WorldWideScience

Sample records for beta-toxin induces lung

  1. Evidence of the protective immunogenicity of native and recombinant Clostridium haemolyticum phospholipase C (beta toxin) in guinea pigs.

    Science.gov (United States)

    Hauer, Paul J; Yeary, Teresa J; Rosenbusch, Ricardo F

    2006-01-12

    The immunogenic effects of the beta toxin of Clostridium haemolyticum were investigated in guinea pigs. Guinea pigs passively immunized with toxin-neutralizing monoclonal antibodies were protected from a 100 LD(50) spore challenge that was lethal to nonvaccinated controls. Guinea pigs actively immunized with varying doses of immunoaffinity-purified native beta toxin were similarly protected. In a third experiment, a recombinant toxoid was prepared from E. coli expressing the beta toxin gene. Guinea pigs immunized three times with recombinant toxoid also were protected against challenge. In each experiment, protection was correlated to the presence of anti-beta toxin antibodies in the serum. Taken together, these results indicate that a neutralizing antibody response to the beta toxin is a key component of protective immunity to C. haemolyticum in guinea pigs.

  2. Ventilator-induced lung injury.

    Science.gov (United States)

    Ricard, J D; Dreyfuss, D; Saumon, G

    2003-08-01

    During mechanical ventilation, high end-inspiratory lung volume (whether it be because of large tidal volume (VT) and/or high levels of positive end-expiratory pressure) results in a permeability type pulmonary oedema, called ventilator-induced lung injury (VILI). Previous injury sensitises lung to mechanical ventilation. This experimental concept has recently received a resounding clinical illustration after a 22% reduction of mortality was observed in acute respiratory distress syndrome patients whose VT had been reduced. In addition, it has been suggested that repetitive opening and closing of distal units at low lung volume could induce lung injury but this notion has been challenged both conceptually and clinically after the negative results of the Acute Respiratory Distress Syndrome clinical Network Assessment of Low tidal Volume and Elevated end-expiratory volume to Obviate Lung Injury (ARDSNet ALVEOLI) study. Experimentally and clinically, involvement of inflammatory cytokines in VILI has not been unequivocally demonstrated. Cellular response to mechanical stretch has been increasingly investigated, both on the epithelial and the endothelial side. Lipid membrane trafficking has been thought to be a means by which cells respond to stress failure. Alterations in the respiratory system pressure/volume curve during ventilator-induced lung injury that include decrease in compliance and position of the upper inflection point are due to distal obstruction of airways that reduce aerated lung volume. Information from this curve could help avoid potentially harmful excessive tidal volume reduction.

  3. Cloning and molecular characterization of the beta toxin (phospholipase C) gene of Clostridium haemolyticum.

    Science.gov (United States)

    Hauer, Paul J; Yeary, Teresa J; Rosenbusch, Ricardo F

    2004-08-01

    The phospholipase C (PLPC) gene from Clostridium haemolyticum was amplified using the polymerase chain reaction. Primers were selected from a consensus sequence of closely related clostridial PLPC genes and used to amplify an 871-base pair internal segment of the gene. The internal sequence was used to design nested primers that, together with adapter-specific primers, were used to amplify upstream and downstream sequences. The sequences of upstream and downstream segments were aligned with the internal segment to obtain the entire gene sequence. Primers were selected from the aligned sequence, and the entire gene was amplified, and the PCR product was inserted by ligatation into the pCR 2.1 plasmid. An open reading frame that encodes a 399-amino acid protein, containing a 27-amino acid signal sequence, was identified (GenBank Accession Number AF525415). The molecular weight of the active protein was 42869 Da. A 16-amino acid N-terminal sequence, determined by Edman degradation, exactly matched the putative amino acid sequence of the gene product. Together, N-terminal peptide sequencing and tryptic digestion followed by MALDI-ToF mass spectroscopy verified 48% of the amino acid sequences of the active beta toxin. Comparison of the nucleotide and amino acid sequences with Gene-bank databases demonstrated that the beta toxin of C. haemolyticum exhibits high homology with other bacterial PLPCs. The N-terminal portion of the beta toxin contains zinc-binding residues common to clostridial and other bacterial PLPCs, and it shows 34% homology to the N-terminal domain of bovine arachidonate 5-lipoxygenase. The C-terminal domain of the beta toxin protein shows considerable homology with the C-terminal domains of C. novyi type A PLPC, C. perfringens alpha toxin, C. bifermentens PLPC, although the percent identity between the N-terminal regions is much higher overall than that in the C-terminal domain.

  4. Bleomycin-Induced Lung Injury

    Directory of Open Access Journals (Sweden)

    Tomás Reinert

    2013-01-01

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

  5. Oxidative Lung Injury in Virus-Induced Wheezing

    Science.gov (United States)

    2014-05-01

    antioxidant enzyme (AOE) genes in the lung. Thus, we propose a new molecular pathway by which respiratory viruses induce lung inflammation, with implication...AOE) genes in the lung. Thus, we propose a new molecular pathway by which respiratory viruses induce lung inflammation, with implication for novel...model of infection, with significant amelioration of oxidative stress, which is an important pathogenetic component of viral-induced lung disease

  6. Acute and subacute chemical-induced lung injuries: HRCT findings

    Energy Technology Data Exchange (ETDEWEB)

    Akira, Masanori, E-mail: Akira@kch.hosp.go.jp [Department of Radiology, National Hospital Organization Kinki-Chuo Chest Medical Center, 1180 Nagasone-cho, Kita-ku, Sakai City, Osaka 591-8555 (Japan); Suganuma, Narufumi [Department of Environmental Medicine, Kochi Medical School (Japan)

    2014-08-15

    Lung injury caused by chemicals includes bronchitis, bronchiolitis, chemical pneumonitis, pulmonary edema, acute respiratory distress syndrome, organizing pneumonia, hypersensitivity pneumonitis, acute eosinophilic pneumonia, and sarcoid-like granulomatous lung disease. Each chemical induces variable pathophysiology and the situation resembles to the drug induced lung disease. The HRCT features are variable and nonspecific, however HRCT may be useful in the evaluation of the lung injuries and so we should know about HRCT features of lung parenchymal abnormalities caused by chemicals.

  7. Radiation-induced lung injury

    International Nuclear Information System (INIS)

    Rosiello, R.A.; Merrill, W.W.

    1990-01-01

    The use of radiation therapy is limited by the occurrence of the potentially fatal clinical syndromes of radiation pneumonitis and fibrosis. Radiation pneumonitis usually becomes clinically apparent from 2 to 6 months after completion of radiation therapy. It is characterized by fever, cough, dyspnea, and alveolar infiltrates on chest roentgenogram and may be difficult to differentiate from infection or recurrent malignancy. The pathogenesis is uncertain, but appears to involve both direct lung tissue toxicity and an inflammatory response. The syndrome may resolve spontaneously or may progress to respiratory failure. Corticosteroids may be effective therapy if started early in the course of the disease. The time course for the development of radiation fibrosis is later than that for radiation pneumonitis. It is usually present by 1 year following irradiation, but may not become clinically apparent until 2 years after radiation therapy. It is characterized by the insidious onset of dyspnea on exertion. It most often is mild, but can progress to chronic respiratory failure. There is no known successful treatment for this condition. 51 references

  8. Lung emphysema induced by cigarette smoke: Studies in mice

    NARCIS (Netherlands)

    Eijl, Teunis Jan Ahasuerus van

    2006-01-01

    The experiments described in this thesis were designed to shed some more light on the mechanisms underlying cigarette smoke-induced lung emphysema. We used elastase instillation to induce lung emphysema, and subsequently perfused the lungs ex-vivo with buffer at a range of flows to measure changes

  9. Pathology of radiation induced lung damage

    International Nuclear Information System (INIS)

    Kawabata, Yoshinori; Murata, Yoshihiko; Ogata, Hideo; Katagiri, Shiro; Sugita, Hironobu; Iwai, Kazuo; Sakurai, Isamu.

    1985-01-01

    We examined pathological findings of radiation induced lung damage. Twenty-three cases are chosen from our hospital autopsy cases for 9 years, which fulfil strict criteria of radiation lung damage. Lung damage could be classified into 3 groups : 1) interstitial pneumonia type (9 cases), 2) intermediate pneumonia type (8 cases), and 3) alveolar pneumonia type (6 cases), according to the degree of intra-luminal exudation. These classification is well correlated with clinical findings. Pathological alveolar pneumonia type corresponds to symptomatic, radiologic ground glass pneumonic shadow. And pathologic interstitial type corresponds to clinical asymptomatic, radiologic reticulo-nodular shadow. From the clinico-pathological view point these classification is reasonable one. Radiation affects many lung structures and showed characteristic feature of repair. Elastofibrosis of the alveolar wall is observed in every cases, obstructive bronchiolitis are observed in 5 cases, and obstructive bronchiolitis in 9 cases. They are remarkable additional findings. Thickening of the interlobular septum, broncho-vascular connective tissue, and pleural layer are observed in every cases together with vascular lesions. (author)

  10. Clostridium perfringens delta toxin is sequence related to beta toxin, NetB, and Staphylococcus pore-forming toxins, but shows functional differences.

    Directory of Open Access Journals (Sweden)

    Maria Manich

    Full Text Available Clostridium perfringens produces numerous toxins, which are responsible for severe diseases in man and animals. Delta toxin is one of the three hemolysins released by a number of C. perfringens type C and possibly type B strains. Delta toxin was characterized to be cytotoxic for cells expressing the ganglioside G(M2 in their membrane. Here we report the genetic characterization of Delta toxin and its pore forming activity in lipid bilayers. Delta toxin consists of 318 amino acids, its 28 N-terminal amino acids corresponding to a signal peptide. The secreted Delta toxin (290 amino acids; 32619 Da is a basic protein (pI 9.1 which shows a significant homology with C. perfringens Beta toxin (43% identity, with C. perfringens NetB (40% identity and, to a lesser extent, with Staphylococcus aureus alpha toxin and leukotoxins. Recombinant Delta toxin showed a preference for binding to G(M2, in contrast to Beta toxin, which did not bind to gangliosides. It is hemolytic for sheep red blood cells and cytotoxic for HeLa cells. In artificial diphytanoyl phosphatidylcholine membranes, Delta and Beta toxin formed channels. Conductance of the channels formed by Delta toxin, with a value of about 100 pS to more than 1 nS in 1 M KCl and a membrane potential of 20 mV, was higher than those formed by Beta toxin and their distribution was broader. The results of zero-current membrane potential measurements and single channel experiments suggest that Delta toxin forms slightly anion-selective channels, whereas the Beta toxin channels showed a preference for cations under the same conditions. C. perfringens Delta toxin shows a significant sequence homolgy with C. perfringens Beta and NetB toxins, as well as with S. aureus alpha hemolysin and leukotoxins, but exhibits different channel properties in lipid bilayers. In contrast to Beta toxin, Delta toxin recognizes G(M2 as receptor and forms anion-selective channels.

  11. Allicin Protects against Lipopolysaccharide-Induced Acute Lung ...

    African Journals Online (AJOL)

    Purpose: To investigate the effect of allicin, an active component of garlic, on lipopolysaccharide (LPS)- induced acute lung injury. Methods: Wistar rats were subjected to LPS intravenous injection with or without allicin treatment to induce acute lung injury (ALI) model. Also, A549 cells were stimulated with LPS in the ...

  12. 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

  13. Combined prednisolone and pirfenidone in bleomycin-induced lung disease

    Directory of Open Access Journals (Sweden)

    Preyas J Vaidya

    2016-01-01

    Full Text Available Bleomycin is a cytostatic drug commonly employed in the treatment of Hodgkin's disease, seminomas, and choriocarcinoma. Bleomycin may induce a chronic pulmonary inflammation that may progress to fibrosis. So far, only corticosteroids have been used in the treatment of bleomycin-induced lung disease with variable results. Pirfenidone is an antifibrotic drug that has been approved for the treatment of idiopathic pulmonary fibrosis. We report two cases of bleomycin-induced lung disease treated successfully with pirfenidone and oral corticosteroids.

  14. Radiation induced lung injury: prediction, assessment and management.

    Science.gov (United States)

    Giridhar, Prashanth; Mallick, Supriya; Rath, Goura Kishore; Julka, Pramod Kumar

    2015-01-01

    Radiation induced lung injury has long been considered a treatment limiting factor for patients requiring thoracic radiation. This radiation induced lung injury happens early as well as late. Radiation induced lung injury can occur in two phases viz. early (radiation pneumonitis and late (>6 months) when it is called radiation induced lung fibrosis. There are multiple factors that can be patient, disease or treatment related that predict the incidence and severity of radiation pneumonitis. Radiation induced damage to the type I pneumocytes is the triggering factor to initiate such reactions. Over the years, radiation therapy has witnessed a paradigm shift in radiation planning and delivery and successfully reduced the incidence of lung injury. Radiation pneumonitis is usually a diagnosis of exclusion. Steroids, ACE inhibitors and pentoxyphylline constitute the cornerstone of therapy. Radiation induced lung fibrosis is another challenging aspect. The pathophysiology of radiation fibrosis includes continuing inflammation and microvascular changes due to pro-angiogenic and pro- fibrogenic stimuli resembling those in adult bronchiectasis. General supportive management, mobilization of airway secretions, anti-inflammatory therapy and management of acute exacerbations remains the treatment option. Radiation induced lung injury is an inevitable accompaniment of thoracic radiation.

  15. On Academician Behounek's paper ''Lung cancer induced by ionizing radiation''

    International Nuclear Information System (INIS)

    Thomas, J.

    1979-01-01

    The significance and scientific contribution are discussed of the paper ''Lung Cancer Induced by Ionizing Radiation'' submitted by Academician Frantisek Behounek to the nation-wide workshop of the Czechoslovak Society of Pneumology and Oncology in Prague, October 3 and 4, 1952 and published in the Proceedings in 1953. The paper discussed the problem which still remains topical, ie., lung exposure to radon daughters, which Academician Behounek considered to be the true cause of lung cancer in Jachymov miners. (B.S.)

  16. Corilagin Attenuates Aerosol Bleomycin-Induced Experimental Lung Injury

    Science.gov (United States)

    Wang, Zheng; Guo, Qiong-Ya; Zhang, Xiao-Ju; Li, Xiao; Li, Wen-Ting; Ma, Xi-Tao; Ma, Li-Jun

    2014-01-01

    Idiopathic pulmonary fibrosis (IPF) is a progressing lethal disease with few clinically effective therapies. Corilagin is a tannin derivative which shows anti-inflammatory and antifibrotics properties and is potentiated in treating IPF. Here, we investigated the effect of corilagin on lung injury following bleomycin exposure in an animal model of pulmonary fibrosis. Corilagin abrogated bleomycin-induced lung fibrosis as assessed by H&E; Masson’s trichrome staining and lung hydroxyproline content in lung tissue. Corilagin reduced the number of apoptotic lung cells and prevented lung epithelial cells from membrane breakdown, effluence of lamellar bodies and thickening of the respiratory membrane. Bleomycin exposure induced expression of MDA, IKKα, phosphorylated IKKα (p-IKKα), NF-κB P65, TNF-α and IL-1β, and reduced I-κB expression in mice lung tissue or in BALF. These changes were reversed by high-dose corilagin (100 mg/kg i.p) more dramatically than by low dose (10 mg/kg i.p). Last, corilagin inhibits TGF-β1 production and α-SMA expression in lung tissue samples. Taken together, these findings confirmed that corilagin attenuates bleomycin-induced epithelial injury and fibrosis via inactivation of oxidative stress, proinflammatory cytokine release and NF-κB and TGF-β1 signaling. Corilagin may serve as a promising therapeutic agent for pulmonary fibrosis. PMID:24886817

  17. Increased isoprostane levels in oleic acid-induced lung injury

    Energy Technology Data Exchange (ETDEWEB)

    Ono, Koichi [Department of Anesthesiology and Resuscitation, Shinshu University School of Medicine, Matsumoto (Japan); Koizumi, Tomonobu, E-mail: tomonobu@shinshu-u.ac.jp [First Department of Internal Medicine, Shinshu University School of Medicine, Matsumoto (Japan); Tsushima, Kenji; Yoshikawa, Sumiko; Yokoyama, Toshiki [First Department of Internal Medicine, Shinshu University School of Medicine, Matsumoto (Japan); Nakagawa, Rikimaru [Department of Anesthesiology and Resuscitation, Shinshu University School of Medicine, Matsumoto (Japan); Obata, Toru [Department of Molecular Cell Biology, Institute of DNA Medicine, Jikei University School of Medicine, Tokyo (Japan)

    2009-10-16

    The present study was performed to examine a role of oxidative stress in oleic acid-induced lung injury model. Fifteen anesthetized sheep were ventilated and instrumented with a lung lymph fistula and vascular catheters for blood gas analysis and measurement of isoprostanes (8-epi prostaglandin F2{alpha}). Following stable baseline measurements, oleic acid (0.08 ml/kg) was administered and observed 4 h. Isoprostane was measured by gas chromatography mass spectrometry with the isotope dilution method. Isoprostane levels in plasma and lung lymph were significantly increased 2 h after oleic acid administration and then decreased at 4 h. The percent increases in isoprostane levels in plasma and lung lymph at 2 h were significantly correlated with deteriorated oxygenation at the same time point, respectively. These findings suggest that oxidative stress is involved in the pathogenesis of the pulmonary fat embolism-induced acute lung injury model in sheep and that the increase relates with the deteriorated oxygenation.

  18. Niacinamide mitigated the acute lung injury induced by phorbol myristate acetate in isolated rat's lungs

    Directory of Open Access Journals (Sweden)

    Lin Chia-Chih

    2012-03-01

    Full Text Available Abstract Background Phorbol myristate acetate (PMA is a strong neutrophil activator and has been used to induce acute lung injury (ALI. Niacinamide (NAC is a compound of B complex. It exerts protective effects on the ALI caused by various challenges. The purpose was to evaluate the protective effects of niacinamide (NAC on the PMA-induced ALI and associated changes. Methods The rat's lungs were isolated in situ and perfused with constant flow. A total of 60 isolated lungs were randomized into 6 groups to received Vehicle (DMSO 100 μg/g, PMA 4 μg/g (lung weight, cotreated with NAC 0, 100, 200 and 400 mg/g (lung weight. There were 10 isolated lungs in each group. We measured the lung weight and parameters related to ALI. The pulmonary arterial pressure and capillary filtration coefficient (Kfc were determined in isolated lungs. ATP (adenotriphosphate and PARP [poly(adenosine diphophate-ribose polymerase] contents in lung tissues were detected. Real-time PCR was employed to display the expression of inducible and endothelial NO synthases (iNOS and eNOS. The neutrophil-derived mediators in lung perfusate were determined. Results PMA caused increases in lung weight parameters. This agent produced pulmonary hypertension and increased microvascular permeability. It resulted in decrease in ATP and increase in PARP. The expression of iNOS and eNOS was upregulated following PMA. PMA increased the neutrophil-derived mediators. Pathological examination revealed lung edema and hemorrhage with inflammatory cell infiltration. Immunohistochemical stain disclosed the presence of iNOS-positive cells in macrophages and endothelial cells. These pathophysiological and biochemical changes were diminished by NAC treatment. The NAC effects were dose-dependent. Conclusions Our results suggest that neutrophil activation and release of neutrophil-derived mediators by PMA cause ALI and associated changes. NO production through the iNOS-producing cells plays a detrimental

  19. Niacinamide mitigated the acute lung injury induced by phorbol myristate acetate in isolated rat's lungs.

    Science.gov (United States)

    Lin, Chia-Chih; Hsieh, Nan-Kuang; Liou, Huey Ling; Chen, Hsing I

    2012-03-01

    Phorbol myristate acetate (PMA) is a strong neutrophil activator and has been used to induce acute lung injury (ALI). Niacinamide (NAC) is a compound of B complex. It exerts protective effects on the ALI caused by various challenges. The purpose was to evaluate the protective effects of niacinamide (NAC) on the PMA-induced ALI and associated changes. The rat's lungs were isolated in situ and perfused with constant flow. A total of 60 isolated lungs were randomized into 6 groups to received Vehicle (DMSO 100 μg/g), PMA 4 μg/g (lung weight), cotreated with NAC 0, 100, 200 and 400 mg/g (lung weight). There were 10 isolated lungs in each group. We measured the lung weight and parameters related to ALI. The pulmonary arterial pressure and capillary filtration coefficient (Kfc) were determined in isolated lungs. ATP (adenotriphosphate) and PARP [poly(adenosine diphophate-ribose) polymerase] contents in lung tissues were detected. Real-time PCR was employed to display the expression of inducible and endothelial NO synthases (iNOS and eNOS). The neutrophil-derived mediators in lung perfusate were determined. PMA caused increases in lung weight parameters. This agent produced pulmonary hypertension and increased microvascular permeability. It resulted in decrease in ATP and increase in PARP. The expression of iNOS and eNOS was upregulated following PMA. PMA increased the neutrophil-derived mediators. Pathological examination revealed lung edema and hemorrhage with inflammatory cell infiltration. Immunohistochemical stain disclosed the presence of iNOS-positive cells in macrophages and endothelial cells. These pathophysiological and biochemical changes were diminished by NAC treatment. The NAC effects were dose-dependent. Our results suggest that neutrophil activation and release of neutrophil-derived mediators by PMA cause ALI and associated changes. NO production through the iNOS-producing cells plays a detrimental role in the PMA-induced lung injury. ATP is beneficial

  20. Cannabidiol improves lung function and inflammation in mice submitted to LPS-induced acute lung injury.

    Science.gov (United States)

    Ribeiro, A; Almeida, V I; Costola-de-Souza, C; Ferraz-de-Paula, V; Pinheiro, M L; Vitoretti, L B; Gimenes-Junior, J A; Akamine, A T; Crippa, J A; Tavares-de-Lima, W; Palermo-Neto, J

    2015-02-01

    We have previously shown that the prophylactic treatment with cannabidiol (CBD) reduces inflammation in a model of acute lung injury (ALI). In this work we analyzed the effects of the therapeutic treatment with CBD in mice subjected to the model of lipopolysaccharide (LPS)-induced ALI on pulmonary mechanics and inflammation. CBD (20 and 80 mg/kg) was administered (i.p.) to mice 6 h after LPS-induced lung inflammation. One day (24 h) after the induction of inflammation the assessment of pulmonary mechanics and inflammation were analyzed. The results show that CBD decreased total lung resistance and elastance, leukocyte migration into the lungs, myeloperoxidase activity in the lung tissue, protein concentration and production of pro-inflammatory cytokines (TNF and IL-6) and chemokines (MCP-1 and MIP-2) in the bronchoalveolar lavage supernatant. Thus, we conclude that CBD administered therapeutically, i.e. during an ongoing inflammatory process, has a potent anti-inflammatory effect and also improves the lung function in mice submitted to LPS-induced ALI. Therefore the present and previous data suggest that in the future cannabidiol might become a useful therapeutic tool for the attenuation and treatment of inflammatory lung diseases.

  1. CXCR2 is critical for dsRNA-induced lung injury: relevance to viral lung infection

    Directory of Open Access Journals (Sweden)

    Xue Ying

    2005-05-01

    Full Text Available Abstract Background Respiratory viral infections are characterized by the infiltration of leukocytes, including activated neutrophils into the lung that can lead to sustained lung injury and potentially contribute to chronic lung disease. Specific mechanisms recruiting neutrophils to the lung during virus-induced lung inflammation and injury have not been fully elucidated. Since CXCL1 and CXCL2/3, acting through CXCR2, are potent neutrophil chemoattractants, we investigated their role in dsRNA-induced lung injury, where dsRNA (Poly IC is a well-described synthetic agent mimicking acute viral infection. Methods We used 6–8 week old female BALB/c mice to intratracheally inject either single-stranded (ssRNA or double-stranded RNA (dsRNA into the airways. The lungs were then harvested at designated timepoints to characterize the elicited chemokine response and resultant lung injury following dsRNA exposure as demonstrated qualititatively by histopathologic analysis, and quantitatively by FACS, protein, and mRNA analysis of BAL fluid and tissue samples. We then repeated the experiments by first pretreating mice with an anti-PMN or corresponding control antibody, and then subsequently pretreating a separate cohort of mice with an anti-CXCR2 or corresponding control antibody prior to dsRNA exposure. Results Intratracheal dsRNA led to significant increases in neutrophil infiltration and lung injury in BALB/c mice at 72 h following dsRNA, but not in response to ssRNA (Poly C; control treatment. Expression of CXCR2 ligands and CXCR2 paralleled neutrophil recruitment to the lung. Neutrophil depletion studies significantly reduced neutrophil infiltration and lung injury in response to dsRNA when mice were pretreated with an anti-PMN monoclonal Ab. Furthermore, inhibition of CXCR2 ligands/CXCR2 interaction by pretreating dsRNA-exposed mice with an anti-CXCR2 neutralizing Ab also significantly attenuated neutrophil sequestration and lung injury. Conclusion

  2. Titanium Dioxide Exposure Induces Acute Eosinophilic Lung Inflammation in Rabbits

    Science.gov (United States)

    CHOI, Gil Soon; OAK, Chulho; CHUN, Bong-Kwon; WILSON, Donald; JANG, Tae Won; KIM, Hee-Kyoo; JUNG, Mannhong; TUTKUN, Engin; PARK, Eun-Kee

    2014-01-01

    Titanium dioxide (TiO2) is increasingly widely used in industrial, commercial and home products. TiO2 aggravates respiratory symptoms by induction of pulmonary inflammation although the mechanisms have not been well investigated. We aimed to investigate lung inflammation in rabbits after intratracheal instillation of P25 TiO2. One ml of 10, 50 and 250 µg of P25 TiO2 was instilled into one of the lungs of rabbits, chest computed-tomography was performed, and bronchoalveolar lavage (BAL) fluid was collected before, at 1 and 24 h after P25 TiO2 exposure. Changes in inflammatory cells in the BAL fluids were measured. Lung pathological assay was also carried out at 24 h after P25 TiO2 exposure. Ground glass opacities were noted in both lungs 1 h after P25 TiO2 and saline (control) instillation. Although the control lung showed complete resolution at 24 h, the lung exposed to P25 TiO2 showed persistent ground glass opacities at 24 h. The eosinophil counts in BAL fluid were significantly increased after P25 TiO2 exposure. P25 TiO2 induced a dose dependent increase of eosinophils in BAL fluid but no significant differences in neutrophil and lymphocyte cell counts were detected. The present findings suggest that P25 TiO2 induces lung inflammation in rabbits which is associated with eosinophilic inflammation. PMID:24705802

  3. The Role of Radiation Induced Injury on Lung Cancer

    Directory of Open Access Journals (Sweden)

    Stephanie Puukila

    2017-07-01

    Full Text Available This manuscript evaluates the role of cell killing, tissue disorganization, and tissue damage on the induction of lung cancer following low dose rate radiation exposures from internally deposited radioactive materials. Beagle dogs were exposed by inhalation to 90Y, 91Y, 144Ce, or 90Sr in fused clay particles. Dogs lived out their life span with complete pathology conducted at the time of death. The radiation dose per cell turnover was characterized and related to the cause of death for each animal. Large doses per cell turnover resulted in acute death from lung damage with extensive cell killing, tissue disorganization, chronic inflammatory disease, fibrosis, and pneumonitis. Dogs with lower doses per cell turnover developed a very high frequency of lung cancer. As the dose per cell turnover was further decreased, no marked tissue damage and no significant change in either life span or lung cancer frequency was observed. Radiation induced tissue damage and chronic inflammatory disease results in high cancer frequencies in the lung. At doses where a high frequency of chromosome damage and mutations would be predicted to occur there was no decrease in life span or increase in lung cancer. Such research suggests that cell killing and tissue damage and the physiological responses to that damage are important mechanisms in radiation induced lung cancer.

  4. Rituximab-induced interstitial lung disease

    DEFF Research Database (Denmark)

    Naqibullah, Matiuallah; Shaker, Saher B; Bach, Karen S

    2015-01-01

    , rheumatoid arthritis, and autoimmune hemolytic anemia. Recently, RTX has also been suggested for the treatment of certain connective tissue disease-related interstitial lung diseases (ILD) and hypersensitivity pneumonitis. Rare but serious pulmonary adverse reactions are reported. To raise awareness about...

  5. Molecular characterization of radon-induced rat lung tumors

    International Nuclear Information System (INIS)

    Guillet Bastide, K.

    2008-11-01

    The radon gas is a well known lung carcinogenic factor in human at high doses but the cancer risk at low doses is not established. Indeed, epidemiological studies at low doses are difficult to conduct because of the human exposure to other lung carcinogenic factors. These data underlined the necessity to conduct experiments on lung tumors developed on animal model. The aim of this work was to characterize rat lung tumors by working on a series of radon-induced tumors that included adenocarcinomas (A.C.), squamous cell carcinomas (S.C.C.) and adeno-squamous carcinomas (A.S.C.), that are mixed tumors with both A.C. and S.C.C. cellular components. A C.G.H. analysis of the three types of tumors allowed us to define chromosomal recurrent unbalances and to target candidate genes potentially implicated in lung carcinogenesis, as p16Ink4a, p19Arf, Rb1, K-Ras or c-Myc. A more precise analysis of the p16Ink4a/Cdk4/Rb1 and p19Arf/Mdm2/Tp53 pathways was performed and indicated that the Rb1 pathway was frequently inactivated through an absence of p16 Ink4a protein expression, indicating that it has a major role in rat lung carcinogenesis. Finally, a comparative transcriptomic analysis of the three types of tumors allowed us to show for the first time that the complex tumors A.S.C. have a transcriptomic profile in accordance with their mixed nature but that they also display their own expression profiles specificities. This work allowed us to find molecular characteristics common to murine and human lung tumors, indicating that the model of lung tumors in rat is pertinent to search for radiation-induced lung tumors specificities and to help for a better molecular identification of this type of tumors in human. (author)

  6. Lung irradiation induces pulmonary vascular remodelling resembling pulmonary arterial hypertension.

    Science.gov (United States)

    Ghobadi, G; Bartelds, B; van der Veen, S J; Dickinson, M G; Brandenburg, S; Berger, R M F; Langendijk, J A; Coppes, R P; van Luijk, P

    2012-04-01

    Pulmonary arterial hypertension (PAH) is a commonly fatal pulmonary vascular disease that is often diagnosed late and is characterised by a progressive rise in pulmonary vascular resistance resulting from typical vascular remodelling. Recent data suggest that vascular damage plays an important role in the development of radiation-induced pulmonary toxicity. Therefore, the authors investigated whether irradiation of the lung also induces pulmonary hypertension. Different sub-volumes of the rat lung were irradiated with protons known to induce different levels of pulmonary vascular damage. Early loss of endothelial cells and vascular oedema were observed in the irradiation field and in shielded parts of the lung, even before the onset of clinical symptoms. 8 weeks after irradiation, irradiated volume-dependent vascular remodelling was observed, correlating perfectly with pulmonary artery pressure, right ventricle hypertrophy and pulmonary dysfunction. The findings indicate that partial lung irradiation induces pulmonary vascular remodelling resulting from acute pulmonary endothelial cell loss and consequential pulmonary hypertension. Moreover, the close resemblance of the observed vascular remodelling with vascular lesions in PAH makes partial lung irradiation a promising new model for studying PAH.

  7. Retrospective analysis of steroid therapy for radiation-induced lung injury in lung cancer patients

    International Nuclear Information System (INIS)

    Sekine, Ikuo; Sumi, Minako; Ito, Yoshinori; Nokihara, Hiroshi; Yamamoto, Noboru; Kunitoh, Hideo; Ohe, Yuichiro; Kodama, Tetsuro; Saijo, Nagahiro; Tamura, Tomohide

    2006-01-01

    Purpose: To disclose characteristics of lung cancer patients developing radiation-induced lung injury treated with or without corticosteroid therapy. Methods and materials: Radiographic changes, symptoms, history of corticosteroid prescription, and clinical course after 50-70 Gy of thoracic radiotherapy were retrospectively evaluated in 385 lung cancer patients. Results: Radiation-induced lung injury was stable without corticosteroid in 307 patients (Group 1), stable with corticosteroid in 64 patients (Group 2), and progressive to death despite corticosteroid in 14 patients (Group 3). Fever and dyspnea were noted in 11%, 50% and 86% (p < 0.001), and in 13%, 44% and 57% (p < 0.001) patients in Groups 1-3, respectively. Median weeks between the end of radiotherapy and the first radiographic change were 9.9, 6.7 and 2.4 for Groups 1-3, respectively (p < 0.001). The initial prednisolone equivalent dose was 30-40 mg daily in 52 (67%) patients. A total of 16 (4.2%) patients died of radiation pneumonitis or steroid complication with a median survival of 45 (range, 8-107) days. Conclusion: Development of fever and dyspnea, and short interval between the end of radiotherapy and the first radiographic change were associated with fatal radiation-induced lung injury. Prednisolone 30-40 mg daily was selected for the treatment in many patients

  8. Inflammation-induced preterm lung maturation: lessons from animal experimentation.

    Science.gov (United States)

    Moss, Timothy J M; Westover, Alana J

    2017-06-01

    Intrauterine inflammation, or chorioamnionitis, is a major contributor to preterm birth. Prematurity per se is associated with considerable morbidity and mortality resulting from lung immaturity but exposure to chorioamnionitis reduces the risk of neonatal respiratory distress syndrome (RDS) in preterm infants. Animal experiments have identified that an increase in pulmonary surfactant production by the preterm lungs likely underlies this decreased risk of RDS in infants exposed to chorioamnionitis. Further animal experimentation has shown that infectious or inflammatory agents in amniotic fluid exert their effects on lung development by direct effects within the developing respiratory tract, and probably not by systemic pathways. Differences in the effects of intrauterine inflammation and glucocorticoids demonstrate that canonical glucocorticoid-mediated lung maturation is not responsible for inflammation-induced changes in lung development. Animal experimentation is identifying alternative lung maturational pathways, and transgenic animals and cell culture techniques will allow identification of novel mechanisms of lung maturation that may lead to new treatments for the prevention of RDS. Copyright © 2016. Published by Elsevier Ltd.

  9. Fibrogenic Lung Injury Induces Non-Cell-Autonomous Fibroblast Invasion.

    Science.gov (United States)

    Ahluwalia, Neil; Grasberger, Paula E; Mugo, Brian M; Feghali-Bostwick, Carol; Pardo, Annie; Selman, Moisés; Lagares, David; Tager, Andrew M

    2016-06-01

    Pathologic accumulation of fibroblasts in pulmonary fibrosis appears to depend on their invasion through basement membranes and extracellular matrices. Fibroblasts from the fibrotic lungs of patients with idiopathic pulmonary fibrosis (IPF) have been demonstrated to acquire a phenotype characterized by increased cell-autonomous invasion. Here, we investigated whether fibroblast invasion is further stimulated by soluble mediators induced by lung injury. We found that bronchoalveolar lavage fluids from bleomycin-challenged mice or patients with IPF contain mediators that dramatically increase the matrix invasion of primary lung fibroblasts. Further characterization of this non-cell-autonomous fibroblast invasion suggested that the mediators driving this process are produced locally after lung injury and are preferentially produced by fibrogenic (e.g., bleomycin-induced) rather than nonfibrogenic (e.g., LPS-induced) lung injury. Comparison of invasion and migration induced by a series of fibroblast-active mediators indicated that these two forms of fibroblast movement are directed by distinct sets of stimuli. Finally, knockdown of multiple different membrane receptors, including platelet-derived growth factor receptor-β, lysophosphatidic acid 1, epidermal growth factor receptor, and fibroblast growth factor receptor 2, mitigated the non-cell-autonomous fibroblast invasion induced by bronchoalveolar lavage from bleomycin-injured mice, suggesting that multiple different mediators drive fibroblast invasion in pulmonary fibrosis. The magnitude of this mediator-driven fibroblast invasion suggests that its inhibition could be a novel therapeutic strategy for pulmonary fibrosis. Further elaboration of the molecular mechanisms that drive non-cell-autonomous fibroblast invasion consequently may provide a rich set of novel drug targets for the treatment of IPF and other fibrotic lung diseases.

  10. Fibrogenic Lung Injury Induces Non–Cell-Autonomous Fibroblast Invasion

    Science.gov (United States)

    Grasberger, Paula E.; Mugo, Brian M.; Feghali-Bostwick, Carol; Pardo, Annie; Selman, Moisés; Lagares, David

    2016-01-01

    Pathologic accumulation of fibroblasts in pulmonary fibrosis appears to depend on their invasion through basement membranes and extracellular matrices. Fibroblasts from the fibrotic lungs of patients with idiopathic pulmonary fibrosis (IPF) have been demonstrated to acquire a phenotype characterized by increased cell-autonomous invasion. Here, we investigated whether fibroblast invasion is further stimulated by soluble mediators induced by lung injury. We found that bronchoalveolar lavage fluids from bleomycin-challenged mice or patients with IPF contain mediators that dramatically increase the matrix invasion of primary lung fibroblasts. Further characterization of this non–cell-autonomous fibroblast invasion suggested that the mediators driving this process are produced locally after lung injury and are preferentially produced by fibrogenic (e.g., bleomycin-induced) rather than nonfibrogenic (e.g., LPS-induced) lung injury. Comparison of invasion and migration induced by a series of fibroblast-active mediators indicated that these two forms of fibroblast movement are directed by distinct sets of stimuli. Finally, knockdown of multiple different membrane receptors, including platelet-derived growth factor receptor-β, lysophosphatidic acid 1, epidermal growth factor receptor, and fibroblast growth factor receptor 2, mitigated the non–cell-autonomous fibroblast invasion induced by bronchoalveolar lavage from bleomycin-injured mice, suggesting that multiple different mediators drive fibroblast invasion in pulmonary fibrosis. The magnitude of this mediator-driven fibroblast invasion suggests that its inhibition could be a novel therapeutic strategy for pulmonary fibrosis. Further elaboration of the molecular mechanisms that drive non–cell-autonomous fibroblast invasion consequently may provide a rich set of novel drug targets for the treatment of IPF and other fibrotic lung diseases. PMID:26600305

  11. Radiation-Induced Differentiation in Human Lung Fibroblast

    Energy Technology Data Exchange (ETDEWEB)

    Park, Sa-Rah; Ahn, Ji-Yeon; Han, Young-Soo; Shim, Jie-Young; Yun, Yeon-Sook; Song, Jie-Young [Korea Institute of Radiological and Medical Sciences, Seoul (Korea, Republic of)

    2007-10-15

    One of the most common tumors in many countries is lung cancer and patients with lung cancer may take radiotherapy. Although radiotherapy may have its own advantages, it can also induce serious problems such as acute radiation pneumonitis and pulmonary fibrosis. Pulmonary fibrosis is characterized by excessive production of {alpha}-SMA and accumulation of extracellular matrix (ECM) such as collagen and fibronectin. There has been a great amount of research about fibrosis but the exact mechanism causing the reaction is not elucidated especially in radiation-induced fibrosis. Until now it has been known that several factors such as transforming growth factor (TGF-{beta}), tumor necrosis factor (TNF), interleukin (IL)-1, IL-6, platelet-derived growth factor (PDGF) and fibroblast growth factor (FGF) are related to fibrosis. Among them TGF-{beta} with Smad signaling is known to be the main stream and other signaling molecules such as MAPK, ERK and JNK (3) also participates in the process. In addition to those above factors, it is thought that more diverse and complicate mechanisms may involve in the radiationinduced fibrosis. Therefore, to investigate the underlying mechanisms in radiation induced fibrosis, first of all, we confirmed whether radiation induces trans differentiation in human normal lung fibroblasts. Here, we suggest that not only TGF-{beta} but also radiation can induce trans differentiation in human lung fibroblast WI-38 and IMR-90.

  12. Pleurotus eryngii Ameliorates Lipopolysaccharide-Induced Lung Inflammation in Mice

    Directory of Open Access Journals (Sweden)

    Junya Kawai

    2014-01-01

    Full Text Available Pleurotus eryngii (P. eryngii is consumed as a fresh cultivated mushroom worldwide and demonstrated to have multiple beneficial effects. We investigated the anti-inflammatory effect of P. eryngii in mice with acute lung injury (ALI. Intranasal instillation of lipopolysaccharide (LPS (10 μg/site/mouse induced marked lung inflammation (increase in the number of inflammatory cells, protein leakage, and production of nitric oxide in bronchoalveolar lavage fluid as well as histopathological damage in the lung, 6 h after treatment. Mice administered heat-treated P. eryngii (0.3–1 g/kg, p.o. (HTPE 1 h before LPS challenge showed decreased pulmonary inflammation and ameliorated histopathological damage. These results suggest that HTPE has anti-inflammatory effects against ALI. Thus, P. eryngii itself may also have anti-inflammatory effects and could be a beneficial food for the prevention of ALI induced by bacterial infection.

  13. Cardiac dysfunction in pneumovirus-induced lung injury in mice

    NARCIS (Netherlands)

    Bem, Reinout A.; van den Berg, Elske; Suidgeest, Ernst; van der Weerd, Louise; van Woensel, Job B. M.; Grotenhuis, Heynric B.

    2013-01-01

    To determine biventricular cardiac function in pneumovirus-induced acute lung injury in spontaneously breathing mice. Experimental animal study. Animal laboratory. C57Bl/6 mice. Mice were inoculated with the rodent pneumovirus, pneumonia virus of mice. Pneumonia virus of mice-infected mice were

  14. Farmer's Lung: Causes and Symptoms of Mold and Dust Induced Respiratory Illness

    Science.gov (United States)

    ... Youth VCE Publications / 442 / 442-602 Farmer's Lung: Causes and Symptoms of Mold and Dust Induced Respiratory ... Date August 18, 2014 Available As Farmer's Lung: Causes and Symptoms of Mold and Dust Induced Respiratory ...

  15. Role of heme in bromine-induced lung injury

    Science.gov (United States)

    Lam, Adam; Vetal, Nilam; Matalon, Sadis; Aggarwal, Saurabh

    2016-01-01

    Bromine (Br2) gas inhalation poses an environmental and occupational hazard resulting in high morbidity and mortality. In this review, we underline the acute lung pathology (within 24 hours of exposure) and potential therapeutic interventions that may be utilized to mitigate Br2-induced human toxicity. We will discuss our latest published data, which suggests that an increase in heme-dependent tissue injury underlies the pathogenesis of Br2 toxicity. Our study was based on previous findings that demonstrated that Br2 upregulates the heme-degrading enzyme heme oxygenase-1 (HO-1), which converts toxic heme into billiverdin. Interestingly, following Br2 inhalation, heme levels were indeed elevated in bronchoalveolar lavage fluid, plasma, and whole lung tissue in C57BL/6 mice. High heme levels correlated with increased lung oxidative stress, lung inflammation, respiratory acidosis, lung edema, higher airway resistance, and mortality. However, therapeutic reduction of heme levels, by either scavenging with hemopexin or degradation by HO-1, improved lung function and survival. Therefore, heme attenuation may prove a useful adjuvant therapy to treat patients after Br2 exposure. PMID:27244263

  16. Acute lung injury induces cardiovascular dysfunction

    DEFF Research Database (Denmark)

    Suda, Koichi; Tsuruta, Masashi; Eom, Jihyoun

    2011-01-01

    Acute lung injury (ALI) is associated with systemic inflammation and cardiovascular dysfunction. IL-6 is a biomarker of this systemic response and a predictor of cardiovascular events, but its possible causal role is uncertain. Inhaled corticosteroids and long-acting β2 agonists (ICS/LABA) down......-regulate the systemic expression of IL-6, but whether they can ameliorate the cardiovascular dysfunction related to ALI is uncertain. We sought to determine whether IL-6 contributes to the cardiovascular dysfunction related to ALI, and whether budesonide/formoterol ameliorates this process. Wild-type mice were...... the rise in the systemic expression of IL-6 (P cardiovascular dysfunction related to LPS, and pretreatment with budesonide/formoterol reduces the systemic expression of IL-6 and improves cardiovascular dysfunction. ICS/LABA may reduce acute cardiovascular...

  17. Role of Lung-marginated Monocytes in an In Vivo Mouse Model of Ventilator-induced Lung Injury

    NARCIS (Netherlands)

    Wilson, M.; O'Dea, K.P.; Zhang, D.; Shearman, A.D.; Rooijen, van N.; Takata, M.

    2009-01-01

    Rationale: Recruited leukocytes play an important role in ventilator-induced lung injury, although studies have focused predominantly on neutrophils. Inflammatory subset Gr-1(high) monocytes are recruited to sites of inflammation and have been implicated in acute lung injury induced by systemic

  18. The cationic amino acid transporter 2 is induced in inflammatory lung models and regulates lung fibrosis

    Directory of Open Access Journals (Sweden)

    Rothenberg Marc E

    2010-06-01

    Full Text Available Abstract Background Arginine is an amino acid that serves as a substrate for the enzymes nitric oxide synthase (NOS and arginase, leading to synthesis of NO and ornithine, respectively. As such, arginine has the potential to influence diverse fundamental processes in the lung. Methods We used mice deficient in cationic amino acid transporter (CAT 2 in models of allergic airway inflammation and pulmonary fibrosis. Results We report that the arginine transport protein CAT2 was over-expressed in the lung during the induction of allergic airway inflammation. Furthermore, CAT2 mRNA was strongly induced by transgenically over-expressed IL-4, and allergen-induced expression was dependent upon signal-transducer-and-activator-of-transcription (STAT 6. In situ mRNA hybridization demonstrated marked staining of CAT2, predominantly in scattered mononuclear cells. Analysis of allergic airway inflammation and bleomycin-induced inflammation in CAT2-deficient mice revealed that while inflammation was independent of CAT2 expression, bleomycin-induced fibrosis was dependent upon CAT2. Mechanistic analysis revealed that arginase activity in macrophages was partly dependent on CAT2. Conclusion Taken together, these results identify CAT2 as a regulator of fibrotic responses in the lung.

