (GSE) has extensive pharmacological effects with minimal toxicity. Although it has been found that GSE can improve the lung collagen deposition and fibrosis pathology induced by bleomycin in rat, its effects on pulmonary function, inflammation, growth factors, matrix metalloproteinases and epithelial-mesenchymal transition remain to be researched. In the present study, we studied whether GSE provided protection against bleomycin (BLM)-induced mouse pulmonary fibrosis. ICR strain mice were treated with BLM in order to establish pulmonary fibrosis models. GSE was given daily via intragastric administration for three weeks starting at one day after intratracheal instillation. GSE at 50 or 100mg/kg significantly reduced BLM-induced inflammatory cells infiltration, proinflammatory factor protein expression, and hydroxyproline in lung tissues, and improved pulmonary function in mice. Additionally, treatment with GSE also significantly impaired BLM-induced increases in lung fibrotic marker expression (collagen type I alpha 1 and fibronectin 1) and decreases in an anti-fibrotic marker (E-cadherin). Further investigation indicated that the possible molecular targets of GSE are matrix metalloproteinases-9 (MMP-9) and TGF-β1, given that treatment with GSE significantly prevented BLM-induced increases in MMP-9 and TGF-β1 expression in the lungs. Together, these results suggest that supplementation with GSE may improve the quality of life of lung fibrosis patients by inhibiting MMP-9 and TGF-β1 expression in the lungs. Copyright © 2017 Elsevier B.V. All rights reserved.

  18. History of Lung Transplantation.

    Science.gov (United States)

    Dabak, Gül; Şenbaklavacı, Ömer

    2016-04-01

    History of lung transplantation in the world can be traced back to the early years of the 20 th century when experimental vascular anastomotic techniques were developed by Carrel and Guthrie, followed by transplantation of thoracic organs on animal models by Demikhov and finally it was James Hardy who did the first lung transplantation attempt on human. But it was not until the discovery of cyclosporine and development of better surgical techniques that success could be achieved in that field by the Toronto Lung Transplant Group led by Joel Cooper. Up to the present day, over 51.000 lung transplants were performed in the world at different centers. The start of lung transplantation in Turkey has been delayed for various reasons. From 1998 on, there were several attempts but the first successful lung transplant was performed at Sureyyapasa Hospital in 2009. Today there are four lung transplant centers in Turkey; two in Istanbul, one in Ankara and another one in Izmir. Three lung transplant centers from Istanbul which belong to private sector have newly applied for licence from the Ministry of Health.

  19. Lung Cancer Indicators Recurrence

    Science.gov (United States)

    This study describes prognostic factors for lung cancer spread and recurrence, as well as subsequent risk of death from the disease. The investigators observed that regardless of cancer stage, grade, or type of lung cancer, patients in the study were more

  20. Lung Cancer Screening

    Science.gov (United States)

    ... detected on a lung CT scan. If your doctor finds another health problem, you may undergo further testing and, possibly, invasive treatments that wouldn't have been pursued if you hadn't had lung cancer ... need to: Inform your doctor if you have a respiratory tract infection. If ...

  1. Lung cancer in women

    Directory of Open Access Journals (Sweden)

    Barrera-Rodriguez R

    2012-12-01

    Full Text Available Raúl Barrera-Rodriguez,1 Jorge Morales-Fuentes2 1Biochemistry and Environmental Medicine Laboratory, National Institute of Respiratory Disease, 2Lung Cancer Medical Service, National Institute of Respiratory Disease, Tlalpan, Mexico City, Distrito Federal, Mexico Both authors contributed equally to this workAbstract: Recent biological advances in tumor research provide clear evidence that lung cancer in females is different from that in males. These differences appear to have a direct impact on the clinical presentation, histology, and outcomes of lung cancer. Women are more likely to present with lung adenocarcinoma, tend to receive a diagnosis at an earlier age, and are more likely to be diagnosed with localized disease. Women may also be more predisposed to molecular aberrations resulting from the carcinogenic effects of tobacco, but do not appear to be more susceptible than men to developing lung cancer. The gender differences found in female lung cancer make it mandatory that gender stratification is used in clinical trials in order to improve the survival rates of patients with lung cancer.Keywords: lung cancer, adenocarcinoma, women, genetic susceptibility, genetic differences, tobacco

  2. Screening for lung cancer

    DEFF Research Database (Denmark)

    Infante, Maurizio V; Pedersen, Jesper H

    2010-01-01

    In lung cancer screening with low-dose spiral computed tomography (LDCT), the proportion of stage I disease is 50-85%, and the survival rate for resected stage I disease can exceed 90%, but proof of real benefit in terms of lung cancer mortality reduction must come from the several randomized...

  3. MRI of the lung

    Energy Technology Data Exchange (ETDEWEB)

    Kauczor, Hans-Ulrich (ed.) [University Clinic Heidelberg (Germany). Diagnostic and Interventional Radiology

    2009-07-01

    For a long time, only chest X-ray and CT were used to image lung structure, while nuclear medicine was employed to assess lung function. During the past decade significant developments have been achieved in the field of magnetic resonance imaging (MRI), enabling MRI to enter the clinical arena of chest imaging. Standard protocols can now be implemented on up-to-date scanners, allowing MRI to be used as a first-line imaging modality for various lung diseases, including cystic fibrosis, pulmonary hypertension and even lung cancer. The diagnostic benefits stem from the ability of MRI to visualize changes in lung structure while simultaneously imaging different aspects of lung function, such as perfusion, respiratory motion, ventilation and gas exchange. On this basis, novel quantitative surrogates for lung function can be obtained. This book provides a comprehensive overview of how to use MRI for imaging of lung disease. Special emphasis is placed on benign diseases requiring regular monitoring, given that it is patients with these diseases who derive the greatest benefit from the avoidance of ionizing radiation. (orig.)

  4. Expression analysis of asthma candidate genes during human and murine lung development.

    Science.gov (United States)

    Melén, Erik; Kho, Alvin T; Sharma, Sunita; Gaedigk, Roger; Leeder, J Steven; Mariani, Thomas J; Carey, Vincent J; Weiss, Scott T; Tantisira, Kelan G

    2011-06-23

    Little is known about the role of most asthma susceptibility genes during human lung development. Genetic determinants for normal lung development are not only important early in life, but also for later lung function. To investigate the role of expression patterns of well-defined asthma susceptibility genes during human and murine lung development. We hypothesized that genes influencing normal airways development would be over-represented by genes associated with asthma. Asthma genes were first identified via comprehensive search of the current literature. Next, we analyzed their expression patterns in the developing human lung during the pseudoglandular (gestational age, 7-16 weeks) and canalicular (17-26 weeks) stages of development, and in the complete developing lung time series of 3 mouse strains: A/J, SW, C57BL6. In total, 96 genes with association to asthma in at least two human populations were identified in the literature. Overall, there was no significant over-representation of the asthma genes among genes differentially expressed during lung development, although trends were seen in the human (Odds ratio, OR 1.22, confidence interval, CI 0.90-1.62) and C57BL6 mouse (OR 1.41, CI 0.92-2.11) data. However, differential expression of some asthma genes was consistent in both developing human and murine lung, e.g. NOD1, EDN1, CCL5, RORA and HLA-G. Among the asthma genes identified in genome wide association studies, ROBO1, RORA, HLA-DQB1, IL2RB and PDE10A were differentially expressed during human lung development. Our data provide insight about the role of asthma susceptibility genes during lung development and suggest common mechanisms underlying lung morphogenesis and pathogenesis of respiratory diseases.

  5. Estimation of Lung Ventilation

    Science.gov (United States)

    Ding, Kai; Cao, Kunlin; Du, Kaifang; Amelon, Ryan; Christensen, Gary E.; Raghavan, Madhavan; Reinhardt, Joseph M.

    Since the primary function of the lung is gas exchange, ventilation can be interpreted as an index of lung function in addition to perfusion. Injury and disease processes can alter lung function on a global and/or a local level. MDCT can be used to acquire multiple static breath-hold CT images of the lung taken at different lung volumes, or with proper respiratory control, 4DCT images of the lung reconstructed at different respiratory phases. Image registration can be applied to this data to estimate a deformation field that transforms the lung from one volume configuration to the other. This deformation field can be analyzed to estimate local lung tissue expansion, calculate voxel-by-voxel intensity change, and make biomechanical measurements. The physiologic significance of the registration-based measures of respiratory function can be established by comparing to more conventional measurements, such as nuclear medicine or contrast wash-in/wash-out studies with CT or MR. An important emerging application of these methods is the detection of pulmonary function change in subjects undergoing radiation therapy (RT) for lung cancer. During RT, treatment is commonly limited to sub-therapeutic doses due to unintended toxicity to normal lung tissue. Measurement of pulmonary function may be useful as a planning tool during RT planning, may be useful for tracking the progression of toxicity to nearby normal tissue during RT, and can be used to evaluate the effectiveness of a treatment post-therapy. This chapter reviews the basic measures to estimate regional ventilation from image registration of CT images, the comparison of them to the existing golden standard and the application in radiation therapy.

  6. Evidence for tankyrases as antineoplastic targets in lung cancer

    International Nuclear Information System (INIS)

    Busch, Alexander M; Johnson, Kevin C; Stan, Radu V; Sanglikar, Aarti; Ahmed, Yashi; Dmitrovsky, Ethan; Freemantle, Sarah J

    2013-01-01

    human and murine lung cancer models. Repressing TNKS activity through either genetic or pharmacological approaches antagonized canonical Wnt signaling, reduced murine and human lung cancer cell line growth, and decreased tumor formation in mouse models. Taken together, these findings implicate the use of TNKS inhibitors to target the Wnt pathway to combat lung cancer

  7. Up-regulation of ALG-2 in hepatomas and lung cancer tissue

    DEFF Research Database (Denmark)

    la Cour, Jonas Marstrand; Mollerup, Jens; Winding, Pernille

    2003-01-01

    , a result confirmed by immunohistochemical analysis. Staining of four different lung cancer tissue microarrays including specimens of 263 patients showed that ALG-2 is mainly localized to epithelial cells and significantly up-regulated in small-cell lung cancers and in non-small-cell lung cancers. Our...... using Western blot analysis and immunohistochemistry. Western blot analysis of 15 different adult mouse tissues demonstrated that ALG-2 is ubiquitously expressed. We found that ALG-2 was more than threefold overexpressed in rat liver hepatoma compared to normal rat liver using Western blot analysis...

  8. Gravity in mammalian organ development: differentiation of cultured lung and pancreas rudiments during spaceflight

    Science.gov (United States)

    Spooner, B. S.; Hardman, P.; Paulsen, A.

    1994-01-01

    Organ culture of embryonic mouse lung and pancreas rudiments has been used to investigate development and differentiation, and to assess the effects of microgravity on culture differentiation, during orbital spaceflight of the shuttle Endeavour (mission STS-54). Lung rudiments continue to grow and branch during spaceflight, an initial result that should allow future detailed study of lung morphogenesis in microgravity. Cultured embryonic pancreas undergoes characteristic exocrine acinar tissue and endocrine islet tissue differentiation during spaceflight, and in ground controls. The rudiments developing in the microgravity environment of spaceflight appear to grow larger than their ground counterparts, and they may have differentiated more rapidly than controls, as judged by exocrine zymogen granule presence.

  9. The injured lung: clinical issues and experimental models

    OpenAIRE

    Jugg, B. J. A.; Smith, A. J.; Rudall, S. J.; Rice, P.

    2011-01-01

    Exposure of military and civilian populations to inhaled toxic chemicals can take place as a result of deliberate release (warfare, terrorism) or following accidental releases from industrial concerns or transported chemicals. Exposure to inhaled toxic chemicals can result in an acute lung injury, and in severe cases acute respiratory distress syndrome, for which there is currently no specific medical therapy, treatment remaining largely supportive. This treatment often requires intensive car...

  10. Wine, Spirits and the Lung: Good, Bad or Indifferent?

    OpenAIRE

    Kamholz, Stephan L

    2006-01-01

    The putative cardiovascular risks and benefits of the ingestion of wine and alcohol-containing spirits have been well publicized; however, less attention has been focused upon the health effects of wine and spirits consumption on the respiratory system. This paper will highlight epidemiologic, clinical and experimental data on the effects of wine and distilled spirits [and the chemical components thereof] on lung function, chronic obstructive pulmonary disease progression, lung cancer risk, r...

  11. Development and proof-of-concept of three-dimensional lung histology volumes

    Science.gov (United States)

    Mathew, Lindsay; Alabousi, Mostafa; Wheatley, Andrew; Aladl, Usaf; Slipetz, Deborah; Hogg, James C.; Fenster, Aaron; Parraga, Grace

    2012-03-01

    Most medical imaging is inherently three-dimensional (3D) but for validation of pathological findings, histopathology is commonly used and typically histopathology images are acquired as twodimensional slices with quantitative analysis performed in a single dimension. Histopathology is invasive, labour-intensive, and the analysis cannot be performed in real time, yet it remains the gold standard for the pathological diagnosis and validation of clinical or radiological diagnoses of disease. A major goal worldwide is to improve medical imaging resolution, sensitivity and specificity to better guide therapy and biopsy and to one day delay or replace biopsy. A key limitation however is the lack of tools to directly compare 3D macroscopic imaging acquired in patients with histopathology findings, typically provided in a single dimension (1D) or in two dimensions (2D). To directly address this, we developed methods for 2D histology slice visualization/registration to generate 3D volumes and quantified tissue components in the 3D volume for direct comparison to volumetric micro-CT and clinical CT. We used the elastase-instilled mouse emphysema lung model to evaluate our methods with murine lungs sectioned (5 μm thickness/10 μm gap) and digitized with 2μm in-plane resolution. 3D volumes were generated for wildtype and elastase mouse lung sections after semi-automated registration of all tissue slices. The 1D mean linear intercept (Lm) for wildtype (WT) (47.1 μm +/- 9.8 μm) and elastase mouse lung (64.5 μm +/- 14.0 μm) was significantly different (p<.001). We also generated 3D measurements based on tissue and airspace morphometry from the 3D volumes and all of these were significantly different (p<.0001) when comparing elastase and WT mouse lung. The ratio of the airspace-to-lung volume for the entire lung volume was also significantly and strongly correlated with Lm.

  12. Hedgehog Pathway Inhibition Radiosensitizes Non-Small Cell Lung Cancers

    Energy Technology Data Exchange (ETDEWEB)

    Zeng, Jing; Aziz, Khaled; Chettiar, Sivarajan T. [Department of Radiation Oncology and Molecular Radiation Sciences, The Johns Hopkins University School of Medicine, Baltimore, Maryland (United States); Aftab, Blake T. [Department of Medical Oncology, The Johns Hopkins University School of Medicine, Baltimore, Maryland (United States); Armour, Michael; Gajula, Rajendra; Gandhi, Nishant; Salih, Tarek; Herman, Joseph M.; Wong, John [Department of Radiation Oncology and Molecular Radiation Sciences, The Johns Hopkins University School of Medicine, Baltimore, Maryland (United States); Rudin, Charles M. [Department of Medical Oncology, The Johns Hopkins University School of Medicine, Baltimore, Maryland (United States); Tran, Phuoc T. [Department of Radiation Oncology and Molecular Radiation Sciences, The Johns Hopkins University School of Medicine, Baltimore, Maryland (United States); Department of Medical Oncology, The Johns Hopkins University School of Medicine, Baltimore, Maryland (United States); Hales, Russell K., E-mail: rhales1@jhmi.edu [Department of Radiation Oncology and Molecular Radiation Sciences, The Johns Hopkins University School of Medicine, Baltimore, Maryland (United States)

    2013-05-01

    Purpose: Despite improvements in chemoradiation, local control remains a major clinical problem in locally advanced non-small cell lung cancer. The Hedgehog pathway has been implicated in tumor recurrence by promoting survival of tumorigenic precursors and through effects on tumor-associated stroma. Whether Hedgehog inhibition can affect radiation efficacy in vivo has not been reported. Methods and Materials: We evaluated the effects of a targeted Hedgehog inhibitor (HhAntag) and radiation on clonogenic survival of human non-small cell lung cancer lines in vitro. Using an A549 cell line xenograft model, we examined tumor growth, proliferation, apoptosis, and gene expression changes after concomitant HhAntag and radiation. In a transgenic mouse model of Kras{sup G12D}-induced and Twist1-induced lung adenocarcinoma, we assessed tumor response to radiation and HhAntag by serial micro-computed tomography (CT) scanning. Results: In 4 human lung cancer lines in vitro, HhAntag showed little or no effect on radiosensitivity. By contrast, in both the human tumor xenograft and murine inducible transgenic models, HhAntag enhanced radiation efficacy and delayed tumor growth. By use of the human xenograft model to differentiate tumor and stromal effects, mouse stromal cells, but not human tumor cells, showed significant and consistent downregulation of Hedgehog pathway gene expression. This was associated with increased tumor cell apoptosis. Conclusions: Targeted Hedgehog pathway inhibition can increase in vivo radiation efficacy in lung cancer preclinical models. This effect is associated with pathway suppression in tumor-associated stroma. These data support clinical testing of Hedgehog inhibitors as a component of multimodality therapy for locally advanced non-small cell lung cancer.

  13. Diet and lung cancer

    DEFF Research Database (Denmark)

    Fabricius, P; Lange, Peter

    2003-01-01

    Lung cancer is the leading cause of cancer-related deaths worldwide. While cigarette smoking is of key importance, factors such as diet also play a role in the development of lung cancer. MedLine and Embase were searched with diet and lung cancer as the key words. Recently published reviews and l...... are only ameliorated to a minor degree by a healthy diet.......Lung cancer is the leading cause of cancer-related deaths worldwide. While cigarette smoking is of key importance, factors such as diet also play a role in the development of lung cancer. MedLine and Embase were searched with diet and lung cancer as the key words. Recently published reviews...... and large well designed original articles were preferred to form the basis for the present article. A diet rich in fruit and vegetables reduces the incidence of lung cancer by approximately 25%. The reduction is of the same magnitude in current smokers, ex-smokers and never smokers. Supplementation...

  14. Twist1 suppresses senescence programs and thereby accelerates and maintains mutant Kras-induced lung tumorigenesis.

    Directory of Open Access Journals (Sweden)

    Phuoc T Tran

    Full Text Available KRAS mutant lung cancers are generally refractory to chemotherapy as well targeted agents. To date, the identification of drugs to therapeutically inhibit K-RAS have been unsuccessful, suggesting that other approaches are required. We demonstrate in both a novel transgenic mutant Kras lung cancer mouse model and in human lung tumors that the inhibition of Twist1 restores a senescence program inducing the loss of a neoplastic phenotype. The Twist1 gene encodes for a transcription factor that is essential during embryogenesis. Twist1 has been suggested to play an important role during tumor progression. However, there is no in vivo evidence that Twist1 plays a role in autochthonous tumorigenesis. Through two novel transgenic mouse models, we show that Twist1 cooperates with Kras(G12D to markedly accelerate lung tumorigenesis by abrogating cellular senescence programs and promoting the progression from benign adenomas to adenocarcinomas. Moreover, the suppression of Twist1 to physiological levels is sufficient to cause Kras mutant lung tumors to undergo senescence and lose their neoplastic features. Finally, we analyzed more than 500 human tumors to demonstrate that TWIST1 is frequently overexpressed in primary human lung tumors. The suppression of TWIST1 in human lung cancer cells also induced cellular senescence. Hence, TWIST1 is a critical regulator of cellular senescence programs, and the suppression of TWIST1 in human tumors may be an effective example of pro-senescence therapy.

  15. Cloning, characterization and targeting of the mouse HEXA gene

    Energy Technology Data Exchange (ETDEWEB)

    Wakamatsu, N.; Trasler, J.M.; Gravel, R.A. [McGill Univ., Quebec (Canada)] [and others

    1994-09-01

    The HEXA gene, encoding the {alpha} subunit of {beta}-hexosaminidase A, is essential for the metabolism of ganglioside G{sub M2}, and defects in this gene cause Tay-Sachs disease in humans. To elucidate the role of the gene in the nervous system of the mouse and to establish a mouse model of Tay-Sachs disease, we have cloned and characterized the HEXA gene and targeted a disruption of the gene in mouse ES cells. The mouse HEXA gene spans {approximately}26 kb and consists of 14 exons, similar to the human gene. A heterogeneous transcription initiation site was identified 21-42 bp 5{prime} of the initiator ATG, with two of the sites fitting the consensus CTCA (A = start) as seen for some weak initiator systems. Promoter analysis showed that the first 150 bp 5{prime} of the ATG contained 85% of promoter activity observed in constructs containing up to 1050 bp of 5{prime} sequence. The active region contained a sequence matching that of the adenovirus major late promoter upstream element factor. A survey of mouse tissues showed that the highest mRNA levels were in (max to min): testis (5.5 x brain cortex), adrenal, epididymis, heart, brain, lung, kidney, and liver (0.3 x brain cortex). A 12 kb BstI/SalI fragment containing nine exons was disrupted with the insertion of the bacterial neo{sup r} gene in exon 11 and was targeted into 129/Sv ES cells by homologous recombination. Nine of 153 G418 resistant clones were correctly targeted as confirmed by Southern blotting. The heterozygous ES cells were microinjected into mouse blastocysts and implanted into pseudo-pregnant mice. Nine male chimeric mice, showing that 40-95% chimerism for the 129/Sv agouti coat color marker, are being bred in an effort to generate germline transmission of the disrupted HEXA gene.

  16. Cigarette Smoke Exposure during Pregnancy Alters Fetomaternal Cell Trafficking Leading to Retention of Microchimeric Cells in the Maternal Lung

    Science.gov (United States)

    Vogelgesang, Anja; Scapin, Cristina; Barone, Caroline; Tam, Elaine

    2014-01-01

    Cigarette smoke exposure causes chronic oxidative lung damage. During pregnancy, fetal microchimeric cells traffic to the mother. Their numbers are increased at the site of acute injury. We hypothesized that milder chronic diffuse smoke injury would attract fetal cells to maternal lungs. We used a green-fluorescent-protein (GFP) mouse model to study the effects of cigarette smoke exposure on fetomaternal cell trafficking. Wild-type female mice were exposed to cigarette smoke for about 4 weeks and bred with homozygote GFP males. Cigarette smoke exposure continued until lungs were harvested and analyzed. Exposure to cigarette smoke led to macrophage accumulation in the maternal lung and significantly lower fetal weights. Cigarette smoke exposure influenced fetomaternal cell trafficking. It was associated with retention of GFP-positive fetal cells in the maternal lung and a significant reduction of fetal cells in maternal livers at gestational day 18, when fetomaternal cell trafficking peaks in the mouse model. Cells quickly clear postpartum, leaving only a few, difficult to detect, persisting microchimeric cells behind. In our study, we confirmed the postpartum clearance of cells in the maternal lungs, with no significant difference in both groups. We conclude that in the mouse model, cigarette smoke exposure during pregnancy leads to a retention of fetal microchimeric cells in the maternal lung, the site of injury. Further studies will be needed to elucidate the effect of cigarette smoke exposure on the phenotypic characteristics and function of these fetal microchimeric cells, and confirm its course in cigarette smoke exposure in humans. PMID:24832066

  17. Drug induced lung disease

    International Nuclear Information System (INIS)

    Schaefer-Prokop, Cornelia; Eisenhuber, Edith

    2010-01-01

    There is an ever increasing number of drugs that can cause lung disease. Imaging plays an important role in the diagnosis, since the clinical symptoms are mostly nonspecific. Various HRCT patterns can be correlated - though with overlaps - to lung changes caused by certain groups of drugs. Alternative diagnosis such as infection, edema or underlying lung disease has to be excluded by clinical-radiological means. Herefore is profound knowledge of the correlations of drug effects and imaging findings essential. History of drug exposure, suitable radiological findings and response to treatment (corticosteroids and stop of medication) mostly provide the base for the diagnosis. (orig.)

  18. Disentegrating lung tumor

    International Nuclear Information System (INIS)

    Mamedbekov, Eh.N.; Kyazimova, L.G.; Mamed''yarova, F.A.

    1992-01-01

    Clinical and roentgenological appearances of tuberculosis and tumoral lesions of bronchi and lungs are similar. It makes possible of wrong diagnosis of disease. Complications in diagnosis are connected with that fact that increase of frequency of pulmonary carcinoma both in patients with active tuberculosis and in persons with residual posttuberculous changes in respiratory organs is observed. Patients with specific processes in the lungs was presented. Additional X-ray examination was carried out on the base of clinical symptoms and results of X-ray examination. The diagnosis was established: disintegrating blastoma of the right lung with metastases to mediastinum lymph nodes

  19. Insulin and the Lung

    DEFF Research Database (Denmark)

    Singh, Suchita; Prakash, Y S; Linneberg, Allan

    2013-01-01

    , molecular understanding is necessary. Insulin resistance is a strong, independent risk factor for asthma development, but it is unknown whether a direct effect of insulin on the lung is involved. This review summarizes current knowledge regarding the effect of insulin on cellular components of the lung...... and highlights the molecular consequences of insulin-related metabolic signaling cascades that could adversely affect lung structure and function. Examples include airway smooth muscle proliferation and contractility and regulatory signaling networks that are associated with asthma. These aspects of insulin...

  20. Fibroblast Activation Protein (FAP) Accelerates Collagen Degradation and Clearance from Lungs in Mice

    DEFF Research Database (Denmark)

    Fan, Ming-Hui; Zhu, Qiang; Li, Hui-Hua

    2016-01-01

    , intratracheal bleomycin instillation and thoracic irradiation, we find increased mortality and increased lung fibrosis in FAP-deficient mice compared with wild-type mice. Lung extracellular matrix analysis reveals accumulation of intermediate-sized collagen fragments in FAP-deficient mouse lungs, consistent...... within vitrostudies showing that FAP mediates ordered proteolytic processing of matrix metalloproteinase (MMP)-derived collagen cleavage products. FAP-mediated collagen processing leads to increased collagen internalization without altering expression of the endocytic collagen receptor, Endo180....... Pharmacologic FAP inhibition decreases collagen internalization as expected. Conversely, restoration of FAP expression in the lungs of FAP-deficient mice decreases lung hydroxyproline content after intratracheal bleomycin to levels comparable with that of wild-type controls. Our findings indicate that FAP...