  19. A Case of Lung Lesions Induced by a soccer Ball

    Directory of Open Access Journals (Sweden)

    Masaaki Takemoto

    2013-01-01

    Full Text Available An 18-year-old youth soccer forward received a direct hit from a kicked soccer ball on the anterior right chest when the goal keeper kicked the ball from a distance of 1 meter. Immediately following the hit, the subject experienced dypnea, chest pain and had a cough, with several milliliters of hemoptysis. His symptoms subsided after 20 minutes of rest. However, he still felt mild discomfort and was taken to our department for evaluation. On examination, all vital signs were normal. A computed tomography scan of the chest was obtained, and revealed a small area of opacification in the right lung field suggesting a pulmonary contusion or traumatic lung edema. Ten days after the initial injury, he was cleared for full participation. We herein reported the first case of a lung lesion induced by a soccer ball. Conservative treatment resulted in a favorable outcome.

  20. Circular RNA profiles in mouse lung tissue induced by radon.

    Science.gov (United States)

    Pei, Weiwei; Tao, Lijing; Zhang, Leshuai W; Zhang, Shuyu; Cao, Jianping; Jiao, Yang; Tong, Jian; Nie, Jihua

    2017-04-07

    Radon is a known human lung carcinogen, whose underlying carcinogenic mechanism remains unclear. Recently, circular RNA (circRNA), a class of endogenous non-protein coding RNAs that contain a circular loop, was found to exhibit multiple biological effects. In this study, circRNA profiles in mouse lung tissues between control and radon exposure were analyzed. Six mice were exposed to radon at concentration of 100,000 Bq/m 3 , 12 h/d, for up to cumulative doses of 60 working level months (WLM). H&E staining and immunohistochemistry of caspase-3 were used to detect the damages in lung tissue. The lung tissue of control and exposed group were selected for circRNA microarray study. The circRNA/microRNA interaction was analyzed by starBase prediction software. 5 highest expressing circRNAs were selected by real-time PCR to validate the consistency in mouse lung tissue exposed to radon. Inflammatory reaction was found in mouse lung tissue exposed to radon, and caspase-3 expression was significantly increased. Microarray screening revealed 107 up-regulated and 83 down-regulated circRNAs, among which top 30 circRNAs with the highest fold changes were chosen for further analysis, with 5 microRNAs binding sites listed for each circRNA. Consistency of the top 5 circRNAs with the highest expressions were confirmed in mice exposed with 60WLM of radon. Mouse lung tissue was severely injured when exposed to radon through pathological diagnosis and immunohistochemical analysis. A series of differentially expressed circRNAs demonstrated that they may play an important role in pulmonary toxicity induced by radon.

  1. Unusual progression and subsequent improvement in cystic lung disease in a child with radiation-induced lung injury

    Energy Technology Data Exchange (ETDEWEB)

    Wolf, Michael S. [Monroe Carell Jr. Children' s Hospital at Vanderbilt, Department of Pediatrics, Nashville, TN (United States); Chadha, Ashley D. [Vanderbilt University School of Medicine, Division of Pulmonary Medicine, Department of Pediatrics, Nashville, TN (United States); Carroll, Clinton M.; Borinstein, Scott C. [Vanderbilt University School of Medicine, Division of Hematology and Oncology, Department of Pediatrics, Nashville, TN (United States); Young, Lisa R. [Vanderbilt University School of Medicine, Division of Pulmonary Medicine, Department of Pediatrics, Nashville, TN (United States); Vanderbilt University School of Medicine, Division of Allergy, Pulmonary and Critical Care, Department of Medicine, Nashville, TN (United States); Vanderbilt University School of Medicine, Division of Pulmonary Medicine, Nashville, TN (United States)

    2015-07-15

    Radiation-induced lung disease is a known complication of therapeutic lung irradiation, but the features have not been well described in children. We report the clinical, radiologic and histologic features of interstitial lung disease (ILD) in a 4-year-old child who had previously received lung irradiation as part of successful treatment for metastatic Wilms tumor. Her radiologic abnormalities and clinical symptoms developed in an indolent manner. Clinical improvement gradually occurred with corticosteroid therapy. However, the observed radiologic progression from interstitial and reticulonodular opacities to diffuse cystic lung disease, with subsequent improvement, is striking and has not been previously described in children. (orig.)

  2. ROS Mediates Radiation-Induced Differentiation in Human Lung Fibroblast

    Energy Technology Data Exchange (ETDEWEB)

    Park, Sa Rah; Ahn, Ji Yeon; Kim, Mi Hyeung; Lim, Min Jin; Yun, Yeon Sook; Song, Jie Young [Korea Institute of Radiological and Medical Sciences, Seoul (Korea, Republic of)

    2009-05-15

    One of the most common tumors worldwide is lung cancer and the number of patients with lung cancer received radiotherapy is increasing rapidly. Although radiotherapy may have lots of advantages, it can also induce serious adverse effects such as acute radiation pneumonitis and pulmonary fibrosis. Pulmonary fibrosis is characterized by excessive production of smooth muscle actin-alpha (a-SMA) and accumulation of extracellular matrix (ECM) such as collagen and fibronectin. There has been a great amount of research about fibrosis but the exact mechanism causing the reaction is not elucidated especially in radiation-induced fibrosis. Until now it has been known that several factors such as transforming growth factor (TGF-b), tumor necrosis factor (TNF), IL-6, platelet-derived growth factor (PDGF) and reactive oxygen species are related to fibrosis. It is also reported that reactive oxygen species (ROS) can be induced by radiation and can act as a second messenger in various signaling pathways. Therefore we focused on the role of ROS in radiation induced fibrosis. Here, we suggest that irradiation generate ROS mainly through NOX4, result in differentiation of lung fibroblast into myofibroblast.

  3. Suspended animation inducer hydrogen sulfide is protective in an in vivo model of ventilator-induced lung injury

    NARCIS (Netherlands)

    Aslami, H.; Heinen, A.; Roelofs, J.J.T.H.; Zuurbier, C.J.; Schultz, M.J.; Juffermans, N.P.

    2010-01-01

    Acute lung injury is characterized by an exaggerated inflammatory response and a high metabolic demand. Mechanical ventilation can contribute to lung injury, resulting in ventilator-induced lung injury (VILI). A suspended-animation-like state induced by hydrogen sulfide (H2S) protects against

  4. Effects of sevoflurane on ventilator induced lung injury in a healthy lung experimental model.

    Science.gov (United States)

    Romero, A; Moreno, A; García, J; Sánchez, C; Santos, M; García, J

    2016-01-01

    Ventilator-induced lung injury (VILI) causes a systemic inflammatory response in tissues, with an increase in IL-1, IL-6 and TNF-α in blood and tissues. Cytoprotective effects of sevoflurane in different experimental models are well known, and this protective effect can also be observed in VILI. The objective of this study was to assess the effects of sevoflurane in VILI. A prospective, randomized, controlled study was designed. Twenty female rats were studied. The animals were mechanically ventilated, without sevoflurane in the control group and sevoflurane 3% in the treated group (SEV group). VILI was induced applying a maximal inspiratory pressure of 35 cmH2O for 20 min without any positive end-expiratory pressure for 20 min (INJURY time). The animals were then ventilated 30 min with a maximal inspiratory pressure of 12 cmH2O and 3 cmH2O positive end-expiratory pressure (time 30 min POST-INJURY), at which time the animals were euthanized and pathological and biomarkers studies were performed. Heart rate, invasive blood pressure, pH, PaO2, and PaCO2 were recorded. The lung wet-to-dry weight ratio was used as an index of lung edema. No differences were found in the blood gas analysis parameters or heart rate between the 2 groups. Blood pressure was statistically higher in the control group, but still within the normal clinical range. The percentage of pulmonary edema and concentrations of TNF-α and IL-6 in lung tissue in the SEV group were lower than in the control group. Sevoflurane attenuates VILI in a previous healthy lung in an experimental subclinical model in rats. Copyright © 2015 Sociedad Española de Anestesiología, Reanimación y Terapéutica del Dolor. Publicado por Elsevier España, S.L.U. All rights reserved.

  5. Montelukast Induces Apoptosis-Inducing Factor-Mediated Cell Death of Lung Cancer Cells

    Directory of Open Access Journals (Sweden)

    Ming-Ju Tsai

    2017-06-01

    Full Text Available Developing novel chemo-prevention techniques and advancing treatment are key elements to beating lung cancer, the most common cause of cancer mortality worldwide. Our previous cohort study showed that cysteinyl leukotriene receptor antagonists, mainly montelukast, decreased the lung cancer risk in asthma patients. In the current study, we conducted in vivo and in vitro experiments to demonstrate the inhibiting effect of montelukast on lung cancer and to investigate the underlying mechanisms. Using Lewis lung carcinoma-bearing mice, we showed that feeding montelukast significantly delayed the tumor growth in mice (p < 0.0001. Montelukast inhibited cell proliferation and colony formation and induced the cell death of lung cancer cells. Further investigation showed the down-regulation of B-cell lymphoma 2 (Bcl-2, up-regulation of Bcl-2 homologous antagonist/killer (Bak, and nuclear translocation of apoptosis-inducing factor (AIF in montelukast-treated lung cancer cells. Montelukast also markedly decreased the phosphorylation of several proteins, such as with no lysine 1 (WNK1, protein kinase B (Akt, extracellular signal-regulated kinase 1/2 (Erk1/2, MAPK/Erk kinase (MEK, and proline-rich Akt substrate of 40-kDa (PRAS40, which might contribute to cell death. In conclusion, montelukast induced lung cancer cell death via the nuclear translocation of AIF. This study confirmed the chemo-preventive effect of montelukast shown in our previous cohort study. The utility of montelukast in cancer prevention and treatment thus deserves further studies.

  6. Sex and smoking sensitive model of radon induced lung cancer

    International Nuclear Information System (INIS)

    Zhukovsky, M.; Yarmoshenko, I.

    2006-01-01

    Radon and radon progeny inhalation exposure are recognized to cause lung cancer. Only strong evidence of radon exposure health effects was results of epidemiological studies among underground miners. Any single epidemiological study among population failed to find reliable lung cancer risk due to indoor radon exposure. Indoor radon induced lung cancer risk models were developed exclusively basing on extrapolation of miners data. Meta analyses of indoor radon and lung cancer case control studies allowed only little improvements in approaches to radon induced lung cancer risk projections. Valuable data on characteristics of indoor radon health effects could be obtained after systematic analysis of pooled data from single residential radon studies. Two such analyses are recently published. Available new and previous data of epidemiological studies of workers and general population exposed to radon and other sources of ionizing radiation allow filling gaps in knowledge of lung cancer association with indoor radon exposure. The model of lung cancer induced by indoor radon exposure is suggested. The key point of this model is the assumption that excess relative risk depends on both sex and smoking habits of individual. This assumption based on data on occupational exposure by radon and plutonium and also on the data on external radiation exposure in Hiroshima and Nagasaki and the data on external exposure in Mayak nuclear facility. For non-corrected data of pooled European and North American studies the increased sensitivity of females to radon exposure is observed. The mean value of ks for non-corrected data obtained from independent source is in very good agreement with the L.S.S. study and Mayak plutonium workers data. Analysis of corrected data of pooled studies showed little influence of sex on E.R.R. value. The most probable cause of such effect is the change of men/women and smokers/nonsmokers ratios in corrected data sets in North American study. More correct

  7. Escin attenuates acute lung injury induced by endotoxin in mice.

    Science.gov (United States)

    Xin, Wenyu; Zhang, Leiming; Fan, Huaying; Jiang, Na; Wang, Tian; Fu, Fenghua

    2011-01-18

    Endotoxin causes multiple organ dysfunctions, including acute lung injury (ALI). The current therapeutic strategies for endotoxemia are designed to neutralize one or more of the inflammatory mediators. Accumulating experimental evidence suggests that escin exerts anti-inflammatory and anti-edematous effects. The aim of this study was to evaluate the effect of escin on ALI induced by endotoxin in mice. ALI was induced by injection of lipopolysaccharide (LPS) intravenously. The mice were given dexamethasone or escin before injection of LPS. The mortality rate was recorded. Tumor necrosis factor-α (TNF-α), interleukin 1β (IL-1β) and nitric oxide (NO) were measured. Pulmonary superoxide dismutase (SOD), glutathione peroxidase (GPx) activity, glutathione (GSH), malondialdehyde (MDA) contents, and myeloperoxidase (MPO) activity were also determined. The expression of glucocorticoid receptor (GR) level was detected by Western blotting. Pretreatment with escin could decrease the mortality rate, attenuate lung injury resulted from LPS, down-regulate the level of the inflammation mediators, including NO, TNF-α, and IL-1β, enhance the endogenous antioxidant capacity, and up-regulating the GR expression in lung. The results suggest that escin may have potent protective effect on the LPS-induced ALI by inhibiting of the inflammatory response, and its mechanism involves in up-regulating the GR and enhancing the endogenous antioxidant capacity. Copyright © 2010 Elsevier B.V. All rights reserved.

  8. Histomorphologic change of radiation pneumonitis in rat lungs: captopril reduces rat lung injury induced by irradiation

    Energy Technology Data Exchange (ETDEWEB)

    Kim, Jin Hee [College of Medicine, Keimhyung Univ., Taegu (Korea, Republic of)

    1999-09-01

    To assess the histomorphologic changes in the rat lung injury induced by radiation, to determine whether captopril reduces the rat lung injury and to evaluate change in TNF-{alpha} and TGF {beta} and rat lung damage by radiation and captopril. Right lungs in male Sprague-Dawley rats were divided irradiation alone (10, 20, 30 Gy) or radiation (same dose with radiation alone group) with captopril (500 mg/L). Radiation alone group were sacrificed at twelve hours and eleven weeks after radiation and radiation with captopril group (captopril group) were sacrificed at eleven weeks after radiation with captopril. We examined the light microscope and electron microscopic features in the groups. In radiation alone group, there were patch parenchymal collapse and consolidation at twelve hours after radiation. The increase of radiation dose shows more prominent the severity and broader the affected areas. Eleven weeks after radiation, the severity and areas of fibrosis had increased in proportion to radiation dose given in the radiation alone group. There was notable decrease of lung fibrosis in captopril group than in radiation alone group. The number of mast cells rapidly increased with increase of radiation dose in radiation alone group and the degree of increase of mast cell number and severity of collagen accumulation more decreased in captopril group than in radiation alone group. In radiation alone group expression of TNF-{alpha} and TGF-{beta}] increased according to increase of radiation dose at twelve hours after radiation in both group. At eleven weeks after radiation, expression of TGF- P increased according to increase of radiation dose in radiation group but somewhat decreased in captopril group. In the captopril group the collagen deposition increased but less dense than those of radiation alone group. The severity of perivascular thickening, capillary change, the number and degranulation of mast cells more decreased in the captopril group than in the radiation

  9. Andrographolide protects against radiation-induced lung injury in mice

    International Nuclear Information System (INIS)

    Kang Yahui; Wang Jinfeng; Zhang Qu; Huang Guanhong; Ma Jianxin; Yang Baixia; He Xiangfeng; Wang Zhongming

    2014-01-01

    Objective: To investigate the protective effect of andrographolide against radiation-induced lung injury (RILI) in C57BL/6 mice. Methods: Eighty C57BL mice were randomly divided into four groups: un-irradiated and normal saline-treated group (n = 20, control group), un-irradiated and andrographolide-treated group (n = 20, drug group), radiation plus normal saline-treated group (n = 20, radiation group) and radiation plus andrographolide-treated group (n = 20, treatment group). Before radiation, the mice in drug group and treatment group were administered daily via gavage with andrographolide (20 mg·kg -1 ·d -1 )) for 30 d, while the same volume of normal saline solution was given daily in the control and radiation groups. The model of RILI in C57BL mice was established by irradiating whole mouse chest with a single dose of 15 Gy of 6 MV X-rays. The pathological changes of the lung stained with HE/Masson were observed with a light microscope. The transforming growth factor-β1 (TGF-β1) and tumor necrosis factor-α (TNF-α) in serum were examined by enzyme-linked immunosorbent assay. The activities of malondialdehyde (MDA) and superoxide dismutase (SOD) and the content of hydroxyproline in lung tissues were examined by corresponding kits. Results: Compared with radiation group, there was an obvious amelioration in pathological injury of lung tissue in the treatment group. The lung coefficient, the activities of lung tissue MDA, the content of Hyp, the serum content of hydroxide free radical, and the serum levels of TGF-β1 and TNF-α in the treatment group were significantly lower than those in radiation group at 24 th week, (t lung coefficient = 1.60, t MDA = 7.06, t Hyp = 17.44, t TGF-β1 = 16.67, t TNF-α = 14.03, P < 0.05), while slightly higher than those in control group. The activity of SOD was significantly higher in the treatment group than that in radiation group (t = 60.81, P < 0.05), while lower than those in control group and drug group. There were no

  10. Autotaxin and Endotoxin-Induced Acute Lung Injury

    Science.gov (United States)

    Oikonomou, Nikos; Katsifa, Aggeliki; Prestwich, Glenn D.; Kaffe, Eleanna; Aidinis, Vassilis

    2015-01-01

    Acute Lung Injury (ALI) is a life-threatening, diffuse heterogeneous lung injury characterized by acute onset, pulmonary edema and respiratory failure. Lipopolysaccharide (LPS) is a common cause of both direct and indirect lung injury and when administered to a mouse induces a lung phenotype exhibiting some of the clinical characteristics of human ALI. Here, we report that LPS inhalation in mice results in increased bronchoalveolar lavage fluid (BALF) levels of Autotaxin (ATX, Enpp2), a lysophospholipase D largely responsible for the conversion of lysophosphatidylcholine (LPC) to lysophosphatidic acid (LPA) in biological fluids and chronically inflamed sites. In agreement, gradual increases were also detected in BALF LPA levels, following inflammation and pulmonary edema. However, genetic or pharmacologic targeting of ATX had minor effects in ALI severity, suggesting no major involvement of the ATX/LPA axis in acute inflammation. Moreover, systemic, chronic exposure to increased ATX/LPA levels was shown to predispose to and/or to promote acute inflammation and ALI unlike chronic inflammatory pathophysiological situations, further suggesting a differential involvement of the ATX/LPA axis in acute versus chronic pulmonary inflammation. PMID:26196781

  11. Autotaxin and Endotoxin-Induced Acute Lung Injury.

    Directory of Open Access Journals (Sweden)

    Marios-Angelos Mouratis

    Full Text Available Acute Lung Injury (ALI is a life-threatening, diffuse heterogeneous lung injury characterized by acute onset, pulmonary edema and respiratory failure. Lipopolysaccharide (LPS is a common cause of both direct and indirect lung injury and when administered to a mouse induces a lung phenotype exhibiting some of the clinical characteristics of human ALI. Here, we report that LPS inhalation in mice results in increased bronchoalveolar lavage fluid (BALF levels of Autotaxin (ATX, Enpp2, a lysophospholipase D largely responsible for the conversion of lysophosphatidylcholine (LPC to lysophosphatidic acid (LPA in biological fluids and chronically inflamed sites. In agreement, gradual increases were also detected in BALF LPA levels, following inflammation and pulmonary edema. However, genetic or pharmacologic targeting of ATX had minor effects in ALI severity, suggesting no major involvement of the ATX/LPA axis in acute inflammation. Moreover, systemic, chronic exposure to increased ATX/LPA levels was shown to predispose to and/or to promote acute inflammation and ALI unlike chronic inflammatory pathophysiological situations, further suggesting a differential involvement of the ATX/LPA axis in acute versus chronic pulmonary inflammation.

  12. Radiation-induced Pulmonary Damage in Lung Cancer Patients

    International Nuclear Information System (INIS)

    Chung, Su Mi; Choi, Ihl Bohng; Kang, Mi Mun; Kim, In Ah; Shinn, Kyung Sub

    1993-01-01

    Purpose: A retrospective analysis was performed to evaluate the incidence of radiation induced lung damage after the radiation therapy for the patients with carcinoma of the lung. Method and Materials: Sixty-six patients with lung cancer (squamous cell carcinoma 27, adenocarcinoma 14, large cell carcinoma 2, small cell carcinoma 13, unknown 10) were treated with definitive, postoperative or palliative radiation therapy with or without chemotherapy between July 1987 and December 1991. There were 50 males and 16 females with median age of 63 years(range: 33-80 years). Total lung doses ranged from 500 to 6,660 cGy (median 3960 cGy) given in 2 to 38 fractions (median 20) over a range of 2 to 150 days (median 40 days) using 6 MV or 15 MV linear accelerator. To represent different fractionation schedules of equivalent biological effect, the estimated single dose(ED) model, ED=D·N-0.377·T-0.058 was used in which D was the lung dose in cGy, N was the number of fractions, and T was the overall treatment time in days. The range of ED was 370 to 1357. The endpoint was a visible increase in lung density within the irradiated volume on chest X-ray as observed independently by three diagnostic radiologists. Patients were grouped according to ED, treatment duration, treatment modality and age, and the percent incidence of pulmonary damage for each group was determined. Result: In 40 of 66 patients, radiation induced change was seen on chest radiographs between 11 days and 314 days after initiation of radiation therapy. The incidence of radiation pneumonitis was increased according to increased ED, which was statistically significant (p=0.001). Roentgenographic charges consistent with radiation pneumonitis were seen in 100% of patients receiving radiotherapy after lobectomy or pneumonectomy, which was not statistically significant. In 32 patients who also received chemotherapy, there was no difference in the incidence of radiation induced charge between the group with radiation

  13. The Effects of Resveratrol on Hyperoxia-induced Lung Injury in Neonatal Rats

    Directory of Open Access Journals (Sweden)

    Özmert M.A. Özdemir

    2014-10-01

    Conclusion: This experimental study showed that oxidative stress and NO contributed to the pathogenesis of hyperoxia-induced lung injury, and that resveratrol had a preventive effect on hyperoxic lung injury through its anti-inflammatory and antioxidant properties.

  14. Riboflavin attenuates lipopolysaccharide-induced lung injury in rats.

    Science.gov (United States)

    Al-Harbi, Naif O; Imam, Faisal; Nadeem, Ahmed; Al-Harbi, Mohammed M; Korashy, Hesham M; Sayed-Ahmed, Mohammed M; Hafez, Mohamed M; Al-Shabanah, Othman A; Nagi, Mahmoud N; Bahashwan, Saleh

    2015-01-01

    Riboflavin (vitamin B2) is an easily absorbed micronutrient with a key role in maintaining health in humans and animals. It is the central component of the cofactors flavin adenine dinucleotide (FAD) and flavin mononucleotide (FMN) and is therefore required by all flavoproteins. Riboflavin also works as an antioxidant by scavenging free radicals. The present study was designed to evaluate the effects of riboflavin against acute lungs injury induced by the administration of a single intranasal dose (20 μg/rat) of lipopolysaccharides (LPS) in experimental rats. Administration of LPS resulted in marked increase in malondialdehyde (MDA) level (p riboflavin in a dose-dependent manner (30 and 100 mg/kg, respectively). Riboflavin (100 mg/kg, p.o.) showed similar protective effects as dexamethasone (1 mg/kg, p.o.). Administration of LPS showed marked cellular changes including interstitial edema, hemorrhage, infiltration of PMNs, etc., which were reversed by riboflavin administration. Histopathological examinations showed normal morphological structures of lungs tissue in the control group. These biochemical and histopathological examination were appended with iNOS and CAT gene expression. The iNOS mRNA expression was increased significantly (p riboflavin significantly (p riboflavin caused a protective effect against LPS-induced ALI. These results suggest that riboflavin may be used to protect against toxic effect of LPS in lungs.

  15. Inhibition of lipopolysaccharide induced acute inflammation in lung by chlorination

    Energy Technology Data Exchange (ETDEWEB)

    Zhang, Jinshan; Xue, Jinling; Xu, Bi; Xie, Jiani [Environmental Simulation and Pollution Control State Key Joint Laboratory, School of Environment, Tsinghua University, Beijing 100084 (China); Qiao, Juan, E-mail: qjuan@tsinghua.edu.cn [Department of Chemistry, Tsinghua University, Beijing 100084 (China); Lu, Yun, E-mail: luyun@tsinghua.edu.cn [Environmental Simulation and Pollution Control State Key Joint Laboratory, School of Environment, Tsinghua University, Beijing 100084 (China)

    2016-02-13

    Highlights: • Chlorination is effective to reduce the inflammation inducing capacity of LPS in lung. • LAL-detected endotoxin activity is not correlated to the potency of inflammation induction. • Alkyl chain of LPS was chlorinated in chlorination process. • LPS aggregate size decreases after chlorination. - Abstract: Lipopolysaccharide (LPS, also called endotoxin) is a pro-inflammatory constituent of gram negative bacteria and cyanobacteria, which causes a potential health risk in the process of routine urban application of reclaimed water, such as car wash, irrigation, scenic water refilling, etc. Previous studies indicated that the common disinfection treatment, chlorination, has little effect on endotoxin activity removal measured by Limulus amebocyte lysate (LAL) assay. However, in this study, significant decrease of acute inflammatory effects was observed in mouse lung, while LAL assay still presented a moderate increase of endotoxin activity. To explore the possible mechanisms, the nuclear magnetic resonance (NMR) results showed the chlorination happened in alkyl chain of LPS molecules, which could affect the interaction between LPS and LPS-binding protein. Also the size of LPS aggregates was found to drop significantly after treatment, which could be another results of chlorination caused polarity change. In conclusion, our observation demonstrated that chlorination is effective to reduce the LPS induced inflammation in lung, and it is recommended to use health effect-based methods to assess risk removal of water treatment technologies.

  16. Lung Lavage and Surfactant Replacement During Ex Vivo Lung Perfusion for Treatment of Gastric Acid Aspiration-Induced Donor Lung Injury.

    Science.gov (United States)

    Nakajima, Daisuke; Liu, Mingyao; Ohsumi, Akihiro; Kalaf, Ricardo; Iskender, Ilker; Hsin, Michael; Kanou, Takashi; Chen, Manyin; Baer, Brandon; Coutinho, Rafael; Maahs, Lucas; Behrens, Paula; Azad, Sassan; Martinu, Tereza; Waddell, Thomas K; Lewis, James F; Post, Martin; Veldhuizen, Ruud A W; Cypel, Marcelo; Keshavjee, Shaf

    2017-05-01

    Ex vivo lung perfusion (EVLP) provides opportunities to treat injured donor lungs before transplantation. We investigated whether lung lavage, to eliminate inflammatory inhibitory components, followed by exogenous surfactant replacement, could aid lung recovery and improve post-transplant lung function after gastric aspiration injury. Gastric acid aspiration was induced in donor pigs, which were ventilated for 6 hours to develop lung injury. After retrieval and 10 hours of cold preservation, EVLP was performed for 6 hours. The lungs were randomly divided into 4 groups (n = 5, each): (1) no treatment (control), (2) lung lavage, (3) surfactant administration, and (4) lung lavage, followed by surfactant administration. After another 2-hour period of cold preservation, the left lung was transplanted and reperfused for 4 hours. Physiologic lung function significantly improved after surfactant administration during EVLP. The EVLP perfusate from the lavage + surfactant group showed significantly lower levels of interleukin (IL)-1β, IL-6, IL-8, and secretory phospholipase A 2 . Total phosphatidylcholine was increased, and minimum surface tension was recovered to normal levels (≤5 mN/m) in the bronchioalveolar fluid after surfactant administration. Lysophosphatidylcholine in bronchioalveolar fluid was significantly lower in the lavage + surfactant group than in the surfactant group. Post-transplant lung function was significantly better in the lavage + surfactant group compared with all other groups. Lung lavage, followed by surfactant replacement during EVLP, reduced inflammatory mediators and prevented hydrolysis of phosphatidylcholine, which contributed to the superior post-transplant function in donor lungs with aspiration injury. Copyright © 2017 International Society for Heart and Lung Transplantation. Published by Elsevier Inc. All rights reserved.

  17. Rosmarinic acid potentiates carnosic acid induced apoptosis in lung fibroblasts.

    Directory of Open Access Journals (Sweden)

    Sana Bahri

    Full Text Available Pulmonary fibrosis is characterized by over-population and excessive activation of fibroblasts and myofibroblasts disrupting normal lung structure and functioning. Rosemary extract rich in carnosic acid (CA and rosmarinic acid (RA was reported to cure bleomycin-(BLM-induced pulmonary fibrosis. We demonstrate that CA decreased human lung fibroblast (HLF viability with IC50 value of 17.13±1.06 μM, while RA had no cytotoxic effect. In the presence of 50 μM of RA, dose-response for CA shifted to IC50 value of 11.70±1.46 μM, indicating synergic action. TGFβ-transformed HLF, rat lung fibroblasts and L929 cells presented similar sensitivity to CA and CA+RA (20μM+100μM, respectively treatment. Rat alveolar epithelial cells died only under CA+RA treatment, while A549 cells were not affected. Annexin V staining and DNA quantification suggested that HLF are arrested in G0/G1 cell cycle phase and undergo apoptosis. CA caused sustained activation of phospho-Akt and phospho-p38 expression and inhibition of p21 protein.Addition of RA potentiated these effects, while RA added alone had no action.Only triple combination of inhibitors (MAPK-p38, pan-caspase, PI3K/Akt/autophagy partially attenuated apoptosis; this suggests that cytotoxicity of CA+RA treatment has a complex mechanism involving several parallel signaling pathways. The in vivo antifibrotic effect of CA and RA was compared with that of Vitamine-E in BLM-induced fibrosis model in rats. We found comparable reduction in fibrosis score by CA, RA and CA+RA, attenuation of collagen deposition and normalization of oxidative stress markers. In conclusion, antifibrotic effect of CA+RA is due to synergistic pro-apoptotic action on lung fibroblasts and myofibroblasts.

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

    Science.gov (United States)

    Guo, Liang; Xu, Jun-mei; Liu, Lei; Liu, Su-mei; Zhu, Rong

    2015-01-01

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

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

    Directory of Open Access Journals (Sweden)

    Liang Guo

    2015-01-01

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

  20. Lipopolysaccharide induced inflammation in the perivascular space in lungs

    Directory of Open Access Journals (Sweden)

    Pabst Reinhard

    2008-07-01

    Full Text Available Abstract Background Lipopolysaccharide (LPS contained in tobacco smoke and a variety of environmental and occupational dusts is a toxic agent causing lung inflammation characterized by migration of neutrophils and monocytes into alveoli. Although migration of inflammatory cells into alveoli of LPS-treated rats is well characterized, the dynamics of their accumulation in the perivascular space (PVS leading to a perivascular inflammation (PVI of pulmonary arteries is not well described. Methods Therefore, we investigated migration of neutrophils and monocytes into PVS in lungs of male Sprague-Dawley rats treated intratracheally with E. coli LPS and euthanized after 1, 6, 12, 24 and 36 hours. Control rats were treated with endotoxin-free saline. H&E stained slides were made and immunohistochemistry was performed using a monocyte marker and the chemokine Monocyte-Chemoattractant-Protein-1 (MCP-1. Computer-assisted microscopy was performed to count infiltrating cells. Results Surprisingly, the periarterial infiltration was not a constant finding in each animal although LPS-induced alveolitis was present. A clear tendency was observed that neutrophils were appearing in the PVS first within 6 hours after LPS application and were decreasing at later time points. In contrast, mononuclear cell infiltration was observed after 24 hours. In addition, MCP-1 expression was present in perivascular capillaries, arteries and the epithelium. Conclusion PVI might be a certain lung reaction pattern in the defense to infectious attacks.

  1. Branching geometry induced by lung self-regulated growth

    Science.gov (United States)

    Clément, Raphaël; Douady, Stéphane; Mauroy, Benjamin

    2012-12-01

    Branching morphogenesis is a widely spread phenomenon in nature. In organogenesis, it results from the inhomogeneous growth of the epithelial sheet, leading to its repeated branching into surrounding mesoderm. Lung morphogenesis is an emblematic example of tree-like organogenesis common to most mammals. The core signalling network is well identified, notably the Fgf10/Shh couple, required to initiate and maintain branching. In a previous study, we showed that the restriction by SHH of Fgf10 expression domain to distal mesenchyme spontaneously induces differential epithelial proliferation leading to branching. A simple Laplacian model qualitatively reproduced FGF10 dynamics in the mesenchyme and the spontaneous self-avoiding branching morphogenesis. However, early lung geometry has several striking features that remain to be addressed. In this paper, we investigate, through simulations and data analysis, if the FGF10-diffusion scenario accounts for the following aspects of lung morphology: size dispersion, asymmetry of branching events, and distal epithelium-mesothelium equilibrium. We report that they emerge spontaneously in the model, and that most of the underlying mechanisms can be understood as dynamical interactions between gradients and shape. This suggests that specific regulation may not be required for the emergence of these striking geometrical features.

  2. Ventilator-induced Lung Injury : Similarity and Differences between Children and Adults

    NARCIS (Netherlands)

    Kneyber, Martin C.J.; Zhang, Haibo; Slutsky, Arthur S.

    2014-01-01

    It is well established that mechanical ventilation can injure the lung, producing an entity known as ventilator-induced lung injury (VILI). There are various forms of VILI, including volutrauma (i.e., injury caused by overdistending the lung), atelectrauma (injury due to repeated opening/closing of

  3. Effects of pentoxifylline on TNF-alpha and lung histopathology in HCL-induced lung injury

    Directory of Open Access Journals (Sweden)

    Itamar Souza de Oliveira-Júnior

    2008-01-01

    Full Text Available OBJECTIVE: To evaluate the effects of pentoxifylline on hydrochloric acid-induced lung lesions in rats subjected to mechanical ventilation. METHODS: Twenty male, adult Wistar-EPM-1 rats were anesthetized and randomly grouped (n=5 animals per group as follows: control-MV (mechanical ventilation, MV group; bilateral instillation of HCl (HCl group; bilateral instillation of HCl followed by pentoxifylline (50 mg/kg bw infusion (HCl+PTX group and pentoxifylline infusion followed by bilateral instillation of HCl (PTX+HCl group. At 20, 30, 90 and 180 min after treatments, the blood partial pressures of CO2 and O2 were measured. The animals were euthanized, and bronchoalveolar lavages were taken to determine the contents of total proteins, corticosterone and TNF-alpha. Samples of lung tissue were used for histomorphometric studies and determining the wet-to-dry (W/D lung weight ratio. RESULTS: In the MV group, rats had alveolar septal congestion, and, in the HCl group, a remarkable recruitment of neutrophils and macrophages into the alveoli was noticed; these events were reduced in the animals with PTX+HCl. The partial pressure of oxygen increased in PTX+HCl animals (121±5 mmHg as compared with the HCl (62±6 mmHg and HCl+PTX (67±3 mmHg groups within 30 minutes. TNF-alpha levels in bronchoalveolar lavage were significantly higher in the HCl group (458±50 pg/mL, reduced in the HCl+PTX group (329±45 pg/mL and lowest in the PTX+HCl group (229±41 pg/mL. The levels of corticosterone in bronchoalveolar lavage were significantly lower in the HCl (8±1.3 ng/mL and HCl+PTX group (16±2 ng/mL and were highest in the PTX+HCl (27±1.9 ng/mL. CONCLUSION: Pretreatment with PTX improves oxygenation, reduces TNF-alpha concentration and increases the concentration of corticosterone in bronchoalveolar lavage upon lung lesion induced by HCl.

  4. [Expression of various matrix metalloproteinases in mice with hyperoxia-induced acute lung injury].

    Science.gov (United States)

    Zhang, Xiang-feng; Ding, Shao-fang; Gao, Yuan-ming; Liang, Ying; Foda, Hussein D

    2006-08-01

    To investigate the role of matrix metalloproteinases (MMPs) and extracellular matrix metalloproteinase inducer (EMMPRIN) in the pathogenesis of acute lung injury induced by hyperoxia. Fifty four mice were exposed in sealed cages to >98% oxygen (for 24-72 hours), and another 18 mice to room air. The severity of lung injury was assessed, and the expression of mRNA and protein of MMP-2, MMP-9 and EMMPRIN in lung tissue, after exposure for 24, 48 and 72 hours of hyperoxia were studied by reverse transcription-polymerase chain reaction (RT-PCR) and immunohistochemistry. Hyperoxia caused acute lung injury; this was accompanied by increased expression of an upregulation of MMP-2, MMP-9 and EMMPRIN mRNA and protein in lung tissues. Hyperoxia causes acute lung injury in mice; increases in MMP-2, MMP-9 and EMMPRIN may play an important role in the development of hyperoxia induced lung injury in mice.

  5. Cannabidiol reduces lung injury induced by hypoxic-ischemic brain damage in newborn piglets.

    Science.gov (United States)

    Arruza, Luis; Pazos, Maria Ruth; Mohammed, Nagat; Escribano, Natalia; Lafuente, Hector; Santos, Martín; Alvarez-Díaz, Francisco J; Hind, William; Martínez-Orgado, Jose

    2017-07-01

    BackgroundBrain hypoxic-ischemic (HI) damage induces distant inflammatory lung damage in newborn pigs. We aimed to investigate the effects of cannabidiol (CBD) on lung damage in this scenario.MethodsNewborn piglets received intravenous vehicle, CBD, or CBD+WAY100635 (5-HT 1A receptor antagonist) after HI brain damage (carotid flow interruption and FiO 2 0.10 for 30 min). Total lung compliance (TLC), oxygenation index (OI), and extravascular lung water content (EVLW) were monitored for 6 h. Histological damage, interleukin (IL)-1β concentration, and oxidative stress were assessed in brain and lung tissue. Total protein content was determined in bronchoalveolar lavage fluid (BALF).ResultsCBD prevented HI-induced deleterious effects on TLC and OI and reduced lung histological damage, modulating inflammation (decreased leukocyte infiltration and IL-1 concentration) and reducing protein content in BALF and EVLW. These effects were related to CBD-induced anti-inflammatory changes in the brain. HI did not increase oxidative stress in the lungs. In the lungs, WAY100635 blunted the beneficial effects of CBD on histological damage, IL-1 concentration, and EVLW.ConclusionsCBD reduced brain HI-induced distant lung damage, with 5-HT 1A receptor involvement in these effects. Whether the effects of CBD on the lungs were due to the anti-inflammatory effects on the brain or due to the direct effects on the lungs remains to be elucidated.

  6. Creation of lung-targeted dexamethasone immunoliposome and its therapeutic effect on bleomycin-induced lung injury in rats.

    Directory of Open Access Journals (Sweden)

    Xue-Yuan Chen

    Full Text Available OBJECTIVE: Acute lung injury (ALI, is a major cause of morbidity and mortality, which is routinely treated with the administration of systemic glucocorticoids. The current study investigated the distribution and therapeutic effect of a dexamethasone(DXM-loaded immunoliposome (NLP functionalized with pulmonary surfactant protein A (SP-A antibody (SPA-DXM-NLP in an animal model. METHODS: DXM-NLP was prepared using film dispersion combined with extrusion techniques. SP-A antibody was used as the lung targeting agent. Tissue distribution of SPA-DXM-NLP was investigated in liver, spleen, kidney and lung tissue. The efficacy of SPA-DXM-NLP against lung injury was assessed in a rat model of bleomycin-induced acute lung injury. RESULTS: The SPA-DXM-NLP complex was successfully synthesized and the particles were stable at 4°C. Pulmonary dexamethasone levels were 40 times higher with SPA-DXM-NLP than conventional dexamethasone injection. Administration of SPA-DXM-NLP significantly attenuated lung injury and inflammation, decreased incidence of infection, and increased survival in animal models. CONCLUSIONS: The administration of SPA-DXM-NLP to animal models resulted in increased levels of DXM in the lungs, indicating active targeting. The efficacy against ALI of the immunoliposomes was shown to be superior to conventional dexamethasone administration. These results demonstrate the potential of actively targeted glucocorticoid therapy in the treatment of lung disease in clinical practice.

  7. Sulforaphane?induced apoptosis in Xuanwei lung adenocarcinoma cell line XWLC?05

    OpenAIRE

    Zhou, Lan; Yao, Qian; Li, Yan; Huang, Yun?chao; Jiang, Hua; Wang, Chuan?qiong; Fan, Lei

    2016-01-01

    Background Xuanwei district in Yunnan Province has the highest incidence of lung cancer in China, especially among non?smoking women. Cruciferous vegetables can reduce lung cancer risk by prompting a protective mechanism against respiratory tract inflammation caused by air pollution, and are rich in sulforaphane, which can induce changes in gene expression. We investigated the effect of sulforaphane?induced apoptosis in Xuanwei lung adenocarcinoma cell line (XWCL?05) to explore the value of s...

  8. Bone Marrow Mesenchymal Stem Cells Ameliorates Seawater-Exposure-Induced Acute Lung Injury by Inhibiting Autophagy in Lung Tissue

    Directory of Open Access Journals (Sweden)

    Qiu-ping Liu

    2014-01-01

    Full Text Available Seawater drowning can lead to acute lung injury (ALI. Several studies have shown that bone marrow mesenchymal stem cells (BMSC treatment could attenuate ALI. However, the mechanisms underlying this phenomenon still remain elusive. Therefore, this study aimed to investigate whether BMSC treatment can ameliorate seawater-induced ALI and its underlying mechanisms in a rat model. In this study, arterial blood gas, lung weight coefficient, and TNF-α, and IL-8 in bronchoalveolar lavage fluid (BALF, as well as histopathology examination, were used to detect the lung injury of seawater exposure. Moreover, western blot and RT-PCR were used to explore autophagy in lung tissues. The results demonstrated that seawater exposure induced ALI including impaired arterial blood gas, pulmonary edema, histopathologic changes, and inflammatory response in lung tissues. What is more, these changes were partly ameliorated by BMSC treatment through inhibition of autophagy in lung tissues. The application of BMSC may be a potential effective treatment for seawater-induced ALI.

  9. Cadmium induces lung inflammation independent of lung cell proliferation: a molecular approach

    Directory of Open Access Journals (Sweden)

    Kundu Subhadip

    2009-06-01

    Full Text Available Abstract Background Cadmium is one of the inflammation-related xenobiotics and has been regarded as a potent carcinogen. The relationship between inflammation and cell proliferation due to chronic infection has been studied, but the mechanism is not fully clear. Though the mode of cadmium toxicity is well characterized in animal cells, still it requires some further investigations. Previously we reported that cadmium induces immune cell death in Swiss albino mice. In the present study we showed that instead of inducing cell death mechanism, cadmium in low concentration triggers proliferation in mice lung cell and our results reveals that prior to the induction of proliferation it causes severe inflammation. Methods Swiss albino mice were treated with different concentrations of cadmium to determine the LD50. Mice were subdivided (5 mice each according to the exposure period (15, 30, 45, 60 days and were given sub lethal dose (5 mg/Kg body weight of cadmium chloride and ibuprofen (50 mg/Kg body weight, recommended dose once in a week. SEM and histology were performed as evidence of changes in cellular morphology. Inflammation was measured by the expression of Cox-2 and MMPs. Expression of proinflammatory cytokines (Cox-2, IL-6, signaling and cell cycle regulatory molecules (STAT3, Akt, CyclinD1 were measured by western blot, ELISA and immunoprecipitation. Mutagenecity was evidenced by comet assay. Cell proliferation was determined by cell count, cell cycle and DNA analysis. Results Prolonged exposure of low concentration of cadmium resulted in up regulation of proinflammatory cytokines and cell cycle regulatory molecules. Though NSAIDs like Ibuprofen reduces the expression of inflammatory cytokines, but it did not show any inhibitory effect on cadmium adopted lung cell proliferation. Conclusion Our results prove that cadmium causes both inflammation and cell proliferation when applied in a low dose but proliferative changes occur independent of

  10. Oxidative Stress Mediates Radiation Lung Injury by Inducing Apoptosis

    International Nuclear Information System (INIS)

    Zhang Yu; Zhang Xiuwu; Rabbani, Zahid N.; Jackson, Isabel L.; Vujaskovic, Zeljko

    2012-01-01

    Purpose: Apoptosis in irradiated normal lung tissue has been observed several weeks after radiation. However, the signaling pathway propagating cell death after radiation remains unknown. Methods and Materials: C57BL/6J mice were irradiated with 15 Gy to the whole thorax. Pro-apoptotic signaling was evaluated 6 weeks after radiation with or without administration of AEOL10150, a potent catalytic scavenger of reactive oxygen and nitrogen species. Results: Apoptosis was observed primarily in type I and type II pneumocytes and endothelium. Apoptosis correlated with increased PTEN expression, inhibition of downstream PI3K/AKT signaling, and increased p53 and Bax protein levels. Transforming growth factor-β1, Nox4, and oxidative stress were also increased 6 weeks after radiation. Therapeutic administration of AEOL10150 suppressed pro-apoptotic signaling and dramatically reduced the number of apoptotic cells. Conclusion: Increased PTEN signaling after radiation results in apoptosis of lung parenchymal cells. We hypothesize that upregulation of PTEN is influenced by Nox4-derived oxidative stress. To our knowledge, this is the first study to highlight the role of PTEN in radiation-induced pulmonary toxicity.

  11. Oxidative Stress Mediates Radiation Lung Injury by Inducing Apoptosis

    Energy Technology Data Exchange (ETDEWEB)

    Zhang Yu; Zhang Xiuwu; Rabbani, Zahid N. [Department of Radiation Oncology, Duke University Medical Center, Durham, NC (United States); Jackson, Isabel L. [Department of Pathology, Duke University Medical Center, Durham, NC (United States); Vujaskovic, Zeljko, E-mail: vujas@radonc.duke.edu [Department of Radiation Oncology, Duke University Medical Center, Durham, NC (United States); Department of Pathology, Duke University Medical Center, Durham, NC (United States)

    2012-06-01

    Purpose: Apoptosis in irradiated normal lung tissue has been observed several weeks after radiation. However, the signaling pathway propagating cell death after radiation remains unknown. Methods and Materials: C57BL/6J mice were irradiated with 15 Gy to the whole thorax. Pro-apoptotic signaling was evaluated 6 weeks after radiation with or without administration of AEOL10150, a potent catalytic scavenger of reactive oxygen and nitrogen species. Results: Apoptosis was observed primarily in type I and type II pneumocytes and endothelium. Apoptosis correlated with increased PTEN expression, inhibition of downstream PI3K/AKT signaling, and increased p53 and Bax protein levels. Transforming growth factor-{beta}1, Nox4, and oxidative stress were also increased 6 weeks after radiation. Therapeutic administration of AEOL10150 suppressed pro-apoptotic signaling and dramatically reduced the number of apoptotic cells. Conclusion: Increased PTEN signaling after radiation results in apoptosis of lung parenchymal cells. We hypothesize that upregulation of PTEN is influenced by Nox4-derived oxidative stress. To our knowledge, this is the first study to highlight the role of PTEN in radiation-induced pulmonary toxicity.