  1. The role of Sox2 on lung epithelial airway epithelial differentiation

    NARCIS (Netherlands)

    J.K. Ochieng (Joshua)

    2014-01-01

    markdownabstract__Abstract__ The foregut is crucial for development of respiratory organs including the lungs. Foregut morphogenesis starts around embryonic day 8.0 in mouse when the endoderm epithelial sheet folds ventrally during gastrulation [1,2]. At embryonic day 9.0, the ventral folding

  2. Inhibition of fibroblast growth factor receptor 3-dependent lung adenocarcinoma with a human monoclonal antibody

    Directory of Open Access Journals (Sweden)

    Yongjun Yin

    2016-05-01

    Full Text Available Activating mutations in fibroblast growth factor receptor 3 (FGFR3 have been identified in multiple types of human cancer and in congenital birth defects. In human lung cancer, fibroblast growth factor 9 (FGF9, a high-affinity ligand for FGFR3, is overexpressed in 10% of primary resected non-small cell lung cancer (NSCLC specimens. Furthermore, in a mouse model where FGF9 can be induced in lung epithelial cells, epithelial proliferation and ensuing tumorigenesis is dependent on FGFR3. To develop new customized therapies for cancers that are dependent on FGFR3 activation, we have used this mouse model to evaluate a human monoclonal antibody (D11 with specificity for the extracellular ligand-binding domain of FGFR3, that recognizes both human and mouse forms of the receptor. Here, we show that D11 effectively inhibits signaling through FGFR3 in vitro, inhibits the growth of FGFR3-dependent FGF9-induced lung adenocarcinoma in mice, and reduces tumor-associated morbidity. Given the potency of FGF9 in this mouse model and the absolute requirement for signaling through FGFR3, this study validates the D11 antibody as a potentially useful and effective reagent for treating human cancers or other pathologies that are dependent on activation of FGFR3.

  3. Lung volumes and emphysema in smokers with interstitial lung abnormalities.

    Science.gov (United States)

    Washko, George R; Hunninghake, Gary M; Fernandez, Isis E; Nishino, Mizuki; Okajima, Yuka; Yamashiro, Tsuneo; Ross, James C; Estépar, Raúl San José; Lynch, David A; Brehm, John M; Andriole, Katherine P; Diaz, Alejandro A; Khorasani, Ramin; D'Aco, Katherine; Sciurba, Frank C; Silverman, Edwin K; Hatabu, Hiroto; Rosas, Ivan O

    2011-03-10

    Cigarette smoking is associated with emphysema and radiographic interstitial lung abnormalities. The degree to which interstitial lung abnormalities are associated with reduced total lung capacity and the extent of emphysema is not known. We looked for interstitial lung abnormalities in 2416 (96%) of 2508 high-resolution computed tomographic (HRCT) scans of the lung obtained from a cohort of smokers. We used linear and logistic regression to evaluate the associations between interstitial lung abnormalities and HRCT measurements of total lung capacity and emphysema. Interstitial lung abnormalities were present in 194 (8%) of the 2416 HRCT scans evaluated. In statistical models adjusting for relevant covariates, interstitial lung abnormalities were associated with reduced total lung capacity (-0.444 liters; 95% confidence interval [CI], -0.596 to -0.292; Ppulmonary disease (COPD) (odds ratio, 0.53; 95% CI, 0.37 to 0.76; P<0.001). The effect of interstitial lung abnormalities on total lung capacity and emphysema was dependent on COPD status (P<0.02 for the interactions). Interstitial lung abnormalities were positively associated with both greater exposure to tobacco smoke and current smoking. In smokers, interstitial lung abnormalities--which were present on about 1 of every 12 HRCT scans--were associated with reduced total lung capacity and a lesser amount of emphysema. (Funded by the National Institutes of Health and the Parker B. Francis Foundation; ClinicalTrials.gov number, NCT00608764.).

  4. Lung cancer induced in mice by the envelope protein of jaagsiekte sheep retrovirus (JSRV closely resembles lung cancer in sheep infected with JSRV

    Directory of Open Access Journals (Sweden)

    York Denis

    2006-12-01

    Full Text Available Abstract Background Jaagsiekte sheep retrovirus (JSRV causes a lethal lung cancer in sheep and goats. Expression of the JSRV envelope (Env protein in mouse lung, by using a replication-defective adeno-associated virus type 6 (AAV6 vector, induces tumors resembling those seen in sheep. However, the mouse and sheep tumors have not been carefully compared to determine if Env expression alone in mice can account for the disease features observed in sheep, or whether additional aspects of virus replication in sheep are important, such as oncogene activation following retrovirus integration into the host cell genome. Results We have generated mouse monoclonal antibodies (Mab against JSRV Env and have used these to study mouse and sheep lung tumor histology. These Mab detect Env expression in tumors in sheep infected with JSRV from around the world with high sensitivity and specificity. Mouse and sheep tumors consisted mainly of well-differentiated adenomatous foci with little histological evidence of anaplasia, but at long times after vector exposure some mouse tumors did have a more malignant appearance typical of adenocarcinoma. In addition to epithelial cell tumors, lungs of three of 29 sheep examined contained fibroblastic cell masses that expressed Env and appeared to be separate neoplasms. The Mab also stained nasal adenocarcinoma tissue from one United States sheep, which we show was due to expression of Env from ovine enzootic nasal tumor virus (ENTV, a virus closely related to JSRV. Systemic administration of the AAV6 vector encoding JSRV Env to mice produced numerous hepatocellular tumors, and some hemangiomas and hemangiosarcomas, showing that the Env protein can induce tumors in multiple cell types. Conclusion Lung cancers induced by JSRV infection in sheep and by JSRV Env expression in mice have similar histologic features and are primarily characterized by adenomatous proliferation of peripheral lung epithelial cells. Thus it is

  5. The PCP genes Celsr1 and Vangl2 are required for normal lung branching morphogenesis

    Science.gov (United States)

    Yates, Laura L.; Schnatwinkel, Carsten; Murdoch, Jennifer N.; Bogani, Debora; Formstone, Caroline J.; Townsend, Stuart; Greenfield, Andy; Niswander, Lee A.; Dean, Charlotte H.

    2010-01-01

    The lungs are generated by branching morphogenesis as a result of reciprocal signalling interactions between the epithelium and mesenchyme during development. Mutations that disrupt formation of either the correct number or shape of epithelial branches affect lung function. This, in turn, can lead to congenital abnormalities such as cystadenomatoid malformations, pulmonary hypertension or lung hypoplasia. Defects in lung architecture are also associated with adult lung disease, particularly in cases of idiopathic lung fibrosis. Identifying the signalling pathways which drive epithelial tube formation will likely shed light on both congenital and adult lung disease. Here we show that mutations in the planar cell polarity (PCP) genes Celsr1 and Vangl2 lead to disrupted lung development and defects in lung architecture. Lungs from Celsr1Crsh and Vangl2Lp mouse mutants are small and misshapen with fewer branches, and by late gestation exhibit thickened interstitial mesenchyme and defective saccular formation. We observe a recapitulation of these branching defects following inhibition of Rho kinase, an important downstream effector of the PCP signalling pathway. Moreover, epithelial integrity is disrupted, cytoskeletal remodelling perturbed and mutant endoderm does not branch normally in response to the chemoattractant FGF10. We further show that Celsr1 and Vangl2 proteins are present in restricted spatial domains within lung epithelium. Our data show that the PCP genes Celsr1 and Vangl2 are required for foetal lung development thereby revealing a novel signalling pathway critical for this process that will enhance our understanding of congenital and adult lung diseases and may in future lead to novel therapeutic strategies. PMID:20223754

  6. Differential metabolism of 4-hydroxynonenal in liver, lung and brain of mice and rats

    International Nuclear Information System (INIS)

    Zheng, Ruijin; Dragomir, Ana-Cristina; Mishin, Vladimir; Richardson, Jason R.; Heck, Diane E.; Laskin, Debra L.; Laskin, Jeffrey D.

    2014-01-01

    The lipid peroxidation end-product 4-hydroxynonenal (4-HNE) is generated in tissues during oxidative stress. As a reactive aldehyde, it forms Michael adducts with nucleophiles, a process that disrupts cellular functioning. Liver, lung and brain are highly sensitive to xenobiotic-induced oxidative stress and readily generate 4-HNE. In the present studies, we compared 4-HNE metabolism in these tissues, a process that protects against tissue injury. 4-HNE was degraded slowly in total homogenates and S9 fractions of mouse liver, lung and brain. In liver, but not lung or brain, NAD(P)+ and NAD(P)H markedly stimulated 4-HNE metabolism. Similar results were observed in rat S9 fractions from these tissues. In liver, lung and brain S9 fractions, 4-HNE formed protein adducts. When NADH was used to stimulate 4-HNE metabolism, the formation of protein adducts was suppressed in liver, but not lung or brain. In both mouse and rat tissues, 4-HNE was also metabolized by glutathione S-transferases. The greatest activity was noted in livers of mice and in lungs of rats; relatively low glutathione S-transferase activity was detected in brain. In mouse hepatocytes, 4-HNE was rapidly taken up and metabolized. Simultaneously, 4-HNE-protein adducts were formed, suggesting that 4-HNE metabolism in intact cells does not prevent protein modifications. These data demonstrate that, in contrast to liver, lung and brain have a limited capacity to metabolize 4-HNE. The persistence of 4-HNE in these tissues may increase the likelihood of tissue injury during oxidative stress. - Highlights: • Lipid peroxidation generates 4-hydroxynonenal, a highly reactive aldehyde. • Rodent liver, but not lung or brain, is efficient in degrading 4-hydroxynonenal. • 4-hydroxynonenal persists in tissues with low metabolism, causing tissue damage

  7. Differential metabolism of 4-hydroxynonenal in liver, lung and brain of mice and rats

    Energy Technology Data Exchange (ETDEWEB)

    Zheng, Ruijin; Dragomir, Ana-Cristina; Mishin, Vladimir [Pharmacology and Toxicology, Rutgers University-Ernest Mario School of Pharmacy, Piscataway, NJ (United States); Richardson, Jason R. [Environmental and Occupational Medicine, Rutgers University-Robert Wood Johnson Medical School, Piscataway, NJ (United States); Heck, Diane E. [Environmental Science, School of Health Sciences and Practice, New York Medical College, Valhalla, NY (United States); Laskin, Debra L. [Pharmacology and Toxicology, Rutgers University-Ernest Mario School of Pharmacy, Piscataway, NJ (United States); Laskin, Jeffrey D., E-mail: jlaskin@eohsi.rutgers.edu [Environmental and Occupational Medicine, Rutgers University-Robert Wood Johnson Medical School, Piscataway, NJ (United States)

    2014-08-15

    The lipid peroxidation end-product 4-hydroxynonenal (4-HNE) is generated in tissues during oxidative stress. As a reactive aldehyde, it forms Michael adducts with nucleophiles, a process that disrupts cellular functioning. Liver, lung and brain are highly sensitive to xenobiotic-induced oxidative stress and readily generate 4-HNE. In the present studies, we compared 4-HNE metabolism in these tissues, a process that protects against tissue injury. 4-HNE was degraded slowly in total homogenates and S9 fractions of mouse liver, lung and brain. In liver, but not lung or brain, NAD(P)+ and NAD(P)H markedly stimulated 4-HNE metabolism. Similar results were observed in rat S9 fractions from these tissues. In liver, lung and brain S9 fractions, 4-HNE formed protein adducts. When NADH was used to stimulate 4-HNE metabolism, the formation of protein adducts was suppressed in liver, but not lung or brain. In both mouse and rat tissues, 4-HNE was also metabolized by glutathione S-transferases. The greatest activity was noted in livers of mice and in lungs of rats; relatively low glutathione S-transferase activity was detected in brain. In mouse hepatocytes, 4-HNE was rapidly taken up and metabolized. Simultaneously, 4-HNE-protein adducts were formed, suggesting that 4-HNE metabolism in intact cells does not prevent protein modifications. These data demonstrate that, in contrast to liver, lung and brain have a limited capacity to metabolize 4-HNE. The persistence of 4-HNE in these tissues may increase the likelihood of tissue injury during oxidative stress. - Highlights: • Lipid peroxidation generates 4-hydroxynonenal, a highly reactive aldehyde. • Rodent liver, but not lung or brain, is efficient in degrading 4-hydroxynonenal. • 4-hydroxynonenal persists in tissues with low metabolism, causing tissue damage.

  8. Preanalytics in lung cancer.

    Science.gov (United States)

    Warth, Arne; Muley, Thomas; Meister, Michael; Weichert, Wilko

    2015-01-01

    Preanalytic sampling techniques and preparation of tissue specimens strongly influence analytical results in lung tissue diagnostics both on the morphological but also on the molecular level. However, in contrast to analytics where tremendous achievements in the last decade have led to a whole new portfolio of test methods, developments in preanalytics have been minimal. This is specifically unfortunate in lung cancer, where usually only small amounts of tissue are at hand and optimization in all processing steps is mandatory in order to increase the diagnostic yield. In the following, we provide a comprehensive overview on some aspects of preanalytics in lung cancer from the method of sampling over tissue processing to its impact on analytical test results. We specifically discuss the role of preanalytics in novel technologies like next-generation sequencing and in the state-of the-art cytology preparations. In addition, we point out specific problems in preanalytics which hamper further developments in the field of lung tissue diagnostics.

  9. Lung surgery - discharge

    Science.gov (United States)

    ... Lung biopsy - discharge; Thoracoscopy - discharge; Video-assisted thoracoscopic surgery - discharge; VATS - discharge ... milk) for 2 weeks after video-assisted thoracoscopic surgery and 6 to 8 weeks after open surgery. ...

  10. Diffuse cavitary lung lesions

    Energy Technology Data Exchange (ETDEWEB)

    Grunzke, Mindy; Garrington, Timothy [University of Colorado Denver, Department of Pediatrics, Aurora, CO (United States); The Children' s Hospital, Rick Wilson Center for Cancer and Blood Disorders, Aurora, CO (United States); Hayes, Kari [The Children' s Hospital, Pediatric Radiology, Aurora, CO (United States); Bourland, Wendy [Children' s Hospital at St. Francis, Warren Clinic, Inc., Tulsa, OK (United States)

    2010-02-15

    An 11-year-old girl presented with a 2-month history of progressively worsening cough, daily fevers, and weight loss. A chest radiograph revealed multiple cystic cavitary lung lesions. An extensive infectious work-up was negative. Chest CT verified multiple cavitary lung lesions bilaterally, and [F-18]2-fluoro-2-deoxy-D-glucose ({sup 18}F-FDG) positron emission tomography with CT (PET/CT) showed increased uptake in the lung lesions as well as regional lymph nodes. Subsequent biopsy of an involved lymph node confirmed classical Hodgkin lymphoma, nodular sclerosis type. This case represents an unusual presentation for a child with Hodgkin lymphoma and demonstrates a role for {sup 18}F-FDG PET/CT in evaluating a child with cavitary lung lesions. (orig.)

  11. Diffuse cavitary lung lesions

    International Nuclear Information System (INIS)

    Grunzke, Mindy; Garrington, Timothy; Hayes, Kari; Bourland, Wendy

    2010-01-01

    An 11-year-old girl presented with a 2-month history of progressively worsening cough, daily fevers, and weight loss. A chest radiograph revealed multiple cystic cavitary lung lesions. An extensive infectious work-up was negative. Chest CT verified multiple cavitary lung lesions bilaterally, and [F-18]2-fluoro-2-deoxy-D-glucose ( 18 F-FDG) positron emission tomography with CT (PET/CT) showed increased uptake in the lung lesions as well as regional lymph nodes. Subsequent biopsy of an involved lymph node confirmed classical Hodgkin lymphoma, nodular sclerosis type. This case represents an unusual presentation for a child with Hodgkin lymphoma and demonstrates a role for 18 F-FDG PET/CT in evaluating a child with cavitary lung lesions. (orig.)

  12. Lungs in TSC

    Science.gov (United States)

    ... must be done in the hospital under general anesthesia. In general, lung biopsy is not required to ... be helpful for some LAM patients who have asthma like symptoms of wheezing and intermittent shortness of ...

  13. Traumatic lung hernia

    International Nuclear Information System (INIS)

    Rabaza, M. J.; Alcazar, P. P.; Touma, C.

    2001-01-01

    Lung hernia is an uncommon entity that is defined as the protrusion of the lung parenchyma through a defect in the thoracic cavity. It is classified on the basis of its location (cervical, intercostal and diaphragmatic) and etiology (congenital and acquired). Acquired lung hernias can be further grouped as spontaneous, traumatic or pathological, depending on the responsible mechanism. Nearly half of them are secondary to chest trauma, whether penetrating or blunt. We present a case of lung hernia in a patient with penetrating chest trauma. The diagnosis was suspected from the radiographic images and was confirmed by computed tomography. We also review the literature concerning its classification and incidence, diagnostic methods used and treatment. (Author) 9 refs

  14. PEComa of the lung

    Directory of Open Access Journals (Sweden)

    Vijayabhaskar R

    2010-01-01

    Full Text Available Perivascular epithelioid cell tumor (PEComa, also called clear cell ′′sugar′′ tumor of the lung, is a rare benign tumor arising from perivascular epithelioid cells (PECs. We report a case of a 15-year-old boy who presented with right lower lobe lesion which turned out to be a clear cell tumor of the lung. An [18F]-fluoro-2-deoxy-D-glucose (FDG - positron emission tomography (PET scan revealed mild FDG uptake in the lung lesion (SUV< 1 with no active uptake elsewhere in the body. We discuss the clinical, radiologic and immunohistochemical features of clear cell ′′sugar′′ tumor of lung and compare them with published literature.

  15. Arterioscanning of lungs

    International Nuclear Information System (INIS)

    Petrovskij, B.V.; Rabkin, I.Kh.; Matevosov, A.L.

    1980-01-01

    Studied is lung microcirculation by means of introducting radioactive albumin (MAA 131 I introduction through a catheter) in bronchial vessels. Arterioscanning technique and its peculiarities are described in detail. It is established that results of arterioscanning must be estimated taking into account the nature of MAA 131 I distribution and fixation, counting rate and duration of radioactive registration in the range of pathologic neoplasms. It is shown that arterioscanning permits to reveal the 20-80 μm diameter vessels . This method can be one of the most important ones in the early diagnosis of lung cancer. The data on the diagnostic effectiveness of lung bronchial arteriography and arterioscanning in the cases of chronic inflammatory diseases, tuberculosis and some benigh lung tumours and neoplasms are also presented

  16. Lung cancer imaging

    CERN Document Server

    Ravenel, James G

    2013-01-01

    This book provides a guide to the diagnosis, staging and overview of the management of lung cancer relevant to practicing radiologists so that they can better understand the decision making issues and provide more useful communication to treating physicians.

  17. Lung Cancer Trends

    Science.gov (United States)

    ... the Biggest Cancer Killer in Both Men and Women” Stay Informed Trends for Other Kinds of Cancer Breast Cervical Colorectal (Colon) Ovarian Prostate Skin Cancer Home Lung Cancer Trends Language: English Español (Spanish) Recommend ...

  18. Creb1 regulates late stage mammalian lung development via respiratory epithelial and mesenchymal-independent mechanisms

    Science.gov (United States)

    Antony, N.; McDougall, A. R.; Mantamadiotis, T.; Cole, T. J.; Bird, A. D.

    2016-01-01

    During mammalian lung development, the morphological transition from respiratory tree branching morphogenesis to a predominantly saccular architecture, capable of air-breathing at birth, is dependent on physical forces as well as molecular signaling by a range of transcription factors including the cAMP response element binding protein 1 (Creb1). Creb1−/− mutant mice exhibit complete neonatal lethality consistent with a lack of lung maturation beyond the branching phase. To further define its role in the developing mouse lung, we deleted Creb1 separately in the respiratory epithelium and mesenchyme. Surprisingly, we found no evidence of a morphological lung defect nor compromised neonatal survival in either conditional Creb1 mutant. Interestingly however, loss of mesenchymal Creb1 on a genetic background lacking the related Crem protein showed normal lung development but poor neonatal survival. To investigate the underlying requirement for Creb1 for normal lung development, Creb1−/− mice were re-examined for defects in both respiratory muscles and glucocorticoid hormone signaling, which are also required for late stage lung maturation. However, these systems appeared normal in Creb1−/− mice. Together our results suggest that the requirement of Creb1 for normal mammalian lung morphogenesis is not dependent upon its expression in lung epithelium or mesenchyme, nor its role in musculoskeletal development. PMID:27150575

  19. Gene Expression Analysis to Assess the Relevance of Rodent Models to Human Lung Injury.

    Science.gov (United States)

    Sweeney, Timothy E; Lofgren, Shane; Khatri, Purvesh; Rogers, Angela J

    2017-08-01

    The relevance of animal models to human diseases is an area of intense scientific debate. The degree to which mouse models of lung injury recapitulate human lung injury has never been assessed. Integrating data from both human and animal expression studies allows for increased statistical power and identification of conserved differential gene expression across organisms and conditions. We sought comprehensive integration of gene expression data in experimental acute lung injury (ALI) in rodents compared with humans. We performed two separate gene expression multicohort analyses to determine differential gene expression in experimental animal and human lung injury. We used correlational and pathway analyses combined with external in vitro gene expression data to identify both potential drivers of underlying inflammation and therapeutic drug candidates. We identified 21 animal lung tissue datasets and three human lung injury bronchoalveolar lavage datasets. We show that the metasignatures of animal and human experimental ALI are significantly correlated despite these widely varying experimental conditions. The gene expression changes among mice and rats across diverse injury models (ozone, ventilator-induced lung injury, LPS) are significantly correlated with human models of lung injury (Pearson r = 0.33-0.45, P human lung injury. Predicted therapeutic targets, peptide ligand signatures, and pathway analyses are also all highly overlapping. Gene expression changes are similar in animal and human experimental ALI, and provide several physiologic and therapeutic insights to the disease.

  20. Dosimetric lung models

    International Nuclear Information System (INIS)

    James, A.C.; Roy, M.

    1986-01-01

    The anatomical and physiological factors that vary with age and influence the deposition of airborne radionuclides in the lung are reviewed. The efficiency with which aerosols deposit in the lung for a given exposure at various ages from birth to adulthood is evaluated. Deposition within the lung is considered in relation to the clearance mechanisms acting in different regions or compartments. The procedure for evaluating dose to sensitive tissues in lung and transfer to other organs that is being considered by the Task Group established by ICRP to review the Lung Model is outlined. Examples of the application of this modelling procedure to evaluate lung dose as a function of age are given, for exposure to radon daughters in dwellings, and for exposure to an insoluble 239 Pu aerosol. The former represents exposure to short-lived radionuclides that deliver relatively high doses to bronchial tissue. In this case, dose rates are marginally higher in children than in adults. Plutonium exposure represents the case where dose is predominantly delivered to respiratory tissue and lymph nodes. In this case, the life-time doses tend to be lower for exposure in childhood. Some of the uncertainties in this modelling procedure are noted

  1. Pan-PPAR agonist IVA337 is effective in experimental lung fibrosis and pulmonary hypertension.

    Science.gov (United States)

    Avouac, Jerome; Konstantinova, Irena; Guignabert, Christophe; Pezet, Sonia; Sadoine, Jeremy; Guilbert, Thomas; Cauvet, Anne; Tu, Ly; Luccarini, Jean-Michel; Junien, Jean-Louis; Broqua, Pierre; Allanore, Yannick

    2017-11-01

    To evaluate the antifibrotic effects of the pan-peroxisome proliferator-activated receptor (PPAR) agonist IVA337 in preclinical mouse models of pulmonary fibrosis and related pulmonary hypertension (PH). IVA337 has been evaluated in the mouse model of bleomycin-induced pulmonary fibrosis and in Fra-2 transgenic mice, this latter being characterised by non-specific interstitial pneumonia and severe vascular remodelling of pulmonary arteries leading to PH. Mice received two doses of IVA337 (30 mg/kg or 100 mg/kg) or vehicle administered by daily oral gavage up to 4 weeks. IVA337 demonstrated at a dose of 100 mg/kg a marked protection from the development of lung fibrosis in both mouse models compared with mice receiving 30 mg/kg of IVA337 or vehicle. Histological score was markedly reduced by 61% in the bleomycin model and by 50% in Fra-2 transgenic mice, and total lung hydroxyproline concentrations decreased by 28% and 48%, respectively, as compared with vehicle-treated mice. IVA337 at 100 mg/kg also significantly decreased levels of fibrogenic markers in lesional lungs of both mouse models. In addition, IVA337 substantially alleviated PH in Fra-2 transgenic mice by improving haemodynamic measurements and vascular remodelling. In primary human lung fibroblasts, IVA337 inhibited in a dose-dependent manner fibroblast to myofibroblasts transition induced by TGF-β and fibroblast proliferation mediated by PDGF. We demonstrate that treatment with 100 mg/kg IVA337 prevents lung fibrosis in two complementary animal models and substantially attenuates PH in the Fra-2 mouse model. These findings confirm that the pan-PPAR agonist IVA337 is an appealing therapeutic candidate for these cardiopulmonary involvements. © Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2017. All rights reserved. No commercial use is permitted unless otherwise expressly granted.

  2. Effects of genistein following fractionated lung irradiation in mice

    International Nuclear Information System (INIS)

    Para, Andrea E.; Bezjak, Andrea; Yeung, Ivan W.T.; Van Dyk, Jake; Hill, Richard P.

    2009-01-01

    Background and purpose: This study investigated protection of lung injury by genistein following fractionated doses of radiation and its effect on tumor response. Material and methods: C3H/HeJ mice were irradiated (100 kVp X-rays) with 9 fractions of 3.1 Gy over 30 days (approximately equivalent to 10 Gy single dose) and were maintained on a genistein diet (∼10 mg/kg). Damage was assessed over 28 weeks in lung cells by a cytokinesis block micronucleus (MN) assay and by changes in breathing rate and histology. Tumor protection was assessed using a colony assay to determine cell survival following in situ irradiation of small lung nodules (KHT fibrosarcoma). Results: Genistein caused about a 50% reduction in the MN damage observed during the fractionated radiation treatment and this damage continued to decrease at later times to background levels by 16 weeks. In mice not receiving Genistein MN levels remained well above background out to 28 weeks after irradiation. Genistein reduced macrophage accumulation by 22% and reduced collagen deposition by 28%. There was minimal protection against increases in breathing rate or severe morbidity during pneumonitis. No tumor protection by genistein treatment was observed. Conclusions: Genistein at the dose levels used in this study partially reduced the extent of fibrosis developing in mouse lung caused by irradiation but gave minimal protection against pneumonitis. There was no evidence that genistein caused protection of small tumors growing in the lung.