  12. Low-voltage electricity-induced lung injury.

    Science.gov (United States)

    Truong, Thai; Le, Thuong Vu; Smith, David L; Kantrow, Stephen P; Tran, Van Ngoc

    2018-02-01

    We report a case of bilateral pulmonary infiltrates and haemoptysis following low-voltage electricity exposure in an agricultural worker. A 58-year-old man standing in water reached for an electric watering machine and sustained an exposure to 220 V circuit for an uncertain duration. The electricity was turned off by another worker, and the patient was asymptomatic for the next 10 h until he developed haemoptysis. A chest radiograph demonstrated bilateral infiltrates, and chest computed tomography (CT) revealed ground-glass opacities with interstitial thickening. Evaluations, including electrocardiogram, serum troponin, N-terminal pro-B-type natriuretic peptide (NT-pro BNP), coagulation studies, and echocardiogram, found no abnormality. The patient was treated for suspected electricity-induced lung injury and bleeding with tranexamic acid and for rhabdomyolysis with volume resuscitation. He recovered with complete resolution of chest radiograph abnormalities by Day 7. This is the first reported case of bilateral lung oedema and/or injury after electricity exposure without cardiac arrest.

  13. Effects of positive end-expiratory pressure titration and recruitment maneuver on lung inflammation and hyperinflation in experimental acid aspiration-induced lung injury.

    Science.gov (United States)

    Ambrosio, Aline M; Luo, Rubin; Fantoni, Denise T; Gutierres, Claudia; Lu, Qin; Gu, Wen-Jie; Otsuki, Denise A; Malbouisson, Luiz M S; Auler, Jose O C; Rouby, Jean-Jacques

    2012-12-01

    In acute lung injury positive end-expiratory pressure (PEEP) and recruitment maneuver are proposed to optimize arterial oxygenation. The aim of the study was to evaluate the impact of such a strategy on lung histological inflammation and hyperinflation in pigs with acid aspiration-induced lung injury. Forty-seven pigs were randomly allocated in seven groups: (1) controls spontaneously breathing; (2) without lung injury, PEEP 5 cm H2O; (3) without lung injury, PEEP titration; (4) without lung injury, PEEP titration + recruitment maneuver; (5) with lung injury, PEEP 5 cm H2O; (6) with lung injury, PEEP titration; and (7) with lung injury, PEEP titration + recruitment maneuver. Acute lung injury was induced by intratracheal instillation of hydrochloric acid. PEEP titration was performed by incremental and decremental PEEP from 5 to 20 cm H2O for optimizing arterial oxygenation. Three recruitment maneuvers (pressure of 40 cm H2O maintained for 20 s) were applied to the assigned groups at each PEEP level. Proportion of lung inflammation, hemorrhage, edema, and alveolar wall disruption were recorded on each histological field. Mean alveolar area was measured in the aerated lung regions. Acid aspiration increased mean alveolar area and produced alveolar wall disruption, lung edema, alveolar hemorrhage, and lung inflammation. PEEP titration significantly improved arterial oxygenation but simultaneously increased lung inflammation in juxta-diaphragmatic lung regions. Recruitment maneuver during PEEP titration did not induce additional increase in lung inflammation and alveolar hyperinflation. In a porcine model of acid aspiration-induced lung injury, PEEP titration aimed at optimizing arterial oxygenation, substantially increased lung inflammation. Recruitment maneuvers further improved arterial oxygenation without additional effects on inflammation and hyperinflation.

  14. Tumor-Induced CD8+ T-Cell Dysfunction in Lung Cancer Patients

    Directory of Open Access Journals (Sweden)

    Heriberto Prado-Garcia

    2012-01-01

    Full Text Available Lung cancer is the leading cause of cancer deaths worldwide and one of the most common types of cancers. The limited success of chemotherapy and radiotherapy regimes have highlighted the need to develop new therapies like antitumor immunotherapy. CD8+ T-cells represent a major arm of the cell-mediated anti-tumor response and a promising target for developing T-cell-based immunotherapies against lung cancer. Lung tumors, however, have been considered to possess poor immunogenicity; even so, lung tumor-specific CD8+ T-cell clones can be established that possess cytotoxicity against autologous tumor cells. This paper will focus on the alterations induced in CD8+ T-cells by lung cancer. Although memory CD8+ T-cells infiltrate lung tumors, in both tumor-infiltrating lymphocytes (TILs and malignant pleural effusions, these cells are dysfunctional and the effector subset is reduced. We propose that chronic presence of lung tumors induces dysfunctions in CD8+ T-cells and sensitizes them to activation-induced cell death, which may be associated with the poor clinical responses observed in immunotherapeutic trials. Getting a deeper knowledge of the evasion mechanisms lung cancer induce in CD8+ T-cells should lead to further understanding of lung cancer biology, overcome tumor evasion mechanisms, and design improved immunotherapeutic treatments for lung cancer.

  15. Lysyl oxidase promotes bleomycin-induced lung fibrosis through modulating inflammation.

    Science.gov (United States)

    Cheng, Tao; Liu, Qingbo; Zhang, Rui; Zhang, Ying; Chen, Jianfeng; Yu, Ronghuan; Ge, Gaoxiang

    2014-12-01

    Enzymes involved in collagen biosynthesis, including lysyl oxidase (LOX), have been proposed as potential therapeutic targets for idiopathic pulmonary fibrosis. LOX expression is significantly upregulated in bleomycin (BLM)-induced lung fibrosis, and knockdown of LOX expression or inhibition of LOX activity alleviates the lung fibrosis. Unexpectedly, treatment of the mice with LOX inhibitor at the inflammatory stage, but not the fibrogenic stage, efficiently reduces collagen deposition and normalizes lung architecture. Inhibition of LOX impairs inflammatory cell infiltration, TGF-β signaling, and myofibroblast accumulation. Furthermore, ectopic expression of LOX sensitizes the fibrosis-resistant Balb/c mice to BLM-induced inflammation and lung fibrosis. These results suggest that LOX is indispensable for the progression of BLM-induced experimental lung fibrosis by aggravating the inflammatory response and subsequent fibrosis process after lung injury. © The Author (2014). Published by Oxford University Press on behalf of Journal of Molecular Cell Biology, IBCB, SIBS, CAS. All rights reserved.

  16. Preemptive hemodynamic intervention restricting the administration of fluids attenuates lung edema progression in oleic acid-induced lung injury.

    Science.gov (United States)

    Gil Cano, A; Gracia Romero, M; Monge García, M I; Guijo González, P; Ruiz Campos, J

    2017-04-01

    A study is made of the influence of preemptive hemodynamic intervention restricting fluid administration upon the development of oleic acid-induced lung injury. A randomized in vivo study in rabbits was carried out. University research laboratory. Sixteen anesthetized, mechanically ventilated rabbits. Hemodynamic measurements obtained by transesophageal Doppler signal. Respiratory mechanics computed by a least square fitting method. Lung edema assessed by the ratio of wet weight to dry weight of the right lung. Histological examination of the left lung. Animals were randomly assigned to either the early protective lung strategy (EPLS) (n=8) or the early protective hemodynamic strategy (EPHS) (n=8). In both groups, lung injury was induced by the intravenous infusion of oleic acid (OA) (0.133mlkg -1 h -1 for 2h). At the same time, the EPLS group received 15mlkg -1 h -1 of Ringer lactate solution, while the EPHS group received 30mlkg -1 h -1 . Measurements were obtained at baseline and 1 and 2h after starting OA infusion. After 2h, the cardiac index decreased in the EPLS group (pedema was greater in the EPHS group (pedema progression was attenuated by preemptively restricting the administration of fluids. Copyright © 2016 Elsevier España, S.L.U. y SEMICYUC. All rights reserved.

  17. Epidermal growth factor receptor expression in radiation-induced dog lung tumors by immunocytochemical localization

    Energy Technology Data Exchange (ETDEWEB)

    Leung, F.L.; Park, J.F.; Dagle, G.E.

    1993-06-01

    In studies to determine the role of growth factors in radiation-induced lung cancer, epidermal growth factor (EGFR) expression was examined by immunocytochemistry in 51 lung tumors from beagle dogs exposed to inhaled plutonium; 21 of 51 (41%) tumors were positive for EGFR. The traction of tumors positive for EGFR and the histological type of EGFR-positive tumors in the plutonium-exposed dogs were not different from spontaneous dog lung tumors, In which 36% were positive for EGFR. EGFR involvement in Pu-induced lung tumors appeared to be similar to that in spontaneous lung tumors. However, EGFR-positive staining was observed in only 1 of 16 tumors at the three lowest Pu exposure levels, compared to 20 of 35 tumors staining positive at the two highest Pu exposure levels. The results in dogs were in good agreement with the expression of EGFR reported in human non-small cell carcinoma of the lung, suggesting that Pu-induced lung tumors in the dog may be a suitable animal model to investigate the role of EGFR expression in lung carcinogenesis. In humans, EGFR expression in lung tumors has been primarily related to histological tumor types. In individual dogs with multiple primary lung tumors, the tumors were either all EGFR positive or EGFR negative, suggesting that EGFR expression may be related to the response of the individual dog as well as to the histological type of tumor.

  18. Loss of Hypoxia-Inducible Factor 2 Alpha in the Lung Alveolar Epithelium of Mice Leads to Enhanced Eosinophilic Inflammation in Cobalt-Induced Lung Injury

    Science.gov (United States)

    Proper, Steven P.; Saini, Yogesh; LaPres, John J.

    2014-01-01

    Hard metal lung disease (HMLD) is an occupational lung disease specific to inhalation of cobalt-containing particles whose mechanism is largely unknown. Cobalt is a known hypoxia mimic and stabilizer of the alpha subunits of hypoxia-inducible factors (HIFs). Previous work revealed that though HIF1α contrib utes to cobalt toxicity in vitro, loss of HIF1α in the alveolar epithelial cells does not provide in vivo protection from cobalt-induced lung inflammation. HIF1α and HIF2α show unique tissue expression profiles, and HIF2α is known to be the predominant HIF mRNA isoform in the adult lung. Thus, if HIF2α activation by cobalt contributes to pathophysiology of HMLD, we hypothesized that loss of HIF2α in lung epithelium would provide protection from cobalt-induced inflammation. Mice with HIF2α-deficiency in Club and alveolar type II epithelial cells (ATIIs) (HIF2αΔ/Δ) were exposed to cobalt (60 µg/day) or saline using a subacute occupational exposure model. Bronchoalveolar lavage cellularity, cytokines, qRT-PCR, and histopathology were analyzed. Results show that loss of HIF2α leads to enhanced eosinophilic inflammation and increased goblet cell metaplasia. Additionally, control mice demonstrated a mild recovery from cobalt-induced lung injury compared with HIF2αΔ/Δ mice, suggesting a role for epithelial HIF2α in repair mechanisms. The expression of important cytokines, such as interleukin (IL)-5 and IL-10, displayed significant differences following cobalt exposure when HIF2αΔ/Δ and control mice were compared. In summary, our data suggest that although loss of HIF2α does not afford protection from cobalt-induced lung inflammation, epithelial HIF2α signaling does play an important role in modulating the inflammatory and repair response in the lung. PMID:24218148

  19. Mustard vesicant-induced lung injury: Advances in therapy

    International Nuclear Information System (INIS)

    Weinberger, Barry; Malaviya, Rama; Sunil, Vasanthi R.; Venosa, Alessandro; Heck, Diane E.; Laskin, Jeffrey D.; Laskin, Debra L.

    2016-01-01

    Most mortality and morbidity following exposure to vesicants such as sulfur mustard is due to pulmonary toxicity. Acute injury is characterized by epithelial detachment and necrosis in the pharynx, trachea and bronchioles, while long-term consequences include fibrosis and, in some instances, cancer. Current therapies to treat mustard poisoning are primarily palliative and do not target underlying pathophysiologic mechanisms. New knowledge about vesicant-induced pulmonary disease pathogenesis has led to the identification of potentially efficacious strategies to reduce injury by targeting inflammatory cells and mediators including reactive oxygen and nitrogen species, proteases and proinflammatory/cytotoxic cytokines. Therapeutics under investigation include corticosteroids, N-acetyl cysteine, which has both mucolytic and antioxidant properties, inducible nitric oxide synthase inhibitors, liposomes containing superoxide dismutase, catalase, and/or tocopherols, protease inhibitors, and cytokine antagonists such as anti-tumor necrosis factor (TNF)-α antibody and pentoxifylline. Antifibrotic and fibrinolytic treatments may also prove beneficial in ameliorating airway obstruction and lung remodeling. More speculative approaches include inhibitors of transient receptor potential channels, which regulate pulmonary epithelial cell membrane permeability, non-coding RNAs and mesenchymal stem cells. As mustards represent high priority chemical threat agents, identification of effective therapeutics for mitigating toxicity is highly significant.

  20. APRV Mode in Ventilator Induced Lung Injury (VILI

    Directory of Open Access Journals (Sweden)

    Ata Mahmoodpoor

    2014-01-01

    Full Text Available Ventilator-Induced Lung Injury (VILI, being a significant iatrogenic complication in the ICU patients, is associated with high morbidity and mortality. Numerous approaches, protocols and ventilation modes have been introduced and examined to decrease the incidence of VILI in the ICU patients. Airway pressure release ventilation (APRV, firstly introduced by Stock and Downs in 1987, applies higher Continuous Positive Airway Pressure (CPAP levels in prolonged periods (P and T high in order to preserve satisfactory lung volume and consequently alveolar recruitment. This mode benefits a time-cycled release phase to a lower set of pressure for a short period of time (P and T low i.e. release time (1,2. While some advantages have been introduced for APRV such as efficiently recruited alveoli over time, more homogeneous ventilation, less volutrauma, probable stabilization of patent alveoli and reduction in atelectrauma, protective effects of APRV on lung damage only seem to be substantial if spontaneous breathing responds to more than 30% of total minute ventilation (3. APRV in ARDS patients should be administered cautiously; T low<0.6 seconds, for recruiting collapsed alveoli; however overstretching of alveoli especially during P high should not be neglected and appropriate sedation considered. The proposed advantages for APRV give the impression of being outstanding; however, APRV, as a non-physiologic inverse ratio mode of ventilation, might result in inflammation mainly due to impaired patient-ventilator interaction explaining the negative or minimally desirable effects of APRV on inflammation (4. Consequently, continuous infusion of neuromuscular blocking drugs during ARDS has been reported to reduce mortality (5. There are insufficient confirming data on the superiority of APRV above other ventilatory methods in regard to oxygenation, hemodynamics, regional blood flow, patient comfort and length of mechanical ventilation. Based on current findings

  1. Subamolide A Induces Mitotic Catastrophe Accompanied by Apoptosis in Human Lung Cancer Cells

    OpenAIRE

    Hung, Jen-Yu; Wen, Ching-Wen; Hsu, Ya-Ling; Lin, En-Shyh; Huang, Ming-Shyan; Chen, Chung-Yi; Kuo, Po-Lin

    2013-01-01

    This study investigated the anticancer effects of subamolide A (Sub-A), isolated from Cinnamomum subavenium, on human nonsmall cell lung cancer cell lines A549 and NCI-H460. Treatment of cancer cells with Sub-A resulted in decreased cell viability of both lung cancer cell lines. Sub-A induced lung cancer cell death by triggering mitotic catastrophe with apoptosis. It triggered oxidant stress, indicated by increased cellular reactive oxygen species (ROS) production and decreased glutathione le...

  2. Role of sphingolipids in murine radiation-induced lung injury: protection by sphingosine 1-phosphate analogs

    OpenAIRE

    Mathew, Biji; Jacobson, Jeffrey R.; Berdyshev, Evgeny; Huang, Yong; Sun, Xiaoguang; Zhao, Yutong; Gerhold, Lynnette M.; Siegler, Jessica; Evenoski, Carrie; Wang, Ting; Zhou, Tong; Zaidi, Rafe; Moreno-Vinasco, Liliana; Bittman, Robert; Chen, Chin Tu

    2011-01-01

    Clinically significant radiation-induced lung injury (RILI) is a common toxicity in patients administered thoracic radiotherapy. Although the molecular etiology is poorly understood, we previously characterized a murine model of RILI in which alterations in lung barrier integrity surfaced as a potentially important pathobiological event and genome-wide lung gene mRNA levels identified dysregulation of sphingolipid metabolic pathway genes. We hypothesized that sphingolipid signaling components...

  3. Mesenchymal Stem Cells Promoted Lung Wound Repair through Hox A9 during Endotoxemia-Induced Acute Lung Injury

    Directory of Open Access Journals (Sweden)

    Xi Xin

    2017-01-01

    Full Text Available Objectives. Acute lung injury (ALI is a common clinical critical disease. Stem cells transplantation is recognized as an effective way to repair injured lung tissues. The present study was designed to evaluate the effects of mesenchymal stem cells (MSCs on repair of lung and its mechanism. Methods. MSCs carrying GFP were administrated via trachea into wild-type SD rats 4 hours later after LPS administration. The lung histological pathology and the distribution of MSCs were determined by HE staining and fluorescence microscopy, respectively. Next, differentially expressed HOX genes were screened by using real-time PCR array and abnormal expression and function of Hox A9 were analyzed in the lung and the cells. Results. MSCs promoted survival rate of ALI animals. The expression levels of multiple HOX genes had obvious changes after MSCs administration and HOX A9 gene increased by 5.94-fold after MSCs administration into ALI animals. HOX A9 was distributed in endothelial cells and epithelial cells in animal models and overexpression of Hox A9 can promote proliferation and inhibit inflammatory adhesion of MSCs. Conclusion. HoxA9 overexpression induced by MSCs may be closely linked with lung repair after endotoxin shock.

  4. 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.

  5. Selective HDAC6 inhibition prevents TNF-α-induced lung endothelial cell barrier disruption and endotoxin-induced pulmonary edema.

    Science.gov (United States)

    Yu, Jinyan; Ma, Zhongsen; Shetty, Sreerama; Ma, Mengshi; Fu, Jian

    2016-07-01

    Lung endothelial damage contributes to the pathogenesis of acute lung injury. New strategies against lung endothelial barrier dysfunction may provide therapeutic benefits against lung vascular injury. Cell-cell junctions and microtubule cytoskeleton are basic components in maintaining endothelial barrier integrity. HDAC6, a deacetylase primarily localized in the cytoplasm, has been reported to modulate nonnuclear protein function through deacetylation. Both α-tubulin and β-catenin are substrates for HDAC6. Here, we examined the effects of tubastatin A, a highly selective HDAC6 inhibitor, on TNF-α induced lung endothelial cell barrier disruption and endotoxin-induced pulmonary edema. Selective HDAC6 inhibition by tubastatin A blocked TNF-α-induced lung endothelial cell hyperpermeability, which was associated with increased α-tubulin acetylation and microtubule stability. Tubastatin A pretreatment inhibited TNF-α-induced endothelial cell contraction and actin stress fiber formation with reduced myosin light chain phosphorylation. Selective HDAC6 inhibition by tubastatin A also induced β-catenin acetylation in human lung endothelial cells, which was associated with increased membrane localization of β-catenin and stabilization of adherens junctions. HDAC6 knockdown by small interfering RNA also prevented TNF-α-induced barrier dysfunction and increased α-tubulin and β-catenin acetylation in endothelial cells. Furthermore, in a mouse model of endotoxemia, tubastatin A was able to prevent endotoxin-induced deacetylation of α-tubulin and β-catenin in lung tissues, which was associated with reduced pulmonary edema. Collectively, our data indicate that selective HDAC6 inhibition by tubastatin A is a potent approach against lung endothelial barrier dysfunction. Copyright © 2016 the American Physiological Society.

  6. Protective effects of edaravone combined puerarin on inhalation lung injury induced by black gunpowder smog.

    Science.gov (United States)

    Wang, Zhengguan; Li, Ruibing; Liu, Yifan; Liu, Xiaoting; Chen, Wenyan; Xu, Shumin; Guo, Yuni; Duan, Jinyang; Chen, Yihong; Wang, Chengbin

    2015-05-01

    The present study aimed to investigate the combined effects of puerarin with edaravone on inhalation lung injury induced by black gunpowder smog. Male Wistar rats were divided into five groups (control group, edaravone group, puerarin group, edaravone combined with puerarin group and inhalation group). The severity of pulmonary injuries was evaluated after inducing acute lung injury. Arterial blood gas, inflammatory cytokines, biochemical, parameters, cell counting, W/D weight ratio and histopathology were analyzed. Results in lung tissues, either edaravone or puerarin treatment alone showed significant protective effects against neutrophil infiltration and tissue injury, as demonstrated by myeloperoxidase activity and histopathological analysis (all psmog-induced lung injury, compared with single treatment. Combination of edaravone and puerarin shows promise as a new treatment option for acute lung injury/acute respiratory distress syndrome patients. Copyright © 2015 Elsevier B.V. All rights reserved.

  7. Idh2 Deficiency Exacerbates Acrolein-Induced Lung Injury through Mitochondrial Redox Environment Deterioration

    Directory of Open Access Journals (Sweden)

    Jung Hyun Park

    2017-01-01

    Full Text Available Acrolein is known to be involved in acute lung injury and other pulmonary diseases. A number of studies have suggested that acrolein-induced toxic effects are associated with depletion of antioxidants, such as reduced glutathione and protein thiols, and production of reactive oxygen species. Mitochondrial NADP+-dependent isocitrate dehydrogenase (idh2 regulates mitochondrial redox balance and reduces oxidative stress-induced cell injury via generation of NADPH. Therefore, we evaluated the role of idh2 in acrolein-induced lung injury using idh2 short hairpin RNA- (shRNA- transfected Lewis lung carcinoma (LLC cells and idh2-deficient (idh2−/− mice. Downregulation of idh2 expression increased susceptibility to acrolein via induction of apoptotic cell death due to elevated mitochondrial oxidative stress. Idh2 deficiency also promoted acrolein-induced lung injury in idh2 knockout mice through the disruption of mitochondrial redox status. In addition, acrolein-induced toxicity in idh2 shRNA-transfected LLC cells and in idh2 knockout mice was ameliorated by the antioxidant, N-acetylcysteine, through attenuation of oxidative stress resulting from idh2 deficiency. In conclusion, idh2 deficiency leads to mitochondrial redox environment deterioration, which causes acrolein-mediated apoptosis of LLC cells and acrolein-induced lung injury in idh2−/− mice. The present study supports the central role of idh2 deficiency in inducing oxidative stress resulting from acrolein-induced disruption of mitochondrial redox status in the lung.

  8. Idh2 Deficiency Exacerbates Acrolein-Induced Lung Injury through Mitochondrial Redox Environment Deterioration.

    Science.gov (United States)

    Park, Jung Hyun; Ku, Hyeong Jun; Lee, Jin Hyup; Park, Jeen-Woo

    2017-01-01

    Acrolein is known to be involved in acute lung injury and other pulmonary diseases. A number of studies have suggested that acrolein-induced toxic effects are associated with depletion of antioxidants, such as reduced glutathione and protein thiols, and production of reactive oxygen species. Mitochondrial NADP + -dependent isocitrate dehydrogenase ( idh2 ) regulates mitochondrial redox balance and reduces oxidative stress-induced cell injury via generation of NADPH. Therefore, we evaluated the role of idh2 in acrolein-induced lung injury using idh2 short hairpin RNA- (shRNA-) transfected Lewis lung carcinoma (LLC) cells and idh2 -deficient ( idh2 -/- ) mice. Downregulation of idh2 expression increased susceptibility to acrolein via induction of apoptotic cell death due to elevated mitochondrial oxidative stress. Idh2 deficiency also promoted acrolein-induced lung injury in idh2 knockout mice through the disruption of mitochondrial redox status. In addition, acrolein-induced toxicity in idh2 shRNA-transfected LLC cells and in idh2 knockout mice was ameliorated by the antioxidant, N-acetylcysteine, through attenuation of oxidative stress resulting from idh2 deficiency. In conclusion, idh2 deficiency leads to mitochondrial redox environment deterioration, which causes acrolein-mediated apoptosis of LLC cells and acrolein-induced lung injury in idh2 -/- mice. The present study supports the central role of idh2 deficiency in inducing oxidative stress resulting from acrolein-induced disruption of mitochondrial redox status in the lung.

  9. Hypertonic saline reduces inflammation and enhances the resolution of oleic acid induced acute lung injury

    Directory of Open Access Journals (Sweden)

    Costello Joseph F

    2008-07-01

    Full Text Available Abstract Background Hypertonic saline (HTS reduces the severity of lung injury in ischemia-reperfusion, endotoxin-induced and ventilation-induced lung injury. However, the potential for HTS to modulate the resolution of lung injury is not known. We investigated the potential for hypertonic saline to modulate the evolution and resolution of oleic acid induced lung injury. Methods Adult male Sprague Dawley rats were used in all experiments. Series 1 examined the potential for HTS to reduce the severity of evolving oleic acid (OA induced acute lung injury. Following intravenous OA administration, animals were randomized to receive isotonic (Control, n = 12 or hypertonic saline (HTS, n = 12, and the extent of lung injury assessed after 6 hours. Series 2 examined the potential for HTS to enhance the resolution of oleic acid (OA induced acute lung injury. Following intravenous OA administration, animals were randomized to receive isotonic (Control, n = 6 or hypertonic saline (HTS, n = 6, and the extent of lung injury assessed after 6 hours. Results In Series I, HTS significantly reduced bronchoalveolar lavage (BAL neutrophil count compared to Control [61.5 ± 9.08 versus 102.6 ± 11.89 × 103 cells.ml-1]. However, there were no between group differences with regard to: A-a O2 gradient [11.9 ± 0.5 vs. 12.0 ± 0.5 KPa]; arterial PO2; static lung compliance, or histologic injury. In contrast, in Series 2, hypertonic saline significantly reduced histologic injury and reduced BAL neutrophil count [24.5 ± 5.9 versus 46.8 ± 4.4 × 103 cells.ml-1], and interleukin-6 levels [681.9 ± 190.4 versus 1365.7 ± 246.8 pg.ml-1]. Conclusion These findings demonstrate, for the first time, the potential for HTS to reduce pulmonary inflammation and enhance the resolution of oleic acid induced lung injury.

  10. Prevention of cigarette smoke induced lung cancer by low let ionizing radiation

    International Nuclear Information System (INIS)

    Sanders, Charles L.

    2008-01-01

    Lung cancer is the most prevalent global cancer, ∼90% of which is caused by cigarette smoking. The LNT hypothesis has been inappropriately applied to estimate lung cancer risk due to ionizing radiation. A threshold of ∼1 Gy for lung cancer has been observed in never smokers. Lung cancer risk among nuclear workers, radiologists and diagnostically exposed patients was typically reduced by ∼40% following exposure to <100 mSv low LET radiation. The consistency and magnitude of reduced lung cancer in nuclear workers and occurrence of reduced lung cancer in exposed non-worker populations could not be explained by the HWE. Ecologic studies of indoor radon showed highly significant reductions in lung cancer risk. A similar reduction in lung cancer was seen in a recent well designed case-control study of indoor radon, indicating that exposure to radon at the EPA action level is associated with a decrease of ∼60% in lung cancer. A cumulative whole-body dose of ∼1 Gy gamma rays is associated with a marked decrease in smoking-induced lung cancer in plutonium workers. Low dose, low LET radiation appears to increase apoptosis mediated removal of α-particle and cigarette smoke transformed pulmonary cells before they can develop into lung cancer

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

    LENUS (Irish Health Repository)

    Robb, W B

    2010-03-01

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

  12. Chemoprevention with Acetylsalicylic Acid, Vitamin D and Calcium Reduces Risk of Carcinogen-induced Lung Tumors

    DEFF Research Database (Denmark)

    Pommergaard, Hans-Christian; Burcharth, Jakob; Rosenberg, J

    2013-01-01

    Background/Aim: Research has shown that chemoprevention may be effective against the development of lung cancer. The purpose of the present study was to evaluate the effect of oral chemoprevention in a mouse model of tobacco carcinogen-induced lung tumor....

  13. Inhibition or knock out of Inducible nitric oxide synthase result in resistance to bleomycin-induced lung injury

    Directory of Open Access Journals (Sweden)

    Crimi Nunzio

    2005-06-01

    Full Text Available Abstract Background In the present study, by comparing the responses in wild-type mice (WT and mice lacking (KO the inducible (or type 2 nitric oxide synthase (iNOS, we investigated the role played by iNOS in the development of on the lung injury caused by bleomycin administration. When compared to bleomycin-treated iNOSWT mice, iNOSKO mice, which had received bleomycin, exhibited a reduced degree of the (i lost of body weight, (ii mortality rate, (iii infiltration of the lung with polymorphonuclear neutrophils (MPO activity, (iv edema formation, (v histological evidence of lung injury, (vi lung collagen deposition and (vii lung Transforming Growth Factor beta1 (TGF-β1 expression. Methods Mice subjected to intratracheal administration of bleomycin developed a significant lung injury. Immunohistochemical analysis for nitrotyrosine revealed a positive staining in lungs from bleomycin-treated iNOSWT mice. Results The intensity and degree of nitrotyrosine staining was markedly reduced in tissue section from bleomycin-iNOSKO mice. Treatment of iNOSWT mice with of GW274150, a novel, potent and selective inhibitor of iNOS activity (5 mg/kg i.p. also significantly attenuated all of the above indicators of lung damage and inflammation. Conclusion Taken together, our results clearly demonstrate that iNOS plays an important role in the lung injury induced by bleomycin in the mice.

  14. Cerium-144-induced lung gumors in two strains of mice

    Energy Technology Data Exchange (ETDEWEB)

    Hahn, F.F.; Griffith, W.C.

    1995-12-01

    A major problem in the extrapolation of radiation cancer risk factors from one species or population to another is the choice of the risk model to use, either absolute or relative. The purpose of this study was to compare absolute and relative risk models in predicting the lung-tumor risks between a low lung-tumor incidence strain of mice and a high-incidence strain of mice. The conclusion from this study is that absolute risk is more accurate than relative risk for predicting lung tumor risk from high to low lung-tumor incidence strains of mice.

  15. Graphene-induced apoptosis in lung epithelial cells through EGFR

    Science.gov (United States)

    Tsai, Shih-Ming; Bangalore, Preeti; Chen, Eric Y.; Lu, David; Chiu, Meng-Hsuen; Suh, Andrew; Gehring, Matthew; Cangco, John P.; Garcia, Santiago G.; Chin, Wei-Chun

    2017-07-01

    Expanding interest in nanotechnology applied to electronic and biomedical fields has led to fast-growing development of various nanomaterials. Graphene is a single-atom thick, two-dimensional sheet of hexagonally arranged carbon atoms with unique physical and chemical properties. Recently, graphene has been used in many studies on electronics, photonics, composite materials, energy generation and storage, sensors, and biomedicine. However, the current health risk assessment for graphene has been relatively limited and inconclusive. This study evaluated the toxicity effects of graphene on the airway epithelial cell line BEAS-2B, which represents the first barrier of the human body to interact with airborne graphene particles. Our result showed that graphene can induce the cellular Ca2+ by phospholipase C (PLC) associated pathway by activating epidermal growth factor receptor (EGFR). Subsequently, inositol 1,4,5-triphosphate (IP3) receptors activate the release of Ca2+ from the endoplasmic reticulum (ER) Ca2+ stores. Those Ca2+ signals further trigger the calcium-regulated apoptosis in the cell. Furthermore, the stimulation can cause EGFR upregulation, which have been demonstrated to associate with diseases such as lung cancer, chronic obstructive pulmonary disease (COPD), and cardiovascular diseases. This study highlights the additional health risk considering that it can function as a contributing factor for other respiratory diseases.

  16. β2-Microglobulin participates in development of lung emphysema by inducing lung epithelial cell senescence.

    Science.gov (United States)

    Gao, Na; Wang, Ying; Zheng, Chun-Ming; Gao, Yan-Li; Li, Hui; Li, Yan; Fu, Ting-Ting; Xu, Li-Li; Wang, Wei; Ying, Sun; Huang, Kewu

    2017-05-01

    β 2 -Microglobulin (β 2 M), the light chain of the major histocompatibility complex class I (MHC I), has been identified as a proaging factor and is involved in the pathogenesis of neurodegenerative disorders by driving cognitive and regenerative impairments. However, little attention has focused on the effect of β 2 M in the development of lung emphysema. Here, we found that concentrations of β 2 M in plasma were significantly elevated in patients with lung emphysema than those in normal control subjects (1.89 ± 0.12 vs. 1.42 ± 0.06 mg/l, P lung tissue of emphysema (39.90 ± 1.97 vs. 23.94 ± 2.11%, P lung emphysema through induction of lung epithelial cell senescence and inhibition. Copyright © 2017 the American Physiological Society.

  17. Trauma hemorrhagic shock-induced lung injury involves a gut-lymph-induced TLR4 pathway in mice.

    Directory of Open Access Journals (Sweden)

    Diego C Reino

    Full Text Available Injurious non-microbial factors released from the stressed gut during shocked states contribute to the development of acute lung injury (ALI and multiple organ dysfunction syndrome (MODS. Since Toll-like receptors (TLR act as sensors of tissue injury as well as microbial invasion and TLR4 signaling occurs in both sepsis and noninfectious models of ischemia/reperfusion (I/R injury, we hypothesized that factors in the intestinal mesenteric lymph after trauma hemorrhagic shock (T/HS mediate gut-induced lung injury via TLR4 activation.The concept that factors in T/HS lymph exiting the gut recreates ALI is evidenced by our findings that the infusion of porcine lymph, collected from animals subjected to global T/HS injury, into naïve wildtype (WT mice induced lung injury. Using C3H/HeJ mice that harbor a TLR4 mutation, we found that TLR4 activation was necessary for the development of T/HS porcine lymph-induced lung injury as determined by Evan's blue dye (EBD lung permeability and myeloperoxidase (MPO levels as well as the induction of the injurious pulmonary iNOS response. TRIF and Myd88 deficiency fully and partially attenuated T/HS lymph-induced increases in lung permeability respectively. Additional studies in TLR2 deficient mice showed that TLR2 activation was not involved in the pathology of T/HS lymph-induced lung injury. Lastly, the lymph samples were devoid of bacteria, endotoxin and bacterial DNA and passage of lymph through an endotoxin removal column did not abrogate the ability of T/HS lymph to cause lung injury in naïve mice.Our findings suggest that non-microbial factors in the intestinal mesenteric lymph after T/HS are capable of recreating T/HS-induced lung injury via TLR4 activation.

  18. Iron supplementation at high altitudes induces inflammation and oxidative injury to lung tissues in rats

    Energy Technology Data Exchange (ETDEWEB)

    Salama, Samir A., E-mail: salama.3@buckeyemail.osu.edu [High Altitude Research Center, Taif University, Al-Haweiah, Taif 21974 (Saudi Arabia); Department of Biochemistry, Faculty of Pharmacy, Al-Azhar University, Cairo 11751 (Egypt); Department of Pharmacology and GTMR Unit, College of Clinical Pharmacy, Taif University, Al-Haweiah, Taif 21974 (Saudi Arabia); Omar, Hany A. [Department of Pharmacology, Faculty of Pharmacy, Beni-Suef University, Beni-Suef 62514 (Egypt); Maghrabi, Ibrahim A. [Department of Clinical Pharmacy, College of Clinical Pharmacy, Taif University, Al-Haweiah, Taif 21974 (Saudi Arabia); AlSaeed, Mohammed S. [Department of Surgery, College of Medicine, Taif University, Al-Haweiah, Taif 21974 (Saudi Arabia); EL-Tarras, Adel E. [High Altitude Research Center, Taif University, Al-Haweiah, Taif 21974 (Saudi Arabia)

    2014-01-01

    Exposure to high altitudes is associated with hypoxia and increased vulnerability to oxidative stress. Polycythemia (increased number of circulating erythrocytes) develops to compensate the high altitude associated hypoxia. Iron supplementation is, thus, recommended to meet the demand for the physiological polycythemia. Iron is a major player in redox reactions and may exacerbate the high altitudes-associated oxidative stress. The aim of this study was to explore the potential iron-induced oxidative lung tissue injury in rats at high altitudes (6000 ft above the sea level). Iron supplementation (2 mg elemental iron/kg, once daily for 15 days) induced histopathological changes to lung tissues that include severe congestion, dilatation of the blood vessels, emphysema in the air alveoli, and peribronchial inflammatory cell infiltration. The levels of pro-inflammatory cytokines (IL-1β, IL-6, and TNF-α), lipid peroxidation product and protein carbonyl content in lung tissues were significantly elevated. Moreover, the levels of reduced glutathione and total antioxidant capacity were significantly reduced. Co-administration of trolox, a water soluble vitamin E analog (25 mg/kg, once daily for the last 7 days of iron supplementation), alleviated the lung histological impairments, significantly decreased the pro-inflammatory cytokines, and restored the oxidative stress markers. Together, our findings indicate that iron supplementation at high altitudes induces lung tissue injury in rats. This injury could be mediated through excessive production of reactive oxygen species and induction of inflammatory responses. The study highlights the tissue injury induced by iron supplementation at high altitudes and suggests the co-administration of antioxidants such as trolox as protective measures. - Highlights: • Iron supplementation at high altitudes induced lung histological changes in rats. • Iron induced oxidative stress in lung tissues of rats at high altitudes. • Iron

  19. Protective role of vascular endothelial growth factor in endotoxin-induced acute lung injury in mice

    Directory of Open Access Journals (Sweden)

    Adachi Yoshiyuki

    2007-08-01

    Full Text Available Abstract Background Vascular endothelial growth factor (VEGF, a substance that stimulates new blood vessel formation, is an important survival factor for endothelial cells. Although overexpressed VEGF in the lung induces pulmonary edema with increased lung vascular permeability, the role of VEGF in the development of acute lung injury remains to be determined. Methods To evaluate the role of VEGF in the pathogenesis of acute lung injury, we first evaluated the effects of exogenous VEGF and VEGF blockade using monoclonal antibody on LPS-induced lung injury in mice. Using the lung specimens, we performed TUNEL staining to detect apoptotic cells and immunostaining to evaluate the expression of apoptosis-associated molecules, including caspase-3, Bax, apoptosis inducing factor (AIF, and cytochrome C. As a parameter of endothelial permeability, we measured the albumin transferred across human pulmonary artery endothelial cell (HPAEC monolayers cultured on porous filters with various concentrations of VEGF. The effect of VEGF on apoptosis HPAECs was also examined by TUNEL staining and active caspase-3 immunoassay. Results Exogenous VEGF significantly decreased LPS-induced extravascular albumin leakage and edema formation. Treatment with anti-VEGF antibody significantly enhanced lung edema formation and neutrophil emigration after intratracheal LPS administration, whereas extravascular albumin leakage was not significantly changed by VEGF blockade. In lung pathology, pretreatment with VEGF significantly decreased the numbers of TUNEL positive cells and those with positive immunostaining of the pro-apoptotic molecules examined. VEGF attenuated the increases in the permeability of the HPAEC monolayer and the apoptosis of HPAECs induced by TNF-α and LPS. In addition, VEGF significantly reduced the levels of TNF-α- and LPS-induced active caspase-3 in HPAEC lysates. Conclusion These results suggest that VEGF suppresses the apoptosis induced by

  20. Surfactant Protein D is a candidate biomarker for subclinical tobacco smoke-induced lung damage

    DEFF Research Database (Denmark)

    Lock Johansson, Sofie; Tan, Qihua; Holst, Rene

    2014-01-01

    Variation in Surfactant Protein D (SP-D) is associated with lung function in tobacco smoke-induced chronic respiratory disease. We hypothesized that the same association exists in the general population and could be used to identify individuals sensitive to smoke-induced lung damage. The associat......Variation in Surfactant Protein D (SP-D) is associated with lung function in tobacco smoke-induced chronic respiratory disease. We hypothesized that the same association exists in the general population and could be used to identify individuals sensitive to smoke-induced lung damage...... or haplotypes, and expiratory lung function were assessed using twin study methodology and mixed-effects models. Significant inverse associations were evident between sSP-D and the forced expiratory volume in 1 second and forced vital capacity in the presence of current tobacco smoking but not in non...... with lung function measures in interaction with tobacco smoking. The obtained data suggest sSP-D as a candidate biomarker in risk assessments for subclinical tobacco smoke-induced lung damage. The data and derived conclusion warrant confirmation in a longitudinal population following chronic obstructive...

  1. Alda-1 Protects Against Acrolein-Induced Acute Lung Injury and Endothelial Barrier Dysfunction.

    Science.gov (United States)

    Lu, Qing; Mundy, Miles; Chambers, Eboni; Lange, Thilo; Newton, Julie; Borgas, Diana; Yao, Hongwei; Choudhary, Gaurav; Basak, Rajshekhar; Oldham, Mahogany; Rounds, Sharon

    2017-12-01

    Inhalation of acrolein, a highly reactive aldehyde, causes lung edema. The underlying mechanism is poorly understood and there is no effective treatment. In this study, we demonstrated that acrolein not only dose-dependently induced lung edema but also promoted LPS-induced acute lung injury. Importantly, acrolein-induced lung injury was prevented and rescued by Alda-1, an activator of mitochondrial aldehyde dehydrogenase 2. Acrolein also dose-dependently increased monolayer permeability, disrupted adherens junctions and focal adhesion complexes, and caused intercellular gap formation in primary cultured lung microvascular endothelial cells (LMVECs). These effects were attenuated by Alda-1 and the antioxidant N-acetylcysteine, but not by the NADPH inhibitor apocynin. Furthermore, acrolein inhibited AMP-activated protein kinase (AMPK) and increased mitochondrial reactive oxygen species levels in LMVECs-effects that were associated with impaired mitochondrial respiration. AMPK total protein levels were also reduced in lung tissue of mice and LMVECs exposed to acrolein. Activation of AMPK with 5-aminoimidazole-4-carboxamide-1-β-4-ribofuranoside blunted an acrolein-induced increase in endothelial monolayer permeability, but not mitochondrial oxidative stress or inhibition of mitochondrial respiration. Our results suggest that acrolein-induced mitochondrial dysfunction may not contribute to endothelial barrier dysfunction. We speculate that detoxification of acrolein by Alda-1 and activation of AMPK may be novel approaches to prevent and treat acrolein-associated acute lung injury, which may occur after smoke inhalation.

  2. The receptor for advanced glycation end products in ventilator-induced lung injury

    NARCIS (Netherlands)

    Kuipers, Maria T.; Aslami, Hamid; Tuinman, Pieter Roel; Tuip-de Boer, Anita M.; Jongsma, Geartsje; van der Sluijs, Koenraad F.; Choi, Goda; Wolthuis, Esther K.; Roelofs, Joris J. T. H.; Bresser, Paul; Schultz, Marcus J.; van der Poll, Tom; Wieland, Catharina W.

    2014-01-01

    Mechanical ventilation (MV) can cause ventilator-induced lung injury (VILI). The innate immune response mediates this iatrogenic inflammatory condition. The receptor for advanced glycation end products (RAGE) is a multiligand receptor that can amplify immune and inflammatory responses. We

  3. The receptor for advanced glycation end products in ventilator-induced lung injury

    NARCIS (Netherlands)

    Kuipers, Maria T; Aslami, Hamid; Tuinman, Pieter Roel; Tuip-de Boer, Anita M; Jongsma, Geartsje; van der Sluijs, Koenraad F; Choi, Goda; Wolthuis, Esther K; Roelofs, Joris Jth; Bresser, Paul; Schultz, Marcus J; van der Poll, Tom; Wieland, Catharina W

    2014-01-01

    BACKGROUND: Mechanical ventilation (MV) can cause ventilator-induced lung injury (VILI). The innate immune response mediates this iatrogenic inflammatory condition. The receptor for advanced glycation end products (RAGE) is a multiligand receptor that can amplify immune and inflammatory responses.

  4. Ventilation and Perfusion Lung Scintigraphy of Allergen-Induced Airway Responses in Atopic Asthmatic Subjects

    Directory of Open Access Journals (Sweden)

    Krishnan Parameswaran

    2007-01-01

    Full Text Available BACKGROUND: Both ventilation (V and perfusion (Q of the lungs are altered in asthma, but their relationships with allergen-induced airway responses and gas exchange are not well described.

  5. Adrenal-derived stress hormones modulate ozone-induced lung injury and inflammation

    Data.gov (United States)

    U.S. Environmental Protection Agency — This data set shows high throughput gene expression assessment using RNAseq to examine how ozone-induced transcriptional changes in the lung are influenced by...

  6. Comparison of lung alveolar and tissue cells in silica-induced inflammation.

    Science.gov (United States)

    Sjöstrand, M; Absher, P M; Hemenway, D R; Trombley, L; Baldor, L C

    1991-01-01

    The silicon dioxide mineral, cristobalite (CRS) induces inflammation involving both alveolar cells and connective tissue compartments. In this study, we compared lung cells recovered by whole lung lavage and by digestion of lung tissue from rats at varying times after 8 days of exposure to aerosolized CRS. Control and exposed rats were examined between 2 and 36 wk after exposure. Lavaged cells were obtained by bronchoalveolar lavage with phosphate-buffered saline. Lung wall cells were prepared via collagenase digestion of lung tissue slices. Cells from lavage and lung wall were separated by Percoll density centrifugation. The three upper fractions, containing mostly macrophages, were cultured, and the conditioned medium was assayed for effect on lung fibroblast growth and for activity of the lysosomal enzyme, N-acetyl-beta-D-glucosaminidase. Results demonstrated that the cells separated from the lung walls exhibited different reaction patterns compared with those cells recovered by lavage. The lung wall cells exhibited a progressive increase in the number of macrophages and lymphocytes compared with a steady state in cells of the lung lavage. This increase in macrophages apparently was due to low density cells, which showed features of silica exposure. Secretion of a fibroblast-stimulating factor was consistently high by lung wall macrophages, whereas lung lavage macrophages showed inconsistent variations. The secretion of NAG was increased in lung lavage macrophages, but decreased at most observation times in lung wall macrophages. No differences were found among cells in the different density fractions regarding fibroblast stimulation and enzyme secretion.(ABSTRACT TRUNCATED AT 250 WORDS)

  7. Ventilator induced lung injury (VILI) in acute respiratory distress ...

    African Journals Online (AJOL)

    The lung protective ventilation strategy- Low tidal volume ventilation has shown some reduction in mortality in patients with ARDS but mortality is still high in patient with severe ARDS secondary to Pneumocystis jiroveci pneumonia (PJP) despite of lung protective ventilation strategy. In patients with Severe ARDS due to PJP ...