  3. Multimodal imaging of lung cancer and its microenvironment (Conference Presentation)

    Science.gov (United States)

    Hariri, Lida P.; Niederst, Matthew J.; Mulvey, Hillary; Adams, David C.; Hu, Haichuan; Chico Calero, Isabel; Szabari, Margit V.; Vakoc, Benjamin J.; Hasan, Tayyaba; Bouma, Brett E.; Engelman, Jeffrey A.; Suter, Melissa J.

    2016-03-01

    Despite significant advances in targeted therapies for lung cancer, nearly all patients develop drug resistance within 6-12 months and prognosis remains poor. Developing drug resistance is a progressive process that involves tumor cells and their microenvironment. We hypothesize that microenvironment factors alter tumor growth and response to targeted therapy. We conducted in vitro studies in human EGFR-mutant lung carcinoma cells, and demonstrated that factors secreted from lung fibroblasts results in increased tumor cell survival during targeted therapy with EGFR inhibitor, gefitinib. We also demonstrated that increased environment stiffness results in increased tumor survival during gefitinib therapy. In order to test our hypothesis in vivo, we developed a multimodal optical imaging protocol for preclinical intravital imaging in mouse models to assess tumor and its microenvironment over time. We have successfully conducted multimodal imaging of dorsal skinfold chamber (DSC) window mice implanted with GFP-labeled human EGFR mutant lung carcinoma cells and visualized changes in tumor development and microenvironment facets over time. Multimodal imaging included structural OCT to assess tumor viability and necrosis, polarization-sensitive OCT to measure tissue birefringence for collagen/fibroblast detection, and Doppler OCT to assess tumor vasculature. Confocal imaging was also performed for high-resolution visualization of EGFR-mutant lung cancer cells labeled with GFP, and was coregistered with OCT. Our results demonstrated that stromal support and vascular growth are essential to tumor progression. Multimodal imaging is a useful tool to assess tumor and its microenvironment over time.

  4. Prediction of acute inhalation toxicity using in vitro lung surfactant inhibition.

    Science.gov (United States)

    Sørli, Jorid B; Huang, Yishi; Da Silva, Emilie; Hansen, Jitka S; Zuo, Yi Y; Frederiksen, Marie; Nørgaard, Asger W; Ebbehøj, Niels E; Larsen, Søren T; Hougaard, Karin S

    2018-01-01

    Private consumers and professionals may experience acute inhalation toxicity after inhaling aerosolized impregnation products. The distinction between toxic and non-toxic products is difficult to make for producers and product users alike, as there is no clearly described relationship between the chemical composition of the products and induction of toxicity. The currently accepted method for determination of acute inhalation toxicity is based on experiments on animals; it is time-consuming, expensive and causes stress for the animals. Impregnation products are present on the market in large numbers and amounts and exhibit great variety. Therefore, an alternative method to screen for acute inhalation toxicity is needed. The aim of our study was to determine if inhibition of lung surfactant by impregnation products in vitro could accurately predict toxicity in vivo in mice. We tested 21 impregnation products using the constant flow through set-up of the constrained drop surfactometer to determine if the products inhibited surfactant function or not. The same products were tested in a mouse inhalation bioassay to determine their toxicity in vivo. The sensitivity was 100%, i.e., the in vitro method predicted all the products that were toxic for mice to inhale. The specificity of the in vitro test was 63%, i.e., the in vitro method found three false positives in the 21 tested products. Six of the products had been involved in accidental human inhalation where they caused acute inhalation toxicity. All of these six products inhibited lung surfactant function in vitro and were toxic to mice.

  5. Increased Expression of FoxM1 Transcription Factor in Respiratory Epithelium Inhibits Lung Sacculation and Causes Clara Cell Hyperplasia

    Science.gov (United States)

    Wang, I-Ching; Zhang, Yufang; Snyder, Jonathan; Sutherland, Mardi J.; Burhans, Michael S.; Shannon, John M.; Park, Hyun Jung; Whitsett, Jeffrey A.; Kalinichenko, Vladimir V.

    2010-01-01

    Foxm1 is a member of the Forkhead Box (Fox) family of transcription factors. Foxm1 (previously called Foxm1b, HFH-11B, Trident, Win, or MPP2) is expressed in multiple cell types and plays important roles in cellular proliferation, differentiation and tumorigenesis. Genetic deletion of Foxm1 from mouse respiratory epithelium during initial stages of lung development inhibits lung maturation and causes respiratory failure after birth. However, the role of Foxm1 during postnatal lung morphogenesis remains unknown. In the present study, Foxm1 expression was detected in epithelial cells of conducting and peripheral airways and changing dynamically with lung maturation. To discern the biological role of Foxm1 in the prenatal and postnatal lung, a novel transgenic mouse line that expresses a constitutively active form of FoxM1 (FoxM1 N-terminal deletion mutant or FoxM1-ΔN) under the control of lung epithelial-specific SPC promoter was produced. Expression of the FoxM1-ΔN transgene during embryogenesis caused epithelial hyperplasia, inhibited lung sacculation and expression of the type II epithelial marker, pro-SPC. Expression of FoxM1-ΔN mutant during the postnatal period did not influence alveologenesis but caused focal airway hyperplasia and increased proliferation of Clara cells. Likewise, expression of FoxM1-ΔN mutant in conducting airways with Scgb1a1 promoter was sufficient to induce Clara cell hyperplasia. Furthermore, FoxM1-ΔN cooperated with activated K-Ras to induce lung tumor growth in vivo. Increased activity of Foxm1 altered lung sacculation, induced proliferation in the respiratory epithelium and accelerated lung tumor growth, indicating that precise regulation of Foxm1 is critical for normal lung morphogenesis and development of lung cancer. PMID:20816795

  6. The aging lung

    Directory of Open Access Journals (Sweden)

    Lowery EM

    2013-11-01

    Full Text Available Erin M Lowery,1 Aleah L Brubaker,2 Erica Kuhlmann,1 Elizabeth J Kovacs31Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine at Loyola University Medical Center, 2Loyola University Stritch School of Medicine, 3Department of Surgery, Loyola University Medical Center, Maywood, IL, USAAbstract: There are many age-associated changes in the respiratory and pulmonary immune system. These changes include decreases in the volume of the thoracic cavity, reduced lung volumes, and alterations in the muscles that aid respiration. Muscle function on a cellular level in the aging population is less efficient. The elderly population has less pulmonary reserve, and cough strength is decreased in the elderly population due to anatomic changes and muscle atrophy. Clearance of particles from the lung through the mucociliary elevator is decreased and associated with ciliary dysfunction. Many complex changes in immunity with aging contribute to increased susceptibility to infections including a less robust immune response from both the innate and adaptive immune systems. Considering all of these age-related changes to the lungs, pulmonary disease has significant consequences for the aging population. Chronic lower respiratory tract disease is the third leading cause of death in people aged 65 years and older. With a large and growing aging population, it is critical to understand how the body changes with age and how this impacts the entire respiratory system. Understanding the aging process in the lung is necessary in order to provide optimal care to our aging population. This review focuses on the nonpathologic aging process in the lung, including structural changes, changes in muscle function, and pulmonary immunologic function, with special consideration of obstructive lung disease in the elderly.Keywords: aging, lung, pulmonary immunology, COPD

  7. Linking the generation of DNA adducts to lung cancer.

    Science.gov (United States)

    Ceppi, Marcello; Munnia, Armelle; Cellai, Filippo; Bruzzone, Marco; Peluso, Marco E M

    2017-09-01

    Worldwide, lung cancer is the leading cause of cancer death. DNA adducts are considered a reliable biomarker that reflects carcinogen exposure to tobacco smoke, but the central question is what is the relationship of DNA adducts and cancer? Therefore, we investigated this relationship by a meta-analysis of twenty-two studies with bronchial adducts for a total of 1091 subjects, 887 lung cancer cases and 204 apparently healthy individuals with no evidence of lung cancer. Our study shows that these adducts are significantly associated to increase lung cancer risk. The value of Mean Ratio lung-cancer (MR) of bronchial adducts resulting from the random effects model was 2.64, 95% C.I. 2.00-3.50, in overall lung cancer cases as compared to controls. The significant difference, with lung cancer patients having significant higher levels of bronchial adducts than controls, persisted after stratification for smoking habits. The MR lung-cancer value between lung cancer patients and controls for smokers was 2.03, 95% C.I. 1.42-2.91, for ex-smokers 3.27, 95% C.I. 1.49-7.18, and for non-smokers was 3.81, 95% C.I. 1.85-7.85. Next, we found that the generation of bronchial adducts is significantly related to inhalation exposure to tobacco smoke carcinogens confirming its association with volatile carcinogens. The MR smoking estimate of bronchial adducts resulting from meta-regression was 2.28, 95% Confidence Interval (C.I.) 1.10-4.73, in overall smokers in respect to non-smokers. The present work provides strengthening of the hypothesis that bronchial adducts are not simply relate to exposure, but are a cause of chemical-induced lung cancer. Copyright © 2017 Elsevier B.V. All rights reserved.

  8. Circulating histones are mediators of trauma-associated lung injury.

    Science.gov (United States)

    Abrams, Simon T; Zhang, Nan; Manson, Joanna; Liu, Tingting; Dart, Caroline; Baluwa, Florence; Wang, Susan Siyu; Brohi, Karim; Kipar, Anja; Yu, Weiping; Wang, Guozheng; Toh, Cheng-Hock

    2013-01-15

    Acute lung injury is a common complication after severe trauma, which predisposes patients to multiple organ failure. This syndrome largely accounts for the late mortality that arises and despite many theories, the pathological mechanism is not fully understood. Discovery of histone-induced toxicity in mice presents a new dimension for elucidating the underlying pathophysiology. To investigate the pathological roles of circulating histones in trauma-induced lung injury. Circulating histone levels in patients with severe trauma were determined and correlated with respiratory failure and Sequential Organ Failure Assessment (SOFA) scores. Their cause-effect relationship was studied using cells and mouse models. In a cohort of 52 patients with severe nonthoracic blunt trauma, circulating histones surged immediately after trauma to levels that were toxic to cultured endothelial cells. The high levels were significantly associated with the incidence of acute lung injury and SOFA scores, as well as markers of endothelial damage and coagulation activation. In in vitro systems, histones damaged endothelial cells, stimulated cytokine release, and induced neutrophil extracellular trap formation and myeloperoxidase release. Cellular toxicity resulted from their direct membrane interaction and resultant calcium influx. In mouse models, cytokines and markers for endothelial damage and coagulation activation significantly increased immediately after trauma or histone infusion. Pathological examinations showed that lungs were the predominantly affected organ with edema, hemorrhage, microvascular thrombosis, and neutrophil congestion. An anti-histone antibody could reduce these changes and protect mice from histone-induced lethality. This study elucidates a new mechanism for acute lung injury after severe trauma and proposes that circulating histones are viable therapeutic targets for improving survival outcomes in patients.

  9. Circulating Histones Are Mediators of Trauma-associated Lung Injury

    Science.gov (United States)

    Abrams, Simon T.; Zhang, Nan; Manson, Joanna; Liu, Tingting; Dart, Caroline; Baluwa, Florence; Wang, Susan Siyu; Brohi, Karim; Kipar, Anja; Yu, Weiping

    2013-01-01

    Rationale: Acute lung injury is a common complication after severe trauma, which predisposes patients to multiple organ failure. This syndrome largely accounts for the late mortality that arises and despite many theories, the pathological mechanism is not fully understood. Discovery of histone-induced toxicity in mice presents a new dimension for elucidating the underlying pathophysiology. Objectives: To investigate the pathological roles of circulating histones in trauma-induced lung injury. Methods: Circulating histone levels in patients with severe trauma were determined and correlated with respiratory failure and Sequential Organ Failure Assessment (SOFA) scores. Their cause–effect relationship was studied using cells and mouse models. Measurements and Main Results: In a cohort of 52 patients with severe nonthoracic blunt trauma, circulating histones surged immediately after trauma to levels that were toxic to cultured endothelial cells. The high levels were significantly associated with the incidence of acute lung injury and SOFA scores, as well as markers of endothelial damage and coagulation activation. In in vitro systems, histones damaged endothelial cells, stimulated cytokine release, and induced neutrophil extracellular trap formation and myeloperoxidase release. Cellular toxicity resulted from their direct membrane interaction and resultant calcium influx. In mouse models, cytokines and markers for endothelial damage and coagulation activation significantly increased immediately after trauma or histone infusion. Pathological examinations showed that lungs were the predominantly affected organ with edema, hemorrhage, microvascular thrombosis, and neutrophil congestion. An anti-histone antibody could reduce these changes and protect mice from histone-induced lethality. Conclusions: This study elucidates a new mechanism for acute lung injury after severe trauma and proposes that circulating histones are viable therapeutic targets for improving survival

  10. Zn/Ga−DFO iron–chelating complex attenuates the inflammatory process in a mouse model of asthma

    Directory of Open Access Journals (Sweden)

    Haim Bibi

    2014-01-01

    Conclusion: In this mouse model of allergic asthma, Zn/Ga−DFO attenuated allergic airway inflammation. The beneficial effects of treatment were in accord with iron overload abatement in asthmatic lungs by Zn/Ga−DFO. The findings in both cellular and tissue levels supported the existence of a significant anti-inflammatory effect of Zn/Ga−DFO.

  11. The innate immune response in fetal lung mesenchymal cells targets VEGFR2 expression and activity.

    Science.gov (United States)

    Medal, Rachel M; Im, Amanda M; Yamamoto, Yasutoshi; Lakhdari, Omar; Blackwell, Timothy S; Hoffman, Hal M; Sahoo, Debashis; Prince, Lawrence S

    2017-06-01

    In preterm infants, soluble inflammatory mediators target lung mesenchymal cells, disrupting airway and alveolar morphogenesis. However, how mesenchymal cells respond directly to microbial stimuli remains poorly characterized. Our objective was to measure the genome-wide innate immune response in fetal lung mesenchymal cells exposed to the bacterial endotoxin lipopolysaccharide (LPS). With the use of Affymetrix MoGene 1.0st arrays, we showed that LPS induced expression of unique innate immune transcripts heavily weighted toward CC and CXC family chemokines. The transcriptional response was different between cells from E11, E15, and E18 mouse lungs. In all cells tested, LPS inhibited expression of a small core group of genes including the VEGF receptor Vegfr2 Although best characterized in vascular endothelial populations, we demonstrated here that fetal mouse lung mesenchymal cells express Vegfr2 and respond to VEGF-A stimulation. In mesenchymal cells, VEGF-A increased cell migration, activated the ERK/AKT pathway, and promoted FOXO3A nuclear exclusion. With the use of an experimental coculture model of epithelial-mesenchymal interactions, we also showed that VEGFR2 inhibition prevented formation of three-dimensional structures. Both LPS and tyrosine kinase inhibition reduced three-dimensional structure formation. Our data suggest a novel mechanism for inflammation-mediated defects in lung development involving reduced VEGF signaling in lung mesenchyme. Copyright © 2017 the American Physiological Society.

  12. Anti-Podocalyxin Monoclonal Antibody 47-mG2a Detects Lung Cancers by Immunohistochemistry.

    Science.gov (United States)

    Yamada, Shinji; Itai, Shunsuke; Kaneko, Mika K; Kato, Yukinari

    2018-04-01

    Lung cancer is one of the leading causes of cancer-related deaths in the world. Regardless of the advances in lung cancer treatments, the prognosis is still poor. Podocalyxin (PODXL) is a highly glycosylated type I transmembrane protein that is expressed in normal tissues, including the heart, pancreas, and breast. It is also found and used as a diagnostic marker in many cancers, such as renal, brain, breast, oral, and lung cancers. We previously developed specific and sensitive anti-PODXL monoclonal antibodies, PcMab-47 (mouse IgG 1 , kappa) and its mouse IgG 2a -type (47-mG 2a ), both of which were suitable for immunohistochemical analyses of oral cancers. In this study, we investigated the utility of PcMab-47 and 47-mG 2a for the immunohistochemical analyses of lung cancers. PcMab-47 stained 51/70 (72.9%) cases of lung cancer, whereas 47-mG 2a stained 59/70 (84.3%) cases, indicating that the latter antibody is more sensitive and is useful for detecting PODXL in lung cancers.

  13. Lung Development and Aging.

    Science.gov (United States)

    Bush, Andrew

    2016-12-01

    The onset of chronic obstructive pulmonary disease (COPD) can arise either from failure to attain the normal spirometric plateau or from an accelerated decline in lung function. Despite reports from numerous big cohorts, no single adult life factor, including smoking, accounts for this accelerated decline. By contrast, five childhood risk factors (maternal and paternal asthma, maternal smoking, childhood asthma and respiratory infections) are strongly associated with an accelerated rate of lung function decline and COPD. Among adverse effects on lung development are transgenerational (grandmaternal smoking), antenatal (exposure to tobacco and pollution), and early childhood (exposure to tobacco and pollution including pesticides) factors. Antenatal adverse events can operate by causing structural changes in the developing lung, causing low birth weight and prematurity and altered immunological responses. Also important are mode of delivery, early microbiological exposures, and multiple early atopic sensitizations. Early bronchial hyperresponsiveness, before any evidence of airway inflammation, is associated with adverse respiratory outcomes. Overlapping cohort studies established that spirometry tracks from the preschool years to late middle age, and those with COPD in the sixth decade already had the worst spirometry at age 10 years. Alveolar development is now believed to continue throughout somatic growth and is adversely impacted by early tobacco smoke exposure. Genetic factors are also important, with genes important in lung development and early wheezing also being implicated in COPD. The inescapable conclusion is that the roots of COPD are in early life, and COPD is a disease of childhood adverse factors interacting with genetic factors.

  14. Lung cancer screening: Update

    Energy Technology Data Exchange (ETDEWEB)

    Kim, Hyea Young [Dept. of Radiology, Center for Lung Cancer, National Cancer Center, Goyang (Korea, Republic of)

    2015-09-15

    Lung cancer is the leading cause of cancer deaths worldwide as well as in Korea. A recent National Lung Screening Trial in U.S. revealed that low-dose CT (LDCT) screening reduced lung cancer specific mortality by 20% in high risk individuals as compared to chest radiograph screening. Based on this evidence, several expert societies in U.S. and Korean multisociety collaborative committee developed guidelines for recommendation of lung cancer screening using annual LDCT in high risk populations. In most of the societies high risk groups are defined as persons aged 55 to 74 years, who are current smokers with history of smoking of more than 30 packs per year or ex-smokers, who quit smoking up to 15 or more years ago. The benefits of LDCT screening are modestly higher than the harms in high risk individuals. The harms included a high rate of false-positive findings, over-diagnosis and radiation-related deaths. Invasive diagnostic procedure due to false positive findings may lead to complications. LDCT should be performed in qualified hospitals and interpreted by expert radiologists. Recently, the American College of Radiology released the current version of Lung cancer CT screening Reporting and Data Systems. Education and actions to stop smoking must be offered to current smokers.

  15. Recent lung imaging studies

    International Nuclear Information System (INIS)

    Taplin, G.V.; Chopra, S.K.

    1976-01-01

    Radionuclide lung imaging procedures have been available for 11 years but only the perfusion examination has been used extensively and mainly for the diagnosis of pulmonary embolism (P.E.). Its ability to reveal localized ischemia makes it a valuable test of regional lung function as well as a useful diagnostic aid in P.E. Although it had been recognized for several years that chronic obstructive pulmonary disease (COPD) can cause lung perfusion defects which may simulate pulmonary embolism, relatively little use has been made of either the radioxenon or the radioaerosol inhalation lung imaging procedures until the last few years as a means of distinguishing P.E. from COPD. In this review emphasis is placed on our recent experience with both of these inhalation procedures in comparison with pulmonary function tests and roentgenography for the early detection of COPD in population studies. Equal emphasis is given to simultaneous aerosol ventilation-perfusion (V/P) imaging for a functional diagnosis of P.E. Two new developments in regional lung diffusion imaging, performed after the inhalation of radioactive gases and/or rapidly absorbed radioaerosols are described. The experimental basis for their potential clinical application in pulmonary embolism detection is presented

  16. Lung cancer screening: Update

    International Nuclear Information System (INIS)

    Kim, Hyea Young

    2015-01-01

    Lung cancer is the leading cause of cancer deaths worldwide as well as in Korea. A recent National Lung Screening Trial in U.S. revealed that low-dose CT (LDCT) screening reduced lung cancer specific mortality by 20% in high risk individuals as compared to chest radiograph screening. Based on this evidence, several expert societies in U.S. and Korean multisociety collaborative committee developed guidelines for recommendation of lung cancer screening using annual LDCT in high risk populations. In most of the societies high risk groups are defined as persons aged 55 to 74 years, who are current smokers with history of smoking of more than 30 packs per year or ex-smokers, who quit smoking up to 15 or more years ago. The benefits of LDCT screening are modestly higher than the harms in high risk individuals. The harms included a high rate of false-positive findings, over-diagnosis and radiation-related deaths. Invasive diagnostic procedure due to false positive findings may lead to complications. LDCT should be performed in qualified hospitals and interpreted by expert radiologists. Recently, the American College of Radiology released the current version of Lung cancer CT screening Reporting and Data Systems. Education and actions to stop smoking must be offered to current smokers

  17. Lung Mass in Smokers.

    Science.gov (United States)

    Washko, George R; Kinney, Gregory L; Ross, James C; San José Estépar, Raúl; Han, MeiLan K; Dransfield, Mark T; Kim, Victor; Hatabu, Hiroto; Come, Carolyn E; Bowler, Russell P; Silverman, Edwin K; Crapo, James; Lynch, David A; Hokanson, John; Diaz, Alejandro A

    2017-04-01

    Emphysema is characterized by airspace dilation, inflammation, and irregular deposition of elastin and collagen in the interstitium. Computed tomographic studies have reported that lung mass (LM) may be increased in smokers, a finding attributed to inflammatory and parenchymal remodeling processes observed on histopathology. We sought to examine the epidemiologic and clinical associations of LM in smokers. Baseline epidemiologic, clinical, and computed tomography (CT) data (n = 8156) from smokers enrolled into the COPDGene Study were analyzed. LM was calculated from the CT scan. Changes in lung function at 5 years' follow-up were available from 1623 subjects. Regression analysis was performed to assess for associations of LM with forced expiratory volume in 1 second (FEV 1 ) and FEV 1 decline. Subjects with Global Initiative for Chronic Obstructive Lung Disease (GOLD) 1 chronic obstructive pulmonary disease had greater LM than either smokers with normal lung function or those with GOLD 2-4 chronic obstructive pulmonary disease (P smokers: the presence of such nonlinearity must be accounted for in longitudinal computed tomographic studies. Baseline LM predicts the decline in lung function. Copyright © 2017 The Association of University Radiologists. Published by Elsevier Inc. All rights reserved.

  18. Lung cancer - non-small cell

    Science.gov (United States)

    Cancer - lung - non-small cell; Non-small cell lung cancer; NSCLC; Adenocarcinoma - lung; Squamous cell carcinoma - lung ... Research shows that smoking marijuana may help cancer cells grow. But there is no direct link between ...

  19. General Information about Small Cell Lung Cancer

    Science.gov (United States)

    ... Lung Cancer Prevention Lung Cancer Screening Research Small Cell Lung Cancer Treatment (PDQ®)–Patient Version General Information About Small Cell Lung Cancer Go to Health Professional Version Key Points Small ...

  20. Stages of Small Cell Lung Cancer

    Science.gov (United States)

    ... Lung Cancer Prevention Lung Cancer Screening Research Small Cell Lung Cancer Treatment (PDQ®)–Patient Version General Information About Small Cell Lung Cancer Go to Health Professional Version Key Points Small ...

  1. Radioprotection of normal tissues of the mouse by hypoxic breathing

    International Nuclear Information System (INIS)

    Stevens, G.N.; Joiner, B.; Denekamp, J.

    1989-01-01

    Hypoxic breathing during irradiation has been advocated as a therapeutic modality, to increase the efficacy of radiotherapy. In this form of treatment, the total and daily X-ray dose is increased by a factor of 1.25, on the assumption that all normal tissues in the beam will be protected to a similar extent by breathing gas containing a reduced oxygen concentration (usually 10%). To test this concept, we have determined the effect of varying the inspired oxygen tension on the radiosensitivity of 3 normal tissues in the mouse (kidney, jejunum and skin), and have compared these results with data from the literature for mouse lung. Reduction of the inspired oxygen tension from 21% (air) to 7-8% led to much greater radioprotection of skin (protection factor 1.37) than of lung (1.09). Protection factors for jejunum and kidney were 1.16 and 1.36 respectively. The results show that the extent of radioprotection afforded by hypoxic breathing is tissue dependent, and that great care must be taken clinically in choosing the increased radiation dose to be used in conjunction with hypoxic breathing

  2. A novel minimal invasive mouse model of extracorporeal circulation.

    Science.gov (United States)

    Luo, Shuhua; Tang, Menglin; Du, Lei; Gong, Lina; Xu, Jin; Chen, Youwen; Wang, Yabo; Lin, Ke; An, Qi

    2015-01-01

    Extracorporeal circulation (ECC) is necessary for conventional cardiac surgery and life support, but it often triggers systemic inflammation that can significantly damage tissue. Studies of ECC have been limited to large animals because of the complexity of the surgical procedures involved, which has hampered detailed understanding of ECC-induced injury. Here we describe a minimally invasive mouse model of ECC that may allow more extensive mechanistic studies. The right carotid artery and external jugular vein of anesthetized adult male C57BL/6 mice were cannulated to allow blood flow through a 1/32-inch external tube. All animals (n = 20) survived 30 min ECC and subsequent 60 min observation. Blood analysis after ECC showed significant increases in levels of tumor necrosis factor α, interleukin-6, and neutrophil elastase in plasma, lung, and renal tissues, as well as increases in plasma creatinine and cystatin C and decreases in the oxygenation index. Histopathology showed that ECC induced the expected lung inflammation, which included alveolar congestion, hemorrhage, neutrophil infiltration, and alveolar wall thickening; in renal tissue, ECC induced intracytoplasmic vacuolization, acute tubular necrosis, and epithelial swelling. Our results suggest that this novel, minimally invasive mouse model can recapitulate many of the clinical features of ECC-induced systemic inflammatory response and organ injury.