  8. Green tea polyphenol induces significant cell death in human lung ...

    African Journals Online (AJOL)

    ... of EGCG on lung cancer cells, including H1155 cells, both in vitro and in vivo. The induction of reactive oxygen species, oxidative DNA damage, and apoptosis were evident following EGCG treatment. Keywords: Green tea, Lung cancer, Catechins, Epigallocatechin-3-gallate, Oxidative stress, Oxidative DNA damage ...

  9. [Penehyclidine hydrochloride attenuates LPS-induced acute lung injury in rats].

    Science.gov (United States)

    Guo, Yan; Wei, Min; Yan, Zhiqiang; Wang, Guoxia

    2017-11-01

    Objective To study the protective effect of penehyclidine hydrochloride (PHCD) against acute lung injury induced by lipopolysaccharide (LPS) in rats. Methods 36 Sprague Dawley (SD) rats were randomly divided into control group, LPS-induced shock group (LPS group), and PHCD treated group (PHCD group). Rat shock model was prepared by intraperitoneal injection of LPS (5 mg/kg). The rats of PHCD group were treated with PHCD (1.0 mg/kg) by caudal vein injection. Rat blood gas analysis was performed 6 hours after the injection. Lung wet/dry mass ratio (W/D) was detected after the rats were sacrificed. The levels of tumor necrosis factor α (TNF-α), interleukin 8 (IL-8), and IL-6 in bronchoalveolar lavage fluid (BALF) were tested by ELISA. The lung tissue inflammation was observed by HE staining. The expression of inducible nitric oxide synthase (iNOS) was detected by real-time quantitative PCR and Western blot analysis. Results Compared with the control group, lung W/D and blood lactate acid (LAC) increased significantly in the LPS group, while the blood pH and the arterial oxygen partial pressure (PaO 2 ) decreased markedly. The levels of TNF-α, IL-8 and IL-6 significantly increased in lung BALF of the LPS-induced rats, and the expression of iNOS increased significantly. HE staining showed that LPS treatment caused pulmonary edema, congestion and inflammatory cell infiltration. After PHCD treatment, lung W/D and LAC were reduced; the pH and PaO 2 were elevated compared with LPS-induced rats; the levels of TNF-α, IL-8 and IL-6 in BALF were evidently down-regulated; the expression of iNOS decreased obviously. HE staining showed that the lung inflammation was attenuated by PHCD treatment. Conclusion PHCD attenuates lung injury by inhibiting LPS-induced lung inflammation.

  10. Antioxidant intervention of smoking-induced lung tumor in mice by vitamin E and quercetin

    International Nuclear Information System (INIS)

    Yang, Jie; Li, Jun-Wen; Wang, Lu; Chen, Zhaoli; Shen, Zhi-Qiang; Jin, Min; Wang, Xin-Wei; Zheng, Yufei; Qiu, Zhi-Gang; Wang, Jing-feng

    2008-01-01

    Epidemiological and in vitro studies suggest that antioxidants such as quercetin and vitamin E (VE) can prevent lung tumor caused by smoking; however, there is limited evidence from animal studies. In the present study, Swiss mouse was used to examine the potential of quercetin and VE for prevention lung tumor induced by smoking. Our results suggest that the incidence of lung tumor and tumor multiplicity were 43.5% and 1.00 ± 0.29 in smoking group; Quercetin has limited effects on lung tumor prevention in this in vivo model, as measured by assays for free radical scavenging, reduction of smoke-induced DNA damage and inhibition of apoptosis. On the other hand, vitamin E drastically decreased the incidence of lung tumor and tumor multiplicity which were 17.0% and 0.32 ± 0.16, respectively (p < 0.05); and demonstrated prominent antioxidant effects, reduction of DNA damage and decreased cell apoptosis (p < 0.05). Combined treatment with quercetin and VE in this animal model did not demonstrate any effect greater than that due to vitamin E alone. In addition, gender differences in the occurrence of smoke induced-lung tumor and antioxidant intervention were also observed. We conclude that VE might prevent lung tumor induced by smoking in Swiss mice

  11. Number 2 Feibi Recipe Reduces PM2.5-Induced Lung Injury in Rats

    Directory of Open Access Journals (Sweden)

    Zhaoheng Liu

    2018-01-01

    Full Text Available Air pollution is the main cause of respiratory diseases. Fine particulates with the diameter below 2.5 μm can get into the alveoli and then enter the blood circulation through the lung tissue ventilation function and cause multiple systemic diseases especially the respiratory diseases. This study investigated the pathological mechanism of the lungs injury in rats induced by PM2.5 and the effect and mechanism of the Chinese herbal medicine number 2 Feibi Recipe (number 2 FBR on lungs injury. In this experiment, Wistar rats were used. Lungs injury was induced by PM2.5. Number 2 FBR was used to treat the rats. The result showed that number 2 FBR could improve the lung injury in the rats. Meanwhile, it significantly reduced pathological response and inflammatory mediators including interleukin-6 (IL-6, interleukin-13 (IL-13, interleukin-17 (IL17, monocyte chemotactic protein-1 (MCP-1, and transforming growth factor-α (TNF-α and upregulated glutathione peroxidase (GSH-Px in the PM2.5 induced lung injury in the rats. Collectively, number 2 FBR appears to attenuate the lungs injury in rats induced by PM2.5.

  12. Transplantation of hamster lung lesions induced by 239PuO2 or benz(a)pyrene

    International Nuclear Information System (INIS)

    McDonald, K.E.; Sanders, C.L.

    1980-01-01

    None(0%) of 1000 recipients of lung lesions for 239 PuO 2 -exposed hamsters that were transplanted into other hamsters' cheek pouches, developed tumors, whereas 90% of transplants from benz(a)pyrene-induced lung lesions were malignant

  13. Over-expression of phosphorylated MARCKS in the nicotine-derived nitrosamine ketone induced lung cancer mice

    Directory of Open Access Journals (Sweden)

    Zhen Chen

    2015-03-01

    Full Text Available Lung cancer is the most frequently occurring lethal cancers in men and women population. The aim of the present study is to observe the over-expression pattern of phosphorylated MARCKS in the nicotine-derived nitrosamine ketone (NNK induced lung cancer mice. Pathogen-free female A/J mice were used for the present experiment to induce lung cancer by the carcinogen namely, NNK. At different time intervals namely, 5th, 6th and 7th month after NNK injection, lung tissue samples were collected. Immunohistochemistry in accordance with the immunoblotting techniques were used to confirm the over-expression of phosphorylated MARCKS in the NNK induced lung cancer mice model. The present study concludes that the phosphorylated MARCKS was over-expressed in the NNK induced lung cancer mice during the early stages of lung cancer and it may be used as a tool to detect the lung cancer in the initial stages.

  14. [18F]fluorodeoxyglucose Uptake Patterns in Lung Before Radiotherapy Identify Areas More Susceptible to Radiation-Induced Lung Toxicity in Non-Small-Cell Lung Cancer Patients

    International Nuclear Information System (INIS)

    Petit, Steven F.; Elmpt, Wouter J.C. van; Oberije, Cary J.G.; Vegt, Erik; Dingemans, Anne-Marie C.; Lambin, Philippe; Dekker, Andre L.A.J.; De Ruysscher, Dirk

    2011-01-01

    Purpose: Our hypothesis was that pretreatment inflammation in the lung makes pulmonary tissue more susceptible to radiation damage. The relationship between pretreatment [ 18 F]fluorodeoxyglucose ([ 18 F]FDG) uptake in the lungs (as a surrogate for inflammation) and the delivered radiation dose and radiation-induced lung toxicity (RILT) was investigated. Methods and Materials: We retrospectively studied a prospectively obtained cohort of 101 non-small-cell lung cancer patients treated with (chemo)radiation therapy (RT). [ 18 F]FDG-positron emission tomography-computed tomography (PET-CT) scans used for treatment planning were studied. Different parameters were used to describe [ 18 F]FDG uptake patterns in the lungs, excluding clinical target volumes, and the interaction with radiation dose. An increase in the dyspnea grade of 1 (Common Terminology Criteria for Adverse Events version 3.0) or more points compared to the pre-RT score was used as an endpoint for analysis of RILT. The effect of [ 18 F]FDG and CT-based variables, dose, and other patient or treatment characteristics that effected RILT was studied using logistic regression. Results: Increased lung density and pretreatment [ 18 F]FDG uptake were related to RILT after RT with univariable logistic regression. The 95th percentile of the [ 18 F]FDG uptake in the lungs remained significant in multivariable logistic regression (p = 0.016; odds ratio [OR] = 4.3), together with age (p = 0.029; OR = 1.06), and a pre-RT dyspnea score of ≥1 (p = 0.005; OR = 0.20). Significant interaction effects were demonstrated among the 80th, 90th, and 95th percentiles and the relative lung volume receiving more than 2 and 5 Gy. Conclusions: The risk of RILT increased with the 95th percentile of the [ 18 F]FDG uptake in the lungs, excluding clinical tumor volume (OR = 4.3). The effect became more pronounced as the fraction of the 5%, 10%, and 20% highest standardized uptake value voxels that received more than 2 Gy to 5 Gy

  15. Asbestos-induced lung disease in small-scale clutch manufacturing workers.

    Science.gov (United States)

    Gothi, Dipti; Gahlot, Tanushree; Sah, Ram B; Saxena, Mayank; Ojha, U C; Verma, Anand K; Spalgais, Sonam

    2016-01-01

    The crocidolite variety of asbestos is banned. However, chrysotile, which is not prohibited, is still used in developing countries in making products such as clutch plate. Fourteen workers from a small-scale clutch plate-manufacturing factory were analyzed for asbestos-induced lung disease as one of their colleagues had expired due to asbestosis. This study was conducted to evaluate the awareness of workers, the prevalence and type of asbestos-induced lung disease, and the sensitivity and specificity of diffusion test. History, examination, chest radiograph, spirometry with diffusion, and high resolution computed tomography (HRCT) thorax was performed in all the workers. The diagnosis of asbestos-induced lung disease was suspected on the basis of HRCT. This was subsequently confirmed on transbronchial lung biopsy (TBLB). None of the workers had detailed information about asbestos and its ill effects. Eleven out of 14 (71.42%) workers had asbestos-induced lung disease. All 11 had small airway disease (SAD). Three had SAD alone, 6 had additional interstitial lung disease (ILD), and 2 patients had additional ILD and chronic obstructive pulmonary disease. Sensitivity and specificity of residual volume (RV) or total lung capacity (TLC) for detecting SAD was 90% and 100%, respectively, and that of diffusion capacity of lung for carbon monoxide (DLCO) for detecting ILD was 100%. The awareness about asbestos in small-scale clutch-plate manufacturing industry is poor. The usage of chrysotile should be strictly regulated as morbidity and mortality is high. DLCO and RV/TLC are sensitive and specific in detecting nonmalignant asbestos induced lung disease.

  16. Role of reactive nitrogen species generated via inducible nitric oxide synthase in vesicant-induced lung injury, inflammation and altered lung functioning

    Energy Technology Data Exchange (ETDEWEB)

    Sunil, Vasanthi R., E-mail: sunilvr@eohsi.rutgers.edu [Department of Pharmacology and Toxicology, Rutgers University, Ernest Mario School of Pharmacy Piscataway, NJ (United States); Shen, Jianliang; Patel-Vayas, Kinal; Gow, Andrew J. [Department of Pharmacology and Toxicology, Rutgers University, Ernest Mario School of Pharmacy Piscataway, NJ (United States); Laskin, Jeffrey D. [Department of Environmental and Occupational Medicine, University of Medicine and Dentistry of New Jersey, Robert Wood Johnson Medical School, Piscataway, NJ (United States); Laskin, Debra L. [Department of Pharmacology and Toxicology, Rutgers University, Ernest Mario School of Pharmacy Piscataway, NJ (United States)

    2012-05-15

    Pulmonary toxicity induced by sulfur mustard and related vesicants is associated with oxidative stress. In the present studies we analyzed the role of reactive nitrogen species (RNS) generated via inducible nitric oxide synthase (iNOS) in lung injury and inflammation induced by vesicants using 2-chloroethyl ethyl sulfide (CEES) as a model. C57Bl/6 (WT) and iNOS −/− mice were sacrificed 3 days or 14 days following intratracheal administration of CEES (6 mg/kg) or control. CEES intoxication resulted in transient (3 days) increases in bronchoalveolar lavage (BAL) cell and protein content in WT, but not iNOS −/− mice. This correlated with expression of Ym1, a marker of oxidative stress in alveolar macrophages and epithelial cells. In contrast, in iNOS −/− mice, Ym1 was only observed 14 days post-exposure in enlarged alveolar macrophages, suggesting that they are alternatively activated. This is supported by findings that lung tumor necrosis factor and lipocalin Lcn2 expression, mediators involved in tissue repair were also upregulated at this time in iNOS −/− mice. Conversely, CEES-induced increases in the proinflammatory genes, monocyte chemotactic protein-1 and cyclooxygenase-2, were abrogated in iNOS −/− mice. In WT mice, CEES treatment also resulted in increases in total lung resistance and decreases in compliance in response to methacholine, effects blunted by loss of iNOS. These data demonstrate that RNS, generated via iNOS play a role in the pathogenic responses to CEES, augmenting oxidative stress and inflammation and suppressing tissue repair. Elucidating inflammatory mechanisms mediating vesicant-induced lung injury is key to the development of therapeutics to treat mustard poisoning. -- Highlights: ► Lung injury, inflammation and oxidative stress are induced by the model vesicant CEES ► RNS generated via iNOS are important in the CEES-induced pulmonary toxicity ► iNOS −/− mice are protected from CEES-induced lung toxicity and

  17. Role of reactive nitrogen species generated via inducible nitric oxide synthase in vesicant-induced lung injury, inflammation and altered lung functioning

    International Nuclear Information System (INIS)

    Sunil, Vasanthi R.; Shen, Jianliang; Patel-Vayas, Kinal; Gow, Andrew J.; Laskin, Jeffrey D.; Laskin, Debra L.

    2012-01-01

    Pulmonary toxicity induced by sulfur mustard and related vesicants is associated with oxidative stress. In the present studies we analyzed the role of reactive nitrogen species (RNS) generated via inducible nitric oxide synthase (iNOS) in lung injury and inflammation induced by vesicants using 2-chloroethyl ethyl sulfide (CEES) as a model. C57Bl/6 (WT) and iNOS −/− mice were sacrificed 3 days or 14 days following intratracheal administration of CEES (6 mg/kg) or control. CEES intoxication resulted in transient (3 days) increases in bronchoalveolar lavage (BAL) cell and protein content in WT, but not iNOS −/− mice. This correlated with expression of Ym1, a marker of oxidative stress in alveolar macrophages and epithelial cells. In contrast, in iNOS −/− mice, Ym1 was only observed 14 days post-exposure in enlarged alveolar macrophages, suggesting that they are alternatively activated. This is supported by findings that lung tumor necrosis factor and lipocalin Lcn2 expression, mediators involved in tissue repair were also upregulated at this time in iNOS −/− mice. Conversely, CEES-induced increases in the proinflammatory genes, monocyte chemotactic protein-1 and cyclooxygenase-2, were abrogated in iNOS −/− mice. In WT mice, CEES treatment also resulted in increases in total lung resistance and decreases in compliance in response to methacholine, effects blunted by loss of iNOS. These data demonstrate that RNS, generated via iNOS play a role in the pathogenic responses to CEES, augmenting oxidative stress and inflammation and suppressing tissue repair. Elucidating inflammatory mechanisms mediating vesicant-induced lung injury is key to the development of therapeutics to treat mustard poisoning. -- Highlights: ► Lung injury, inflammation and oxidative stress are induced by the model vesicant CEES ► RNS generated via iNOS are important in the CEES-induced pulmonary toxicity ► iNOS −/− mice are protected from CEES-induced lung toxicity and

  18. Laser-induced thermotherapy of lung metastases and primary lung tumors; Laserinduzierte Thermotherapie von Lungenmetastasen und primaeren Lungentumoren

    Energy Technology Data Exchange (ETDEWEB)

    Vogl, T.J. (Institut fuer Diagnostische und Interventionelle Radiologie, Klinikum der J.-W.-Goethe-Universitaet Frankfurt; Institut fuer Diagnostische und Interventionelle Radiologie, Klinikum der J.-W.-Goethe-Universitaet, Theodor-Stern-Kai 7, 60590, Frankfurt); Fieguth, H.G. (Klinik fuer Thorax-, Herz- und thorakale Gefaesschirurgie, Klinikum der J.-W.-Goethe-Universitaet Frankfurt); Eichler, K.; Straub, R.; Lehnert, T.; Zangos, S.; Mack, M. (Institut fuer Diagnostische und Interventionelle Radiologie, Klinikum der J.-W.-Goethe-Universitaet Frankfurt)

    2004-07-01

    We present laser-induced thermotherapy (LITT) of primary and secondary lung tumors analysing indications and technical concepts. Thirty patients with lung metastases of different primary tumors (n=24) as well as localized lung tumors (n=6) were prospectively treated in 41 sessions using laser-induced thermotherapy (LITT). An MR-compatible puncture system was used with direct puncture technique. The puncture was performed via CT guidance in care vision technique. Eight patients were thermoablated using MR tomographical monitoring, 22 patients using CT monitoring. Local therapy effects, tumor control rate, side effects, complications, and survival were evaluated. In 74% of cases (28/38 lesions) of 24 patients with lung metastases and in all cases of the 6 patients with lung carcinoma a complete local ablation could be achieved. The complication rate (pneumothorax) was 9,8%. One patient with bronchial carcinoma had to be thoracotomized and resected. 93% of the patients are still alive. Percutaneous LITT of lung tumors permits a complete ablation of lung metastases and lung carcinomas with a low complication rate. Indications for the procedure were defined for patients with no more than 5 metastases up to 3 cm in size. (orig.) [German] Wir stellen nachfolgend die Ergebnisse der laserinduzierten Thermotherapie (LITT) primaerer und sekundaerer Lungentumoren vor und analysieren die Indikationsstellung und die Interventionstechnik. Dreissig Patienten mit Lungenmetastasen unterschiedlicher Primaertumoren (n=24) sowie lokalisierten Bronchialkarzinomen (n=6) wurden prospektiv in 41 Sitzungen mittels MR-gesteuerter LITT therapiert. Zum Einsatz kam ein MR-kompatibles Punktionssystem in direkter Punktionstechnik; die Punktion erfolgte jeweils unter CT-Steuerung in Care-vision-Technik. Acht Patienten wurden mittels MR-tomographischem Monitoring thermoablatiert, 22 Patienten mittels CT-Monitoring. Evaluiert wurden die lokalen Therapieeffekte, Tumorkontrollrate, und die Frage von

  19. Prostaglandin E₂ protects murine lungs from bleomycin-induced pulmonary fibrosis and lung dysfunction.

    Science.gov (United States)

    Dackor, Ryan T; Cheng, Jennifer; Voltz, James W; Card, Jeffrey W; Ferguson, Catherine D; Garrett, Ryan C; Bradbury, J Alyce; DeGraff, Laura M; Lih, Fred B; Tomer, Kenneth B; Flake, Gordon P; Travlos, Gregory S; Ramsey, Randle W; Edin, Matthew L; Morgan, Daniel L; Zeldin, Darryl C

    2011-11-01

    Prostaglandin E(2) (PGE(2)) is a lipid mediator that is produced via the metabolism of arachidonic acid by cyclooxygenase enzymes. In the lung, PGE(2) acts as an anti-inflammatory factor and plays an important role in tissue repair processes. Although several studies have examined the role of PGE(2) in the pathogenesis of pulmonary fibrosis in rodents, results have generally been conflicting, and few studies have examined the therapeutic effects of PGE(2) on the accompanying lung dysfunction. In this study, an established model of pulmonary fibrosis was used in which 10-12-wk-old male C57BL/6 mice were administered a single dose (1.0 mg/kg) of bleomycin via oropharyngeal aspiration. To test the role of prostaglandins in this model, mice were dosed, via surgically implanted minipumps, with either vehicle, PGE(2) (1.32 μg/h), or the prostacyclin analog iloprost (0.33 μg/h) beginning 7 days before or 14 days after bleomycin administration. Endpoints assessed at 7 days after bleomycin administration included proinflammatory cytokine levels and measurement of cellular infiltration into the lung. Endpoints assessed at 21 days after bleomycin administration included lung function assessment via invasive (FlexiVent) analysis, cellular infiltration, lung collagen content, and semiquantitative histological analysis of the degree of lung fibrosis (Ashcroft method). Seven days after bleomycin administration, lymphocyte numbers and chemokine C-C motif ligand 2 expression were significantly lower in PGE(2)- and iloprost-treated animals compared with vehicle-treated controls (P bleomycin challenge, PGE(2) also protected against the decline in lung static compliance, lung fibrosis, and collagen production that is associated with 3 wk of bleomycin exposure. However, PGE(2) had no therapeutic effect on these parameters when administered 14 days after bleomycin challenge. In summary, PGE(2) prevented the decline in lung static compliance and protected against lung fibrosis when it

  20. Prostaglandin E2 protects murine lungs from bleomycin-induced pulmonary fibrosis and lung dysfunction

    Science.gov (United States)

    Dackor, Ryan T.; Cheng, Jennifer; Voltz, James W.; Card, Jeffrey W.; Ferguson, Catherine D.; Garrett, Ryan C.; Bradbury, J. Alyce; DeGraff, Laura M.; Lih, Fred B.; Tomer, Kenneth B.; Flake, Gordon P.; Travlos, Gregory S.; Ramsey, Randle W.; Edin, Matthew L.; Morgan, Daniel L.

    2011-01-01

    Prostaglandin E2 (PGE2) is a lipid mediator that is produced via the metabolism of arachidonic acid by cyclooxygenase enzymes. In the lung, PGE2 acts as an anti-inflammatory factor and plays an important role in tissue repair processes. Although several studies have examined the role of PGE2 in the pathogenesis of pulmonary fibrosis in rodents, results have generally been conflicting, and few studies have examined the therapeutic effects of PGE2 on the accompanying lung dysfunction. In this study, an established model of pulmonary fibrosis was used in which 10–12-wk-old male C57BL/6 mice were administered a single dose (1.0 mg/kg) of bleomycin via oropharyngeal aspiration. To test the role of prostaglandins in this model, mice were dosed, via surgically implanted minipumps, with either vehicle, PGE2 (1.32 μg/h), or the prostacyclin analog iloprost (0.33 μg/h) beginning 7 days before or 14 days after bleomycin administration. Endpoints assessed at 7 days after bleomycin administration included proinflammatory cytokine levels and measurement of cellular infiltration into the lung. Endpoints assessed at 21 days after bleomycin administration included lung function assessment via invasive (FlexiVent) analysis, cellular infiltration, lung collagen content, and semiquantitative histological analysis of the degree of lung fibrosis (Ashcroft method). Seven days after bleomycin administration, lymphocyte numbers and chemokine C-C motif ligand 2 expression were significantly lower in PGE2- and iloprost-treated animals compared with vehicle-treated controls (P bleomycin challenge, PGE2 also protected against the decline in lung static compliance, lung fibrosis, and collagen production that is associated with 3 wk of bleomycin exposure. However, PGE2 had no therapeutic effect on these parameters when administered 14 days after bleomycin challenge. In summary, PGE2 prevented the decline in lung static compliance and protected against lung fibrosis when it was administered

  1. Eosinophilic lung inflammation in particulate-induced lung injury: technical consideration in isolating RNA for gene expression studies.

    Science.gov (United States)

    Kodavanti, U P; Jaskot, R H; Bonner, J; Badgett, A; Dreher, K L

    1996-01-01

    Particulate and other pollutant exposures are associated with lung injury and inflammation. The purpose of this study was to develop an approach by which intact RNA could be obtained from inflamed lung tissue from particulate-exposed animals in order to correlate injury with specific gene expression. Male Sprague Dawley (SD) and Fischer-344 (F-344) rats were intratracheally instilled with saline or residual oil fly ash (ROFA) particles, 8.3 mg/kg body weight in saline. At various time points following ROFA instillation, lungs were either lavaged or used for RNA isolation. ROFA exposure produced an increase in bronchoalveolar lavage fluid (BALF) neutrophils in both SD and F-344 rats. A time-dependent increase in eosinophils occurred only in SD rats but not in F-344 rats. Extraction of inflamed pulmonary tissue having a high influx of eosinophils for RNA using the conventional acid guanidinium thiocyanate phenol-chloroform (AGPC) procedure failed to provide undegraded RNA suitable for RT-PCR and Northern blot analysis of beta-actin mRNA expression. Mixing intact total RNA from saline control rat lungs with degraded RNA samples from inflamed lung yielded a gel profile of degraded RNA, indicating the presence of ribonuclease-like activity in the RNA extracted from lung tissues having eosinophil influx. Evidently, the conventional AGPC procedure failed to completely remove ribonuclease activity associated with ROFA-induced pulmonary eosinophil influx. This study reports a single-step modification to the AGPC extraction method that does not require additional reagents or additional precipitation steps for extracting undegraded RNA from nuclease-rich inflamed lung tissue. The aqueous layer resulting from mixing homogenate and chloroform is extracted a second time using an equal volume of AGPC buffer followed by addition of chloroform and centrifugation. The second aqueous phase is then treated as described in the conventional RNA extraction protocol. This simple and

  2. Gastrodin protects against LPS-induced acute lung injury by activating Nrf2 signaling pathway.

    Science.gov (United States)

    Zhang, Zhuo; Zhou, Jie; Song, Daqiang; Sun, Yuhong; Liao, Changli; Jiang, Xian

    2017-05-09

    Gastrodin (GAS), a phenolic glucoside derived from Gastrodiaelata Blume, has been reported to have anti-inflammatory effect. The aim of this study was to investigate the effects of GAS on LPS-induced acute lung injury in mice. ALI was induced by the intranasal administration of LPS and GAS was given 1 h or 12 h after LPS treatment. The results indicated that GAS treatment markedly attenuated the damage of lung injury induced by LPS. GAS attenuated the activity of myeloperoxidase (MPO) and down-regulated the levels of pro-inflammatory cytokines TNF-α, IL-6 and IL-1β in BALF. LPS-induced lung edema and lung function were also reversed by GAS. Furthermore, GAS was found to inhibit LPS-induced inflammatory cells infiltration. In addition, treatment of GAS inhibited LPS-induced NF-κB activation and up-regulated the expression of Nrf2 and HO-1. In conclusion, our results indicated that GAS had anti-inflammatory effects on LPS-induced acute lung injury. The anti-inflammatory mechanism of GAS was through the inhibition of NF-κB and activation of Nrf2 signaling pathways.

  3. Linalool inhibits cigarette smoke-induced lung inflammation by inhibiting NF-κB activation.

    Science.gov (United States)

    Ma, Jianqun; Xu, Hai; Wu, Jun; Qu, Changfa; Sun, Fenglin; Xu, Shidong

    2015-12-01

    Linalool, a natural compound that exists in the essential oils of several aromatic plants species, has been reported to have anti-inflammatory effects. However, the effects of linalool on cigarette smoke (CS)-induced acute lung inflammation have not been reported. In the present study, we investigated the protective effects of linalool on CS-induced acute lung inflammation in mice. Linalool was given i.p. to mice 2h before CS exposure daily for five consecutive days. The numbers of macrophages and neutrophils in bronchoalveolar lavage fluid (BALF) were measured. The production of TNF-α, IL-6, IL-1β, IL-8 and MCP-1 were detected by ELISA. The expression of NF-κB was detected by Western blotting. Our results showed that treatment of linalool significantly attenuated CS-induced lung inflammation, coupled with inhibited the infiltration of inflammatory cells and TNF-α, IL-6, IL-1β, IL-8 and MCP-1 production. Meanwhile, treatment of linalool inhibited CS-induced lung MPO activity and pathological changes. Furthermore, linalool suppressed CS-induced NF-κB activation in a dose-dependent manner. In conclusion, our results demonstrated that linalool protected against CS-induced lung inflammation through inhibiting CS-induced NF-κB activation. Copyright © 2015 Elsevier B.V. All rights reserved.

  4. Cold stress aggravates inflammatory responses in an LPS-induced mouse model of acute lung injury

    Science.gov (United States)

    Joo, Su-Yeon; Park, Mi-Ju; Kim, Kyun-Ha; Choi, Hee-Jung; Chung, Tae-Wook; Kim, Yong Jin; Kim, Joung Hee; Kim, Keuk-Jun; Joo, Myungsoo; Ha, Ki-Tae

    2016-08-01

    Although the relationship between environmental cold temperature and susceptibility to respiratory infection is generally accepted, the effect of ambient cold temperature on host reactivity in lung inflammation has not been fully studied. To examine the function of ambient cold temperature on lung inflammation, mice were exposed to 4 °C for 8 h each day for 14 days. In the lungs of mice exposed to cold stress, inflammatory cells in bronchoalveolar lavage (BAL) fluid and lung tissues were slightly increased by about twofold. However, the structures of pulmonary epithelial cells were kept within normal limits. Next, we examined the effect of cold stress on the inflammatory responses in a lipopolysaccharide (LPS)-induced acute lung injury (ALI) mouse model. The infiltration of neutrophils and inflammation of lung tissue determined by histology were significantly increased by exposure to ambient cold temperature. In addition, the production of pro-inflammatory cytokines including interleukin (IL)-12, IL-17, and monokine induced by gamma interferon (MIG) was elevated by exposure to cold stress. Therefore, we suggest that cold stress is a factor that exacerbates lung inflammation including ALI. To our knowledge, this is the first report on the relationship between cold stress and severity of lung inflammation.

  5. N-acetylcysteine alleviates the meconium-induced acute lung injury.

    Science.gov (United States)

    Mokra, D; Drgova, A; Petras, M; Mokry, J; Antosova, M; Calkovska, A

    2015-01-01

    Meconium aspiration in newborns causes lung inflammation and injury, which may lead to meconium aspiration syndrome (MAS). In this study, the effect of the antioxidant N-acetylcysteine on respiratory and inflammatory parameters were studied in a model of MAS. Oxygen-ventilated rabbits were intratracheally given 4 mL/kg of meconium (25 mg/mL) or saline. Thirty minutes later, meconium-instilled animals were administered N-acetylcysteine (10 mg/kg; i.v.), or were left without treatment. The animals were oxygen-ventilated for additional 5 h. Ventilatory pressures, oxygenation, right-to-left pulmonary shunts, and leukocyte count were measured. At the end of experiment, trachea and lung were excised. The left lung was saline-lavaged and a total and differential count of cells in bronchoalveolar lavage fluid (BAL) was determined. Right lung tissue strips were used for detection of lung edema (expressed as wet/dry weight ratio) and peroxidation (expressed by thiobarbituric acid-reactive substances, TBARS). In lung and tracheal strips, airway reactivity to acetylcholine was measured. In addition, TBARS and total antioxidant status were determined in the plasma. Meconium instillation induced polymorphonuclear-derived inflammation and oxidative stress. N-acetylcysteine improved oxygenation, reduced lung edema, decreased polymorphonuclears in BAL fluid, and diminished peroxidation and meconium-induced airway hyperreactivity compared with untreated animals. In conclusion, N-acetylcysteine effectively improved lung functions in an animal model of MAS.

  6. Low Level Laser Therapy Reduces the Development of Lung Inflammation Induced by Formaldehyde Exposure.

    Directory of Open Access Journals (Sweden)

    Cristiane Miranda da Silva

    Full Text Available Lung diseases constitute an important public health problem and its growing level of concern has led to efforts for the development of new therapies, particularly for the control of lung inflammation. Low Level Laser Therapy (LLLT has been highlighted as a non-invasive therapy with few side effects, but its mechanisms need to be better understood and explored. Considering that pollution causes several harmful effects on human health, including lung inflammation, in this study, we have used formaldehyde (FA, an environmental and occupational pollutant, for the induction of neutrophilic lung inflammation. Our objective was to investigate the local and systemic effects of LLLT after FA exposure. Male Wistar rats were exposed to FA (1% or vehicle (distillated water during 3 consecutive days and treated or not with LLLT (1 and 5 hours after each FA exposure. Non-manipulated rats were used as control. 24 h after the last FA exposure, we analyzed the local and systemic effects of LLLT. The treatment with LLLT reduced the development of neutrophilic lung inflammation induced by FA, as observed by the reduced number of leukocytes, mast cells degranulated, and a decreased myeloperoxidase activity in the lung. Moreover, LLLT also reduced the microvascular lung permeability in the parenchyma and the intrapulmonary bronchi. Alterations on the profile of inflammatory cytokines were evidenced by the reduced levels of IL-6 and TNF-α and the elevated levels of IL-10 in the lung. Together, our results showed that LLLT abolishes FA-induced neutrophilic lung inflammation by a reduction of the inflammatory cytokines and mast cell degranulation. This study may provide important information about the mechanisms of LLLT in lung inflammation induced by a pollutant.

  7. Endogenous PGI2 signaling through IP inhibits neutrophilic lung inflammation in LPS-induced acute lung injury mice model.

    Science.gov (United States)

    Toki, Shinji; Zhou, Weisong; Goleniewska, Kasia; Reiss, Sara; Dulek, Daniel E; Newcomb, Dawn C; Lawson, William E; Peebles, R Stokes

    2018-04-13

    Endogenous prostaglandin I 2 (PGI 2 ) has inhibitory effects on immune responses against pathogens or allergens; however, the immunomodulatory activity of endogenous PGI 2 signaling in endotoxin-induced inflammation is unknown. To test the hypothesis that endogenous PGI 2 down-regulates endotoxin-induced lung inflammation, C57BL/6 wild type (WT) and PGI 2 receptor (IP) KO mice were challenged intranasally with LPS. Urine 6-keto-PGF 1α , a stable metabolite of PGI 2, was significantly increased following the LPS-challenge, suggesting that endogenous PGI 2 signaling modulates the host response to LPS-challenge. IPKO mice had a significant increase in neutrophils in the BAL fluid as well as increased proteins of KC, LIX, and TNF-α in lung homogenates compared with WT mice. In contrast, IL-10 was decreased in LPS-challenged IPKO mice compared with WT mice. The PGI 2 analog cicaprost significantly decreased LPS-induced KC, and TNF-α, but increased IL-10 and AREG in bone marrow-derived dendritic cells (BMDCs) and bone marrow-derived macrophages (BMMs) compared with vehicle-treatment. These results indicated that endogenous PGI 2 signaling attenuated neutrophilic lung inflammation through the reduced inflammatory cytokine and chemokine and enhanced IL-10. Copyright © 2018. Published by Elsevier Inc.

  8. Th17/Treg immunoregulation and implications in treatment of sulfur mustard gas-induced lung diseases.

    Science.gov (United States)

    Iman, Maryam; Rezaei, Ramazan; Azimzadeh Jamalkandi, Sadegh; Shariati, Parvin; Kheradmand, Farrah; Salimian, Jafar

    2017-12-01

    Sulfur mustard (SM) is an extremely toxic gas used in chemical warfare to cause massive lung injury and death. Victims exposed to SM gas acutely present with inhalational lung injury, but among those who survive, some develop obstructive airway diseases referred to as SM-lung syndrome. Pathophysiologically, SM-lung shares many characteristics with smoking-induced chronic obstructive pulmonary disease (COPD), including airway remodeling, goblet cell metaplasia, and obstructive ventilation defect. Some of the hallmarks of COPD pathogenesis, which include dysregulated lung inflammation, neutrophilia, recruitment of interleukin 17A (IL -17A) expressing CD4 + T cells (Th17), and the paucity of lung regulatory T cells (Tregs), have also been described in SM-lung. Areas covered: A literature search was performed using the MEDLINE, EMBASE, and Web of Science databases inclusive of all literature prior to and including May 2017. Expert commentary: Here we review some of the recent findings that suggest a role for Th17 cell-mediated inflammatory changes associated with pulmonary complications in SM-lung and suggest new therapeutic approaches that could potentially alter disease progression with immune modulating biologics that can restore the lung Th17/Treg balance.

  9. Early administration of IL-6RA does not prevent radiation-induced lung injury in mice

    Directory of Open Access Journals (Sweden)

    Inoue Takehiro

    2010-04-01

    Full Text Available Abstract Background Radiation pneumonia and subsequent radiation lung fibrosis are major dose-limiting complications for patients undergoing thoracic radiotherapy. Interleukin-6 (IL-6 is a pleiotropic cytokine and plays important roles in the regulation of immune response and inflammation. The purpose of this study was to investigate whether anti-IL-6 monoclonal receptor antibody (IL-6RA could ameliorate radiation-induced lung injury in mice. Methods BALB/cAnNCrj mice having received thoracic irradiation of 21 Gy were injected intraperitoneally with IL-6RA (MR16-1 or control rat IgG twice, immediately and seven days after irradiation. Enzyme-linked immunosorbent assay was used to examine the plasma level of IL-6 and serum amyloid A (SAA. Lung injury was assessed by histological staining with haematoxylin and eosin or Azan, measuring lung weight, and hydroxyproline. Results The mice treated with IL-6RA did not survive significantly longer than the rat IgG control. We observed marked up-regulation of IL-6 in mice treated with IL-6RA 150 days after irradiation, whereas IL-6RA temporarily suppressed early radiation-induced increase in the IL-6 release level. Histopathologic assessment showed no differences in lung section or lung weight between mice treated with IL-6RA and control. Conclusions Our findings suggest that early treatment with IL-6RA after irradiation alone does not protect against radiation-induced lung injury.

  10. Adult Lung Spheroid Cells Contain Progenitor Cells and Mediate Regeneration in Rodents With Bleomycin-Induced Pulmonary Fibrosis.

    Science.gov (United States)

    Henry, Eric; Cores, Jhon; Hensley, M Taylor; Anthony, Shirena; Vandergriff, Adam; de Andrade, James B M; Allen, Tyler; Caranasos, Thomas G; Lobo, Leonard J; Cheng, Ke

    2015-11-01

    Lung diseases are devastating conditions and ranked as one of the top five causes of mortality worldwide according to the World Health Organization. Stem cell therapy is a promising strategy for lung regeneration. Previous animal and clinical studies have focused on the use of mesenchymal stem cells (from other parts of the body) for lung regenerative therapies. We report a rapid and robust method to generate therapeutic resident lung progenitors from adult lung tissues. Outgrowth cells from healthy lung tissue explants are self-aggregated into three-dimensional lung spheroids in a suspension culture. Without antigenic sorting, the lung spheroids recapitulate the stem cell niche and contain a natural mixture of lung stem cells and supporting cells. In vitro, lung spheroid cells can be expanded to a large quantity and can form alveoli-like structures and acquire mature lung epithelial phenotypes. In severe combined immunodeficiency mice with bleomycin-induced pulmonary fibrosis, intravenous injection of human lung spheroid cells inhibited apoptosis, fibrosis, and infiltration but promoted angiogenesis. In a syngeneic rat model of pulmonary fibrosis, lung spheroid cells outperformed adipose-derived mesenchymal stem cells in reducing fibrotic thickening and infiltration. Previously, lung spheroid cells (the spheroid model) had only been used to study lung cancer cells. Our data suggest that lung spheroids and lung spheroid cells from healthy lung tissues are excellent sources of regenerative lung cells for therapeutic lung regeneration. The results from the present study will lead to future human clinical trials using lung stem cell therapies to treat various incurable lung diseases, including pulmonary fibrosis. The data presented here also provide fundamental knowledge regarding how injected stem cells mediate lung repair in pulmonary fibrosis. ©AlphaMed Press.

  11. Infliximab attenuates activated charcoal and polyethylene glycol aspiration-induced lung injury in rats.

    Science.gov (United States)

    Güzel, Aygül; Günaydin, Mithat; Güzel, Ahmet; Alaçam, Hasan; Murat, Naci; Gacar, Ayhan; Güvenç, Tolga

    2012-04-01

    Aspiration is a serious complication of gastrointestinal (GI) decontamination procedure. Studies have shown that tumor necrosis factor-α (TNF-α) blockers have beneficial effects on lung injury. Therefore, the authors investigated the attenuation by infliximab (INF) on activated charcoal (AC)- and polyethylene glycol (PEG)-induced lung injury in rat model. Forty-two male Sprague-Dawley rats were allotted into 1 of 6 groups: saline (NS), activated charcoal (AC), polyethylene glycol (PEG), NS+INF treated, AC+INF treated, and PEG+INF treated. All materials were aspirated into the lungs at a volume of 1 mL/kg. Before aspiration, the rats were injected subcutaneously with INF. Seven days later, both lungs and serum specimens in all groups were evaluated histopathologically, immunohistochemically, and biochemically. Following aspiration of AC and PEG, evident histopathological changes were assigned in the lung tissue that were associated with increased expression of inducible nitric oxide synthase (iNOS), increased serum levels of oxidative stress markers (malondialdehyde [MDA], surfactant protein-D [SP-D], TNF-α), and decreased antioxidant enzyme (glutathione peroxidase [GSH-Px]) activities. INF treatment significantly decreased the elevated serum MDA and TNF-α levels and increased serum GSH-Px levels. Furthermore, the current results show that there is a significant reduction in the activity of iNOS in lung tissue and increased serum SP-D levels of AC and PEG aspiration-induced lung injury with INF treatment. These findings suggest that INF attenuates lung inflammation and prevents GI decontamination agent-induced lung injury in rats.

  12. Low Tidal Volume Reduces Lung Inflammation Induced by Liquid Ventilation in Piglets With Severe Lung Injury.

    Science.gov (United States)

    Jiang, Lijun; Feng, Huizhen; Chen, Xiaofan; Liang, Kaifeng; Ni, Chengyao

    2017-05-01

    Total liquid ventilation (TLV) is an alternative treatment for severe lung injury. High tidal volume is usually required for TLV to maintain adequate CO 2 clearance. However, high tidal volume may cause alveolar barotrauma. We aim to investigate the effect of low tidal volume on pulmonary inflammation in piglets with lung injury and under TLV. After the establishment of acute lung injury model by infusing lipopolysaccharide, 12 piglets were randomly divided into two groups, TLV with high tidal volume (25 mL/kg) or with low tidal volume (6 mL/kg) for 240 min, respectively. Extracorporeal CO 2 removal was applied in low tidal volume group to improve CO 2 clearance and in high tidal volume group as sham control. Gas exchange and hemodynamic status were monitored every 30 min during TLV. At the end of the study, pulmonary mRNA expression and plasmatic concentration of interleukin-6 (IL-6) and interleukin-8 (IL-8) were measured by collecting lung tissue and blood samples from piglets. Arterial blood pressure, PaO 2 , and PaCO 2 showed no remarkable difference between groups during the observation period. Compared with high tidal volume strategy, low tidal volume resulted in 76% reduction of minute volume and over 80% reduction in peak inspiratory pressure during TLV. In addition, low tidal volume significantly diminished pulmonary mRNA expression and plasmatic level of IL-6 and IL-8. We conclude that during TLV, low tidal volume reduces lung inflammation in piglets with acute lung injury without compromising gas exchange. © 2016 International Center for Artificial Organs and Transplantation and Wiley Periodicals, Inc.

  13. Improving effect of Sivelestat on lipopolysaccharide-induced lung injury in rats.

    Science.gov (United States)

    Yuan, Qing; Jiang, Yan-Wen; Fang, Qiu-Hong

    2014-09-01

    Sepsis causes neutrophil sequestration in the lung, which leads to acute lung injury (ALI). Neutrophil elastase (NE) is thought to play an important role in the pathogenesis of ALI. This study investigated whether Sivelestat, a specific NE inhibitor, can attenuate ALI induced by lipopolysaccharide (LPS). In vivo, 30 male Wistar rats were divided into three groups (n = 10 each groups) on the basis of the reagent used, which were subjected to LPS injection with or without Sivelestat treatments to induce ALI model. Lung injury was assessed by pulmonary histology, lung wet-weight to dry-weight (W/D) ratio, immunohistochemical analysis of intercellular adhesion molecule-1 (ICAM-1), the number of myeloperoxidase (MPO)-positive cells, and gene expression of ICAM-1. In vitro, pulmonary microvascular endothelial cells (PMVECs) were stimulated with LPS in the presence and absence of Sivelestat; nuclear factor-κB (NF-κB) p65 was measured by immunocytochemistry staining and Western blotting. Infusion of LPS induced lung injury, in vivo, as demonstrated by pulmonary edema with infiltration of neutrophils, the increase in lung W/D ratio, the number of MPO-positive cells and enhanced expression of ICAM-1 and ICAM-1 gene. In vitro, the significant increased release of NF-κB p65 and its subsequent translocation into the nucleus in PMVECs. In contrast, Sivelestat treatment significantly ameliorated the LPS-induced lung injury, as judged by the marked improvement in all these indices. These results indicated that inhibition of NE attenuated LPS-induced lung injury through an inhibition of the inflammatory signaling pathway, besides the direct inhibitory effect on NE. © 2014 APMIS. Published by John Wiley & Sons Ltd.

  14. RAGE deficiency attenuates the protective effect of Lidocaine against sepsis-induced acute lung injury.

    Science.gov (United States)

    Zhang, Zhuo; Zhou, Jie; Liao, Changli; Li, Xiaobing; Liu, Minghua; Song, Daqiang; Jiang, Xian

    2017-04-01

    Lidocaine (Lido) is reported to suppress inflammatory responses and exhibit a therapeutic effect in models of cecal ligation and puncture (CLP)-induced acute lung injury (ALI). The receptor for advanced glycation end product (RAGE) exerts pro-inflammatory effects by enhancing pro-inflammatory cytokine production. However, the precise mechanism by which Lido confers protection against ALI is not clear. ALI was induced in RAGE WT and RAGE knockout (KO) rats using cecal ligation and puncture (CLP) operations for 24 h. The results showed that Lido significantly inhibited CLP-induced lung inflammation and histopathological lung injury. Furthermore, Lido significantly reduced CLP-induced upregulation of HMGB1 and RAGE expression and activation of the NF-κB and MAPK signaling pathways. With the use of RAGE KO rats, we demonstrate here that RAGE deficiency attenuates the protective effect of Lido against CLP-induced lung inflammatory cell infiltration and histopathological lung injury. These results suggest that RAGE deficiency attenuates the protective effect of Lido against CLP-induced ALI by attenuating the pro-inflammatory cytokines production.

  15. Taraxacum officinale protects against lipopolysaccharide-induced acute lung injury in mice.

    Science.gov (United States)

    Liu, Liben; Xiong, Huanzhang; Ping, Jiaqi; Ju, Yulin; Zhang, Xuemei

    2010-07-20

    Taraxacum officinale has been frequently used as a remedy for inflammatory diseases. In the present study, we investigated the in vivo protective effect of Taraxacum officinale on acute lung injury (ALI) induced by lipopolysaccharide (LPS) in mice. Taraxacum officinale at 2.5, 5 and 10 mg/kg was orally administered once per day for 5 days consecutively, followed by 500 microg/kg LPS was instilled intranasally. The lung wet/dry weight (W/D) ratio, protein concentration and the number of inflammatory cells in bronchoalveolar lavage fluid (BALF) were determined. Superoxidase dismutase (SOD) and myeloperoxidase (MPO) activities, and histological change in the lungs were examined. The levels of inflammatory cytokine tumor necrosis factor-alpha (TNF-alpha) and interleukin-6 (IL-6) in the BALF were measured using ELISA. We found that Taraxacum officinale decreased the lung W/D ratio, protein concentration and the number of neutrophils in the BALF at 24 h after LPS challenge. Taraxacum officinale decreased LPS-induced MPO activity and increased SOD activity in the lungs. In addition, histopathological examination indicated that Taraxacum officinale attenuated tissue injury of the lungs in LPS-induced ALI. Furthermore, Taraxacum officinale also inhibited the production of inflammatory cytokines TNF-alpha and IL-6 in the BALF at 6h after LPS challenge in a dose-dependent manner. These results suggest that Taraxacum officinale protects against LPS-induced ALI in mice. Copyright 2010 Elsevier Ireland Ltd. All rights reserved.

  16. Wnt and Hedgehog are critical mediators of cigarette smoke-induced lung cancer.

    Directory of Open Access Journals (Sweden)

    Hassan Lemjabbar-Alaoui

    Full Text Available BACKGROUND: Lung cancer is the leading cause of cancer death in the world, and greater than 90% of lung cancers are cigarette smoke-related. Current treatment options are inadequate, because the molecular basis of cigarette-induced lung cancer is poorly understood. METHODOLOGY/PRINCIPAL FINDINGS: Here, we show that human primary or immortalized bronchial epithelial cells exposed to cigarette smoke for eight days in culture rapidly proliferate, show anchorage-independent growth, and form tumors in nude mice. Using this model of the early stages of smoke-induced tumorigenesis, we examined the molecular changes leading to lung cancer. We observed that the embryonic signaling pathways mediated by Hedgehog and Wnt are activated by smoke. Pharmacological inhibition of these pathways blocked the transformed phenotype. CONCLUSIONS/SIGNIFICANCE: These experiments provide a model in which the early stages of smoke-induced tumorigenesis can be elicited, and should permit us to identify molecular changes driving this process. Results obtained so far indicate that smoke-induced lung tumors are driven by activation of two embryonic regulatory pathways, Hedgehog (Hh and Wnt. Based on the current and emerging availability of drugs to inhibit Hh and Wnt signaling, it is possible that an understanding of the role of Hh and Wnt in lung cancer pathogenesis will lead to the development of new therapies.

  17. Cardiac comorbidity is an independent risk factor for radiation-induced lung toxicity in lung cancer patients

    International Nuclear Information System (INIS)

    Nalbantov, Georgi; Kietselaer, Bas; Vandecasteele, Katrien; Oberije, Cary; Berbee, Maaike; Troost, Esther; Dingemans, Anne-Marie; Baardwijk, Angela van; Smits, Kim; Dekker, André; Bussink, Johan; Ruysscher, Dirk De; Lievens, Yolande; Lambin, Philippe

    2013-01-01

    Purpose: To test the hypothesis that cardiac comorbidity before the start of radiotherapy (RT) is associated with an increased risk of radiation-induced lung toxicity (RILT) in lung cancer patients. Material and methods: A retrospective analysis was performed of a prospective cohort of 259 patients with locoregional lung cancer treated with definitive radio(chemo)therapy between 2007 and 2011 (ClinicalTrials.gov Identifiers: NCT00572325 and NCT00573040). We defined RILT as dyspnea CTCv.3.0 grade ⩾2 within 6 months after RT, and cardiac comorbidity as a recorded treatment of a cardiac pathology at a cardiology department. Univariate and multivariate analyses, as well as external validation, were performed. The model-performance measure was the area under the receiver operating characteristic curve (AUC). Results: Prior to RT, 75/259 (28.9%) patients had cardiac comorbidity, 44% of whom (33/75) developed RILT. The odds ratio of developing RILT for patients with cardiac comorbidity was 2.58 (p < 0.01). The cross-validated AUC of a model with cardiac comorbidity, tumor location, forced expiratory volume in 1 s, sequential chemotherapy and pretreatment dyspnea score was 0.72 (p < 0.001) on the training set, and 0.67 (p < 0.001) on the validation set. Conclusion: Cardiac comorbidity is an important risk factor for developing RILT after definite radio(chemo)therapy of lung cancer patients

  18. PM2.5-induced alterations of cell cycle associated gene expression in lung cancer cells and rat lung tissues.

    Science.gov (United States)

    Zhao, Hui; Yang, Biao; Xu, Jia; Chen, Dong-Mei; Xiao, Chun-Ling

    2017-06-01

    The aim of the current study was to investigate the expression of cell cycle-associated genes induced by fine particulate matter (PM 2.5 ) in lung cancer cell line and tissues. The pulmonary lymph node metastasis cells (H292) were treated with PM 2.5 in vitro. Wistar rats were used to perform an in vivo study. Rats were randomly assigned to experiment and control groups and those in the experiment group were exposed to PM 2.5 once every 15 d, while those in the control group were exposed to normal saline. The cell cycle-associated genes expression was analyzed by real-time PCR. Trachea and lung tissues of rats were processed for scanning electron microscopic (SEM) examinations. Exposure of H292 cells to PM 2.5 dramatically increased the expressions of p53 and cyclin-dependent kinase 2 (CDK2) after 24h of exposure (pcell division cycle 2 (Cdc2) and cyclin B after 48h of exposure (p<0.01), while those genes expressions were significantly reduced after 72h of exposure, at which time the expression of p21 was predominant (p<0.01). In vivo studies further demonstrated these results. The results of SEM suggested that both of the trachea and lung tissues were damaged and the degree of damage was time-dependent. In conclusion, PM 2.5 can induce significantly alterations of p53 and CDK2 in the early phase, Cdc2 and cyclin B in mid-term and p21 in long-term exposure. The degree of PM 2.5 -induced damage to the trachea and lung tissue was time-dependent. Copyright © 2017. Published by Elsevier B.V.

  19. Assessment of the mode of action for hexavalent chromium-induced lung cancer following inhalation exposures

    International Nuclear Information System (INIS)

    Proctor, Deborah M.; Suh, Mina; Campleman, Sharan L.; Thompson, Chad M.

    2014-01-01

    Highlights: • No published or well recognized MOA for Cr(VI)-induced lung tumors exists. • MOA analysis for Cr(VI)-induced lung cancer was conducted to inform risk assessment. • Cr(VI) epidemiologic, toxicokinetic, toxicological, mechanistic data were evaluated. • Weight of evidence does not support a mutagenic MOA for Cr(VI)-induced lung cancer. • Non-linear approaches should be considered for evaluating Cr(VI) lung cancer risk. - Abstract: Inhalation of hexavalent chromium [Cr(VI)] is associated with increased lung cancer risk among workers in several industries, most notably chromate production workers exposed to high concentrations of Cr(VI) (≥100 μg/m 3 ), for which clear exposure–response relationships and respiratory irritation and tissue damage have been reported. Data from this industry are used to assess lung cancer risk associated with environmental and current occupational exposures, occurring at concentrations that are significantly lower. There is considerable uncertainty in the low dose extrapolation of historical occupational epidemiology data to assess risk at current exposures because no published or well recognized mode of action (MOA) for Cr(VI)-induced lung tumors exists. We conducted a MOA analysis for Cr(VI)-induced lung cancer evaluating toxicokinetic and toxicological data in humans and rodents and mechanistic data to assess plausibility, dose–response, and temporal concordance for potential MOAs. Toxicokinetic data support that extracellular reduction of Cr(VI), which limits intracellular absorption of Cr(VI) and Cr(VI)-induced toxicity, can be overwhelmed at high exposure levels. In vivo genotoxicity and mutagenicity data are mostly negative and do not support a mutagenic MOA. Further, both chronic bioassays and the epidemiologic literature support that lung cancer occurs at exposures that cause tissue damage. Based on this MOA analysis, the overall weight of evidence supports a MOA involving deposition and accumulation

  20. Hemofiltration in ex vivo lung perfusion-a study in experimentally induced pulmonary edema.

    Science.gov (United States)

    Nilsson, Tobias; Hansson, Christoffer; Wallinder, Andreas; Malm, Carl-Johan; Silverborn, Martin; Ricksten, Sven-Erik; Dellgren, Göran

    2016-02-01

    Ex vivo lung perfusion (EVLP) can potentially reduce pulmonary edema. In a pig model with induced pulmonary edema, we evaluated the effect of hemofiltration (HF) during EVLP on lung function, perfusate oncotic pressure, and lung weight. In anesthetized pigs (n = 14), pulmonary edema was induced by a balloon in the left atrium, combined with crystalloid infusion (20 mL/kg), for 2 hours. The lungs were harvested, stored cold for 2 hours, and randomized to EVLP, with or without a hemofilter (HF and noHF groups, respectively, n = 7 for each). EVLP was performed with cellular perfusate at a hematocrit of 10% to 15%. Oncotic pressure, lung performance, and weight were measured before and after 180 minutes of EVLP reconditioning with or without HF. After in vivo induction of edema, arterial oxygen tension (Pao2)/inspired oxygen fraction (Fio2), and compliance decreased by 63% and 16%, respectively. Pao2/Fio2 was considerably improved at first evaluation ex vivo in both groups. HF increased oncotic pressure by 43% and decreased lung weight by 15%. The effects were negligible in the noHF group. Compliance decreased in both groups during reconditioning, although less so in the HF group (P Pulmonary flow index decreased in both groups, and was partially reversed by nitroglycerin. Dorsal atelectatic consolidations were seen in both groups. In this lung-edema model, EVLP reconditioning with hyperoncotic solution did not affect the degree of lung edema. HF during EVLP increased perfusate oncotic pressure, decreased lung weight with beneficial effects on compliance, but did not improve lung oxygenation capacity. Copyright © 2016 The American Association for Thoracic Surgery. Published by Elsevier Inc. All rights reserved.

  1. Src tyrosine kinase inhibition prevents pulmonary ischemia-reperfusion-induced acute lung injury.

    Science.gov (United States)

    Oyaizu, Takeshi; Fung, Shan-Yu; Shiozaki, Atsushi; Guan, Zehong; Zhang, Qiao; dos Santos, Claudia C; Han, Bing; Mura, Marco; Keshavjee, Shaf; Liu, Mingyao

    2012-05-01

    Pulmonary ischemia-reperfusion is a pathological process seen in several clinical conditions, including lung transplantation, cardiopulmonary bypass, resuscitation for circulatory arrest, atherosclerosis, and pulmonary embolism. A better understanding of its molecular mechanisms is very important. Rat left lung underwent in situ ischemia for 60 min, followed by 2 h of reperfusion. The gene expression profiles and Src protein tyrosine kinase (PTK) phosphorylation were studied over time, and PP2, an Src PTK inhibitor, was intravenously administered 10 min before lung ischemia to determine the role of Src PTK in lung injury. Reperfusion following ischemia significantly changed the expression of 169 genes, with Mmp8, Mmp9, S100a9, and S100a8 being the most upregulated genes. Ischemia alone only affected expression of 9 genes in the lung. However, Src PTK phosphorylation (activation) was increased in the ischemic lung, mainly on the alveolar wall. Src PTK inhibitor pretreatment decreased phosphorylation of Src PTKs, total protein tyrosine phosphorylation, and STAT3 phosphorylation. It increased phosphorylation of the p85α subunit of PI3 kinase, a signal pathway that can inhibit coagulation and inflammation. PP2 reduced leukocyte infiltration in the lung, apoptotic cell death, fibrin deposition, and severity of acute lung injury after reperfusion. Src inhibition also significantly reduced CXCL1 (GRO/KI) and CCL2 (MCP-1) chemokine levels in the serum. During pulmonary ischemia, Src PTK activation, rather than alteration in gene expression, may play a critical role in reperfusion-induced lung injury. Src PTK inhibition presents a new prophylactic treatment for pulmonary ischemia-reperfusion-induced acute lung injury.

  2. Role of metal-induced reactive oxygen species generation in lung ...

    Indian Academy of Sciences (India)

    Unknown

    role of reactive oxygen species (ROS) in ROFA-induced lung injury. ROFA was collected from a precipitator at ... However, cellular oxidant production and tissue injury were observed mostly with the ROFA-total and ..... transition metals are likely the causative agents of ROFA- induced acute injury (Dreher et al 1997).

  3. Endothelial Semaphorin 7A Promotes Inflammation in Seawater Aspiration-Induced Acute Lung Injury

    Directory of Open Access Journals (Sweden)

    Minlong Zhang

    2014-10-01

    Full Text Available Inflammation is involved in the pathogenesis of seawater aspiration-induced acute lung injury (ALI. Although several studies have shown that Semaphorin 7A (SEMA7A promotes inflammation, there are limited reports regarding immunological function of SEMA7A in seawater aspiration-induced ALI. Therefore, we investigated the role of SEMA7A during seawater aspiration-induced ALI. Male Sprague–Dawley rats were underwent seawater instillation. Then, lung samples were collected at an indicated time for analysis. In addition, rat pulmonary microvascular endothelial cells (RPMVECs were cultured and then stimulated with 25% seawater for indicated time point. After these treatments, cells samples were collected for analysis. In vivo, seawater instillation induced lung histopathologic changes, pro-inflammation cytokines release and increased expression of SEMA7A. In vitro, seawater stimulation led to pro-inflammation cytokine release, cytoskeleton remodeling and increased monolayer permeability in pulmonary microvascular endothelial cells. In addition, knockdown of hypoxia-inducible factor (HIF-1α inhibited the seawater induced increase expression of SEMA7A. Meanwhile, knockdown of SEMA7A by specific siRNA inhibited the seawater induced aberrant inflammation, endothelial cytoskeleton remodeling and endothelial permeability. These results suggest that SEMA7A is critical in the development of lung inflammation and pulmonary edema in seawater aspiration-induced ALI, and may be a therapeutic target for this disease.

  4. Endothelial Semaphorin 7A promotes inflammation in seawater aspiration-induced acute lung injury.

    Science.gov (United States)

    Zhang, Minlong; Wang, Li; Dong, Mingqing; Li, Zhichao; Jin, Faguang

    2014-10-28

    Inflammation is involved in the pathogenesis of seawater aspiration-induced acute lung injury (ALI). Although several studies have shown that Semaphorin 7A (SEMA7A) promotes inflammation, there are limited reports regarding immunological function of SEMA7A in seawater aspiration-induced ALI. Therefore, we investigated the role of SEMA7A during seawater aspiration-induced ALI. Male Sprague-Dawley rats were underwent seawater instillation. Then, lung samples were collected at an indicated time for analysis. In addition, rat pulmonary microvascular endothelial cells (RPMVECs) were cultured and then stimulated with 25% seawater for indicated time point. After these treatments, cells samples were collected for analysis. In vivo, seawater instillation induced lung histopathologic changes, pro-inflammation cytokines release and increased expression of SEMA7A. In vitro, seawater stimulation led to pro-inflammation cytokine release, cytoskeleton remodeling and increased monolayer permeability in pulmonary microvascular endothelial cells. In addition, knockdown of hypoxia-inducible factor (HIF)-1α inhibited the seawater induced increase expression of SEMA7A. Meanwhile, knockdown of SEMA7A by specific siRNA inhibited the seawater induced aberrant inflammation, endothelial cytoskeleton remodeling and endothelial permeability. These results suggest that SEMA7A is critical in the development of lung inflammation and pulmonary edema in seawater aspiration-induced ALI, and may be a therapeutic target for this disease.

  5. Sodium butyrate protects against severe burn-induced remote acute lung injury in rats.

    Directory of Open Access Journals (Sweden)

    Xun Liang

    Full Text Available High-mobility group box 1 protein (HMGB1, a ubiquitous nuclear protein, drives proinflammatory responses when released extracellularly. It plays a key role as a distal mediator in the development of acute lung injury (ALI. Sodium butyrate, an inhibitor of histone deacetylase, has been demonstrated to inhibit HMGB1 expression. This study investigates the effect of sodium butyrate on burn-induced lung injury. Sprague-Dawley rats were divided into three groups: 1 sham group, sham burn treatment; 2 burn group, third-degree burns over 30% total body surface area (TBSA with lactated Ringer's solution for resuscitation; 3 burn plus sodium butyrate group, third-degree burns over 30% TBSA with lactated Ringer's solution containing sodium butyrate for resuscitation. The burned animals were sacrificed at 12, 24, and 48 h after burn injury. Lung injury was assessed in terms of histologic changes and wet weight to dry weight (W/D ratio. Tumor necrosis factor (TNF-α and interleukin (IL-8 protein concentrations in bronchoalveolar lavage fluid (BALF and serum were measured by enzyme-linked immunosorbent assay, and HMGB1 expression in the lung was determined by Western blot analysis. Pulmonary myeloperoxidase (MPO activity and malondialdehyde (MDA concentration were measured to reflect neutrophil infiltration and oxidative stress in the lung, respectively. As a result, sodium butyrate significantly inhibited the HMGB1 expressions in the lungs, reduced the lung W/D ratio, and improved the pulmonary histologic changes induced by burn trauma. Furthermore, sodium butyrate administration decreased the TNF-α and IL-8 concentrations in BALF and serum, suppressed MPO activity, and reduced the MDA content in the lungs after severe burn. These results suggest that sodium butyrate attenuates inflammatory responses, neutrophil infiltration, and oxidative stress in the lungs, and protects against remote ALI induced by severe burn, which is associated with inhibiting HMGB1

  6. Praeruptorin D and E attenuate lipopolysaccharide/hydrochloric acid induced acute lung injury in mice.

    Science.gov (United States)

    Yu, Peng-Jiu; Li, Jing-Rong; Zhu, Zheng-Guang; Kong, Huan-Yu; Jin, Hong; Zhang, Jun-Yan; Tian, Yuan-Xin; Li, Zhong-Huang; Wu, Xiao-Yun; Zhang, Jia-Jie; Wu, Shu-Guang

    2013-06-15

    Acute lung injury is a life-threatening syndrome characterized by overwhelming lung inflammation and increased microvascular permeability, which causes a high mortality rate worldwide. The dry root of Peucedanum praeruptorum Dunn has been long used to treat respiratory diseases in China. In the present study, Praeruptorin A, C, D and E (PA, PC, PD and PE), four pyranocoumarins extracted from this herb, have been investigated for the pharmacological effects in experimental lung injury mouse models. In lipopolysaccharide (LPS) challenged mice, PA and PC did not show protective effect against lung injury at the dose of 80 mg/kg. However, PD and PE significantly inhibited the infiltration of activated polymorphonuclear leukocytes (PMNs) and decreased the levels of TNF-α and IL-6 in bronchoalveolar lavage fluid at the same dose. There was no statistically significant difference between PD and PE group. Further study demonstrated that PD and PE suppressed protein extravasations in bronchoalveolar lavage fluid, attenuated myeloperoxidase (MPO) activity and the pathological changes in the lung. Both PD and PE suppressed LPS induced Nuclear Factor-kappa B (NF-κB) pathway activation in the lung by decreasing the cytoplasmic loss of Inhibitor κB-α (IκB-α) protein and inhibiting the translocation of p65 from cytoplasm to nucleus. We also extended our study to acid-induced acute lung injury and found that these two compounds protected mice from hydrochloric acid (HCl)-induced lung injury by inhibiting PMNs influx, IL-6 release and protein exudation. Taken together, these results suggested that PD and PE might be useful in the therapy of lung injury. Copyright © 2013 Elsevier B.V. All rights reserved.

  7. Sodium Butyrate Protects against Severe Burn-Induced Remote Acute Lung Injury in Rats

    Science.gov (United States)

    Liu, Sheng; Guo, Feng; Sun, Li; Wang, Yong-Jie; Sun, Ye-Xiang; Chen, Xu-Lin

    2013-01-01

    High-mobility group box 1 protein (HMGB1), a ubiquitous nuclear protein, drives proinflammatory responses when released extracellularly. It plays a key role as a distal mediator in the development of acute lung injury (ALI). Sodium butyrate, an inhibitor of histone deacetylase, has been demonstrated to inhibit HMGB1 expression. This study investigates the effect of sodium butyrate on burn-induced lung injury. Sprague–Dawley rats were divided into three groups: 1) sham group, sham burn treatment; 2) burn group, third-degree burns over 30% total body surface area (TBSA) with lactated Ringer’s solution for resuscitation; 3) burn plus sodium butyrate group, third-degree burns over 30% TBSA with lactated Ringer’s solution containing sodium butyrate for resuscitation. The burned animals were sacrificed at 12, 24, and 48 h after burn injury. Lung injury was assessed in terms of histologic changes and wet weight to dry weight (W/D) ratio. Tumor necrosis factor (TNF)-α and interleukin (IL)-8 protein concentrations in bronchoalveolar lavage fluid (BALF) and serum were measured by enzyme-linked immunosorbent assay, and HMGB1 expression in the lung was determined by Western blot analysis. Pulmonary myeloperoxidase (MPO) activity and malondialdehyde (MDA) concentration were measured to reflect neutrophil infiltration and oxidative stress in the lung, respectively. As a result, sodium butyrate significantly inhibited the HMGB1 expressions in the lungs, reduced the lung W/D ratio, and improved the pulmonary histologic changes induced by burn trauma. Furthermore, sodium butyrate administration decreased the TNF-α and IL-8 concentrations in BALF and serum, suppressed MPO activity, and reduced the MDA content in the lungs after severe burn. These results suggest that sodium butyrate attenuates inflammatory responses, neutrophil infiltration, and oxidative stress in the lungs, and protects against remote ALI induced by severe burn, which is associated with inhibiting HMGB1

  8. Twist1 suppresses senescence programs and thereby accelerates and maintains mutant Kras-induced lung tumorigenesis

    DEFF Research Database (Denmark)

    Tran, Phuoc T; Shroff, Emelyn H; Burns, Timothy F

    2012-01-01

    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....... 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...

  9. Toxicidade pulmonar induzida pela rapamicina Lung toxicity induced by rapamycin

    Directory of Open Access Journals (Sweden)

    C Damas

    2006-11-01

    Full Text Available As doenças pulmonares induzidas por fármacos constituem uma causa crescente de morbilidade, tendo sido descritas diferentes formas de toxicidade associadas a inúmeras substâncias. O sirolimus (rapamicina é um fármaco imunossupressor usado de forma crescente no contexto do transplante de órgãos sólidos, nomeadamente no transplante renal. A toxicidade pulmonar tem sido descrita como um dos potenciais efeitos laterais, nomeadamente causando formas de pneumonite intersticial ou, mais raramente, hemorragia alveolar. Os autores descrevem os casos de quatro doentes (3 do sexo masculino, 1 do sexo feminino com idades compreendidas entre os 46-71 anos, recipientes de transplante renal (rim cadáver há 3 anos (1 doente e 7 anos (3 doentes. A imunosupressão consistia em micofenolato mofetil, prednisolona e rapamicina. Os quatro doentes foram admitidos por febre, tosse produtiva (2 e dispneia (3. Apresentavam imagem radiológica de infiltrados pulmonares bilaterais de predomínio basal. O LBA mostrou alveolite linfocítica em 3 doentes, tendo-se observado no entanto diferentes relações CD4/CD8., para além de neutrofilia em 2 deles. No restante doente, observou-se hemorragia alveolar grave. Não houve em nenhum dos casos qualquer isolamento de micro organismos patogénicos no LBA. As queixas apresentadas, bem como as alterações radiológicas regrediram com a suspensão do fármaco. Estes quatro casos revelaram alguma variedade, quer na apresentação clínica, quer nos achados dos exames subsidiários efectuados, nomeadamente no LBA. Este facto pode ter como causa diferentes mecanismos fisiopatológicos a nível do pulmão induzidos pelo sirolimus.Drug induced lung diseases (DILD are an increasingly cause of morbidity. Many drugs have been described, causing several patterns of injury. Sirolimus is an immunosuppressive agent increasingly used in renal and other solid organ transplantation. Pulmonary toxicity has been recognised as a potential

  10. Allergic inflammation does not impact chemical-induced carcinogenesis in the lungs of mice

    Directory of Open Access Journals (Sweden)

    Doris Konstantinos

    2010-08-01

    Full Text Available Abstract Background Although the relationship between allergic inflammation and lung carcinogenesis is not clearly defined, several reports suggest an increased incidence of lung cancer in patients with asthma. We aimed at determining the functional impact of allergic inflammation on chemical carcinogenesis in the lungs of mice. Methods Balb/c mice received single-dose urethane (1 g/kg at day 0 and two-stage ovalbumin during tumor initiation (sensitization: days -14 and 0; challenge: daily at days 6-12, tumor progression (sensitization: days 70 and 84; challenge: daily at days 90-96, or chronically (sensitization: days -14 and 0; challenge: daily at days 6-12 and thrice weekly thereafter. In addition, interleukin (IL-5 deficient and wild-type C57BL/6 mice received ten weekly urethane injections. All mice were sacrificed after four months. Primary end-points were number, size, and histology of lung tumors. Secondary end-points were inflammatory cells and mediators in the airspace compartment. Results Ovalbumin provoked acute allergic inflammation and chronic remodeling of murine airways, evident by airspace eosinophilia, IL-5 up-regulation, and airspace enlargement. Urethane resulted in formation of atypical alveolar hyperplasias, adenomas, and adenocarcinomas in mouse lungs. Ovalbumin-induced allergic inflammation during tumor initiation, progression, or continuously did not impact the number, size, or histologic distribution of urethane-induced pulmonary neoplastic lesions. In addition, genetic deficiency in IL-5 had no effect on urethane-induced lung tumorigenesis. Conclusions Allergic inflammation does not impact chemical-induced carcinogenesis of the airways. These findings suggest that not all types of airway inflammation influence lung carcinogenesis and cast doubt on the idea of a mechanistic link between asthma and lung cancer.

  11. Leptin Downregulates LPS-Induced Lung Injury: Role of Corticosterone and Insulin

    Directory of Open Access Journals (Sweden)

    Maristella A. Landgraf

    2014-03-01

    Full Text Available Background/Aims: We investigated the effects of leptin in the development of lipopolysaccharide (LPS-induced acute lung inflammation (ALI in lean mice. Methods: Mice were administered leptin (1.0µg/g or leptin (1.0µg/g followed by LPS (1.5µg/g intranasally. Additionally, some animals were given LPS (1.5µg/g or saline intranasally alone, as a control. Tissue samples and fluids were collected six hours after instillation. Results: We demonstrated that leptin alone did not induce any injury. Local LPS exposure resulted in significant acute lung inflammation, characterized by a substantial increase in total cells, mainly neutrophils, in bronchoalveolar lavages (BAL. We also observed a significant lymphocyte influx into the lungs associated with enhanced lung expression of chemokines and cytokines (KC, RANTES, TNF-α, IFN-γ, GM-CSF and VEGF. LPS-induced ALI was characterized by the enhanced expression of ICAM-1 and iNOS in the lungs. Mice that received LPS showed an increase in insulin levels. Leptin, when administered prior to LPS instillation, abolished all of these effects. LPS induced an increase in corticosterone levels, and leptin potentiated this event. Conclusion: These data suggest that exogenous leptin may promote protection during sepsis, and downregulation of the insulin levels and upregulation of corticosterone may be important mechanisms in the amelioration of LPS-induced ALI.

  12. Romo1 expression contributes to oxidative stress-induced death of lung epithelial cells

    Energy Technology Data Exchange (ETDEWEB)

    Shin, Jung Ar [Department of Internal Medicine, Yonsei University College of Medicine, Yonsei University Health System, Seoul 135-270 (Korea, Republic of); Chung, Jin Sil [Laboratory of Molecular Cell Biology, College of Life Sciences and Biotechnology, Korea University, Seoul 136-713 (Korea, Republic of); Cho, Sang-Ho [Department of Pathology, Pochon CHA University, College of Medicine, Gyeonggi-do (Korea, Republic of); Kim, Hyung Jung, E-mail: khj57@yuhs.ac.kr [Department of Internal Medicine, Yonsei University College of Medicine, Yonsei University Health System, Seoul 135-270 (Korea, Republic of); Yoo, Young Do, E-mail: ydy1130@korea.ac.kr [Laboratory of Molecular Cell Biology, College of Life Sciences and Biotechnology, Korea University, Seoul 136-713 (Korea, Republic of)

    2013-09-20

    Highlights: •Romo1 mediates oxidative stress-induced mitochondrial ROS production. •Romo1 induction by oxidative stress plays an important role in oxidative stress-induced apoptosis. •Romo1 overexpression correlates with epithelial cell death in patients with IPF. -- Abstract: Oxidant-mediated death of lung epithelial cells due to cigarette smoking plays an important role in pathogenesis in lung diseases such as idiopathic pulmonary fibrosis (IPF). However, the exact mechanism by which oxidants induce epithelial cell death is not fully understood. Reactive oxygen species (ROS) modulator 1 (Romo1) is localized in the mitochondria and mediates mitochondrial ROS production through complex III of the mitochondrial electron transport chain. Here, we show that Romo1 mediates mitochondrial ROS production and apoptosis induced by oxidative stress in lung epithelial cells. Hydrogen peroxide (H{sub 2}O{sub 2}) treatment increased Romo1 expression, and Romo1 knockdown suppressed the cellular ROS levels and cell death triggered by H{sub 2}O{sub 2} treatment. In immunohistochemical staining of lung tissues from patients with IPF, Romo1 was mainly localized in hyperplastic alveolar and bronchial epithelial cells. Romo1 overexpression was detected in 14 of 18 patients with IPF. TUNEL-positive alveolar epithelial cells were also detected in most patients with IPF but not in normal controls. These findings suggest that Romo1 mediates apoptosis induced by oxidative stress in lung epithelial cells.

  13. Depletion of tumor associated macrophages slows the growth of chemically-induced mouse lung adenocarcinomas

    Directory of Open Access Journals (Sweden)

    Jason M. Fritz

    2014-11-01

    Full Text Available Chronic inflammation is a risk factor for lung cancer, and low dose aspirin intake reduces lung cancer risk. However, the roles that specific inflammatory cells and their products play in lung carcinogenesis have yet to be fully elucidated. In mice, alveolar macrophage numbers increase as lung tumors progress, and pulmonary macrophage programming changes within 2 weeks of carcinogen exposure. To examine how macrophages specifically affect lung tumor progression, they were depleted in mice bearing urethane-induced lung tumors using clodronate-encapsulated liposomes. Alveolar macrophage populations decreased to ≤ 50% of control levels after 4-6 weeks of liposomal clodronate treatment. Tumor burden decreased by 50% compared to vehicle treated mice, and tumor cell proliferation, as measured by Ki67 staining, was also attenuated. Pulmonary fluid levels of IGF-I, CXCL1, IL-6 and CCL2 diminished with clodronate liposome treatment. Tumor associated macrophages expressed markers of both M1 and M2 programming in vehicle and clodronate liposome treated mice. Mice lacking CCR2 (the receptor for macrophage chemotactic factor CCL2 had comparable numbers of alveolar macrophages and showed no difference in tumor growth rates when compared to similarly treated wild-type mice suggesting that while CCL2 may recruit macrophages to lung tumor microenvironments, redundant pathways can compensate when CCL2/CCR2 signaling is inactivated. Depletion of pulmonary macrophages rather than inhibition of their recruitment may be an advantageous strategy for attenuating lung cancer progression.

  14. Autotaxin induces lung epithelial cell migration through lysoPLD activity-dependent and -independent pathways

    Science.gov (United States)

    Zhao, Jing; He, Donghong; Berdyshev, Evgeny; Zhong, Mintao; Salgia, Ravi; Morris, Andrew J.; Smyth, Susan S.; Natarajan, Viswanathan; Zhao, Yutong

    2013-01-01

    SYNOPSIS Lung cell migration is a crucial step for re-epithelialization that in turn is essential for remodeling and repair after lung injury. We hypothesize that secreted autotaxin (ATX), which exhibits lysophospholipase D (lysoPLD) activity, stimulates lung epithelial cell migration through lysophosphatidic acid (LPA) generation-dependent and -independent pathways. Release of endogenous ATX protein and activity was detected in lung epithelial cell culture medium. ATX with V5 tag (ATX-V5) overexpressed conditional medium had higher LPA levels compared to control medium and stimulated cell migration through Gαi-coupled LPA receptors, cytoskeleton rearrangement, phosphorylation of PKCδ and cortactin at the leading edge of migrating cells. Inhibition of PKCδ attenuated ATX-V5 overexpressed conditional medium-mediated phosphorylation of cortactin. In addition, a recombinant ATX mutant, lacking lysoPLD activity, or heat-inactived ATX also induced lung epithelial cell migration. Extracelluar ATX bound to LPA receptor and integrin β4 complex on A549 cell surface. Finally, intratracheal administration of lipopolysaccharide into mouse airway induced ATX release and LPA production in bronchoalveolar lavage fluid. These results suggested a significant role for ATX in lung epithelial cell migration and remodeling through its ability to induce LPA production-mediated phosphorylation of PKCδ and cortactin. In addition we also demonstrated assocation of ATX with epithelial cell surface LPA receptor and integrin β4. PMID:21696367

  15. Nontypeable Haemophilus influenzae induces sustained lung oxidative stress and protease expression.

    Directory of Open Access Journals (Sweden)

    Paul T King

    Full Text Available Nontypeable Haemophilus influenzae (NTHi is a prevalent bacterium found in a variety of chronic respiratory diseases. The role of this bacterium in the pathogenesis of lung inflammation is not well defined. In this study we examined the effect of NTHi on two important lung inflammatory processes 1, oxidative stress and 2, protease expression. Bronchoalveolar macrophages were obtained from 121 human subjects, blood neutrophils from 15 subjects, and human-lung fibroblast and epithelial cell lines from 16 subjects. Cells were stimulated with NTHi to measure the effect on reactive oxygen species (ROS production and extracellular trap formation. We also measured the production of the oxidant, 3-nitrotyrosine (3-NT in the lungs of mice infected with this bacterium. NTHi induced widespread production of 3-NT in mouse lungs. This bacterium induced significantly increased ROS production in human fibroblasts, epithelial cells, macrophages and neutrophils; with the highest levels in the phagocytic cells. In human macrophages NTHi caused a sustained, extracellular production of ROS that increased over time. The production of ROS was associated with the formation of macrophage extracellular trap-like structures which co-expressed the protease metalloproteinase-12. The formation of the macrophage extracellular trap-like structures was markedly inhibited by the addition of DNase. In this study we have demonstrated that NTHi induces lung oxidative stress with macrophage extracellular trap formation and associated protease expression. DNase inhibited the formation of extracellular traps.

  16. The protective effect of Sambucus ebulus against lung toxicity induced by gamma irradiation in mice

    Directory of Open Access Journals (Sweden)

    Mohammad Karami

    2015-01-01

    Full Text Available The aim of present study was to investigate the potential antioxidant and lung protective activities of Sambucus ebulus (SE against toxicity induced by gamma irradiation. Hydroalcoholic extract of SE (20, 50 and 100 mg/kg was studied for its lung protective activity. Phenol and flavonoid contents of SE were determined. Male C57 mice were divided into ten groups with five mice per group. Only the first and second groups (as negative control received intraperitoneally normal saline fluid. Groups 3 to 5 received only SE extract at doses of 20 mg/kg, 50 mg/kg and 100 mg/kg intraperitoneally; three groups were repeatedly injected for 15 days as chronic group. Groups 6 to 8 received a single-dose of gamma irradiation just 2 hours before irradiation as acute group. The ninth and tenth groups (as positive control received only gamma rays. Animal was exposed whole-body to 6 Gy gamma radiation. After irradiation, tissue sections of lung parenchyma were examined by light microscope for any histopathologic changes. SE at doses 50 and 100 mg/kg improved markedly histopathological changes induced by gamma irradiation in lung. Lung protective effect of SE could be due to attention of lipid peroxidation. Our study demonstrated that SE as a natural product has a protective effect against lung toxicity induced by   gamma irradiation in animal.

  17. Overexpression of matrix metalloproteinase-12 (MMP-12) correlates with radiation-induced lung fibrosis

    Energy Technology Data Exchange (ETDEWEB)

    Jung, Myung Gu; Jeong, Ye Ji; Lee, Haejune [Korea Institute of Radiological and Medical Sciences, Seoul (Korea, Republic of); Lee, Sujae [Hanyang Univ., Seoul (Korea, Republic of)

    2014-05-15

    MMPs are classified into five subgroups: collagenases (MMP-1, MMP-8, MMP-13), gelatinases (MMP-2, MMP-9), stromelysins (MMP-3, MMP-10, MMP-11), as well as metalloelastase (MMP-12), the membrane-type MMPs (MMP14, MMP15), and other MMPS (e. g., MMP-19, and MMP20). MMP-12 (matrix metalloproteinase12), also known as macrophage metalloelastase, was first identified as an elastolytic metalloproteinase secreted by inflammatory macrophages 30 years ago. MMP-12 degrades extracellular matrix (ECM) components to facilitate tissue remodeling. It can degrade elastin and other substrates, such as type IV collagen, fibronectin, laminin, gelatin, vitronectin, entactin, heparin, and chondroitin sulfates. In the lung, MMP-12 is identified in alveolar macrophages of cigarette smokers as an elastolytic MMP. Inactivation of the MMP-12 gene in knockout mice demonstrates a critical role of MMP-12 in smoking-induced chronic obstructive pulmonary disease (COPD). The aim of the present study was to investigate the effects of MMP-12 by radiation in lung, so we evaluate that MMP-12 expression pattern in normal lung tissue and cancer cell following radiation. Radiation induced lung injury most commonly occurs as a result of radiation therapy administered to treat cancer. The present study demonstrates that MMP-12 was highly increased in the lung damaged by radiation Thus, MMP-12 might be of potential relevance as a clinically diagnostic tool and sensitive biomarker for radiation induced lung injury and fibrosis.

  18. Evaluation of N-acetylcysteine treatment in acute pancreatitis-induced lung injury.

    Science.gov (United States)

    Yubero, Sara; Ramudo, Laura; Manso, Manuel A; Collía, Francisco; De Dios, Isabel

    2012-07-01

    Pulmonary complications are frequent during acute pancreatitis (AP). We investigate the effects of N-acetylcysteine (NAC) on lung injury in mild and severe AP. ANIMALS AND TREATMENT: Mild and severe AP was induced in rats by bile-pancreatic duct obstruction (BPDO) and infusion of 3.5 % sodium taurocholate (NaTc) into the bile-pancreatic duct, respectively. NAC (50 mg/kg) was given 1 h before and 1 h after AP. Amylase activity was measured in plasma. Lungs were harvested for mRNA expression analysis of monocyte chemoattractant protein-1 (MCP-1), cytokine-induced neutrophil chemoattractant (CINC), P-selectin and intercellular adhesion molecule-1 (ICAM-1), myeloperoxidase (MPO) activity and histological examination. Hyperamylasemia was reduced by NAC in both AP models. NAC down-regulated MCP-1, CINC and P-selectin in BPDO- but not in NaTc-induced AP. Pulmonary insults did not vary in mild AP and were exacerbated in severe AP by NAC treatment. NAC reduced lung MPO activity in mild but not in severe AP. Although NAC treatment down-regulated inflammatory mediators in lungs during AP it did not prevent leukocyte infiltration, which could be responsible for maintaining the lung injury. As a result, NAC aggravated the lung damage in severe AP and failed to exert beneficial effects in the mild disease model.

  19. Natural antioxidant betanin protects rats from paraquat-induced acute lung injury interstitial pneumonia.

    Science.gov (United States)

    Han, Junyan; Ma, Deshun; Zhang, Miao; Yang, Xuelian; Tan, Dehong

    2015-01-01

    The effect of betanin on a rat paraquat-induced acute lung injury (ALI) model was investigated. Paraquat was injected intraperitoneally at a single dose of 20 mg/kg body weight, and betanin (25 and 100 mg/kg/d) was orally administered 3 days before and 2 days after paraquat administration. Rats were sacrificed 24 hours after the last betanin dosage, and lung tissue and bronchoalveolar lavage fluid (BALF) were collected. In rats treated only with paraquat, extensive lung injury characteristic of ALI was observed, including histological changes, elevation of lung : body weight ratio, increased lung permeability, increased lung neutrophilia infiltration, increased malondialdehyde (MDA) and myeloperoxidase (MPO) activity, reduced superoxide dismutase (SOD) activity, reduced claudin-4 and zonula occluden-1 protein levels, increased BALF interleukin (IL-1) and tumor necrosis factor (TNF)-α levels, reduced BALF IL-10 levels, and increased lung nuclear factor kappa (NF-κB) activity. In rats treated with betanin, paraquat-induced ALI was attenuated in a dose-dependent manner. In conclusion, our results indicate that betanin attenuates paraquat-induced ALI possibly via antioxidant and anti-inflammatory mechanisms. Thus, the potential for using betanin as an auxilliary therapy for ALI should be explored further.

  20. Positive pressure ventilation with the open lung concept optimizes gas exchange and reduces ventilator-induced lung injury in newborn piglets

    NARCIS (Netherlands)

    van Kaam, Anton H.; de Jaegere, Anne; Haitsma, Jack J.; van Aalderen, Wim M.; Kok, Joke H.; Lachmann, Burkhard

    2003-01-01

    Previous studies demonstrated that high-frequency oscillatory ventilation using the open lung concept (OLC resulted in superior gas exchange and a reduction in ventilator-induced lung injury (VILI). We hypothesized that these beneficial effects could also be achieved by applying the OLC during

  1. Green tea polyphenol induces significant cell death in human lung ...

    African Journals Online (AJOL)

    EGCG may be due to the generation of ROS. DISCUSSION. The present study demonstrates that EGCG exhibits significant concentration- dependent inhibitory effects against the growth of lung cancer H1155 cells in tumor xenografts as well as in culture. Furthermore, EGCG markedly increased the levels of ROS in a ...

  2. Tetramethylpyrazine attenuates oleic acid-induced acute lung injury ...

    African Journals Online (AJOL)

    The protein expression of NF-kB in the lung was measured by immunohistochemistry and Western blotting. The results showed an increase in tumor necrosis factor α and interleukin 1β in the ALI/ARDS rat models. The activation of NF-kB was suppressed by TMP in the ALI/ARDS rats. The suppression of those molecules is ...

  3. Carbonic anhydrase inhibitor attenuates ischemia-reperfusion induced acute lung injury.

    Directory of Open Access Journals (Sweden)

    Chou-Chin Lan

    Full Text Available Ischemia-reperfusion (IR-induced acute lung injury (ALI is implicated in several clinical conditions including lung transplantation, cardiopulmonary bypass surgery, re-expansion of collapsed lung from pneumothorax or pleural effusion and etc. IR-induced ALI remains a challenge in the current treatment. Carbonic anhydrase has important physiological function and influences on transport of CO2. Some investigators suggest that CO2 influences lung injury. Therefore, carbonic anhydrase should have the role in ALI. This study was undertaken to define the effect of a carbonic anhydrase inhibitor, acetazolamide (AZA, in IR-induced ALI, that was conducted in a rat model of isolated-perfused lung with 30 minutes of ischemia and 90 minutes of reperfusion. The animals were divided into six groups (n = 6 per group: sham, sham + AZA 200 mg/kg body weight (BW, IR, IR + AZA 100 mg/kg BW, IR + AZA 200 mg/kg BW and IR+ AZA 400 mg/kg BW. IR caused significant pulmonary micro-vascular hyper-permeability, pulmonary edema, pulmonary hypertension, neutrophilic sequestration, and an increase in the expression of pro-inflammatory cytokines. Increases in carbonic anhydrase expression and perfusate pCO2 levels were noted, while decreased Na-K-ATPase expression was noted after IR. Administration of 200mg/kg BW and 400mg/kg BW AZA significantly suppressed the expression of pro-inflammatory cytokines (TNF-α, IL-1, IL-6 and IL-17 and attenuated IR-induced lung injury, represented by decreases in pulmonary hyper-permeability, pulmonary edema, pulmonary hypertension and neutrophilic sequestration. AZA attenuated IR-induced lung injury, associated with decreases in carbonic anhydrase expression and pCO2 levels, as well as restoration of Na-K-ATPase expression.

  4. Faslodex inhibits estradiol-induced extracellular matrix dynamics and lung metastasis in a model of lymphangioleiomyomatosis.