  3. A Novel Minimal Invasive Mouse Model of Extracorporeal Circulation

    Directory of Open Access Journals (Sweden)

    Shuhua Luo

    2015-01-01

    Full Text Available Extracorporeal circulation (ECC is necessary for conventional cardiac surgery and life support, but it often triggers systemic inflammation that can significantly damage tissue. Studies of ECC have been limited to large animals because of the complexity of the surgical procedures involved, which has hampered detailed understanding of ECC-induced injury. Here we describe a minimally invasive mouse model of ECC that may allow more extensive mechanistic studies. The right carotid artery and external jugular vein of anesthetized adult male C57BL/6 mice were cannulated to allow blood flow through a 1/32-inch external tube. All animals (n=20 survived 30 min ECC and subsequent 60 min observation. Blood analysis after ECC showed significant increases in levels of tumor necrosis factor α, interleukin-6, and neutrophil elastase in plasma, lung, and renal tissues, as well as increases in plasma creatinine and cystatin C and decreases in the oxygenation index. Histopathology showed that ECC induced the expected lung inflammation, which included alveolar congestion, hemorrhage, neutrophil infiltration, and alveolar wall thickening; in renal tissue, ECC induced intracytoplasmic vacuolization, acute tubular necrosis, and epithelial swelling. Our results suggest that this novel, minimally invasive mouse model can recapitulate many of the clinical features of ECC-induced systemic inflammatory response and organ injury.

  4. Advances in lung ultrasound

    International Nuclear Information System (INIS)

    Francisco Neto, Miguel Jose; Rahal Junior, Antonio; Vieira, Fabio Augusto Cardillo; Silva, Paulo Savoia Dias da; Funari, Marcelo Buarque de Gusmao

    2016-01-01

    Ultrasound examination of the chest has advanced in recent decades. This imaging modality is currently used to diagnose several pathological conditions and provides qualitative and quantitative information. Acoustic barriers represented by the aerated lungs and the bony framework of the chest generate well-described sonographic artifacts that can be used as diagnostic aids. The normal pleural line and A, B, C, E and Z lines (also known as false B lines) are artifacts with specific characteristics. Lung consolidation and pneumothorax sonographic patterns are also well established. Some scanning protocols have been used in patient management. The Blue, FALLS and C.A.U.S.E. protocols are examples of algorithms using artifact combinations to achieve accurate diagnoses. Combined chest ultrasonography and radiography are often sufficient to diagnose and manage lung and chest wall conditions. Chest ultrasonography is a highly valuable diagnostic tool for radiologists, emergency and intensive care physicians. (author)

  5. Mitochondria in Lung Diseases

    Science.gov (United States)

    Aravamudan, Bharathi; Thompson, Michael A.; Pabelick, Christina M.; Prakash, Y. S.

    2014-01-01

    Summary Mitochondria are autonomous cellular organelles that oversee a variety of functions such as metabolism, energy production, calcium buffering, and cell fate determination. Regulation of their morphology and diverse activities beyond energy production are being recognized as playing major roles in cellular health and dysfunction. This review is aimed at summarizing what is known regarding mitochondrial contributions to pathogenesis of lung diseases. Emphasis is given to understanding the importance of structural and functional aspects of mitochondria in both normal cellular function (based on knowledge from other cell types) and in development and modulation of lung diseases such as asthma, COPD, cystic fibrosis and cancer. Emerging techniques that allow examination of mitochondria, and potential strategies to target mitochondria in the treatment of lung diseases are also discussed. PMID:23978003

  6. Occupational lung diseases.

    Science.gov (United States)

    Furlow, Bryant

    2011-01-01

    Chest radiography and high-resolution computed tomography are indispensable tools in the detection, classification and characterization of occupational lung diseases that are caused by inhaling mineral particles such as asbestos, silicon-containing rock dust and other tissue-damaging antigens, nanomaterials and toxins. Radiographic evidence of occupational lung disease is interpreted with a patient's clinical signs and symptoms and a detailed occupational history in mind because of high variability in radiographic findings. This Directed Reading reviews the history, epidemiology, functional anatomy, pathobiology and medical diagnostic imaging of occupational lung diseases associated with inhalation of fine particulates in the workplace. This article is a Directed Reading. Your access to Directed Reading quizzes for continuing education credit is determined by your CE preference. For access to other quizzes, go to www.asrt.org/store.

  7. Rare lung cancers

    International Nuclear Information System (INIS)

    Berzinec, P.

    2013-01-01

    The RARECARE Project (Rare Cancers in the Europe) supported by the European Union defined the rare cancers by the incidence rate of less than 6/100 000. There are several variants of lung cancer which are rare according to this definition. From the clinical point of view the most interesting are the rare adenocarcinomas and large cell neuroendocrine carcinoma. There are important differences in the diagnostic probability of EGFR and ALK mutations in the mutinous and non-mucin ous adenocarcinomas, in the signet ring cell adenocarcinomas, and large cell carcinomas. The optimal chemotherapy for neuroendocrine large cell carcinomas remains undefined. There is only very limited number of clinical trials aimed on the rare lung cancers and actually none phase III trial. Rare lung cancers continue to be a challenge both for the laboratory and the clinical research. (author)

  8. [Management of Lung Abscess].

    Science.gov (United States)

    Marra, A; Hillejan, L; Ukena, D

    2015-10-01

    A lung abscess is an infectious pulmonary disease characterised by the presence of a pus-filled cavity within the lung parenchyma. The content of an abscess often drains into the airways spontaneously, leading to an air-fluid level visible on chest X-rays and CT scans. Primary lung abscesses occur in patients who are prone to aspiration or in otherwise healthy individuals; secondary lung abscesses typically develop in association with a stenosing lung neoplasm or a systemic disease that compromises immune defences, such as AIDS, or after organ transplantation. The organisms found in abscesses caused by aspiration pneumonia reflect the resident flora of the oropharynx. The most commonly isolated organisms are anaerobic bacteria (Prevotella, Bacteroides, Fusobacterium, Peptostreptococcus) or streptococci; in alcoholics with poor oral hygiene, the spectrum of pathogens includes Staphylococcus aureus, Streptococcus pyogenes and Actinomyces. Chest radiography and computed tomography (CT) are mandatory procedures in the diagnostic algorithm. Standard treatment for a lung abscess consists of systemic antibiotic therapy, which is based on the anticipated or proven bacterial spectrum of the abscess. In most cases, primary abscesses are successfully treated by calculated empiric antibiotic therapy, with an estimated lethality rate of less than 10 %. Secondary abscesses, despite targeted antimicrobial therapy, are associated with a poor prognosis, which depends on the patient's general condition and underlying disease; lethality is as high as 75 %. Negative prognostic factors are old age, severe comorbidities, immunosuppression, bronchial obstruction, and neoplasms. Surgical intervention due to failure of conservative treatment is required in only 10 % of patients, with a success rate of up to 90 % and postoperative mortality rates ranging between 0 and 33 %. Treatment success after endoscopic or percutaneous drainage is achieved in 73 to 100 % of cases, with an

  9. Anatomy and bronchoscopy of the porcine lung. A model for translational respiratory medicine.

    LENUS (Irish Health Repository)

    Judge, Eoin P

    2014-09-01

    The porcine model has contributed significantly to biomedical research over many decades. The similar size and anatomy of pig and human organs make this model particularly beneficial for translational research in areas such as medical device development, therapeutics and xenotransplantation. In recent years, a major limitation with the porcine model was overcome with the successful generation of gene-targeted pigs and the publication of the pig genome. As a result, the role of this model is likely to become even more important. For the respiratory medicine field, the similarities between pig and human lungs give the porcine model particular potential for advancing translational medicine. An increasing number of lung conditions are being studied and modeled in the pig. Genetically modified porcine models of cystic fibrosis have been generated that, unlike mouse models, develop lung disease similar to human cystic fibrosis. However, the scientific literature relating specifically to porcine lung anatomy and airway histology is limited and is largely restricted to veterinary literature and textbooks. Furthermore, methods for in vivo lung procedures in the pig are rarely described. The aims of this review are to collate the disparate literature on porcine lung anatomy, histology, and microbiology; to provide a comparison with the human lung; and to describe appropriate bronchoscopy procedures for the pig lungs to aid clinical researchers working in the area of translational respiratory medicine using the porcine model.

  10. Lung Cancer Precision Medicine Trials

    Science.gov (United States)

    Patients with lung cancer are benefiting from the boom in targeted and immune-based therapies. With a series of precision medicine trials, NCI is keeping pace with the rapidly changing treatment landscape for lung cancer.

  11. Lung commitment in Tuberous Sclerosis

    International Nuclear Information System (INIS)

    Carrillo B, Jorge A; Araque G, Julio Mario; Camargo P, Carlos B

    1992-01-01

    Tuberous sclerosis is a rare hereditary anomaly characterized by hamartomas in many parts of the body. Lung involvement is found in only one of 100 cases. In this case report we present a patient with lung involvement in tuberous sclerosis

  12. Smoking Marijuana and the Lungs

    Science.gov (United States)

    ... C O P Y PATIENT EDUCATION | INFORMATION SERIES Smoking Marijuana and the Lungs Marijuana, also known as ... a safe way to smoke marijuana. How can smoking marijuana damage my lungs? Tobacco smoke of any ...

  13. Risks of Lung Cancer Screening

    Science.gov (United States)

    ... in women. Different factors increase or decrease the risk of lung cancer. Anything that increases your chance ... been studied to see if they decrease the risk of dying from lung cancer. The following screening ...

  14. Can Lung Nodules Be Cancerous?

    Science.gov (United States)

    ... lung nodules be cancerous? Answers from Eric J. Olson, M.D. Yes, lung nodules can be cancerous, ... to determine if it's cancerous. With Eric J. Olson, M.D. AskMayoExpert. Pulmonary nodules. Rochester, Minn.: Mayo ...

  15. Lung radiopharmaceuticals; Radioformacos pulmonares

    Energy Technology Data Exchange (ETDEWEB)

    Gonzalez, B M [Instituto Nacional de Pediatroa (Mexico)

    1994-12-31

    Indication or main clinical use of Lung radiopharmaceuticals is presented and clasification of radiopharmaceuticals as ventilation and perfusion studies. Perfusion radiopharmaceuticals, main controls for administration quality acceptance. Clearence after blood administration and main clinical applications. Ventilation radiopharmaceuticals, gases and aerosols, characteristics of a ideal radioaerosol, techniques of good inhalation procedure, clinical applications. Comparison of several radiopharmaceuticals reflering to retention time as 50% administered dose, percent administered dose at 6 hours post inhalation, blood activity at 30 and 60 minutes post inhalation, initial lung absorbed dose, cumulated activity.Kinetic description of two radiopharmaceuticals, 99mTcDTPA and 99mTc-PYP.

  16. Staging of lung cancer.

    Science.gov (United States)

    de Groot, Patricia M; Carter, Brett W; Betancourt Cuellar, Sonia L; Erasmus, Jeremy J

    2015-06-01

    Primary lung cancer is the leading cause of cancer mortality in the world. Thorough clinical staging of patients with lung cancer is important, because therapeutic options and management are to a considerable degree dependent on stage at presentation. Radiologic imaging is an essential component of clinical staging, including chest radiography in some cases, computed tomography, MRI, and PET. Multiplanar imaging modalities allow assessment of features that are important for surgical, oncologic, and radiation therapy planning, including size of the primary tumor, location and relationship to normal anatomic structures in the thorax, and existence of nodal and/or metastatic disease. Copyright © 2015 Elsevier Inc. All rights reserved.

  17. Carboxylesterases in lipid metabolism: from mouse to human

    Directory of Open Access Journals (Sweden)

    Jihong Lian

    2017-07-01

    Full Text Available ABSTRACT Mammalian carboxylesterases hydrolyze a wide range of xenobiotic and endogenous compounds, including lipid esters. Physiological functions of carboxylesterases in lipid metabolism and energy homeostasis in vivo have been demonstrated by genetic manipulations and chemical inhibition in mice, and in vitro through (overexpression, knockdown of expression, and chemical inhibition in a variety of cells. Recent research advances have revealed the relevance of carboxylesterases to metabolic diseases such as obesity and fatty liver disease, suggesting these enzymes might be potential targets for treatment of metabolic disorders. In order to translate pre-clinical studies in cellular and mouse models to humans, differences and similarities of carboxylesterases between mice and human need to be elucidated. This review presents and discusses the research progress in structure and function of mouse and human carboxylesterases, and the role of these enzymes in lipid metabolism and metabolic disorders.

  18. A Mouse Model for Human Anal Cancer

    Science.gov (United States)

    Stelzer, Marie K.; Pitot, Henry C.; Liem, Amy; Schweizer, Johannes; Mahoney, Charles; Lambert, Paul F.