    Science.gov (United States)

    Li, Chenggang; Zhou, Xiaobo; Sun, Yang; Zhang, Erik; Mancini, John D; Parkhitko, Andrey; Morrison, Tasha A; Silverman, Edwin K; Henske, Elizabeth P; Yu, Jane J

    2013-07-01

    Lymphangioleiomyomatosis (LAM) is a destructive lung disease primarily affecting women. Genetic studies indicate that LAM cells carry inactivating tuberous sclerosis complex (TSC)-2 mutations, and metastasize to the lung. We previously discovered that estradiol increases the metastasis of TSC2-deficient cells in mice carrying xenograft tumors. Here, we investigate the molecular basis underlying the estradiol-induced lung metastasis of TSC2-deficient cells, and test the efficacy of Faslodex (an estrogen receptor antagonist) in a preclinical model of LAM. We used a xenograft tumor model in which estradiol induces the lung metastasis of TSC2-deficient cells. We analyzed the impact of Faslodex on tumor size, the extracellular matrix organization, the expression of matrix metalloproteinase (MMP)-2, and lung metastasis. We also examined the effects of estradiol and Faslodex on MMP2 expression and activity in tuberin-deficient cells in vitro. Estradiol resulted in a marked reduction of Type IV collagen deposition in xenograft tumors, associated with 2-fold greater MMP2 concentrations compared with placebo-treated mice. Faslodex normalized the Type IV collagen changes in xenograft tumors, enhanced the survival of the mice, and completely blocked lung metastases. In vitro, estradiol enhanced MMP2 transcripts, protein accumulation, and activity. These estradiol-induced changes in MMP2 were blocked by Faslodex. In TSC2-deficient cells, estradiol increased MMP2 concentrations in vitro and in vivo, and induced extracellular matrix remodeling. Faslodex inhibits the estradiol-induced lung metastasis of TSC2-deficient cells. Targeting estrogen receptors with Faslodex may be of efficacy in the treatment of LAM.

  5. Sevoflurane suppresses hypoxia-induced growth and metastasis of lung cancer cells via inhibiting hypoxia-inducible factor-1α.

    Science.gov (United States)

    Liang, Hua; Yang, Cheng Xiang; Zhang, Bin; Wang, Han Bing; Liu, Hong Zhen; Lai, Xiao Hong; Liao, Mei Juan; Zhang, Tao

    2015-12-01

    Hypoxia promotes the progression of lung cancer cells. Unfortunately, anesthetic technique might aggravate hypoxia of lung cancer cells. Sevoflurane is a commonly used anesthetic. Its effect on hypoxia-induced aggressiveness of lung cancer cells remains unknown. The aim of the study is to investigate the effects of sevoflurane on hypoxia-induced growth and metastasis of lung cancer cells. As hypoxia-inducible factor-1α (HIF-1α) plays a pivotal role in mediating the adaptation and tolerance of cancer cells under hypoxic microenvironment, the role of HIF-1α in the effect of sevoflurane on hypoxia-induced growth and metastasis has also been elucidated. A549 cells were treated with normoxia, hypoxia, co-treatment of sevoflurane and hypoxia, and dimethyloxaloylglycine (DMOG, a HIF-1α agonist) for 4 h, respectively. MTT assay and colony formation assay were used to evaluate cell growth. Transwell assay was performed to detect invasion and migration ability. The protein level of HIF-1α, X-linked inhibitor of apoptosis protein (XIAP), survivin, fascin, heparanase (HPA), and p38 MAPK were determined by Western blotting. Hypoxia enhanced proliferation and metastatic potential of cells. Sevoflurane could suppress hypoxia-induced growth and metastasis ability of cells. Furthermore, HIF-1α, XIAP, survivin, fascin and HPA were down-regulated significantly by the co-treatment of sevoflurane and hypoxia as compared to hypoxia treatment. DMOG abolished the inhibiting effects of sevoflurane on hypoxia-induced growth and metastasis ability of cells. In addition, sevoflurane partly reversed the increase of p38 MAPK activity that was induced by hypoxia. Sevoflurane could suppress hypoxia-induced growth and metastasis of lung cancer cells, which might be associated with modulating HIF-1α and its down-stream genes. Moreover, p38 MAPK signaling pathway was involved in the regulation of HIF-1α by sevoflurane.

  6. Chemokine (C-C Motif) Receptor-Like 2 is not essential for lung injury, lung inflammation, or airway hyperresponsiveness induced by acute exposure to ozone.

    Science.gov (United States)

    Malik, Farhan; Cromar, Kevin R; Atkins, Constance L; Price, Roger E; Jackson, William T; Siddiqui, Saad R; Spencer, Chantal Y; Mitchell, Nicholas C; Haque, Ikram U; Johnston, Richard A

    2017-12-01

    Inhalation of ozone (O 3 ), a gaseous air pollutant, causes lung injury, lung inflammation, and airway hyperresponsiveness. Macrophages, mast cells, and neutrophils contribute to one or more of these sequelae induced by O 3 Furthermore, each of these aforementioned cells express chemokine (C-C motif) receptor-like 2 (Ccrl2), an atypical chemokine receptor that facilitates leukocyte chemotaxis. Given that Ccrl2 is expressed by cells essential to the development of O 3 -induced lung pathology and that chemerin, a Ccrl2 ligand, is increased in bronchoalveolar lavage fluid (BALF) by O 3 , we hypothesized that Ccrl2 contributes to the development of lung injury, lung inflammation, and airway hyperresponsiveness induced by O 3 To that end, we measured indices of lung injury (BALF protein, BALF epithelial cells, and bronchiolar epithelial injury), lung inflammation (BALF cytokines and BALF leukocytes), and airway responsiveness to acetyl- β -methylcholine chloride (respiratory system resistance) in wild-type and mice genetically deficient in Ccrl2 (Ccrl2-deficient mice) 4 and/or 24 hours following cessation of acute exposure to either filtered room air (air) or O 3 In air-exposed mice, BALF chemerin was greater in Ccrl2-deficient as compared to wild-type mice. O 3 increased BALF chemerin in mice of both genotypes, yet following O 3 exposure, BALF chemerin was greater in Ccrl2-deficient as compared to wild-type mice. O 3 increased indices of lung injury, lung inflammation, and airway responsiveness. Nevertheless, no indices were different between genotypes following O 3 exposure. In conclusion, we demonstrate that Ccrl2 modulates chemerin levels in the epithelial lining fluid of the lungs but does not contribute to the development of O 3 -induced lung pathology. © 2017 The Authors. Physiological Reports published by Wiley Periodicals, Inc. on behalf of The Physiological Society and the American Physiological Society.

  7. Pharmacological inhibition of leukotrienes in an animal model of bleomycin-induced acute lung injury

    Directory of Open Access Journals (Sweden)

    Crimi Nunzio

    2006-11-01

    Full Text Available Abstract Leukotrienes are increased locally in idiopathic pulmonary fibrosis. Furthermore, a role for these arachidonic acid metabolites has been thoroughly characterized in the animal bleomycin model of lung fibrosis by using different gene knock-out settings. We investigated the efficacy of pharmacological inhibition of leukotrienes activity in the development of bleomycin-induced lung injury by comparing the responses in wild-type mice with mice treated with zileuton, a 5-lipoxygenase inhibitor and MK-571, a cys-leukotrienes receptor antagonist. Mice were subjected to intra-tracheal administration of bleomycin or saline and were assigned to receive either MK-571 at 1 mg/Kg or zileuton at 50 mg/Kg daily. One week after bleomycin administration, BAL cell counts, lung histology with van Gieson for collagen staining and immunohistochemical analysis for myeloperoxidase, IL-1 and TNF-α were performed. Following bleomycin administration both MK-571 and zileuton treated mice exhibited a reduced degree of lung damage and inflammation when compared to WT mice as shown by the reduction of:(i loss of body weight, (ii mortality rate, (iii lung infiltration by neutrophils (myeloperoxidase activity, BAL total and differential cell counts, (iv lung edema, (v histological evidence of lung injury and collagen deposition, (vi lung myeloperoxidase, IL-1 and TNF-α staining. This is the first study showing that the pharmacological inhibition of leukotrienes activity attenuates bleomycin-induced lung injury in mice. Given our results as well as those coming from genetic studies, it might be considered meaningful to trial this drug class in the treatment of pulmonary fibrosis, a disease that still represents a major challenge to medical treatment.

  8. COX-2 inhibition attenuates lung injury induced by skeletal muscle ischemia reperfusion in rats.

    Science.gov (United States)

    Wang, Liangrong; Shan, Yuanlu; Ye, Yuzhu; Jin, Lida; Zhuo, Qian; Xiong, Xiangqing; Zhao, Xiyue; Lin, Lina; Miao, JianXia

    2016-02-01

    Skeletal muscle ischemia reperfusion accounts for high morbidity and mortality, and cyclooxygenase (COX)-2 is implicated in causing muscle damage. Downregulation of aquaporin-1 (AQP-1) transmembrane protein is implicated in skeletal muscle ischemia reperfusion induced remote lung injury. The expression of COX-2 in lung tissue and the effect of COX-2 inhibition on AQP-1 expression and lung injury during skeletal muscle ischemia reperfusion are not known. We investigated the role of COX-2 in lung injury induced by skeletal muscle ischemia reperfusion in rats and evaluated the effects of NS-398, a specific COX-2 inhibitor. Twenty-four Sprague Dawley rats were randomized into 4 groups: sham group (SM group), sham+NS-398 group (SN group), ischemia reperfusion group (IR group) and ischemia reperfusion+NS-398 group (IN group). Rats in the IR and IN groups were subjected to 3h of bilateral ischemia followed by 6h of reperfusion in hindlimbs, and intravenous NS-398 8 mg/kg was administered in the IN group. In the SM and SN groups, rubber bands were in place without inflation. At the end of reperfusion, myeloperoxidase (MPO) activity, COX-2 and AQP-1 protein expression in lung tissue, PGE2 metabolite (PGEM), tumor necrosis factor (TNF)-α and interleukin (IL)-1β levels in bronchoalveolar lavage (BAL) fluid were assessed. Histological changes in lung and muscle tissues and wet/dry (W/D) ratio were also evaluated. MPO activity, COX-2 expression, W/D ratio in lung tissue, and PGEM, TNF-α and IL-1β levels in BAL fluid were significantly increased, while AQP-1 protein expression downregulated in the IR group as compared to that in the SM group (Pinjury. COX-2 protein expression was upregulated in lung tissue in response to skeletal muscle ischemia reperfusion. COX-2 inhibition may modulate pulmonary AQP-1 expression and attenuate lung injury. Copyright © 2015 Elsevier B.V. All rights reserved.

  9. Cyclin D expression in plutonium-induced lung tumors in F344 rats

    Energy Technology Data Exchange (ETDEWEB)

    Hahn, F.F.; Kelly, G. [SouthWest Scientific Resources, Inc., Albuquerque, NM (United States)

    1995-12-01

    The genetic mechanisms responsible for {alpha}-radiation-induced lung cancer in rats following inhalation of {sup 239}Pu is an ongoing area of research in our laboratory. Previous studies have examined the status of the p53 gene by immunohistochemistry. Only two tumors (2/26 squamous cell carcinomas) exhibited detectable levels of p53 products. Both were the result of mutations in codons 280 and 283. More recent studies of X-ray-induced lung tumors in rats showed a similar lack of involvement of p53. In conclusion, we found that {alpha}-radiation-induced rat lung tumors have a high incidence (31 of 39) of cyclin D{sub 1} overexpression.

  10. Extracellular Matrix Metalloproteinase Inducer (EMMPRIN) promotes lung fibroblast proliferation, survival and differentiation to myofibroblasts.

    Science.gov (United States)

    Hasaneen, Nadia A; Cao, Jian; Pulkoski-Gross, Ashleigh; Zucker, Stanley; Foda, Hussein D

    2016-02-17

    Idiopathic pulmonary fibrosis (IPF) is a chronic progressively fatal disease. Extracellular Matrix Metalloproteinase Inducer (EMMPRIN) is a glycosylated transmembrane protein that induces the expression of some matrix metalloproteinase (MMP) in neighboring stromal cells through direct epithelial-stromal interactions. EMMPRIN is highly expressed in type II alveolar epithelial cells at the edges of the fibrotic areas in IPF lung sections. However, the exact role of EMMPRIN in IPF is unknown. To determine if EMMPRIN contributes to lung fibroblast proliferation, resistance to apoptosis, and differentiation to myofibroblasts, normal Human lung fibroblasts (NHLF) transiently transfected with either EMMPRIN/GFP or GFP were treated with TGF- β1 from 0 to 10 ng/ml for 48 h and examined for cell proliferation (thymidine incorporation), apoptosis (FACS analysis and Cell Death Detection ELISA assay), cell migration (Modified Boyden chamber) and differentiation to myofibroblasts using Western blot for α-smooth actin of cell lysates. The effect of EMMPRIN inhibition on NHLF proliferation, apoptosis, migration and differentiation to myofibroblasts after TGF- β1 treatment was examined using EMMPRIN blocking antibody. We examined the mechanism by which EMMPRIN induces its effects on fibroblasts by studying the β-catenin/canonical Wnt signaling pathway using Wnt luciferase reporter assays and Western blot for total and phosphorylated β-catenin. Human lung fibroblasts overexpressing EMMPRIN had a significant increase in cell proliferation and migration compared to control fibroblasts. Furthermore, EMMPRIN promoted lung fibroblasts resistance to apoptosis. Lung fibroblasts overexpressing EMMPRIN showed a significantly increased expression of α- smooth muscle actin, a marker of differentiation to myofibroblasts compared to control cells. TGF-β1 increased the expression of EMMPRIN in lung fibroblasts in a dose-dependent manner. Attenuation of EMMPRIN expression with the use of an

  11. Hypoxia-preconditioned mesenchymal stem cells ameliorate ischemia/reperfusion-induced lung injury.

    Directory of Open Access Journals (Sweden)

    Yung-Yang Liu

    Full Text Available Hypoxia preconditioning has been proven to be an effective method to enhance the therapeutic action of mesenchymal stem cells (MSCs. However, the beneficial effects of hypoxic MSCs in ischemia/reperfusion (I/R lung injury have yet to be investigated. In this study, we hypothesized that the administration of hypoxic MSCs would have a positive therapeutic impact on I/R lung injury at molecular, cellular, and functional levels.I/R lung injury was induced in isolated and perfused rat lungs. Hypoxic MSCs were administered in perfusate at a low (2.5×105 cells and high (1×106 cells dose. Rats ventilated with a low tidal volume of 6 ml/kg served as controls. Hemodynamics, lung injury indices, inflammatory responses and activation of apoptotic pathways were determined.I/R induced permeability pulmonary edema with capillary leakage and increased levels of reactive oxygen species (ROS, pro-inflammatory cytokines, adhesion molecules, cytosolic cytochrome C, and activated MAPK, NF-κB, and apoptotic pathways. The administration of a low dose of hypoxic MSCs effectively attenuated I/R pathologic lung injury score by inhibiting inflammatory responses associated with the generation of ROS and anti-apoptosis effect, however this effect was not observed with a high dose of hypoxic MSCs. Mechanistically, a low dose of hypoxic MSCs down-regulated P38 MAPK and NF-κB signaling but upregulated glutathione, prostaglandin E2, IL-10, mitochondrial cytochrome C and Bcl-2. MSCs infused at a low dose migrated into interstitial and alveolar spaces and bronchial trees, while MSCs infused at a high dose aggregated in the microcirculation and induced pulmonary embolism.Hypoxic MSCs can quickly migrate into extravascular lung tissue and adhere to other inflammatory or structure cells and attenuate I/R lung injury through anti-oxidant, anti-inflammatory and anti-apoptotic mechanisms. However, the dose of MSCs needs to be optimized to prevent pulmonary embolism and thrombosis.

  12. Important role of platelets in modulating endotoxin-induced lung inflammation in CFTR-deficient mice.

    Directory of Open Access Journals (Sweden)

    Caiqi Zhao

    Full Text Available Mutation of CFTR (cystic fibrosis transmembrane conductance regulator leads to cystic fibrosis (CF. Patients with CF develop abnormalities of blood platelets and recurrent lung inflammation. However, whether CFTR-mutated platelets play a role in the development of lung inflammation is elusive. Therefore, we intratracheally challenged wildtype and F508del (a common type of CFTR mutation mice with LPS to observe changes of F508del platelets in the peripheral blood and indexes of lung inflammation (BAL neutrophils and protein levels. Furthermore, we investigated whether or not and how F508del platelets modulate the LPS-induced acute lung inflammation by targeting anti-platelet aggregation, depletion of neutrophils, reconstitution of bone marrow or neutrophils, blockade of P-selectin glycoprotein ligand-1 (PSGL-1, platelet activating factor (PAF, and correction of mutated CFTR trafficking. We found that LPS-challenged F508del mice developed severe thrombocytopenia and had higher levels of plasma TXB2 coincided with neutrophilic lung inflammation relative to wildtype control. Inhibition of F508del platelet aggregation or depletion of F508del neutrophils diminished the LPS-induced lung inflammation in the F508del mice. Moreover, wildtype mice reconstituted with either F508del bone marrow or neutrophils developed worse thrombocytopenia. Blocking PSGL-1, platelet activating factor (PAF, or rectifying trafficking of mutated CFTR in F508del mice diminished and alveolar neutrophil transmigration in the LPS-challenged F508del mice. These findings suggest that F508del platelets and their interaction with neutrophils are requisite for the development of LPS-induced lung inflammation and injury. As such, targeting platelets might be an emerging strategy for dampening recurrent lung inflammation in cystic fibrosis patients.

  13. N-methyl-D-aspartate receptor activation mediates lung fibroblast proliferation and differentiation in hyperoxia-induced chronic lung disease in newborn rats.

    Science.gov (United States)

    Wang, YanRui; Yue, ShaoJie; Luo, ZiQiang; Cao, ChuanDing; Yu, XiaoHe; Liao, ZhengChang; Wang, MingJie

    2016-10-21

    Previous studies have suggested that endogenous glutamate and its N-methyl-D-aspartate receptors (NMDARs) play important roles in hyperoxia-induced acute lung injury in newborn rats. We hypothesized that NMDAR activation also participates in the development of chronic lung injury after withdrawal of hyperoxic conditions. In order to rule out the anti-inflammatory effects of NMDAR inhibitor on acute lung injury, the efficacy of MK-801 was evaluated in vivo using newborn Sprague-Dawley rats treated starting 4 days after cessation of hyperoxia exposure (on postnatal day 8). The role of NMDAR activation in hyperoxia-induced lung fibroblast proliferation and differentiation was examined in vitro using primary cells derived from the lungs of 8-day-old Sprague-Dawley rats exposed to hyperoxic conditions. Hyperoxia for 3 days induced acute lung injury in newborn rats. The acute injury almost completely disappeared 4 days after cessation of hyperoxia exposure. However, pulmonary fibrosis, impaired alveolarization, and decreased pulmonary compliance were observed on postnatal days 15 and 22. MK-801 treatment during the recovery period was found to alleviate the chronic damage induced by hyperoxia. Four NMDAR 2 s were found to be upregulated in the lung fibroblasts of newborn rats exposed to hyperoxia. In addition, the proliferation and upregulation of alpha-smooth muscle actin and (pro) collagen I in lung fibroblasts were detected in hyperoxia-exposed rats. MK-801 inhibited these changes. NMDAR activation mediated lung fibroblast proliferation and differentiation and played a role in the development of hyperoxia-induced chronic lung damage in newborn rats.

  14. Protective effect of heme oxygenase-1 on lung injury induced by erythrocyte instillation in rats.

    Science.gov (United States)

    Pang, Qing-Feng; Zhou, Qiao-Mei; Zeng, Si; Dou, Li-Dong; Ji, Yong; Zeng, Yin-Ming

    2008-09-05

    Intratracheal instillation of blood induces self-repaired acute lung injury. However, the mechanism of repair has been unclear. Heme-oxygenase (HO)-1, which catalyzes heme breakdown, acts as an inducible defense against oxidative stress and plays an important role in inflammation. The objective of this study was to test the role of HO-1 in lung injury caused by intratracheal instillation of red cells. Forty healthy, male Sprague-Dawley rats were randomly divided into five groups: normal group, saline group, erythrocyte group, erythrocyte+zinc-protoporphyrin (ZnPP, HO-1 inhibitor) group and saline+ZnPP group. At 2 days after intratracheal instillation of red cells, lung tissues and lavage samples were isolated for biochemical determinations and histological measurements. Histological analysis revealed that administration of ZnPP worsened the acute lung injury induced by instilled erythrocytes. HO-1 was over-expressed in the erythrocyte group and in the erythrocyte + ZnPP group. Compared with the erythrocyte + ZnPP group, the levels of total protein, lactate dehydrogenase and tumor necrosis factor-alpha in the lavage were lower (P < 0.01), while the level of interleukin-10 was higher in the erythrocyte group (P < 0.01). HO-1 protects against erythrocyte-induced inflammatory injury in lung.

  15. Consumption of Hydrogen Water Reduces Paraquat-Induced Acute Lung Injury in Rats

    Directory of Open Access Journals (Sweden)

    Shulin Liu

    2011-01-01

    Full Text Available Exposure to paraquat leads to acute lung injury and oxidative stress is widely accepted as a contributor to paraquat-induced acute lung injury. Recent studies have reported that consumption of water with dissolved molecular hydrogen to a saturated level (hydrogen water prevents oxidative stress-induced diseases. Here, we investigated whether consumption of saturated hydrogen saline protects rats against paraquat-induced acute lung injury. Adult male Sprague-Dawley (SD rats were randomly divided into four groups: Control group; hydrogen water-only group (HW group; paraquat-only group (PQ group; paraquat and hydrogen water group (PQ  +  HW group. The rats in control group and HW group drank pure water or hydrogen water; the rats in PQ group and PQ  +  HW group were intraperitonealy injected with paraquat (35 mg/kg and then provided pure water or hydrogen water. Both biochemical and histological lung alterations were measured. The results showed that hydrogen water ameliorated these alterations, demonstrating that hydrogen water alleviated paraquat-induced acute lung injury possibly by inhibition of oxidative damage.

  16. Effects of alliin on LPS-induced acute lung injury by activating PPARγ.

    Science.gov (United States)

    Wang, Yi-Luan; Guo, Xian-Yang; He, Wei; Chen, Ru-Jie; Zhuang, Rong

    2017-09-01

    Alliin is a garlic organosulfur compound that possesses various pharmacological properties. In the present study, the protective effects and molecular mechanism of alliin on Lipopolysaccharides (LPS)-induced acute lung injury (ALI) were analyzed. LPS-induced ALI was induced in BALB/c mice by intranasal instillation of LPS. Alliin was administered intraperitoneally to mice 1 h after LPS treatment. The results showed that alliin markedly inhibited lung myeloperoxidase (MPO) activity and wet/dry (W/D) ratio induced by LPS. Alliin also inhibited TNF-α and IL-1β in the bronchoalveolar lavage fluid (BALF) induced by LPS. Furthermore, LPS-induced lung pathological injury was attenuated by treatment of alliin. LPS-induced NF-κB activation was significantly inhibited by alliin. In addition, the expression of peroxisome proliferator-activated receptor γ (PPARγ) was up-regulated by treatment of alliin. Taken together, these results suggested that alliin protected against LPS-induced ALI by activating PPARγ, which subsequently inhibited LPS-induced NF-κB activation and inflammatory response. Alliin might be used as an anti-inflammatory agent in the treatment of ALI. Copyright © 2017 Elsevier Ltd. All rights reserved.

  17. Reversible Lansoprazole-Induced Interstitial Lung Disease Showing Improvement after Drug Cessation

    International Nuclear Information System (INIS)

    Hwang, Kyu Won; Woo, Ok Hee; Yong, Hwan Seok; Shin, Bong Kyung; Shim, Jae Jeong; Kang, Eun Young

    2008-01-01

    Lansoprazole is an acid proton-pump inhibitor that is similar to omeprazole. It is used to treat duodenal or gastric ulcers, H. pylori infection, gastroesophageal reflux disease (GERD) or Zollinger-Ellison syndrome. Common adverse effects of lansoprazole are diarrhea, abdominal pain, skin rash and/or itching. Information from U.S. National Library of Medicine warns that this drug can on rare occasion cause cough or cold-like symptoms. The pathophysiological mechanisms of lansoprazole-related pulmonary symptoms are not yet understood. In particular, there are no known reports regarding lansoprazole-induced interstitial lung diseases. We report here a case of interstitial lung disease (ILD) induced by oral administration of lansoprazole, which showed a pattern of nonspecific interstitial pneumonia (NSIP) as detected from a video-assisted thoracoscopic lung biopsy. We believe that this is the first report of a case of pathologically proven lansoprazole-induced ILD for which a surgical lung biopsy was performed. To the best of our knowledge, this is the first description of DI-ILD caused by lansoprazole. The diagnosis was made by considering the radiological, histopathological and clinical findings, including the close temporal relationship between lansoprazole exposure and symptom severity. Other possible causes were excluded due to a lack of a temporal relationship between the symptoms and work history or prednisolone therapy, and no other history of specific allergen exposure. When there is diffuse interstitial lung disease with an unknown etiology, it is important to remember that drugs can be the cause of pulmonary symptoms and it is crucial to take a careful patient history. If there is a recent history of taking lansoprazole in a patient with clinical and radiological findings of diffuse interstitial lung disease, we recommend stopping the medication to see if there is clinical and radiological improvement. That way, one can avoid using invasive procedures to

  18. Mitigation of cadmium-induced lung injury by Nigella sativa oil.

    Science.gov (United States)

    El-Ebiary, Ahmad A; El-Ghaiesh, Sabah; Hantash, Ehab; Alomar, Suliman

    2016-12-01

    Induction of oxidative stress and inflammation are considered the primary mechanism of cadmium (Cd) toxicity. Nigella sativa (NS) seeds and their oil (NSO) have been reported to possess antioxidant and anti-inflammatory potential. This study was conducted to assess the protective effect of NSO on Cd-induced lung damage in rat. Forty adult male Wistar rats were divided equally into 4 groups. Animals in groups I, II, and III received 1 ml of isotonic saline intraperitoneally (IP), 2 mg/kg of cadmium chloride (CdCl 2 ) dissolved in isotonic saline IP, and 1 ml/kg of NSO by gastric gavage, respectively. Group IV rats received NSO an hour prior to CdCl 2 administration via the same routes and doses as previously described. All animals were treated for 28 days. At the end of the study, animals were sacrificed; lungs were harvested for histopathological studies using light and electron microscopy. Saline-treated and NSO-treated rats showed normal lung parenchyma. However, CdCl 2 -treated rats showed massive degenerative changes in alveolar epithelial lining, disrupted interalveolar septa, and hemolytic debris in alveoli. Rats treated with both NSO and CdCl 2 (group IV) showed amelioration of most Cd-induced lung damage with minimal histopathological changes in lung architecture. This study elucidates the protective effects of NSO on Cd-induced lung injury in rats and highlights the possibility of using NSO as a protective agent in individuals at high risk of Cd-induced lung toxicity.

  19. Prominin-1/CD133+ lung epithelial progenitors protect from bleomycin-induced pulmonary fibrosis.

    Science.gov (United States)

    Germano, Davide; Blyszczuk, Przemyslaw; Valaperti, Alan; Kania, Gabriela; Dirnhofer, Stephan; Landmesser, Ulf; Lüscher, Thomas F; Hunziker, Lukas; Zulewski, Henryk; Eriksson, Urs

    2009-05-15

    The mouse model of bleomycin-induced lung injury offers an approach to study idiopathic pulmonary fibrosis, a progressive interstitial lung disease with poor prognosis. Progenitor cell-based treatment strategies might combine antiinflammatory effects and the capacity for tissue repair. To expand progenitor cells with reparative and regenerative capacities and to evaluate their protective effects on pulmonary fibrosis in vivo. Prominin-1/CD133(+) epithelial progenitor cells (PEPs) were expanded from adult mouse lungs after digestion and culture of distal airways. Lung fibrosis was induced in C57Bl/6 mice by instillation of bleomycin. Two hours later, animals were transplanted with PEPs. Inflammation and fibrosis were assessed by immunohistochemistry, bronchoalveolar lavage fluid differentials, and real-time polymerase chain reaction. PEPs expanded from mouse lungs were of bone marrow origin, coexpressed stem and hematopoietic cell markers, and differentiated in vitro into alveolar type II surfactant protein-C(+) epithelial cells. In bleomycin-challenged mice, intratracheally injected PEPs engrafted into the lungs and differentiated into type II pneumocytes. Furthermore, PEPs suppressed proinflammatory and profibrotic gene expression, prevented the recruitment of inflammatory cells, and protected bleomycin-challenged mice from pulmonary fibrosis. Mechanistically, the protective effect depended on upregulation of inducible nitric oxide synthase in PEPs and nitric oxide-mediated suppression of alveolar macrophage proliferation. Accordingly, PEPs from iNOS(-/-) but not iNOS(+/+) mice failed to protect from bleomycin-induced lung injury. The combined antiinflammatory and regenerative capacity of bone marrow-derived pulmonary epithelial progenitors offers a promising approach for development of cell-based therapeutic strategies against pulmonary fibrosis.

  20. Chloroquine attenuates paraquat-induced lung injury in mice by altering inflammation, oxidative stress and fibrosis.

    Science.gov (United States)

    Shen, Haitao; Wu, Na; Wang, Yu; Zhao, Hongyu; Zhang, Lichun; Li, Tiegang; Zhao, Min

    2017-05-01

    Paraquat is one of the most extensively used herbicides and has high toxicity for humans and animals. However, there is no effective treatment for paraquat poisoning. The aim of the present study was to evaluate the effects of chloroquine on paraquat-induced lung injury in mice. Mice received a single intraperitoneal injection of paraquat and a daily intraperitoneal injection of the indicated dosages of chloroquine or dexamethasone. The histological changes, inflammation and oxidative stress in the lungs were examined at day 3, and the degree of pulmonary fibrosis was examined at day 28. H&E staining showed that chloroquine markedly attenuated lung injury induced by paraquat. In addition, the inflammatory responses induced by paraquat were inhibited after treatment with chloroquine, as indicated by the decreased number of leukocytes, the reduced levels of TNF-α, IL-1β and IL-6 in the bronchoalveolar lavage fluid, the reduced NO content, and downregulation of iNOS expression in lung tissues. No different effect was found between high-dose chloroquine and dexamethasone. Additionally, the treatment with chloroquine increased the activity of SOD and decreased the level of MDA in the lung tissues. The expressions of the anti-oxidative proteins, Nrf2, HO-1 and NQO1, were also upregulated by chloroquine treatment. The high-dose chloroquine was more effective than dexamethasone in its anti-oxidation ability. Finally, the results of Masson's staining illustrated that chloroquine markedly attenuated fibrosis in the paraquat-exposed lungs. Immunohistochemistry staining showed that the expressions of the pro-fibrotic proteins TGF-β and α-SMA were downregulated after treatment with chloroquine. In conclusion, chloroquine effectively attenuated paraquat-induced lung injury in mice. Copyright © 2017 Elsevier B.V. All rights reserved.

  1. Molecular and cytogenetic characterization of radon-induced lung tumors in the rat

    International Nuclear Information System (INIS)

    Dano, Laurent

    2000-01-01

    Radon is a natural radioactive gas. This radioelement, which is an α-particle emitter, is omnipresent in the environment. Inhalation of atmospheric radon is the major exposure route in man of natural radioactivity which results in respiratory tract contamination. An increased lung cancer risk associated with radon inhalation has been shown both in humans and animals by epidemiological and experimental studies, respectively. In rats, characterization of dose-effect relationships has led to the construction of statistical models that may help theoretically in the prediction of human health involvements of both occupational and domestic chronic exposure to radon. However, little is known about the cellular and molecular mechanisms of radon-induced lung carcinogenesis. In the laboratory, a model of lung cancers induced in rats after radon inhalation is available. This model represents a good tool to identify and characterize the genetic events contributing to the development of radon-induced lung tumors. Carrying out a global approach based on the combined use of classical and molecular cytogenetic methods, the analysis of 17 neoplasms allowed the identification of chromosomal regions frequently altered in these tumors. Numerous similarities have been found between our results and the cytogenetic data for human lung cancers, suggesting common underlying genetic molecular mechanisms for lung cancer development in both species. Moreover, our study has allowed to point to tumor suppressor genes and proto-oncogenes potentially involved in radon-induced lung carcinogenesis. Thus, our results may aid further molecular studies aimed either at confirming the role of these candidate genes or at demonstrating the involvement of yet to be identified genes. (author) [fr

  2. Consecutive CT-guided core needle tissue biopsy of lung lesions in the same dog at different phases of radiation-induced lung injury.

    Science.gov (United States)

    Yin, Zhongyuan; Deng, Sisi; Liang, Zhiwen; Wang, Qiong

    2016-09-01

    This project aimed to set up a Beagle dog model of radiation-induced lung injury in order to supply fresh lung tissue samples in the different injury phases for gene and protein research. Three dogs received 18 Gy X-ray irradiation in one fraction, another three dogs received 8 Gy in each of three fractions at weekly intervals, and one control dog was not irradiated. Acute pneumonitis was observed during the first 3 months after radiation, and chronic lung fibrosis was found during the next 4-12 months in all the dogs exposed to radiation. CT-guided core needle lung lesion biopsies were extracted from each dog five times over the course of 1 year. The dogs remained healthy after each biopsy, and 50-100 mg fresh lung lesion tissues were collected in each operation. The incidence of pneumothorax and hemoptysis was 20% and 2.8%, respectively, in the 35 tissue biopsies. A successful and stable radiation-induced lung injury dog model was established. Lung lesion tissue samples from dogs in acute stage, recovery stage and fibrosis stage were found to be sufficient to support cytology, genomics and proteomics research. This model safely supplied fresh tissue samples that would allow future researchers to more easily explore and develop treatments for radiation-induced lung injury. © The Author 2016. Published by Oxford University Press on behalf of The Japan Radiation Research Society and Japanese Society for Radiation Oncology.

  3. Effects of different recruitment maneuvers on bacterial translocation and ventilator- induced lung injury.

    Science.gov (United States)

    Ergin Özcan, Perihan; Akıncı, Özkan İbrahim; Edipoğlu, İpek; Şentürk, Evren; Baylan, Sevil; Cağatay, Atahan Arif; Türköz, Kemal H; Esen, Figen; Telci, Lütfi; Çakar, Nahit

    2016-03-01

    Investigated in the present study were the effects of various recruitment maneuvers (RMs) using the same inflation pressure-time product on bacterial translocation from lung to blood, and ventilator-induced lung injury (VILI). Tracheotomy was performed on anesthetized rats, and ventilation was initiated using pressure-controlled mode. Subsequently, Pseudomonas aeruginosa was inoculated through the tracheotomy tube and ventilated for 30 minutes before rats were randomly separated into 4 groups. Group 1 underwent sustained inflation (SI), Group 2 underwent low-pressure SI, Group 3 underwent modified sigh, and Group 4 was a control group. Blood cultures were taken at baseline, 15 minutes after randomization (after each RM for the first hour), and finally at 75 minutes after the last RM. The rats were euthanized and the lungs were extirpated. The left lung was taken for measurement of wet:dry weight ratio, and the right lung was used for pathologic evaluation. Positive blood cultures were found to be higher in Group 3 at early study periods. Total pathological scores were also higher in Group 3. Higher severity of ventilator-induced lung injury occurred in the modified sigh group, evidenced by bacterial translocation and results of histopathological evaluation.

  4. The role of alveolar epithelium in radiation-induced lung injury.

    Directory of Open Access Journals (Sweden)

    Celine Almeida

    Full Text Available Pneumonitis and fibrosis are major lung complications of irradiating thoracic malignancies. In the current study, we determined the effect of thoracic irradiation on the lungs of FVB/N mice. Survival data showed a dose-dependent increase in morbidity following thoracic irradiation with single (11-13 Gy and fractionated doses (24-36 Gy of (137Cs γ-rays. Histological examination showed a thickening of vessel walls, accumulation of inflammatory cells, collagen deposition, and regional fibrosis in the lungs 14 weeks after a single 12 Gy dose and a fractionated 30 Gy dose; this damage was also seen 5 months after a fractionated 24 Gy dose. After both single and fractionated doses, i] aquaporin-5 was markedly decreased, ii] E-cadherin was reduced and iii] prosurfactant Protein C (pro-SP-c, the number of pro-SP-c(+ cells and vimentin expression were increased in the lungs. Immunofluorescence analysis revealed co-localization of pro-SP-c and α-smooth muscle actin in the alveoli after a single dose of 12 Gy. These data suggest that, i] the FVB/N mouse strain is sensitive to thoracic radiation ii] aquaporin-5, E-cadherin, and pro-SP-c may serve as sensitive indicators of radiation-induced lung injury; and iii] the epithelial-to-mesenchymal transition may play an important role in the development of radiation-induced lung fibrosis.

  5. Prostaglandin D2 Attenuates Bleomycin-Induced Lung Inflammation and Pulmonary Fibrosis.

    Science.gov (United States)

    Kida, Taiki; Ayabe, Shinya; Omori, Keisuke; Nakamura, Tatsuro; Maehara, Toko; Aritake, Kosuke; Urade, Yoshihiro; Murata, Takahisa

    2016-01-01

    Pulmonary fibrosis is a progressive and fatal lung disease with limited therapeutic options. Although it is well known that lipid mediator prostaglandins are involved in the development of pulmonary fibrosis, the role of prostaglandin D2 (PGD2) remains unknown. Here, we investigated whether genetic disruption of hematopoietic PGD synthase (H-PGDS) affects the bleomycin-induced lung inflammation and pulmonary fibrosis in mouse. Compared with H-PGDS naïve (WT) mice, H-PGDS-deficient mice (H-PGDS-/-) represented increased collagen deposition in lungs 14 days after the bleomycin injection. The enhanced fibrotic response was accompanied by an increased mRNA expression of inflammatory mediators, including tumor necrosis factor-α, monocyte chemoattractant protein-1, and cyclooxygenase-2 on day 3. H-PGDS deficiency also increased vascular permeability on day 3 and infiltration of neutrophils and macrophages in lungs on day 3 and 7. Immunostaining showed that the neutrophils and macrophages expressed H-PGDS, and its mRNA expression was increased on day 3and 7 in WT lungs. These observations suggest that H-PGDS-derived PGD2 plays a protective role in bleomycin-induced lung inflammation and pulmonary fibrosis.

  6. Prostaglandin D2 Attenuates Bleomycin-Induced Lung Inflammation and Pulmonary Fibrosis.

    Directory of Open Access Journals (Sweden)

    Taiki Kida

    Full Text Available Pulmonary fibrosis is a progressive and fatal lung disease with limited therapeutic options. Although it is well known that lipid mediator prostaglandins are involved in the development of pulmonary fibrosis, the role of prostaglandin D2 (PGD2 remains unknown. Here, we investigated whether genetic disruption of hematopoietic PGD synthase (H-PGDS affects the bleomycin-induced lung inflammation and pulmonary fibrosis in mouse. Compared with H-PGDS naïve (WT mice, H-PGDS-deficient mice (H-PGDS-/- represented increased collagen deposition in lungs 14 days after the bleomycin injection. The enhanced fibrotic response was accompanied by an increased mRNA expression of inflammatory mediators, including tumor necrosis factor-α, monocyte chemoattractant protein-1, and cyclooxygenase-2 on day 3. H-PGDS deficiency also increased vascular permeability on day 3 and infiltration of neutrophils and macrophages in lungs on day 3 and 7. Immunostaining showed that the neutrophils and macrophages expressed H-PGDS, and its mRNA expression was increased on day 3and 7 in WT lungs. These observations suggest that H-PGDS-derived PGD2 plays a protective role in bleomycin-induced lung inflammation and pulmonary fibrosis.

  7. Bixin protects mice against ventilation-induced lung injury in an NRF2-dependent manner.

    Science.gov (United States)

    Tao, Shasha; Rojo de la Vega, Montserrat; Quijada, Hector; Wondrak, Georg T; Wang, Ting; Garcia, Joe G N; Zhang, Donna D

    2016-01-05

    Mechanical ventilation (MV) is a therapeutic intervention widely used in the clinic to assist patients that have difficulty breathing due to lung edema, trauma, or general anesthesia. However, MV causes ventilator-induced lung injury (VILI), a condition characterized by increased permeability of the alveolar-capillary barrier that results in edema, hemorrhage, and neutrophil infiltration, leading to exacerbated lung inflammation and oxidative stress. This study explored the feasibility of using bixin, a canonical NRF2 inducer identified during the current study, to ameliorate lung damage in a murine VILI model. In vitro, bixin was found to activate the NRF2 signaling pathway through blockage of ubiquitylation and degradation of NRF2 in a KEAP1-C151 dependent manner; intraperitoneal (IP) injection of bixin led to pulmonary upregulation of the NRF2 response in vivo. Remarkably, IP administration of bixin restored normal lung morphology and attenuated inflammatory response and oxidative DNA damage following MV. This observed beneficial effect of bixin derived from induction of the NRF2 cytoprotective response since it was only observed in Nrf2(+/+) but not in Nrf2(-/-) mice. This is the first study providing proof-of-concept that NRF2 activators can be developed into pharmacological agents for clinical use to prevent patients from lung injury during MV treatment.

  8. Nicotine prevents the apoptosis induced by menadione in human lung cancer cells

    International Nuclear Information System (INIS)

    Zhang Tao; Lu Heng; Shang Xuan; Tian Yihao; Zheng Congyi; Wang Shiwen; Cheng Hanhua; Zhou Rongjia

    2006-01-01

    Approximately 50% of long-term cigarette smokers die prematurely from the adverse effects of smoking, including on lung cancer and other illnesses. Nicotine is a main component in tobacco and has been implicated as a potential factor in the pathogenesis of human lung cancer. However, the mechanism of nicotine action in the development of lung cancer remains largely unknown. In the present study, we designed a nicotine-apoptosis system, by pre-treatment of nicotine making lung cancer cell A549 to be in a physiological nicotine environment, and observed that nicotine promoted cell proliferation and prevented the menadione-induced apoptosis, and exerts its role of anti-apoptosis by shift of apoptotic stage induced by menadione from late apoptotic stage to early apoptotic stage, in which NF-κB was up-regulated. Interference analysis of NF-κB in A549 cells showed that knock down of NF-κB resulted in apoptosis promotion and counteracted the protective effect of nicotine. The findings suggest that nicotine has potential effect in lung cancer genesis, especially in patients with undetectable early tumor development and development of specific NF-κB inhibitors would represent a potentially exciting new pharmacotherapy for tobacco-related lung cancer

  9. Platelets induce neutrophil extracellular traps in transfusion-related acute lung injury.

    Science.gov (United States)

    Caudrillier, Axelle; Kessenbrock, Kai; Gilliss, Brian M; Nguyen, John X; Marques, Marisa B; Monestier, Marc; Toy, Pearl; Werb, Zena; Looney, Mark R

    2012-07-01

    There is emerging evidence that platelets are major contributors to inflammatory processes through intimate associations with innate immune cells. Here, we report that activated platelets induce the formation of neutrophil extracellular traps (NETs) in transfusion-related acute lung injury (TRALI), which is the leading cause of death after transfusion therapy. NETs are composed of decondensed chromatin decorated with granular proteins that function to trap extracellular pathogens; their formation requires the activation of neutrophils and release of their DNA in a process that may or may not result in neutrophil death. In a mouse model of TRALI that is neutrophil and platelet dependent, NETs appeared in the lung microvasculature and NET components increased in the plasma. We detected NETs in the lungs and plasma of human TRALI and in the plasma of patients with acute lung injury. In the experimental TRALI model, targeting platelet activation with either aspirin or a glycoprotein IIb/IIIa inhibitor decreased NET formation and lung injury. We then directly targeted NET components with a histone blocking antibody and DNase1, both of which protected mice from TRALI. These data suggest that NETs contribute to lung endothelial injury and that targeting NET formation may be a promising new direction for the treatment of acute lung injury.

  10. Assessment of Mycoplasma hyopneumoniae-induced Pneumonia using Different Lung Lesion Scoring Systems: a Comparative Review.

    Science.gov (United States)

    Garcia-Morante, B; Segalés, J; Fraile, L; Pérez de Rozas, A; Maiti, H; Coll, T; Sibila, M

    2016-01-01

    Mycoplasma hyopneumoniae is the primary aetiological agent of swine enzootic pneumonia (EP) and one of the major contributors to the porcine respiratory disease complex (PRDC). Gross lung lesions in pigs affected by EP consist of cranioventral pulmonary consolidation (CVPC), usually distributed bilaterally in the apical, intermediate, accessory and cranial parts of the diaphragmatic lobes. Several lung scoring methods are currently in place for the evaluation of CVPC. The aims of this study were (1) to review the lung lesion scoring systems used to assess pneumonia associated with M. hyopneumoniae infection, and (2) to evaluate eight of these scoring systems by applying them to the lungs of 76 pigs with experimentally-induced M. hyopneumoniae pneumonia. A significant correlation between all lung lesion scoring systems was observed and the coefficients of determination in a regression analysis were very high between each pair-wise comparison, except for a unique scoring system based on image analysis. A formula of equivalence between lung scoring methods was developed in order to compare the results obtained with these methods. The present review provides a basis for comparison (even retrospectively) of lesions evaluated using different lung scoring systems. Copyright © 2015. Published by Elsevier Ltd.

  11. Lansoprazole-induced acute lung and liver injury: a case report.

    Science.gov (United States)

    Atkins, Christopher; Maheswaran, Tina; Rushbrook, Simon; Kamath, Ajay

    2014-12-01

    A 61-year old woman was admitted with increasing dyspnea and deranged liver function tests. A chest X-ray revealed small volume lungs with reticulo-nodular shadowing. High resolution computed tomography of the chest revealed interlobular septal thickening. The patient subsequently underwent an open lung biopsy and ultrasound-guided liver biopsy, which were consistent with a hypersensitivity pneumonitis and drug-induced liver injury respectively. The patient had previously been commenced on lansoprazole 10 days before the onset of symptoms; this had been stopped at diagnosis. High dose prednisolone was commenced, and the patient went on to make a full recovery. Hypersensitivity pneumonitis is a form of interstitial lung disease that is rarely associated with lansoprazole; this is the first report of it causing an idiosyncratic reaction affecting the lung and liver simultaneously. This case demonstrates the importance of obtaining a full drug history, as early identification of the offending agent will improve outcomes.

  12. Histopathological investigation of differences between female and male rats on radiation-induced acute lung toxicity

    Directory of Open Access Journals (Sweden)

    Bilal BU

    2014-06-01

    Full Text Available Radiation-induced acute and chronic lung toxicity is one of the important adverse events that has a negative influence on quality of life. It is widely accepted today that there are important factors such as personal sensibility and genetic differences between patients which effect both treatment response and treatment toxicity. In this study, the influence of gender differences on acute lung toxicity due to radiotherapy is investigated. Accordingly, it is examined if there is a relation between gender and histopathologically proven vasculitis and pneumonia in the lung tissues of male and female rats that are sacrificed 6 weeks after radiotherapy. It is concluded that the gender differences in rats have no effect on lung toxicity.

  13. Tristetraprolin mediates radiation-induced TNF-α production in lung macrophages.

    Directory of Open Access Journals (Sweden)

    Dipankar Ray

    Full Text Available The efficacy of radiation therapy for lung cancer is limited by radiation-induced lung toxicity (RILT. Although tumor necrosis factor-alpha (TNF-α signaling plays a critical role in RILT, the molecular regulators of radiation-induced TNF-α production remain unknown. We investigated the role of a major TNF-α regulator, Tristetraprolin (TTP, in radiation-induced TNF-α production by macrophages. For in vitro studies we irradiated (4 Gy either a mouse lung macrophage cell line, MH-S or macrophages isolated from TTP knockout mice, and studied the effects of radiation on TTP and TNF-α levels. To study the in vivo relevance, mouse lungs were irradiated with a single dose (15 Gy and assessed at varying times for TTP alterations. Irradiation of MH-S cells caused TTP to undergo an inhibitory phosphorylation at Ser-178 and proteasome-mediated degradation, which resulted in increased TNF-α mRNA stabilization and secretion. Similarly, MH-S cells treated with TTP siRNA or macrophages isolated from ttp (-/- mice had higher basal levels of TNF-α, which was increased minimally after irradiation. Conversely, cells overexpressing TTP mutants defective in undergoing phosphorylation released significantly lower levels of TNF-α. Inhibition of p38, a known kinase for TTP, by either siRNA or a small molecule inhibitor abrogated radiation-induced TNF-α release by MH-S cells. Lung irradiation induced TTP(Ser178 phosphorylation and protein degradation and a simultaneous increase in TNF-α production in C57BL/6 mice starting 24 h post-radiation. In conclusion, irradiation of lung macrophages causes TTP inactivation via p38-mediated phosphorylation and proteasome-mediated degradation, leading to TNF-α production. These findings suggest that agents capable of blocking TTP phosphorylation or stabilizing TTP after irradiation could decrease RILT.

  14. Effects of selenium on Pteridium aquilinum and urethane-induced lung carcinogenesis.

    Science.gov (United States)

    Nakahara, Sheila B R; Sanches, Daniel S; Caniceiro, Beatriz D; Wysochi, Harry L; da Silva, Graziela B; Latorre, Andreia O

    2013-10-01

    The results of our previous study demonstrated that ptaquiloside, the main toxic agent found in Pteridium aquilinum, suppresses natural killer (NK) cell-mediated cytotoxicity. However, the ability of ptaquiloside to suppress the cytotoxicity of NK cells was prevented by selenium supplementation. NK cells play an important role in the innate immune response and have the ability to kill tumor cells. Therefore, we hypothesized that selenium may prevent the higher susceptibility to urethane-induced lung carcinogenesis that has been observed in mice treated with P. aquilinum. The immunosuppressive effects of ptaquiloside have been associated with a higher number of urethane-induced lung nodules in mice. Hence, we assessed the effects of P. aquilinum-induced immunosuppression on urethane-induced lung carcinogenesis in C57BL/6 mice that had been supplemented with selenium. For these experiments, mice were treated with both an aqueous extract of P. aquilinum (20 g/kg/day) and selenium (1.3 mg/kg) by gavage once daily for 14 days followed by a once-weekly intraperitoneal injection of urethane (1 g/kg) for 10 weeks that was accompanied by gavage 5 days a week. Lung adenomas in mice that had been treated with P. aquilinum plus urethane occurred with a frequency that was 44% higher than that in mice that had been treated with only urethane. In mice that had been supplemented with selenium and treated with P. aquilinum plus urethane, the occurrence of lung adenomas was reduced to 26%. These results suggest that selenium prevents the immunosuppressive effects of P. aquilinum on urethane-induced lung carcinogenesis.

  15. Saikosaponin a Ameliorates LPS-Induced Acute Lung Injury in Mice.

    Science.gov (United States)

    Du, Zhi-An; Sun, Mei-Na; Hu, Zhan-Sheng

    2018-02-01

    The purpose of this study was to investigate the protective effects of Saikosaponin a (SSa), a triterpene saponin derived from Radix bupleuri, on lipopolysaccharide (LPS)-induced acute lung injury (ALI) using a murine model. The mice were given SSa 1 h after intranasal instillation of LPS. Then, lung histopathological examination, the wet/dry (W/D) ratio, myeloperoxidase (MPO), and inflammatory cytokines in bronchoalveolar lavage fluid (BALF) were detected in this study. The results showed that SSa reduced lung pathological injury induced by LPS. Furthermore, LPS-induced lung W/D ratio, MPO activity, and inflammatory cytokines TNF-α and IL-1β in BALF were significantly inhibited by SSa. In addition, SSa suppressed LPS-induced NF-κB activation and NLRP3 inflammasome expression. In conclusion, we found that SSa played a critical anti-inflammatory effect through inhibition of NF-κB and NLRP3 signaling pathways and protected against LPS-induced ALI.

  16. Hyperglycemia promotes K-Ras-induced lung tumorigenesis through BASCs amplification.

    Directory of Open Access Journals (Sweden)

    Carla Micucci

    Full Text Available Oncogenic K-Ras represents the most common molecular change in human lung adenocarcinomas, the major histologic subtype of non-small cell lung cancer (NSCLC. The presence of K-Ras mutation is associated with a poor prognosis, but no effective treatment strategies are available for K-Ras -mutant NSCLC. Epidemiological studies report higher lung cancer mortality rates in patients with type 2 diabetes. Here, we use a mouse model of K-Ras-mediated lung cancer on a background of chronic hyperglycemia to determine whether elevated circulating glycemic levels could influence oncogenic K-Ras-mediated tumor development. Inducible oncogenic K-Ras mouse model was treated with subtoxic doses of streptozotocin (STZ to induce chronic hyperglycemia. We observed increased tumor mass and higher grade of malignancy in STZ treated diabetic mice analyzed at 4, 12 and 24 weeks, suggesting that oncogenic K-Ras increased lung tumorigenesis in hyperglycemic condition. This promoting effect is achieved by expansion of tumor-initiating lung bronchio-alveolar stem cells (BASCs in bronchio-alveolar duct junction, indicating a role of hyperglycemia in the activity of K-Ras-transformed putative lung stem cells. Notably, after oncogene K-Ras activation, BASCs show upregulation of the glucose transporter (Glut1/Slc2a1, considered as an important player of the active control of tumor cell metabolism by oncogenic K-Ras. Our novel findings suggest that anti-hyperglycemic drugs, such as metformin, may act as therapeutic agent to restrict lung neoplasia promotion and progression.

  17. Caffeine Mitigates Lung Inflammation Induced by Ischemia-Reperfusion of Lower Limbs in Rats

    Directory of Open Access Journals (Sweden)

    Wei-Chi Chou

    2015-01-01

    Full Text Available Reperfusion of ischemic limbs can induce inflammation and subsequently cause acute lung injury. Caffeine, a widely used psychostimulant, possesses potent anti-inflammatory capacity. We elucidated whether caffeine can mitigate lung inflammation caused by ischemia-reperfusion (IR of the lower limbs. Adult male Sprague-Dawley rats were randomly allocated to receive IR, IR plus caffeine (IR + Caf group, sham-operation (Sham, or sham plus caffeine (n=12 in each group. To induce IR, lower limbs were bilaterally tied by rubber bands high around each thigh for 3 hours followed by reperfusion for 3 hours. Caffeine (50 mg/kg, intraperitoneal injection was administered immediately after reperfusion. Our histological assay data revealed characteristics of severe lung inflammation in the IR group and mild to moderate characteristic of lung inflammation in the IR + Caf group. Total cells number and protein concentration in bronchoalveolar lavage fluid of the IR group were significantly higher than those of the IR + Caf group (P<0.001 and P=0.008, resp.. Similarly, pulmonary concentrations of inflammatory mediators (tumor necrosis factor-α, interleukin-1β, and macrophage inflammatory protein-2 and pulmonary myeloperoxidase activity of the IR group were significantly higher than those of the IR + Caf group (all P<0.05. These data clearly demonstrate that caffeine could mitigate lung inflammation induced by ischemia-reperfusion of the lower limbs.

  18. Xuebijing Ameliorates Sepsis-Induced Lung Injury by Downregulating HMGB1 and RAGE Expressions in Mice

    Directory of Open Access Journals (Sweden)

    Qiao Wang

    2015-01-01

    Full Text Available Xuebijing (XBJ injection, a traditional Chinese medicine, has been reported as a promising approach in the treatment of sepsis in China. However, its actual molecular mechanisms in sepsis-induced lung injury are yet unknown. Therefore, this study aimed to investigate the beneficial effects of XBJ on inflammation and the underlying mechanisms in a model of caecal ligation and puncture-(CLP- induced lung injury. The mice were divided into CLP group, CLP+XBJ group (XBJ, 4 mL/kg per 12 hours, and sham group. The molecular and histological examinations were performed on the lung, serum, and bronchoalveolar lavage (BAL fluid samples of mice at the points of 6, 24, and 48 hours after CLP. The results show that XBJ reduces morphological destruction and neutrophil infiltration in the alveolar space and lung wet/dry weight ratio, which improves mortality of CLP-induced lung injury. Meanwhile, XBJ treatment downregulates high mobility group box protein 1 (HMGB1 and the receptor for advanced glycation end products (RAGE expression, as well as neutrophil counts, production of IL-1β, IL-6, and TNF-α in the BAL fluids. In conclusion, these results indicate that XBJ may reduce the mortality through inhibiting proinflammatory cytokines secretion mediated by HMGB1/RAGE axis.

  19. Salidroside Attenuates Ventilation Induced Lung Injury via SIRT1-Dependent Inhibition of NLRP3 Inflammasome

    Directory of Open Access Journals (Sweden)

    Yan Wang

    2017-05-01

    Full Text Available Background: Salidroside (SDS is the main effective ingredient of Rhodiola rosea L with a variety of pharmacologic properties. We aim to investigate the effects of SDS on ventilation induced lung injury (VILI and explore the possible underlying molecular mechanism. Methods: Lung injury was induced in male ICR mice via mechanical ventilation (30 ml/kg for 4h. The mice were divided in four groups:(1 Control group; (2 Ventilation group; (3 SDS group; (4 Ventilation with SDS group. SDS (50 mg/kg was injected intraperitoneally 1h before operation. Mouse lung vascular endothelial cells (MLVECs were subjected to cyclic stretch for 4h. Results: It was found that SDS attenuated VILI as shown in HE staining, cell count and protein content levels in BAL fluid, W/D and Evans blue dye leakage into the lung tissue. SDS treatment inhibited the activation of NLRP3 inflammasome and subsequent caspase-1 cleavage as well as interleukin (IL-1β secretion both in vivo and in vitro. Moreover, SDS administration up-regulated SIRT1 expression. Importantly, knockdown of SIRT1 reversed the inhibitory effect of SDS on NLRP3 inflammasome activation. Conclusions: Taken together, these findings indicate that SDS may confer protection against ventilation induced lung injury via SIRT1-de-pendent inhibition of NLRP3 inflammasome activation.

  20. Osteopontin protects against hyperoxia-induced lung injury by inhibiting nitric oxide synthases.

    Science.gov (United States)

    Zhang, Xiang-Feng; Liu, Shuang; Zhou, Yu-Jie; Zhu, Guang-Fa; Foda, Hussein D

    2010-04-05

    Exposure of adult mice to more than 95% O(2) produces a lethal injury by 72 hours. Nitric oxide synthase (NOS) is thought to contribute to the pathophysiology of murine hyperoxia-induced acute lung injury (ALI). Osteopontin (OPN) is a phosphorylated glycoprotein produced principally by macrophages. OPN inhibits inducible nitric oxide synthase (iNOS), which generates large amounts of nitric oxide production. However, the relationship between nitric oxide and endogenous OPN in lung tissue during hyperoxia-induced ALI has not yet been elucidated, thus we examined the role that OPN plays in the hyperoxia-induced lung injury and its relationships with NOS. One hundred and forty-four osteopontin knock-out (KO) mice and their matched wild type background control (WT) were exposed in sealed cages > 95% oxygen or room air for 24- 72 hours, and the severity of lung injury was assessed; expression of OPN, endothelial nitric oxide synthase (eNOS) and iNOS mRNA in lung tissues at 24, 48 and 72 hours of hyperoxia were studied by reverse transcription-polymerase chain reaction (RT-PCR); immunohistochemistry (IHC) was performed for the detection of iNOS, eNOS, and OPN protein in lung tissues. OPN KO mice developed more severe acute lung injury at 72 hours of hyperoxia. The wet/dry weight ratio increased to 6.85 +/- 0.66 in the KO mice at 72 hours of hyperoxia as compared to 5.31 +/- 0.92 in the WT group (P < 0.05). iNOS mRNA (48 hours: 1.04 +/- 0.08 vs. 0.63 +/- 0.09, P < 0.01; 72 hours: 0.89 +/- 0.08 vs. 0.72 +/- 0.09, P < 0.05) and eNOS mRNA (48 hours: 0.62 +/- 0.08 vs. 0.43 +/- 0.09, P < 0.05; 72 hours: 0.67 +/- 0.08 vs. 0.45 +/- 0.09, P < 0.05) expression was more significantly increased in OPN KO mice than their matched WT mice when exposed to hyperoxia. IHC study showed higher expression of iNOS (20.54 +/- 3.18 vs. 12.52 +/- 2.46, P < 0.05) and eNOS (19.83 +/- 5.64 vs. 9.45 +/- 3.82, P < 0.05) in lung tissues of OPN KO mice at 72 hours of hyperoxia. OPN can protect against

  1. OPTICAL IMAGING OF LIPOPOLYSACCHARIDE-INDUCED OXIDATIVE STRESS IN ACUTE LUNG INJURY FROM HYPEROXIA AND SEPSIS

    Directory of Open Access Journals (Sweden)

    REYHANEH SEPEHR

    2013-07-01

    Full Text Available Reactive oxygen species (ROS have been implicated in the pathogenesis of many acute and chronic pulmonary disorders such as acute lung injury (ALI in adults and bronchopulmonary dysplasia (BPD in premature infants. Bacterial infection and oxygen toxicity, which result in pulmonary vascular endothelial injury, contribute to impaired vascular growth and alveolar simplification seen in the lungs of premature infants with BPD. Hyperoxia induces ALI, reduces cell proliferation, causes DNA damage and promotes cell death by causing mitochondrial dysfunction. The objective of this study was to use an optical imaging technique to evaluate the variations in fluorescence intensities of the auto-fluorescent mitochondrial metabolic coenzymes, NADH and FAD in four different groups of rats. The ratio of these fluorescence signals (NADH/FAD, referred to as NADH redox ratio (NADH RR has been used as an indicator of tissue metabolism in injuries. Here, we investigated whether the changes in metabolic state can be used as a marker of oxidative stress caused by hyperoxia and bacterial lipopolysaccharide (LPS exposure in neonatal rat lungs. We examined the tissue redox states of lungs from four groups of rat pups: normoxic (21% O2 pups, hyperoxic (90% O2 pups, pups treated with LPS (normoxic + LPS, and pups treated with LPS and hyperoxia (hyperoxic + LPS. Our results show that hyperoxia oxidized the respiratory chain as reflected by a ~ 31% decrease in lung tissue NADH RR as compared to that for normoxic lungs. LPS treatment alone or with hyperoxia had no significant effect on lung tissue NADH RR as compared to that for normoxic or hyperoxic lungs, respectively. Thus, NADH RR serves as a quantitative marker of oxidative stress level in lung injury caused by two clinically important conditions: hyperoxia and LPS exposure.

  2. CD147 deficiency blocks IL-8 secretion and inhibits lung cancer-induced osteoclastogenesis

    Energy Technology Data Exchange (ETDEWEB)

    Wang, Hongkai; Zhuo, Yunyun; Hu, Xu; Shen, Weiwei; Zhang, Ying; Chu, Tongwei, E-mail: chtw@sina.com

    2015-03-06

    Bone is a frequent target of lung cancer metastasis, which is associated with significant morbidity and poor prognosis; however, the molecular basis of this process is still unknown. This study investigated the role of extracellular matrix metalloproteinase inducer (also known as cluster of differentiation (CD)147) in osteoclastogenesis resulting from bone metastasis, based on the enrichment of this glycoprotein on the surface of many malignant bone tumors. RNA interference was used to silence CD147 expression in A549 human lung cancer cells. Compared with conditioned medium (CM) from control cells (A549-CM), CM from CD147-deficient cells (A549-si-CM) suppressed receptor activator of nuclear factor κB ligand-stimulated osteoclastogenesis in RAW 264.7 cells and bone marrow-derived macrophages. The mRNA levels of osteoclast-specific genes such as tartrate-resistant acid phosphatase, calcitonin receptor, and cathepsin K were also reduced in the presence of A549-si-CM. CD147 knockdown in A549 cells decreased interleukin (IL)-8mRNA and protein expression. IL-8 is present in large amounts in A549-CM and mimicked its inductive effect on osteoclastogenesis; this was reversed by depletion of IL-8 from the medium. Taken together, these results indicate that CD147 promotes lung cancer-induced osteoclastogenesis by modulating IL-8 secretion, and suggest that CD147 is a potential therapeutic target for cancer-associated bone resorption in lung cancer patients. - Highlights: • Bone loss frequently results from lung cancer metastasis. • Cluster of differentiation (CD)147 was depleted in A549 lung adenocarcinoma cells. • RAW 264.7 cell osteoclastogenesis was blocked by medium from CD147-deficient cells. • Interleukin (IL)-8 level was reduced in the conditioned medium. • Osteoclastogenesis induced by lung tumor cells requires CD147-mediated IL-8 release.

  3. Amelioration of meconium-induced acute lung injury by parecoxib in a rabbit model

    Science.gov (United States)

    Li, Ai-Min; Zhang, Li-Na; Li, Wen-Zhi

    2015-01-01

    Cyclooxygenase-2 (COX-2) plays important roles in various inflammatory conditions and is significantly increased in meconium-induced lung injury. We investigated the effects of parecoxib on meconium-induced acute lung injury (ALI) in rabbits. Twenty-four rabbits were randomized into sham, control, and parecoxib groups. Rabbits in the control and parecoxib groups underwent tracheal instillation of meconium, followed by intravenous injection of saline or parecoxib and 4 h of ventilation. The airway pressure, dynamic compliance, and ratio of partial pressure of oxygen in arterial blood to fraction of inspired oxygen (PaO2/FiO2 ratio) were recorded at baseline (T0) and 4 h after instillation (T1-T4). The lung tissue wet-to-dry weight ratio; neutrophil percentage; and total protein, tumor necrosis factor-α (TNF-α), interleukin (IL)-1β, IL-8, prostaglandin E2, and malondialdehyde levels in bronchoalveolar lavage fluid (BALF) were evaluated. The myeloperoxidase activity, COX-2 expression, and degree of histopathologic injury in lung tissue were also analyzed. The airway pressure, compliance, and PaO2/FiO2 ratio were significantly improved by parecoxib after meconium instillation. The lung wet-to-dry weight ratio, total protein level, and neutrophil percentage in BALF were lowest in the parecoxib group. The TNF-α, IL-1β, IL-8, prostaglandin E2, and malondialdehyde levels in the BALF were lowest in the parecoxib group. The COX-2 expression and myeloperoxidase activity in lung tissue were significantly reduced by parecoxib. The degree of lung injury was also reduced. In conclusions: Parecoxib effectively ameliorates respiratory function and attenuates meconium-induced ALI. These effects are correlated with prostaglandin E2 and COX-2 inhibition. PMID:26221218

  4. Artificial Ventilation-Induced Acute Lung Lesion: Experimental, Morphological Study

    Directory of Open Access Journals (Sweden)

    A. M. Golubev

    2006-01-01

    Full Text Available Objective: to elucidate the pattern of morphological changes in the lung during artificial ventilation.Materials and methods. Experiments were carried out on 30 non-inbred albino male rats weighing 250—320 g. The anesthetized animals were ventilated for 1—4 hours by a TSE Animal Respirator at a flow of 0.6—4 l/min, a respiration rate of 60 min, a tidal volume of 10—12 ml, and a peak inspiratory pressure of 100—400 mm H2O. Artificial ventilation was not made in control animals. Following 1, 2, and 3 hours and 1, 1.5, 2, and 3 days, the anesthetized animals were withdrawn from the experiment through cardiac vascular fascicle ligation. Lung pieces were fixed in neural 4% formalin and embedded in paraffin. Histological sections were stained with hematoxylin-eosin and the periodic acid Schiff reaction was performed. Morphometric studies were conducted and the data were then statistically processed (Student’s t-test.Results. An hour after artificial ventilation, the interalveolar septa were thickened due to edema and cellular infiltration. There were microatelectases. The bronchioles were deformed; their lumens contained desquamated epithelium and mucus. The alveolar lumens contained red blood cells and macrophages. Perivascular connective tissue was edematous and exhibited epithelial desquamation. Later on, the observed changes increased. There were individual differences in the rate of morphological changes during artificial ventilation (AV.Conclusion. AV is followed by the development of structural changes that are typical of acute lung lesion. 

  5. Changes in expression of cytokines in polyhexamethylene guanidine-induced lung fibrosis in mice: Comparison of bleomycin-induced lung fibrosis.

    Science.gov (United States)

    Kim, Min-Seok; Kim, Sung-Hwan; Jeon, Doin; Kim, Hyeon-Young; Lee, Kyuhong

    2018-01-15

    Inhalation of polyhexamethylene guanidine (PHMG) causes irreversible pulmonary injury, such as pulmonary fibrosis. However, the mechanism underlying PHMG-induced lung injury is unclear. In this study, we compared the difference in time-dependent lung injury between PHMG- and bleomycin (BLM)-treated mice and determined cytokines involved in inducing lung injury by performing cytokine antibody array analysis. Mice were treated once with 1.8mg/kg BLM or 1.2mg/kg PHMG through intratracheal instillation and were sacrificed on days 7 and 28. Bronchoalveolar lavage fluid (BALF) analysis showed that the number of neutrophils was significantly higher in PHMG-treated mice than in BLM-treated mice on day 7. Histopathological analysis showed inflammatory cell infiltration and fibrosis mainly in the terminal bronchioles and alveoli in the lungs of PHMG- and BLM-treated mice. However, continuous macrophage infiltration in the alveolar space and bronchioloalveolar epithelial hyperplasia (BEH) were only observed in PHMG-treated mice. Cytokine antibody array analysis showed that 15 and eight cytokines were upregulated in PHMG- and BLM-treated mice, respectively, on day 7. On day 28, 13 and five cytokines were upregulated in PHMG and BLM-treated mice, respectively. In addition, the expressed cytokines between days 7 and 28 in BLM-treated mice were clearly different, but were similar in PHMG-treated mice. Consequently, between PHMG- and BLM-treated mice, we observed differences in the expression patterns and types of cytokines. These differences are considered to be a result of the inflammatory processes induced by both substances, which may mainly involve macrophage infiltration. Therefore, continuous induction of the inflammatory response by PHMG may play an important role in the development of pulmonary fibrosis. Copyright © 2017 Elsevier B.V. All rights reserved.

  6. Threshold for Radon-Induced Lung Cancer From Inhaled Plutonium Data

    Directory of Open Access Journals (Sweden)

    Jerry M. Cuttler

    2015-11-01

    Full Text Available Cohen’s lung cancer mortality data, from his test of the LNT theory, do not extend to the no observed adverse effects level (NOAEL above which inhaled radon decay products begin to induce excess lung cancer mortality. Since there is concern about the level of radon in homes, it is important to set the radon limit near the NOAEL to avoid the risk of losing a health benefit. Assuming that dogs model humans, data from a study on inhaled plutonium dioxide particulates in dogs were assessed, and the NOAEL for radon-induced lung tumors was estimated to be about 2100 Bq/m3. The US Environmental Protection Agency should consider raising its radon action level from 150 to at least 1000 Bq/m3.

  7. Irradiation induces a biphasic expression of pro-inflammatory cytokines in the lung

    Energy Technology Data Exchange (ETDEWEB)

    Ruebe, C.E.; Wilfert, F.; Palm, J.; Burdak-Rothkamm, S.; Ruebe, C. [Dept. of Radiotherapy - Radiooncology, Saarland Univ., Homburg/Saar (Germany); Koenig, J. [Inst. of Medical Biometrics, Epidemiology and Medical Informatics, Saarland Univ., Homburg/Saar (Germany); Liu Li [Dept. of Radiotherapy - Radiooncology, Saarland Univ., Homburg/Saar (Germany); Cancer Center, Union Hospital Tongji Medical Coll., Huazhong Univ. of Science and Technology, Wuhan (China); Schuck, A.; Willich, N. [Dept. of Radiotherapy - Radiooncology, Univ. of Muenster (Germany)

    2004-07-01

    Background and purpose: the precise pathophysiological mechanisms of radiation-induced lung injury are poorly understood, but have been shown to correlate with dysregulation of different cytokines. The purpose of this study was to evaluate the time course of the pro-inflammatory cytokines tumor necrosis factor-(TNF-){alpha}, interleukin-(IL)-1{alpha} and IL-6 after whole-lung irradiation. Material and methods: the thoraces of C57BL/6J mice were irradiated with 12 Gy. Treated and control mice were sacrificed at 0.5, 1, 3, 6, 12, 24, 48, 72 h, 1, 2, 4, 8, 16, and 24 weeks post irradiation (p.i.). Real-time multiplex RT-PCR (reverse transcriptase polmyerase chain reaction) was established to evaluate the expression of TNF-{alpha}, IL-1{alpha} and IL-6 in the lung tissue of the mice. For histological analysis, lung tissue sections were stained by hematoxylin and eosin. Results: multiplex RT-PCR analysis revealed a biphasic expression of these pro-inflammatory cytokines in the lung tissue after irradiation. After an initial increase at 1 h p.i. for TNF-{alpha} and at 6 h p.i. for IL-1{alpha} and IL-6, the mRNA expression of these pro-inflammatory cytokines returned to basal levels (48 h, 72 h, 1 week, 2 weeks p.i.). During the pneumonic phase, TNF-{alpha}, IL-1{alpha} and IL-6 were significantly elevated and revealed their maximum at 8 weeks p.i. Histopathologic evaluation of the lung sections obtained within 4 weeks p.i. revealed only minor lung damage in 5-30% of the lung tissue. By contrast, at 8, 16, and 24 weeks p.i., 70-90% of the lung tissue revealed histopathologically detectable organizing alveolitis. Conclusion: irradiation induces a biphasic expression of pro-inflammatory cytokines in the lung. The initial transitory cytokine response occurred within the first hours after lung irradiation with no detectable histopathologic alterations. The second, more persistent cytokine elevation coincided with the onset of histologically discernible organizing acute

  8. Hydroxysafflor yellow A suppress oleic acid-induced acute lung injury via protein kinase A

    Energy Technology Data Exchange (ETDEWEB)

    Wang, Chaoyun [School of Pharmaceutical Sciences, Binzhou Medical University, Yantai, Shandong 264003 (China); Huang, Qingxian [Department of Hepatobiliary Surgery, Yantai Yuhuangding Hospital, Yantai, Shandong 264000 (China); Wang, Chunhua; Zhu, Xiaoxi; Duan, Yunfeng; Yuan, Shuai [School of Pharmaceutical Sciences, Binzhou Medical University, Yantai, Shandong 264003 (China); Bai, Xianyong, E-mail: xybai2012@163.com [School of Pharmaceutical Sciences, Binzhou Medical University, Yantai, Shandong 264003 (China)

    2013-11-01

    Inflammation response and oxidative stress play important roles in acute lung injury (ALI). Activation of the cAMP/protein kinase A (PKA) signaling pathway may attenuate ALI by suppressing immune responses and inhibiting the generation of reactive oxygen species (ROS). Hydroxysafflor yellow A (HSYA) is a natural flavonoid compound that reduces oxidative stress and inflammatory cytokine-mediated damage. In this study, we examined whether HSYA could protect the lungs from oleic acid (OA)-induced injury, which was used to mimic ALI, and determined the role of the cAMP/PKA signaling pathway in this process. Arterial oxygen tension (PaO{sub 2}), carbon dioxide tension, pH, and the PaO{sub 2}/fraction of inspired oxygen ratio in the blood were detected using a blood gas analyzer. We measured wet/dry lung weight ratio and evaluated tissue morphology. The protein and inflammatory cytokine levels in the bronchoalveolar lavage fluid and serum were determined using enzyme-linked immunoassay. The activities of superoxide dismutase, glutathione peroxidase, PKA, and nicotinamide adenine dinucleotide phosphate oxidase, and the concentrations of cAMP and malondialdehyde in the lung tissue were detected using assay kits. Bcl-2, Bax, caspase 3, and p22{sup phox} levels in the lung tissue were analyzed using Western blotting. OA increased the inflammatory cytokine and ROS levels and caused lung dysfunction by decreasing cAMP synthesis, inhibiting PKA activity, stimulating caspase 3, and reducing the Bcl-2/Bax ratio. H-89 increased these effects. HSYA significantly increased the activities of antioxidant enzymes, inhibited the inflammatory response via cAMP/PKA pathway activation, and attenuated OA-induced lung injury. Our results show that the cAMP/PKA signaling pathway is required for the protective effect of HSYA against ALI. - Highlights: • Oleic acid (OA) cause acute lung injury (ALI) via inhibiting cAMP/PKA signal pathway. • Blocking protein kinase A (PKA) activation may

  9. Hydroxysafflor yellow A suppress oleic acid-induced acute lung injury via protein kinase A

    International Nuclear Information System (INIS)

    Wang, Chaoyun; Huang, Qingxian; Wang, Chunhua; Zhu, Xiaoxi; Duan, Yunfeng; Yuan, Shuai; Bai, Xianyong

    2013-01-01

    Inflammation response and oxidative stress play important roles in acute lung injury (ALI). Activation of the cAMP/protein kinase A (PKA) signaling pathway may attenuate ALI by suppressing immune responses and inhibiting the generation of reactive oxygen species (ROS). Hydroxysafflor yellow A (HSYA) is a natural flavonoid compound that reduces oxidative stress and inflammatory cytokine-mediated damage. In this study, we examined whether HSYA could protect the lungs from oleic acid (OA)-induced injury, which was used to mimic ALI, and determined the role of the cAMP/PKA signaling pathway in this process. Arterial oxygen tension (PaO 2 ), carbon dioxide tension, pH, and the PaO 2 /fraction of inspired oxygen ratio in the blood were detected using a blood gas analyzer. We measured wet/dry lung weight ratio and evaluated tissue morphology. The protein and inflammatory cytokine levels in the bronchoalveolar lavage fluid and serum were determined using enzyme-linked immunoassay. The activities of superoxide dismutase, glutathione peroxidase, PKA, and nicotinamide adenine dinucleotide phosphate oxidase, and the concentrations of cAMP and malondialdehyde in the lung tissue were detected using assay kits. Bcl-2, Bax, caspase 3, and p22 phox levels in the lung tissue were analyzed using Western blotting. OA increased the inflammatory cytokine and ROS levels and caused lung dysfunction by decreasing cAMP synthesis, inhibiting PKA activity, stimulating caspase 3, and reducing the Bcl-2/Bax ratio. H-89 increased these effects. HSYA significantly increased the activities of antioxidant enzymes, inhibited the inflammatory response via cAMP/PKA pathway activation, and attenuated OA-induced lung injury. Our results show that the cAMP/PKA signaling pathway is required for the protective effect of HSYA against ALI. - Highlights: • Oleic acid (OA) cause acute lung injury (ALI) via inhibiting cAMP/PKA signal pathway. • Blocking protein kinase A (PKA) activation may enhance Cytokine

  10. Chronic cadmium exposure in vitro induces cancer cell characteristics in human lung cells

    International Nuclear Information System (INIS)

    Person, Rachel J.; Tokar, Erik J.; Xu, Yuanyuan; Orihuela, Ruben; Ngalame, Ntube N. Olive; Waalkes, Michael P.

    2013-01-01

    Cadmium is a known human lung carcinogen. Here, we attempt to develop an in vitro model of cadmium-induced human lung carcinogenesis by chronically exposing the peripheral lung epithelia cell line, HPL-1D, to a low level of cadmium. Cells were chronically exposed to 5 μM cadmium, a noncytotoxic level, and monitored for acquired cancer characteristics. By 20 weeks of continuous cadmium exposure, these chronic cadmium treated lung (CCT-LC) cells showed marked increases in secreted MMP-2 activity (3.5-fold), invasion (3.4-fold), and colony formation in soft agar (2-fold). CCT-LC cells were hyperproliferative, grew well in serum-free media, and overexpressed cyclin D1. The CCT-LC cells also showed decreased expression of the tumor suppressor genes p16 and SLC38A3 at the protein levels. Also consistent with an acquired cancer cell phenotype, CCT-LC cells showed increased expression of the oncoproteins K-RAS and N-RAS as well as the epithelial-to-mesenchymal transition marker protein Vimentin. Metallothionein (MT) expression is increased by cadmium, and is typically overexpressed in human lung cancers. The major MT isoforms, MT-1A and MT-2A were elevated in CCT-LC cells. Oxidant adaptive response genes HO-1 and HIF-1A were also activated in CCT-LC cells. Expression of the metal transport genes ZNT-1, ZNT-5, and ZIP-8 increased in CCT-LC cells culminating in reduced cadmium accumulation, suggesting adaptation to the metal. Overall, these data suggest that exposure of human lung epithelial cells to cadmium causes acquisition of cancer cell characteristics. Furthermore, transformation occurs despite the cell's ability to adapt to chronic cadmium exposure. - Highlights: • Chronic cadmium exposure induces cancer cell characteristics in human lung cells. • This provides an in vitro model of cadmium-induced human lung cell transformation. • This occurred with general and lung specific changes typical for cancer cells. • These findings add insight to the relationship

  11. Inhibition of chlorine-induced lung injury by the type 4 phosphodiesterase inhibitor rolipram

    International Nuclear Information System (INIS)

    Chang, Weiyuan; Chen, Jing; Schlueter, Connie F.; Rando, Roy J.; Pathak, Yashwant V.; Hoyle, Gary W.

    2012-01-01

    Chlorine is a highly toxic respiratory irritant that when inhaled causes epithelial cell injury, alveolar-capillary barrier disruption, airway hyperreactivity, inflammation, and pulmonary edema. Chlorine is considered a chemical threat agent, and its release through accidental or intentional means has the potential to result in mass casualties from acute lung injury. The type 4 phosphodiesterase inhibitor rolipram was investigated as a rescue treatment for chlorine-induced lung injury. Rolipram inhibits degradation of the intracellular signaling molecule cyclic AMP. Potential beneficial effects of increased cyclic AMP levels include inhibition of pulmonary edema, inflammation, and airway hyperreactivity. Mice were exposed to chlorine (whole body exposure, 228–270 ppm for 1 h) and were treated with rolipram by intraperitoneal, intranasal, or intramuscular (either aqueous or nanoemulsion formulation) delivery starting 1 h after exposure. Rolipram administered intraperitoneally or intranasally inhibited chlorine-induced pulmonary edema. Minor or no effects were observed on lavage fluid IgM (indicative of plasma protein leakage), KC (Cxcl1, neutrophil chemoattractant), and neutrophils. All routes of administration inhibited chlorine-induced airway hyperreactivity assessed 1 day after exposure. The results of the study suggest that rolipram may be an effective rescue treatment for chlorine-induced lung injury and that both systemic and targeted administration to the respiratory tract were effective routes of delivery. -- Highlights: ► Chlorine causes lung injury when inhaled and is considered a chemical threat agent. ► Rolipram inhibited chlorine-induced pulmonary edema and airway hyperreactivity. ► Post-exposure rolipram treatments by both systemic and local delivery were effective. ► Rolipram shows promise as a rescue treatment for chlorine-induced lung injury.

  12. Bufalin Induces Lung Cancer Cell Apoptosis via the Inhibition of PI3K/Akt Pathway

    Directory of Open Access Journals (Sweden)

    Yunpeng Liu

    2012-02-01

    Full Text Available Bufalin is a class of toxic steroids which could induce the differentiation and apoptosis of leukemia cells, and induce the apoptosis of gastric, colon and breast cancer cells. However, the anti-tumor effects of bufalin have not been demonstrated in lung cancer. In this study we used A549 human lung adenocarcinoma epithelial cell line as the experimental model to evaluate the potential of bufalin in lung cancer chemotherapy. A549 cells were treated with bufalin, then the proliferation was detected by MTT assay and apoptosis was detected by flow cytometry analysis and Giemsa staining. In addition, A549 cells were treated by Akt inhibitor LY294002 in combination with bufalin and the activation of Akt and Caspase-3 as well as the expression levels of Bax, Bcl-2 and livin were examined by Western blot analysis. The results showed that Bufalin inhibited the proliferation of A549 cells and induced the apoptosis of A549 cells in a dose and time dependent manner. Mechanistically, we found that bufalin inhibited the activation of Akt. Moreover, bufalin synergized with Akt inhibitor to induce the apoptosis of A549 cells and this was associated with the upregulation of Bax expression, the downregulation of Bcl-2 and livin expression, and the activation of Caspase-3. In conclusion, our findings demonstrate that bufalin induces lung cancer cell apoptosis via the inhibition of PI3K/Akt pathway and suggest that bufalin is a potential regimen for combined chemotherapy to overcome the resistance of lung cancer cells to chemotherapeutics induced apoptosis.

  13. Inhibition of chlorine-induced lung injury by the type 4 phosphodiesterase inhibitor rolipram

    Energy Technology Data Exchange (ETDEWEB)

    Chang, Weiyuan; Chen, Jing; Schlueter, Connie F. [Department of Environmental and Occupational Health Sciences, School of Public Health and Information Sciences, University of Louisville, Louisville, KY (United States); Rando, Roy J. [Department of Environmental Health Sciences, School of Public Health and Tropical Medicine, Tulane University Health Sciences Center, New Orleans, LA (United States); Pathak, Yashwant V. [College of Pharmacy, University of South Florida, Tampa, FL (United States); Hoyle, Gary W., E-mail: Gary.Hoyle@louisville.edu [Department of Environmental and Occupational Health Sciences, School of Public Health and Information Sciences, University of Louisville, Louisville, KY (United States)

    2012-09-01

    Chlorine is a highly toxic respiratory irritant that when inhaled causes epithelial cell injury, alveolar-capillary barrier disruption, airway hyperreactivity, inflammation, and pulmonary edema. Chlorine is considered a chemical threat agent, and its release through accidental or intentional means has the potential to result in mass casualties from acute lung injury. The type 4 phosphodiesterase inhibitor rolipram was investigated as a rescue treatment for chlorine-induced lung injury. Rolipram inhibits degradation of the intracellular signaling molecule cyclic AMP. Potential beneficial effects of increased cyclic AMP levels include inhibition of pulmonary edema, inflammation, and airway hyperreactivity. Mice were exposed to chlorine (whole body exposure, 228–270 ppm for 1 h) and were treated with rolipram by intraperitoneal, intranasal, or intramuscular (either aqueous or nanoemulsion formulation) delivery starting 1 h after exposure. Rolipram administered intraperitoneally or intranasally inhibited chlorine-induced pulmonary edema. Minor or no effects were observed on lavage fluid IgM (indicative of plasma protein leakage), KC (Cxcl1, neutrophil chemoattractant), and neutrophils. All routes of administration inhibited chlorine-induced airway hyperreactivity assessed 1 day after exposure. The results of the study suggest that rolipram may be an effective rescue treatment for chlorine-induced lung injury and that both systemic and targeted administration to the respiratory tract were effective routes of delivery. -- Highlights: ► Chlorine causes lung injury when inhaled and is considered a chemical threat agent. ► Rolipram inhibited chlorine-induced pulmonary edema and airway hyperreactivity. ► Post-exposure rolipram treatments by both systemic and local delivery were effective. ► Rolipram shows promise as a rescue treatment for chlorine-induced lung injury.

  14. Lung injury during LPS-induced inflammation occurs independently of the receptor P2Y1.

    Science.gov (United States)

    Liverani, Elisabetta

    2017-03-01

    Disruption of the lung endothelial and epithelial barriers during acute inflammation leads to excessive neutrophil migration. It is likely that activated platelets promote pulmonary recruitment of neutrophils during inflammation, and previous studies have found that anti-platelet therapy and depletion of circulating platelets have lung-protective effects in different models of inflammation. Because ADP signaling is important for platelet activation, I investigated the role of the ADP-receptor P2Y 1 , a G protein-coupled receptor expressed on the surface of circulating platelets, during lipopolysaccharide (LPS)-induced inflammation and lung injury in P2Y 1 -null and wild-type mice. Systemic inflammation was induced by a single intraperitoneal dose of LPS (3 mg/kg), and the mice were analyzed 24 h posttreatment. The data show that the LPS-induced inflammation levels were comparable in the P2Y 1 -null and wild-type mice. Specifically, splenomegaly, counts of circulating platelets and white blood cells (lymphocytes and neutrophils), and assessments of lung injury (tissue architecture and cell infiltration) were similar in the P2Y 1 -null and wild-type mice. Based on my results, I conclude that lung injury during LPS-induced inflammation in mice is independent of P2Y 1 signaling. I propose that if a blockade of purinergic signaling in platelets is a potential lung-protective strategy in the treatment of acute inflammation, then it is more likely to be a result of the disruption of the signaling pathway mediated by P2Y 12 , another G protein-coupled receptor that mediates platelet responses to ADP.

  15. Hesperidin as radioprotector against radiation-induced lung damage in rat: A histopathological study

    Directory of Open Access Journals (Sweden)

    Gholam Hassan Haddadi

    2017-01-01

    Full Text Available Reactive oxygen species (ROS are generated by ionizing radiation, and one of the organs commonly affected by ROS is the lung. Radiation-induced lung injury including pneumonia and lung fibrosis is a dose-limiting factor in radiotherapy (RT of patients with thorax irradiation. Administration of antioxidants has been proved to protect against ROS. The present study was aimed to assess the protective effect of hesperidin (HES against radiation-induced lung injury of male rats. Fifty rats were divided into three groups. G1: Received no HES and radiation (sham. G2: Underwent γ-irradiation to the thorax. G3: Received HES and underwent γ-irradiation. The rats were exposed to a single dose of 18 Gy using cobalt-60 unit and were administered HES (100 mg/kg for 7 days before irradiation. Histopathological analysis was performed 24 h and 8 weeks after RT. Histopathological results in 24 h showed radiation-induced inflammation and presence of more inflammatory cells as compared to G1 (P < 0.05. Administration of HES significantly decreased such an effect when compared to G2 (P < 0.05. Histopathological evaluation in 8 weeks showed a significant increase in mast cells, inflammation, inflammatory cells, alveolar thickness, vascular thickness, pulmonary edema, and fibrosis in G2 when compared to G1 (P < 0.05. HES significantly decreased inflammatory response, fibrosis, and mast cells when compared to G2 (P < 0.05. Administration of HES resulted in decreased radiation pneumonitis and radiation fibrosis in the lung tissue. Thus, the present study showed HES to be an efficient radioprotector against radiation-induced damage in the lung of tissue rats.

  16. Protective effect of carvacrol on acute lung injury induced by lipopolysaccharide in mice.

    Science.gov (United States)

    Feng, Xiaosheng; Jia, Aiqing

    2014-08-01

    Carvacrol, the major component of Plectranthus amboinicus, has been known to exhibit anti-inflammatory activities. The aim of this study was to investigate the effects of carvacrol on lipopolysaccharide (LPS)-induced endotoxemia and acute lung injury (ALI) in mice. Mice were injected intraperitoneally (i.p.) with LPS and the mortality of mice for 7 days were observed twice a day. Meanwhile, the protective effect of carvacrol (20, 40 or 80 mg/kg) on LPS-induced endotoxemia were detected. Using an experimental model of LPS-induced ALI, we examined the effect of carvacrol in resolving lung injury. The results showed that carvacrol could improve survival during lethal endotoxemia and attenuate LPS-induced ALI in mice. The anti-inflammatory mechanisms of carvacrol may be due to its ability to inhibit NF-κB and MAPKs signaling pathways, thereby inhibiting inflammatory cytokines TNF-α, IL-6 and IL-1β production.

  17. Effects of surfactant/budesonide therapy on oxidative modifications in the lung in experimental meconium-induced lung injury.