    2010-01-01

    Human anal cancers are associated with high-risk human papillomaviruses (HPVs) that cause other anogenital cancers and head and neck cancers. As with other cancers, HPV16 is the most common high-risk HPV in anal cancers. We describe the generation and characterization of a mouse model for human anal cancer. This model makes use of K14E6 and K14E7 transgenic mice in which the HPV16 E6 and E7 genes are directed in their expression to stratified squamous epithelia. HPV16 E6 and E7 possess oncogenic properties including but not limited to their capacity to inactivate the cellular tumor suppressors p53 and pRb, respectively. Both E6 and E7 were found to be functionally expressed in the anal epithelia of K14E6/K14E7 transgenic mice. To assess the susceptibility of these mice to anal cancer, mice were treated topically with dimethylbenz[a]anthracene (DMBA), a chemical carcinogen that is known to induce squamous cell carcinomas in other sites. Nearly 50% of DMBA-treated HPV16 E6/E7 transgenic mice showed overt signs of tumors; whereas, none of the like treated non-transgenic mice showed tumors. Histopathological analyses confirmed that the HPV16 transgenic mice were increased in their susceptibility to anal cancers and precancerous lesions. Biomarker analyses demonstrated that these mouse anal cancers exhibit properties that are similar to those observed in HPV-positive precursors to human anal cancer. This is the first mouse model for investigating the contributions of viral and cellular factors in anal carcinogenesis, and should provide a platform for assessing new therapeutic modalities for treating and/or preventing this type of cancer. PMID:20947489

  19. Radiodiagnosis of lung picture changes

    International Nuclear Information System (INIS)

    Kamenetskij, M.S.; Lezova, T.F.

    1988-01-01

    The roentgenological picture of changes of the lung picture in the case of different pathological states in the lungs and the heart, is described. A developed diagnostic algorithm for the syndrome of lung picture change and the rules of its application are given. 5 refs.; 9 figs

  20. histological changes in the lungs of adult wistar rats following

    African Journals Online (AJOL)

    Exposure to paint fumes over time is dangerous to the lungs and can cause respiratory distress ... harmful chemicals such as -solvents and volatile ... the death of some factory workers where nanoparticles ... diameter 75cm X 50cm X 30cm hole was bored on the cover of .... and allergic effects in children: A review. Indoor Air ...

  1. Chemical Peels

    Science.gov (United States)

    ... for Every Season How to Choose the Best Skin Care Products In This Section Dermatologic Surgery What is dermatologic ... for Every Season How to Choose the Best Skin Care Products Chemical Peels Uses for Chemical Peels Learn more ...

  2. Chemical Oscillations

    Indian Academy of Sciences (India)

    IMTECH),. Chandigarh. Praveen Kumar is pursuing his PhD in chemical dynamics at. Panjab University,. Chandigarh. Keywords. Chemical oscillations, autoca-. talYSis, Lotka-Volterra model, bistability, hysteresis, Briggs-. Rauscher reaction.

  3. Lymphoma and lung cancer in offspring born to pregnant mice dosed with dibenzo[a,l]pyrene: The importance of in utero vs. lactational exposure

    International Nuclear Information System (INIS)

    Castro, David J.; Loehr, Christiane V.; Fischer, Kay A.; Pereira, Clifford B.; Williams, David E.

    2008-01-01

    The fetus and neonate cannot be viewed as 'little adults'; they are highly sensitive to toxicity from environmental chemicals. This phenomenon contributes to the fetal basis of adult disease. One example is transplacental carcinogenesis. Animal models demonstrate that environmental chemicals, to which pregnant women are daily exposed, can increase susceptibility of the offspring to cancer. It is uncertain to what degree in utero vs. lactational exposure contributes to cancer, especially for hydrophobic chemicals such as polyhalogenated biphenyls, ethers, dioxins, furans, etc., which can partition into breast milk. We developed a pregnant mouse model in which exposure to the polycyclic aromatic hydrocarbon (PAH), dibenzo[a,l]pyrene (DBP), during late gestation, produces an aggressive T-cell lymphoma in offspring between 3 and 6 months of age. Survivors exhibit multiple lung and liver (males) tumors. Here, we adopt a cross-foster design with litters born to dams treated with DBP exchanged with those born to dams treated with vehicle. Exposure to DBP in utero (about 2 days) produced significantly greater mortality than residual DBP exposure only through breast milk (3 weeks of lactation). As previously observed pups in all groups with an ahr b-1/d ('responsive') genotype were more susceptible to lymphoma mortality than ahr d/d ('non-responsive') siblings. At termination of the study at 10 months, mice exposed in utero also had greater lung tumor multiplicity than mice exposed only during lactation. Our results demonstrate that short exposure to DBP during late gestation presents a greater risk to offspring than exposure to this very hydrophobic PAH following 3 weeks of nursing

  4. Tissue-specific metabolic activation and mutagenicity of 3-nitrobenzanthrone in MutaMouse.

    Science.gov (United States)

    Chen, Guosheng; Gingerich, John; Soper, Lynda; Douglas, George R; White, Paul A

    2008-10-01

    3-Nitrobenzanthrone (3-NBA) is a mutagen and suspected human carcinogen detected in diesel exhaust, airborne particulate matter, and urban soil. We investigated the tissue specific mutagenicity of 3-NBA at the lacZ locus of transgenic MutaMouse following acute single dose or 28-day repeated-dose oral administration. In the acute high dose (50 mg/kg) exposure, increased lacZ mutant frequency was observed in bone marrow and colonic epithelium, but not in liver and bladder. In the repeated-dose study, a dose-dependent increase in lacZ mutant frequency was observed in bone marrow and liver (2- and 4-fold increase above control), but not in lung or intestinal epithelium. In addition, a concentration-dependent increase in mutant frequency (8.5-fold above control) was observed for MutaMouse FE1 lung epithelial cells exposed in vitro. 1-Nitropyrene reductase, 3-NBA reductase, and acetyltransferase activities were measured in a variety of MutaMouse specimens in an effort to link metabolic activation and mutagenicity. High 3-NBA nitroreductase activities were observed in lung, liver, colon and bladder, and detectable N-acetyltransferase activities were found in all tissues except bone marrow. The relatively high 3-NBA nitroreductase activity in MutaMouse tissues, as compared with those in Salmonella TA98 and TA100, suggests that 3-NBA is readily reduced and activated in vivo. High 3-NBA nitroreductase levels in liver and colon are consistent with the elevated lacZ mutant frequency values, and previously noted inductions of hepatic DNA adducts. Despite an absence of induced lacZ mutations, the highest 3-NBA reductase activity was detected in lung. Further studies are warranted, especially following inhalation or intratracheal exposures. Published 2008 Wiley-Liss, Inc.

  5. Chemical ecotoxicology

    International Nuclear Information System (INIS)

    Paasivirta, J.

    1991-01-01

    This book discusses risk assessment, chemical cycles, structure-activity relations, organohalogens, oil residues, mercury, sampling and analysis of trace chemicals, and emissions from the forestry industry. Topics include: Cycles of chemicals in the environment. Rick assessment and management, strucuture and toxicity, sampling and analysis of trace chemicals in environment, interpretation of the environmental analysis results, mercury in the environment, organohalogen compounds in the environment, emissions from forestry industry, oil residues in the environment: oil spills in the marine environment

  6. Fibroblast Activation Protein (FAP) Accelerates Collagen Degradation and Clearance from Lungs in Mice*

    Science.gov (United States)

    Fan, Ming-Hui; Zhu, Qiang; Li, Hui-Hua; Ra, Hyun-Jeong; Majumdar, Sonali; Gulick, Dexter L.; Jerome, Jacob A.; Madsen, Daniel H.; Christofidou-Solomidou, Melpo; Speicher, David W.; Bachovchin, William W.; Feghali-Bostwick, Carol; Puré, Ellen

    2016-01-01

    Idiopathic pulmonary fibrosis is a disease characterized by progressive, unrelenting lung scarring, with death from respiratory failure within 2–4 years unless lung transplantation is performed. New effective therapies are clearly needed. Fibroblast activation protein (FAP) is a cell surface-associated serine protease up-regulated in the lungs of patients with idiopathic pulmonary fibrosis as well as in wound healing and cancer. We postulate that FAP is not only a marker of disease but influences the development of pulmonary fibrosis after lung injury. In two different models of pulmonary fibrosis, intratracheal bleomycin instillation and thoracic irradiation, we find increased mortality and increased lung fibrosis in FAP-deficient mice compared with wild-type mice. Lung extracellular matrix analysis reveals accumulation of intermediate-sized collagen fragments in FAP-deficient mouse lungs, consistent with in vitro studies showing that FAP mediates ordered proteolytic processing of matrix metalloproteinase (MMP)-derived collagen cleavage products. FAP-mediated collagen processing leads to increased collagen internalization without altering expression of the endocytic collagen receptor, Endo180. Pharmacologic FAP inhibition decreases collagen internalization as expected. Conversely, restoration of FAP expression in the lungs of FAP-deficient mice decreases lung hydroxyproline content after intratracheal bleomycin to levels comparable with that of wild-type controls. Our findings indicate that FAP participates directly, in concert with MMPs, in collagen catabolism and clearance and is an important factor in resolving scar after injury and restoring lung homeostasis. Our study identifies FAP as a novel endogenous regulator of fibrosis and is the first to show FAP's protective effects in the lung. PMID:26663085

  7. Cigarette smoke regulates VEGFR2-mediated survival signaling in rat lungs

    Directory of Open Access Journals (Sweden)

    Stevenson Christopher S

    2010-02-01

    Full Text Available Abstract Background Vascular endothelial growth factor (VEGF and VEGF receptor 2 (VEGFR2-mediated survival signaling is critical to endothelial cell survival, maintenance of the vasculature and alveolar structure and regeneration of lung tissue. Reduced VEGF and VEGFR2 expression in emphysematous lungs has been linked to increased endothelial cell death and vascular regression. Previously, we have shown that CS down-regulated the VEGFR2 and its downstream signaling in mouse lungs. However, the VEGFR2-mediated survival signaling in response to oxidants/cigarette smoke (CS is not known. We hypothesized that CS exposure leads to disruption of VEGFR2-mediated endothelial survival signaling in rat lungs. Methods Adult male Sprague-Dawley rats were exposed CS for 3 days, 8 weeks and 6 months to investigate the effect of CS on VEGFR2-mediated survival signaling by measuring the Akt/PI3-kinase/eNOS downstream signaling in rat lungs. Results and Discussion We show that CS disrupts VEGFR2/PI3-kinase association leading to decreased Akt and eNOS phosphorylation. This may further alter the phosphorylation of the pro-apoptotic protein Bad and increase the Bad/Bcl-xl association. However, this was not associated with a significant lung cell death as evidenced by active caspase-3 levels. These data suggest that although CS altered the VEGFR2-mediated survival signaling in the rat lungs, but it was not sufficient to cause lung cell death. Conclusion The rat lungs exposed to CS in acute, sub-chronic and chronic levels may be representative of smokers where survival signaling is altered but was not associated with lung cell death whereas emphysema is known to be associated with lung cell apoptosis.

  8. Effect of some chemical radioprotectors on mouse bone marrow

    International Nuclear Information System (INIS)

    Lata, Manju; Ghose, A.; Khanna, C.M.

    1993-01-01

    Effect of 5-hydroxy-L-tryptophan (HT), AET and Se on mice bone marrow has been studied by counting bone marrow micronucleated cells and endogenous spleen colony count (CFU-S). Combination of HT and AET used as a radioprotector has not caused any significant variation in any of the parameter studied when administered once, it increases bone marrow micronucleated cells and decreases CFU-S slightly after daily administration for 7 days. The individual constituent of the combination administered singly does not increase micronucleated cell number. Seven consecutive doses of HT+AET and same in combination with Se enhances micronucleated cells to a higher level. Daily injection of Se alone up to 7 days also causes an increase in micronucleated cells up to same level. CFU-S pool does not show any significant change in number of bone marrow cells through out the study except in the groups where animals were treated with Se. (author). 15 refs., 3 tabs

  9. Chemical sensor

    Science.gov (United States)

    Rauh, R. David (Inventor)

    1990-01-01

    A sensor for detecting a chemical substance includes an insertion element having a structure which enables insertion of the chemical substance with a resulting change in the bulk electrical characteristics of the insertion element under conditions sufficient to permit effective insertion; the change in the bulk electrical characteristics of the insertion element is detected as an indication of the presence of the chemical substance.

  10. Pediatric acute lung injury

    NARCIS (Netherlands)

    Dahlem, P.; van Aalderen, W. M. C.; Bos, A. P.

    2007-01-01

    Among ventilated children, the incidence of acute lung injury (ALI) was 9%; of that latter group 80% developed the acute respiratory distress syndrome (ARDS). The population-based prevalence of pediatric ARDS was 5.5 cases/100.000 inhabitants. Underlying diseases in children were septic shock (34%),

  11. Tuberculosis mimicking lung cancer

    Directory of Open Access Journals (Sweden)

    I. Hammen

    2015-01-01

    Our case report presents two patients, who were referred to the Thorax diagnostic centre at the Department of Respiratory Medicine, Odense University Hospital, with presumptive diagnosis of neoplasm and had proved lung TB with no evidence of malignancy instead. In the first case diagnosis was confirmed after thoracotomy,