    Science.gov (United States)

    Mikolka, P; Kopincova, J; Tomcikova Mikusiakova, L; Kosutova, P; Antosova, M; Calkovska, A; Mokra, D

    2016-02-01

    Meconium aspiration syndrome (MAS) is a serious condition, which can be treated with exogenous surfactant and mechanical ventilation. However, meconium-induced inflammation, lung edema and oxidative damage may inactivate delivered surfactant and thereby reduce effectiveness of the therapy. As we presumed that addition of anti-inflammatory agent into the surfactant may alleviate inflammation and enhance efficiency of the therapy, this study was performed to evaluate effects of surfactant therapy enriched with budesonide versus surfactant-only therapy on markers of oxidative stress in experimental model of MAS. Meconium suspension (25 mg/ml, 4 ml/kg) was instilled into the trachea of young rabbits, whereas one group of animals received saline instead of meconium (C group, n = 6). In meconium-instilled animals, respiratory failure developed within 30 min. Then, meconium-instilled animals were divided into 3 groups according to therapy (n = 6 each): with surfactant therapy (M + S group), with surfactant + budesonide therapy (M + S + B), and without therapy (M group). Surfactant therapy consisted of two bronchoalveolar lavages (BAL) with diluted surfactant (Curosurf, 5 mg phospholipids/ml, 10 ml/kg) followed by undiluted surfactant (100 mg phospholipids/kg), which was in M + S + B group enriched with budesonide (Pulmicort, 0.5 mg/ml). Animals were oxygen-ventilated for additional 5 hours. At the end of experiment, blood sample was taken for differential white blood cell (WBC) count. After euthanizing animals, left lung was saline-lavaged and cell differential in BAL was determined. Oxidative damage, i.e. oxidation of lipids (thiobarbituric acid reactive substance (TBARS) and conjugated dienes) and proteins (dityrosine and lysine-lipoperoxidation products) was estimated in lung homogenate and isolated mitochondria. Total antioxidant capacity was evaluated in lung homogenate and plasma. Meconium instillation increased transmigration of neutrophils and production of free

  18. Protective effect of florfenicol on acute lung injury induced by lipopolysaccharide in mice.

    Science.gov (United States)

    Zhang, Xuemei; Song, Keji; Xiong, Huanzhang; Li, Hongyu; Chu, Xiao; Deng, Xuming

    2009-12-01

    Florfenicol, an antibiotic used to treat infection, has previously been shown to modulate early cytokine responses and increase mouse survival in endotoxemia. In the present study, we investigated in vivo the effect of florfenicol on acute lung injury (ALI) induced by lipopolysaccharide (LPS). In the mouse model of LPS-induced inflammatory lung injury, we found that pretreatment with a single 100mg/kg dose of florfenicol significantly decreases the W/D ratio of lungs and protein concentration in the bronchoalveolar lavage fluid (BALF) and significantly reduces the number of total cells, neutrophils and macrophages in the BALF at 24h after LPS challenge. In addition, histopathological examination indicates that florfenicol significantly attenuates tissue injury of the lungs in LPS-induced ALI. Furthermore, florfenicol also inhibits the production of several inflammatory cytokines, including tumor necrosis factor-alpha (TNF-alpha) at 6 and 12h, interleukin-6 (IL-6) at 12 and 24h, and interleukin-1ss (IL-1ss) at 12h, in the BALF after LPS challenge. These results suggest that florfenicol protects against LPS-induced ALI in mice.

  19. Deletion of ASK1 Protects against Hyperoxia-Induced Acute Lung Injury.

    Directory of Open Access Journals (Sweden)

    Jutaro Fukumoto

    Full Text Available Apoptosis signal-regulating kinase 1 (ASK1, a member of the MAPK kinase kinase kinase (MAP3K family, is activated by various stimuli, which include oxidative stress, endoplasmic reticulum (ER stress, calcium influx, DNA damage-inducing agents and receptor-mediated signaling through tumor necrosis factor receptor (TNFR. Inspiration of a high concentration of oxygen is a palliative therapy which counteracts hypoxemia caused by acute lung injury (ALI-induced pulmonary edema. However, animal experiments so far have shown that hyperoxia itself could exacerbate ALI through reactive oxygen species (ROS. Our previous data indicates that ASK1 plays a pivotal role in hyperoxia-induced acute lung injury (HALI. However, it is unclear whether or not deletion of ASK1 in vivo protects against HALI. In this study, we investigated whether ASK1 deletion would lead to attenuation of HALI. Our results show that ASK1 deletion in vivo significantly suppresses hyperoxia-induced elevation of inflammatory cytokines (i.e. IL-1β and TNF-α, cell apoptosis in the lung, and recruitment of immune cells. In summary, the results from the study suggest that deletion of ASK1 in mice significantly inhibits hyperoxic lung injury.

  20. Chronic Exposure to Particulate Nickel Induces Neoplastic Transformation in Human Lung Epithelial Cells

    Directory of Open Access Journals (Sweden)

    Amie L. Holmes

    2013-11-01

    Full Text Available Nickel is a well-known human lung carcinogen with the particulate form being the most potent; however, the carcinogenic mechanism remains largely unknown. Few studies have investigated the genotoxicity and carcinogenicity of nickel in its target cell, human bronchial epithelial cells. Thus, the goal of this study was to investigate the effects of particulate nickel in human lung epithelial cells. We found that nickel subsulfide induced concentration- and time-dependent increases in both cytotoxicity and genotoxicity in human lung epithelial cells (BEP2D. Chronic exposure to nickel subsulfide readily induced cellular transformation, inducing 2.55, 2.9 and 2.35 foci per dish after exposure to 1, 2.5 and 5 μg/cm2 nickel subsulfide, respectively. Sixty-one, 100 and 70 percent of the foci isolated from 1, 2.5, and 5 μg/cm2 nickel subsulfide treatments formed colonies in soft agar and the degree of soft agar colony growth increased in a concentration-dependent manner. Thus, chronic exposure to particulate nickel induces genotoxicity and cellular transformation in human lung epithelial cells.

  1. Time-response relationship of nano and micro particle induced lung inflammation. Quartz as reference compound

    DEFF Research Database (Denmark)

    Roursgaard, Martin; Poulsen, Steen Seier; Poulsen, Lars K.

    2010-01-01

    An increasing number of engineered particles, including nanoparticles, are being manufactured, increasing the need for simple low-dose toxicological screening methods. This study aimed to investigate the kinetics of biomarkers related to acute and sub-chronic particle-induced lung inflammation of...

  2. Biomarkers of asbestos-induced lung injury: the influence of fiber characteristics and exposure methodology

    Science.gov (United States)

    ATS 2013 Biomarkers of asbestos-induced lung injury: the influence of fiber characteristics and exposure methodology Urmila P Kodavanti, Debora Andrews, Mette C Schaldweiler, Jaime M Cyphert, Darol E Dodd, and Stephen H Gavett NHEERL, U.S. EPA, Research Triangle Park, NC; NIEH...

  3. Tangeretin sensitises human lung cancer cells to TRAIL- induced ...

    African Journals Online (AJOL)

    expression of death receptor 5 and CEBP homologous protein (CHOP) mRNA. The cytotoxic effects of ... mediated TRAIL sensitisation. Conclusions: Tangeretin induces death receptors and enhances TRAIL-induced apoptosis through up- .... cold whole-cell lysate buffer (5 M NaCl, 10 %. Nonidet P-40, 0.2 M sodium ...

  4. Cigarette Smoke Exposure Worsens Endotoxin-Induced Lung Injury and Pulmonary Edema in Mice.

    Science.gov (United States)

    Gotts, Jeffrey E; Abbott, Jason; Fang, Xiaohui; Yanagisawa, Haru; Takasaka, Naoki; Nishimura, Stephen L; Calfee, Carolyn S; Matthay, Michael A

    2017-09-01

    Cigarette smoking (CS) remains a major public health concern and has recently been associated with an increased risk of developing acute respiratory distress syndrome (ARDS). Bronchoalveolar lavage (BAL) experiments in human volunteers have demonstrated that active smokers develop increased alveolar-epithelial barrier permeability to protein after inhaling lipopolysaccharide (LPS). Here we tested the hypothesis that short-term whole-body CS exposure would increase LPS-induced lung edema in mice. Adult mice were exposed in a Teague TE-10 machine to CS from 3R4F cigarettes at 100 mg/m3 total suspended particulates for 12 days, then given LPS or saline intratracheally. Control mice were housed in the same room without CS exposure. Post-mortem measurements included gravimetric lung water and BAL protein, cell counts, and lung histology. Cytokines were measured in lung homogenate by ELISA and in plasma by Luminex and ELISA. In CS-exposed mice, intratracheal LPS caused greater increases in pulmonary edema by gravimetric measurement and histologic scoring. CS-exposed mice also had an increase in BAL neutrophilia, lung IL-6, and plasma CXCL9, a T-cell chemoattractant. Intratracheal LPS concentrated blood hemoglobin to a greater degree in CS-exposed mice, consistent with an increase in systemic vascular permeability. These results demonstrate that CS exposure in endotoxin injured mice increases the severity of acute lung injury. The increased lung IL-6 in CS-exposed LPS-injured mice indicates that this potent cytokine, previously shown to predict mortality in patients with ARDS, may play a role in exacerbating lung injury in smokers and may have utility as a biomarker of tobacco-related lung injury. Our results suggest that short-term CS exposure at levels that cause no overt lung injury may still prime the lung for acute inflammatory damage from a "second hit", a finding that mirrors the increased risk of developing ARDS in patients who smoke. This model may be useful for

  5. Lung Lining Fluid Glutathione Attenuates IL-13–Induced Asthma

    OpenAIRE

    Lowry, Matthew H.; McAllister, Brian P.; Jean, Jyh-Chang; Brown, Lou Ann S.; Hughey, Rebecca P.; Cruikshank, William W.; Amar, Sal; Lucey, Edgar C.; Braun, Kathleen; Johnson, Pamela; Wight, Thomas N.; Joyce-Brady, Martin

    2007-01-01

    GGTenu1 mice, deficient in γ-glutamyl transferase and unable to metabolize extracellular glutathione, develop intracellular glutathione deficiency and oxidant stress. We used intratracheal IL-13 to induce airway inflammation and asthma in wild-type (WT) and GGTenu1 mice to determine the effect of altered glutathione metabolism on bronchial asthma. WT and GGTenu1 mice developed similar degrees of lung inflammation. In contrast, IL-13 induced airway epithelial cell mucous cell hyperplasia, muci...

  6. Idh2 Deficiency Exacerbates Acrolein-Induced Lung Injury through Mitochondrial Redox Environment Deterioration

    OpenAIRE

    Park, Jung Hyun; Ku, Hyeong Jun; Lee, Jin Hyup; Park, Jeen-Woo

    2017-01-01

    Acrolein is known to be involved in acute lung injury and other pulmonary diseases. A number of studies have suggested that acrolein-induced toxic effects are associated with depletion of antioxidants, such as reduced glutathione and protein thiols, and production of reactive oxygen species. Mitochondrial NADP+-dependent isocitrate dehydrogenase (idh2) regulates mitochondrial redox balance and reduces oxidative stress-induced cell injury via generation of NADPH. Therefore, we evaluated the ro...

  7. Neutrophils Promote Mycobacterial Trehalose Dimycolate-Induced Lung Inflammation via the Mincle Pathway.

    Directory of Open Access Journals (Sweden)

    Wook-Bin Lee

    Full Text Available Trehalose 6,6'-dimycolate (TDM, a cord factor of Mycobacterium tuberculosis (Mtb, is an important regulator of immune responses during Mtb infections. Macrophages recognize TDM through the Mincle receptor and initiate TDM-induced inflammatory responses, leading to lung granuloma formation. Although various immune cells are recruited to lung granulomas, the roles of other immune cells, especially during the initial process of TDM-induced inflammation, are not clear. In this study, Mincle signaling on neutrophils played an important role in TDM-induced lung inflammation by promoting adhesion and innate immune responses. Neutrophils were recruited during the early stage of lung inflammation following TDM-induced granuloma formation. Mincle expression on neutrophils was required for infiltration of TDM-challenged sites in a granuloma model induced by TDM-coated-beads. TDM-induced Mincle signaling on neutrophils increased cell adherence by enhancing F-actin polymerization and CD11b/CD18 surface expression. The TDM-induced effects were dependent on Src, Syk, and MAPK/ERK kinases (MEK. Moreover, coactivation of the Mincle and TLR2 pathways by TDM and Pam3CSK4 treatment synergistically induced CD11b/CD18 surface expression, reactive oxygen species, and TNFα production by neutrophils. These synergistically-enhanced immune responses correlated with the degree of Mincle expression on neutrophil surfaces. The physiological relevance of the Mincle-mediated anti-TDM immune response was confirmed by defective immune responses in Mincle⁻/⁻ mice upon aerosol infections with Mtb. Mincle-mutant mice had higher inflammation levels and mycobacterial loads than WT mice. Neutrophil depletion with anti-Ly6G antibody caused a reduction in IL-6 and monocyte chemotactic protein-1 expression upon TDM treatment, and reduced levels of immune cell recruitment during the initial stage of infection. These findings suggest a new role of Mincle signaling on neutrophils

  8. DNaseI Protects against Paraquat-Induced Acute Lung Injury and Pulmonary Fibrosis Mediated by Mitochondrial DNA

    Directory of Open Access Journals (Sweden)

    Guo Li

    2015-01-01

    Full Text Available Background. Paraquat (PQ poisoning is a lethal toxicological challenge that served as a disease model of acute lung injury and pulmonary fibrosis, but the mechanism is undetermined and no effective treatment has been discovered. Methods and Findings. We demonstrated that PQ injures mitochondria and leads to mtDNA release. The mtDNA mediated PBMC recruitment and stimulated the alveolar epithelial cell production of TGF-β1 in vitro. The levels of mtDNA in circulation and bronchial alveolar lavage fluid (BALF were elevated in a mouse of PQ-induced lung injury. DNaseI could protect PQ-induced lung injury and significantly improved survival. Acute lung injury markers, such as TNFα, IL-1β, and IL-6, and marker of fibrosis, collagen I, were downregulated in parallel with the elimination of mtDNA by DNaseI. These data indicate a possible mechanism for PQ-induced, mtDNA-mediated lung injury, which may be shared by other causes of lung injury, as suggested by the same protective effect of DNaseI in bleomycin-induced lung injury model. Interestingly, increased mtDNA in the BALF of patients with amyopathic dermatomyositis-interstitial lung disease can be appreciated. Conclusions. DNaseI targeting mtDNA may be a promising approach for the treatment of PQ-induced acute lung injury and pulmonary fibrosis that merits fast tracking through clinical trials.

  9. Carnosine markedly ameliorates H9N2 swine influenza virus-induced acute lung injury.

    Science.gov (United States)

    Xu, Tong; Wang, Cunlian; Zhang, Ruihua; Xu, Mingju; Liu, Baojian; Wei, Dong; Wang, Guohua; Tian, Shufei

    2015-10-01

    Oxidative stress injury is an important pathogenesis of influenza virus in critically ill patients. The present study investigated the efficacy of carnosine, an antioxidant and free radical scavenger, on a model of acute lung injury (ALI) induced by H9N2 swine influenza virus. Female specific-pathogen-free BALB/c mice were randomized into four groups and treated as follows: (1) H9N2 group, (2) mock control group, (3) H9N2+carnosine group and (4) carnosine control group. The H9N2 group mice were inoculated intranasally with A/Swine/Hebei/012/2008/ (H9N2) virus (100 μl) in allantoic fluid (AF), whilst mock-infected animals were intranasally inoculated with non-infectious AF. Carnosine [10 mg (kg body mass)- 1] was administered orally (100 μl) for 7 days consecutively. The survival rate, lung water content, TNF-α and IL-1β levels, lung histopathology, myeloperoxidase (MPO) activity, and Toll-like receptor (TLR)-4 levels were determined at 2, 4, 6, 8 and 14 days after inoculation. Carnosine treatment effectively decreased the mortality (43 versus 75 %, P lungs and decreased the lung wet/dry mass ratio (P lungs of infected mice (P < 0.05), which supported the use of carnosine for managing severe influenza cases.

  10. 4-Methoxyestradiol-induced oxidative injuries in human lung epithelial cells

    International Nuclear Information System (INIS)

    Cheng Yahsin; Chang, Louis W.; Cheng Lichuan; Tsai, M.-H.; Lin Pinpin

    2007-01-01

    Epidemiological studies indicated that people exposed to dioxins were prone to the development of lung diseases including lung cancer. Animal studies demonstrated that 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) increased liver tumors and promoted lung metaplasia in females. Metabolic changes in 17β-estradiol (E 2 ) resulted from an interaction between TCDD and E 2 could be associated with gender difference. Previously, we reported that methoxylestradiols (MeOE 2 ), especially 4-MeOE 2 , accumulated in human lung cells (BEAS-2B) co-treated with TCDD and E 2 . In the present study, we demonstrate unique accumulation of 4-MeOE 2 , as a result of TCDD/E 2 interaction and revealed its bioactivity in human lung epithelial cell line (H1355). 4-Methoxyestradiol treatment significantly decreased cell growth and increased mitotic index. Elevation of ROS and SOD activity, with a concomitant decrease in the intracellular GSH/GSSG ratio, was also detected in 4-MeOE 2 -treated cells. Quantitative comet assay showed increased oxidative DNA damage in the 4-MeOE 2 -treated H1355 cells, which could be significantly reduced by the anti-oxidant N-acetylcysteine (NAC). However, inhibition of cell growth and increase in mitotic arrest induced by 4-MeOE 2 were unaffected by NAC. We concluded that 4-MeOE 2 accumulation resulting from TCDD and E 2 interaction would contribute to the higher vulnerability on lung pathogenesis in females when exposed to TCDD

  11. Ethanol at Low Concentration Attenuates Diabetes Induced Lung Injury in Rats Model

    Directory of Open Access Journals (Sweden)

    Jun-Feng Hu

    2014-01-01

    Full Text Available To observe the changes of lung injury when diabetic rats were treated with low concentration of ethanol (EtOH and analyze the related mechanisms, male Sprague-Dawley (SD rats were divided into control, diabetic (DM, and EtOH+DM groups. Diabetic rat was mimicked by injection of streptozotocin intraperitoneally. Fasting blood glucose (FBG level, lung weight (LW, body weight (BW, and LW/BW were measured. The changes of lung tissue and Type II alveolar cell were detected. Pulmonary malondialdehyde (MDA content and superoxide dismutase (SOD activity were measured; meanwhile, ALDH2 mRNA and protein expressions were detected by RT-PCR and western blotting, respectively. Compared with control group, in DM group, SOD activity was decreased; FBG level, LW/BW, MDA content, ALDH2 mRNA, and protein expressions were decreased. Compared with DM group, in EtOH+DM group, SOD activity, ALDH2 mRNA, and protein expressions were increased; LW/BW and MDA content were decreased. The structures of lung tissue and lamellar bodies were collapsed in DM group; the injury was attenuated in EtOH+DM group. Our findings suggested that, in diabetic rat, pulmonary ALDH2 expression was decreased accompanying lung injury. EtOH at low concentration decreased diabetes induced lung injury through activating ALDH2 expression.

  12. Attenuating effect of Ginsenoside Rb1 on LPS-induced lung injury in rats.

    Science.gov (United States)

    Yuan, Qing; Jiang, Yan-Wen; Ma, Ting-Ting; Fang, Qiu-Hong; Pan, Lei

    2014-01-01

    Sepsis causes neutrophil sequestration in the lung which leads to acute lung injury (ALI). Radix Ginseng (RG), a traditional herb used as herbal remedy in eastern Asia for thousands of years, which has been traditionally used in China to improve blood circulation and ameliorate pathological hemostasis. This study investigated whether Ginsenoside Rb1, the main components of RG, can attenuate ALI induced by LPS. In vivo, 30 male Wistar rats were divided into three groups (n = 10 each groups) on the basis of the reagent used, which were subjected to LPS injection with or without Ginsenoside Rb1 (5 mg/kg) treatments to induce ALI model. Lung injury was assessed by pulmonary histology, lung wet-weight to dry-weight (W/D) ratio, the number of myeloperoxidase (MPO) positive cells, immunohistochemical analysis of intercellular adhesion molecule-1 (ICAM-1), gene expression of ICAM-1, ultrastructure changes of pulmonary microvasculature, concentration of inflammatory markers and in plasma. In vitro, pulmonary microvascular endothelial cells (PMVECs) were stimulated with LPS in the presence and absence of Ginsenoside Rb1 (50 mM), nuclear factor-κB (NF-κB) p65 was measured by immunocytochemistry staining and western blotting. Infusion of LPS induced lung injury, in vivo, as demonstrated by pulmonary edema with infiltration of neutrophils and hemorrhage, the increase in lung W/D ratio, the number of MPO positive cells, the level of inflammatory markers such as TNF-α, MCP-1 and IL-8, enhanced expression of ICAM-1 and ICAM-1 gene. Moreover, resulted in the changes of intercellular junctions in the endothelial cells of pulmonary microvasculature. In vitro, the significant increased release of NF-κB p65 and its subsequent translocation into the nucleus in PMVECs were observed. In contrast, Ginsenoside Rb1 treatment significantly ameliorated the LPS-induced lung injury, as judged by the marked improvement in all these indices. These results indicate that Ginsenoside Rb1

  13. Protection Against Lung Cancer Patient Plasma-Induced Lymphocyte Suppression by Ganoderma Lucidum Polysaccharides

    Directory of Open Access Journals (Sweden)

    Li-Xin Sun

    2014-01-01

    Full Text Available Background/Aims: This study was conducted to determine the potential of Ganoderma lucidum polysaccharides (Gl-PS in protection against lung cancer patient plasma-induced suppression of lymphocytes. Lung cancer is a major cause of disease and loss of life in the United States and worldwide. Cancer cells release immunosuppressive mediators, such as PGE2, TGF-β, IL-10, and VEGF, to inhibit the immune response to escape from immune surveillance. Gl-PS has been shown to counteract this immune inhibition in an animal cell culture model, and thus to facilitate tumor control. The present study explored whether or not such an effect could also be demonstrated in human lung cancer patients. Methods: Immunofluorescence, flow cytometry, MTT, immunocytochemistry, and western blot analysis were used to assess lymphocyte activation with PHA. Results: The plasma of lung cancer patients suppressed proliferation, CD69 expression, and perforin and granzyme B production in lymphocytes upon activation by PHA, effects that were partially of fully reversed by Gl-PS. Conclusion: Lung cancer patient plasma-induced suppression of lymphocyte activation by phytohemagglutinin may be antagonized fully or partially by Gl-PS, an observation suggesting the potential of Gl-PS in cancer therapy.

  14. Lung Lining Fluid Glutathione Attenuates IL-13–Induced Asthma

    Science.gov (United States)

    Lowry, Matthew H.; McAllister, Brian P.; Jean, Jyh-Chang; Brown, Lou Ann S.; Hughey, Rebecca P.; Cruikshank, William W.; Amar, Sal; Lucey, Edgar C.; Braun, Kathleen; Johnson, Pamela; Wight, Thomas N.; Joyce-Brady, Martin

    2008-01-01

    GGTenu1 mice, deficient in γ-glutamyl transferase and unable to metabolize extracellular glutathione, develop intracellular glutathione deficiency and oxidant stress. We used intratracheal IL-13 to induce airway inflammation and asthma in wild-type (WT) and GGTenu1 mice to determine the effect of altered glutathione metabolism on bronchial asthma. WT and GGTenu1 mice developed similar degrees of lung inflammation. In contrast, IL-13 induced airway epithelial cell mucous cell hyperplasia, mucin and mucin-related gene expression, epidermal growth factor receptor mRNA, and epidermal growth factor receptor activation along with airway hyperreactivity in WT mice but not in GGTenu1 mice. Lung lining fluid (extracellular) glutathione was 10-fold greater in GGTenu1 than in WT lungs, providing increased buffering of inflammation-associated reactive oxygen species. Pharmacologic inhibition of GGT in WT mice produced similar effects, suggesting that the lung lining fluid glutathione protects against epithelial cell induction of asthma. Inhibiting GGT activity in lung lining fluid may represent a novel therapeutic approach for preventing and treating asthma. PMID:18063838

  15. Mesoporous carbon nanomaterials induced pulmonary surfactant inhibition, cytotoxicity, inflammation and lung fibrosis.

    Science.gov (United States)

    Chen, Yunan; Yang, Yi; Xu, Bolong; Wang, Shunhao; Li, Bin; Ma, Juan; Gao, Jie; Zuo, Yi Y; Liu, Sijin

    2017-12-01

    Environmental exposure and health risk upon engineered nanomaterials are increasingly concerned. The family of mesoporous carbon nanomaterials (MCNs) is a rising star in nanotechnology for multidisciplinary research with versatile applications in electronics, energy and gas storage, and biomedicine. Meanwhile, there is mounting concern on their environmental health risks due to the growing production and usage of MCNs. The lung is the primary site for particle invasion under environmental exposure to nanomaterials. Here, we studied the comprehensive toxicological profile of MCNs in the lung under the scenario of moderate environmental exposure. It was found that at a low concentration of 10μg/mL MCNs induced biophysical inhibition of natural pulmonary surfactant. Moreover, MCNs at similar concentrations reduced viability of J774A.1 macrophages and lung epithelial A549 cells. Incubating with nature pulmonary surfactant effectively reduced the cytotoxicity of MCNs. Regarding the pro-inflammatory responses, MCNs activated macrophages in vitro, and stimulated lung inflammation in mice after inhalation exposure, associated with lung fibrosis. Moreover, we found that the size of MCNs played a significant role in regulating cytotoxicity and pro-inflammatory potential of this nanomaterial. In general, larger MCNs induced more pronounced cytotoxic and pro-inflammatory effects than their smaller counterparts. Our results provided valuable information on the toxicological profile and environmental health risks of MCNs, and suggested that fine-tuning the size of MCNs could be a practical precautionary design strategy to increase safety and biocompatibility of this nanomaterial. Copyright © 2017. Published by Elsevier B.V.

  16. Mixed Herbal Medicine Induced Diffuse Infiltrative Lung Disease: The HRCT and Histopathologic Findings

    International Nuclear Information System (INIS)

    Kim, Tae Gyu; Shin, Eun A; Kim, Joung Sook

    2010-01-01

    The purpose of this study was to evaluate the high-resolution CT (HRCT) and pathologic findings of mixed herbal medicine-induced diffuse interstitial lung disease. Eight patients (6 women and 2 men, age range: 31 to 81 years, mean age: 51.4 years) who presented with cough or dyspnea after taking mixed herbal medicine were included in this study. All the patients underwent plain chest radiography and HRCT. We obtained pathologic specimens from 7 patients via fluoroscopy guided large bore cutting needle biopsy and transbronchial lung biopsy. All the patients were treated with steroid therapy. The most common HRCT finding was bilateral diffuse ground glass opacity (n=7), followed by peribronchial consolidation (n=5) and inter- or intralobular septal thickening (n=2). For the disease distribution, the lower lung zone was dominantly involved. The pathologic results of 7 patients were nonspecific interstitial pneumonia (n=3), bronchiolitis obliterans organizing pneumonia (n=2), hypersensitivity pneumonitis (n=1) and eosinophilic pneumonia (n=1). Irrespective of the pathologic results, all 8 patients improved clinically and radiologically after steroid treatment. The HRCT findings of mixed herbal medicine-induced diffuse infiltrative lung disease were mainly bilateral diffuse ground glass opacity, peribronchial consolidation and dominant involvement of the lower lung zone. Those pathologic findings were nonspecific and the differential diagnosis could include interstitial pneumonia, bronchiolitis obliterans organizing pneumonia, hypersensitivity pneumonitis and eosinophilic pneumonia

  17. Mixed Herbal Medicine Induced Diffuse Infiltrative Lung Disease: The HRCT and Histopathologic Findings

    Energy Technology Data Exchange (ETDEWEB)

    Kim, Tae Gyu; Shin, Eun A [Sanggye Paik Hospital, Inje University College of Medicine, Seoul (Korea, Republic of); Kim, Joung Sook [Mokdong Hospital, Ewha Womans University College of Medicine, Seoul (Korea, Republic of)

    2010-12-15

    The purpose of this study was to evaluate the high-resolution CT (HRCT) and pathologic findings of mixed herbal medicine-induced diffuse interstitial lung disease. Eight patients (6 women and 2 men, age range: 31 to 81 years, mean age: 51.4 years) who presented with cough or dyspnea after taking mixed herbal medicine were included in this study. All the patients underwent plain chest radiography and HRCT. We obtained pathologic specimens from 7 patients via fluoroscopy guided large bore cutting needle biopsy and transbronchial lung biopsy. All the patients were treated with steroid therapy. The most common HRCT finding was bilateral diffuse ground glass opacity (n=7), followed by peribronchial consolidation (n=5) and inter- or intralobular septal thickening (n=2). For the disease distribution, the lower lung zone was dominantly involved. The pathologic results of 7 patients were nonspecific interstitial pneumonia (n=3), bronchiolitis obliterans organizing pneumonia (n=2), hypersensitivity pneumonitis (n=1) and eosinophilic pneumonia (n=1). Irrespective of the pathologic results, all 8 patients improved clinically and radiologically after steroid treatment. The HRCT findings of mixed herbal medicine-induced diffuse infiltrative lung disease were mainly bilateral diffuse ground glass opacity, peribronchial consolidation and dominant involvement of the lower lung zone. Those pathologic findings were nonspecific and the differential diagnosis could include interstitial pneumonia, bronchiolitis obliterans organizing pneumonia, hypersensitivity pneumonitis and eosinophilic pneumonia

  18. Effectiveness of liposomal-N-acetylcysteine against LPS-induced lung injuries in rodents.

    Science.gov (United States)

    Mitsopoulos, Panagiotis; Omri, Abdelwahab; Alipour, Misagh; Vermeulen, Natasha; Smith, Milton G; Suntres, Zacharias E

    2008-11-03

    Acute lung injury (ALI) and its most severe form, the acute respiratory distress syndrome (ARDS) are frequent complications in critically ill patients and are responsible for significant morbidity and mortality. So far, experimental evidence supports the role of oxidants and oxidative injury in the pathogenesis of ALI/ARDS. In this study, the antioxidant effects of conventional N-acetylcysteine (NAC) and liposomally entrapped N-acetylcysteine (L-NAC) were evaluated in experimental animals challenged with lipopolysaccharide (LPS). Rats were pretreated with empty liposomes, NAC, or L-NAC (25mg/kg body weight, iv); 4h later were challenged with LPS (E. coli, LPS 0111:B4) and sacrificed 20h later. Challenge of saline (SAL)-pretreated animals with LPS resulted in lung injury as evidenced by increases in wet lung weight (edema), increases in lipid peroxidation (marker of oxidative stress), decreases of lung angiotensin-converting enzyme (ACE) (injury marker for pulmonary endothelial cells) and increases in the pro-inflammatory eicosanoids, thromboxane B(2) and leukotriene B(4). The LPS challenge also increased pulmonary myeloperoxidase activity and chloramine concentrations indicative of neutrophil infiltration and activation of the inflammatory response. Pretreatment of animals with L-NAC resulted in significant increases in the levels of non-protein thiols and NAC levels in lung homogenates (p<0.05) and bronchoalveolar lavage fluids (p<0.001), respectively. L-NAC was significantly (p<0.05) more effective than NAC or empty liposomes in attenuating the LPS-induced lung injuries as indicated by the aforementioned injury markers. Our results suggested that the delivery of NAC as a liposomal formulation improved its prophylactic effectiveness against LPS-induced lung injuries.

  19. Resveratrol Induces Premature Senescence in Lung Cancer Cells via ROS-Mediated DNA Damage

    Science.gov (United States)

    Luo, Hongmei; Yang, Aimin; Schulte, Bradley A.; Wargovich, Michael J.; Wang, Gavin Y.

    2013-01-01

    Resveratrol (RV) is a natural component of red wine and grapes that has been shown to be a potential chemopreventive and anticancer agent. However, the molecular mechanisms underlying RV's anticancer and chemopreventive effects are incompletely understood. Here we show that RV treatment inhibits the clonogenic growth of non-small cell lung cancer (NSCLC) cells in a dose-dependent manner. Interestingly, the tumor-suppressive effect of low dose RV was not associated with any significant changes in the expression of cleaved PARP and activated caspase-3, suggesting that low dose RV treatment may suppress tumor cell growth via an apoptosis-independent mechanism. Subsequent studies reveal that low dose RV treatment induces a significant increase in senescence-associated β–galactosidase (SA-β-gal) staining and elevated expression of p53 and p21 in NSCLC cells. Furthermore, we show that RV-induced suppression of lung cancer cell growth is associated with a decrease in the expression of EF1A. These results suggest that RV may exert its anticancer and chemopreventive effects through the induction of premature senescence. Mechanistically, RV-induced premature senescence correlates with increased DNA double strand breaks (DSBs) and reactive oxygen species (ROS) production in lung cancer cells. Inhibition of ROS production by N-acetylcysteine (NAC) attenuates RV-induced DNA DSBs and premature senescence. Furthermore, we show that RV treatment markedly induces NAPDH oxidase-5 (Nox5) expression in both A549 and H460 cells, suggesting that RV may increase ROS generation in lung cancer cells through upregulating Nox5 expression. Together, these findings demonstrate that low dose RV treatment inhibits lung cancer cell growth via a previously unappreciated mechanism, namely the induction of premature senescence through ROS-mediated DNA damage. PMID:23533664

  20. Antenatal and postnatal corticosteroid and resuscitation induced lung injury in preterm sheep

    Directory of Open Access Journals (Sweden)

    Kallapur Suhas G

    2009-12-01

    Full Text Available Abstract Background Initiation of ventilation using high tidal volumes in preterm lambs causes lung injury and inflammation. Antenatal corticosteroids mature the lungs of preterm infants and postnatal corticosteroids are used to treat bronchopulmonary dysplasia. Objective To test if antenatal or postnatal corticosteroids would decrease resuscitation induced lung injury. Methods 129 d gestational age lambs (n = 5-8/gp; term = 150 d were operatively delivered and ventilated after exposure to either 1 no medication, 2 antenatal maternal IM Betamethasone 0.5 mg/kg 24 h prior to delivery, 3 0.5 mg/kg Dexamethasone IV at delivery or 4 Cortisol 2 mg/kg IV at delivery. Lambs then were ventilated with no PEEP and escalating tidal volumes (VT to 15 mL/kg for 15 min and then given surfactant. The lambs were ventilated with VT 8 mL/kg and PEEP 5 cmH20 for 2 h 45 min. Results High VT ventilation caused a deterioration of lung physiology, lung inflammation and injury. Antenatal betamethasone improved ventilation, decreased inflammatory cytokine mRNA expression and alveolar protein leak, but did not prevent neutrophil influx. Postnatal dexamethasone decreased pro-inflammatory cytokine expression, but had no beneficial effect on ventilation, and postnatal cortisol had no effect. Ventilation increased liver serum amyloid mRNA expression, which was unaffected by corticosteroids. Conclusions Antenatal betamethasone decreased lung injury without decreasing lung inflammatory cells or systemic acute phase responses. Postnatal dexamethasone or cortisol, at the doses tested, did not have important effects on lung function or injury, suggesting that corticosteroids given at birth will not decrease resuscitation mediated injury.

  1. Nox1 oxidase suppresses influenza a virus-induced lung inflammation and oxidative stress.

    Directory of Open Access Journals (Sweden)

    Stavros Selemidis

    Full Text Available Influenza A virus infection is an ongoing clinical problem and thus, there is an urgent need to understand the mechanisms that regulate the lung inflammation in order to unravel novel generic pharmacological strategies. Evidence indicates that the Nox2-containing NADPH oxidase enzyme promotes influenza A virus-induced lung oxidative stress, inflammation and dysfunction via ROS generation. In addition, lung epithelial and endothelial cells express the Nox1 isoform of NADPH oxidase, placing this enzyme at key sites to regulate influenza A virus-induced lung inflammation. The aim of this study was to investigate whether Nox1 oxidase regulates the inflammatory response and the oxidative stress to influenza infection in vivo in mice. Male WT and Nox1-deficient (Nox1(-/y mice were infected with the moderately pathogenic HkX-31 (H3N2, 1×10(4 PFU influenza A virus for analysis of bodyweight, airways inflammation, oxidative stress, viral titre, lung histopathology, and cytokine/chemokine expression at 3 and 7 days post infection. HkX-31 virus infection of Nox1(-/y mice resulted in significantly greater: loss of bodyweight (Day 3; BALF neutrophilia, peri-bronchial, peri-vascular and alveolar inflammation; Nox2-dependent inflammatory cell ROS production and peri-bronchial, epithelial and endothelial oxidative stress. The expression of pro-inflammatory cytokines including CCL2, CCL3, CXCL2, IL-1β, IL-6, GM-CSF and TNF-α was higher in Nox1(-/y lungs compared to WT mice at Day 3, however, the expression of CCL2, CCL3, CXCL2, IFN-γ and the anti-inflammatory cytokine IL-10 were lower in lungs of Nox1(-/y mice vs. WT mice at Day 7. Lung viral titre, and airways infiltration of active CD8(+ and CD4(+ T lymphocytes, and of Tregs were similar between WT and Nox1(-/y mice. In conclusion, Nox1 oxidase suppresses influenza A virus induced lung inflammation and oxidative stress in mice particularly at the early phases of the infection. Nox1 and Nox2 oxidases appear

  2. Flecainide Improve Sepsis Induced Acute Lung Injury by Controlling Inflammatory Response

    Directory of Open Access Journals (Sweden)

    Jia Song

    2016-08-01

    Full Text Available Background: Flecainide is an antiarrhythmic agent that is used primarily in the treatment of cardiac arrhythmias. Some evidences also suggest that flecainide can participate in alveolar fluid clearance and inflammatory responses. This experiment was aimed to evaluate the effects of flecainide on sepsis induced acute lung injury in a rat model. Methods: Rats were treated with subcutaneous infusion of saline or flecainide (0.1 or 0.2 mg/kg/hr by a mini-osmotic pump. Subcutaneous infusion was started 3 hours before and continued until 8 hours after intraperitoneal injection of saline or endotoxin. Animals were sacrificed for analyses of severity of acute lung injury with wet to dry (W/D ratio and lung injury score (LIS in lung and inflammatory responses with level of leukocyte, polymorphonuclear neutrophils (PMNs and inteleukin-8 (IL-8 in bronchoalveolar lavages fluid (BALF. Results: Flecainide markedly improved dose dependently sepsis induced acute lung injury as analysed by W/D ratio (from 2.24 ± 0.11 to 1.76 ± 0.09, p < 0.05 and LIS (from 3 to 1, p < 0.05, and inflammatory response as determined by leukocyte (from 443 ± 127 to 229 ± 95, p < 0.05, PMNs (from 41.43 ± 17.63 to 2.43 ± 2.61, p < 0.05 and IL-8 (from 95.00 ± 15.28 to 40.00 ± 10.21, p < 0.05 in BALF. Conclusions: Flecanide improve sepsis induced acute lung injury in rats by controlling inflammatory responses.

  3. Sulforaphane‐induced apoptosis in Xuanwei lung adenocarcinoma cell line XWLC‐05

    Science.gov (United States)

    Zhou, Lan; Yao, Qian; Huang, Yun‐chao; Jiang, Hua; Wang, Chuan‐qiong; Fan, Lei

    2016-01-01

    Background Xuanwei district in Yunnan Province has the highest incidence of lung cancer in China, especially among non‐smoking women. Cruciferous vegetables can reduce lung cancer risk by prompting a protective mechanism against respiratory tract inflammation caused by air pollution, and are rich in sulforaphane, which can induce changes in gene expression. We investigated the effect of sulforaphane‐induced apoptosis in Xuanwei lung adenocarcinoma cell line (XWCL‐05) to explore the value of sulforaphane in lung cancer prevention and treatment. Methods Cell growth inhibition was determined by methyl thiazolyl tetrazolium assay; cell morphology and apoptosis were observed under transmission electron microscope; cell cycle and apoptosis rates were detected using flow cytometry; B‐cell lymphoma 2 (Bcl‐2) and Bcl‐2‐like protein 4 (Bax) messenger RNA expression were determined by quantitative PCR; and p53, p73, p53 upregulated modulator of apoptosis (PUMA), Bax, Bcl‐2, and caspase‐9 protein expression were detected by Western blotting. Results Sulforaphane inhibited XWLC‐05 cell growth with inhibitory concentration (IC)50 of 4.04, 3.38, and 3.02 μg/mL at 24, 48, and 72 hours, respectively. Sulforaphane affected the XWLC‐05 cell cycle as cells accumulated in the G2/M phase. The proportion of apoptotic cells observed was 27.6%. Compared with the control, the sulforaphane group showed decreased Bcl‐2 and p53 expression, and significantly increased p73, PUMA, Bax, and caspase‐9 protein expression (P Sulforaphane induces Xuanwei lung adenocarcinoma cell apoptosis. Its possible mechanism may involve the upregulation of p73 expression and its effector target genes PUMA and Bax in lung cancer cells, downregulation of the anti‐apoptotic gene B cl ‐2, and activation of caspase‐9. It may also involve downregulation of the mutant p53 protein. PMID:27878984

  4. Anti-inflammatory effects of montelukast on smoke-induced lung injury in rats

    Directory of Open Access Journals (Sweden)

    Basyigit Ilknur

    2010-04-01

    Full Text Available Abstract Aim To evaluate the effects of montelukast in smoke-induced lung injury. Methods 28 Wistar-Albino rats were enrolled into 4 groups with 7 rats per group. The healthy control group was exposed to fresh air while all rats in the 3 experimental groups were exposed to cigarette smoke for 20 weeks for 2 hours per day. After histopathological verification of smoke induced lung injury, montelukast (0.1 mg/kg dissolved in Na2CO3 was given in one group (MON, Na2CO3 only was given in another group (MON control and placebo was injected in the third group (COPD control intraperitoneally for 21 days. At the end of this period blood samples were obtained for serum TNF-α assessment and light and electron microscopy analyses were performed on the lung tissues of sacrificed rats. Results Serum TNF-α levels in the MON group were significantly lower than in the MON control and COPD control groups (38.84 ± 4.9 pg/ml, 77.5 ± 5.8 pg/ml and 79.2 ± 6.9 pg/ml respectively, p 0.05. Light and electron microscopic evaluation of the lungs demonstrated that the total histopathological damage score of the lung samples was significantly lower in the MON group than in MON controls and COPD controls (5.14 ± 0.5, 8.4 ± 0.6 and 8.7 ± 0.4 respectively, p 0.05. Conclusion These findings suggest that montelukast might have a protective effect on smoke-induced lung injury in rats both from a histopathological and inflammatory point of view.

  5. VEGF and IL-18 in induced sputum of lung cancer patients.

    Science.gov (United States)

    Rovina, Nikoletta; Hillas, Georgios; Dima, Efrossini; Vlastos, Fotis; Loukides, Stylianos; Veldekis, Dimitrios; Roussos, Charis; Alhanatis, Manos; Bakakos, Petros

    2011-06-01

    Cytokines are key players in the biological processes of malignant tumors and special interest has been focused on cytokines exerting tumor and anti-tumor properties, such as vascular endothelial growth factor (VEGF) and Interleukin-18 (IL-18). Aim of this study was to assess IL-18 and VEGF levels in induced sputum of lung cancer patients at diagnosis, and assess their possible association with the histological type of cancer, the stage and the overall patient survival. Seventy six patients with a diagnosis of lung cancer were recruited and were followed up for 48months. Thirteen healthy smokers and 16 healthy non-smokers were used as control groups. VEGF and IL-18 were measured by ELISA in sputum supernatants at the time of diagnosis. Lung cancer patients had significantly higher baseline IL-18 and VEGF levels compared to healthy controls (p<0.001). No difference was found in IL-18 and VEGF levels between the various stages in non-small cell lung cancer (NSCLC) and between limited and extended small cell lung cancer (SCLC). However, the ratio of VEGF/IL-18 was significantly higher in NSCLC compared to SCLC patients (p=0.018). In extended SCLC overall survival was inversely associated with baseline sputum VEGF levels (p=0.034) and estimated mortality risk was 1.14 (95% CI 1.006-1.283) for an increase of 100pg/ml in VEGF levels. Such association was not found regarding baseline IL-18 levels. VEGF levels in induced sputum may have a prognostic role in the survival of SCLC. The ratio VEGF/IL-18 in induced sputum differs between NSCLC and SCLC, indicating differences in angiogenesis mechanisms and/or immunological response in these two major histological types of lung cancer. Copyright © 2011 Elsevier Ltd. All rights reserved.

  6. IL-17A deficiency mitigates bleomycin-induced complement activation during lung fibrosis.

    Science.gov (United States)

    Cipolla, Ellyse; Fisher, Amanda J; Gu, Hongmei; Mickler, Elizabeth A; Agarwal, Manisha; Wilke, Carol A; Kim, Kevin K; Moore, Bethany B; Vittal, Ragini

    2017-12-01

    Interleukin 17A (IL-17A) and complement (C') activation have each been implicated in the pathogenesis of idiopathic pulmonary fibrosis (IPF). We have reported that IL-17A induces epithelial injury via TGF-β in murine bronchiolitis obliterans; that TGF-β and the C' cascade present signaling interactions in mediating epithelial injury; and that the blockade of C' receptors mitigates lung fibrosis. In the present study, we investigated the role of IL-17A in regulating C' in lung fibrosis. Microarray analyses of mRNA isolated from primary normal human small airway epithelial cells indicated that IL-17A (100 ng/ml; 24 h; n = 5 donor lungs) induces C' components (C' factor B, C3 , and GPCR kinase isoform 5), cytokines ( IL8 , -6 , and -1B ), and cytokine ligands ( CXCL1 , -2 , -3 , -5 , -6 , and -16 ). IL-17A induces protein and mRNA regulation of C' components and the synthesis of active C' 3a (C3a) in normal primary human alveolar type II epithelial cells (AECs). Wild-type mice subjected to IL-17A neutralization and IL-17A knockout ( il17a -/- ) mice were protected against bleomycin (BLEO)-induced fibrosis and collagen deposition. Further, BLEO-injured il17a -/- mice had diminished levels of circulating Krebs Von Den Lungen 6 (alveolar epithelial injury marker), local caspase-3/7, and local endoplasmic reticular stress-related genes. BLEO-induced local C' activation [C3a, C5a, and terminal C' complex (C5b-9)] was attenuated in il17a -/- mice, and IL-17A neutralization prevented the loss of epithelial C' inhibitors (C' receptor-1 related isoform Y and decay accelerating factor), and an increase in local TUNEL levels. RNAi-mediated gene silencing of il17a in fibrotic mice arrested the progression of lung fibrosis, attenuated cellular apoptosis (caspase-3/7) and lung deposition of collagen and C' (C5b-9). Compared to normals, plasma from IPF patients showed significantly higher hemolytic activity. Our findings demonstrate that limiting complement activation by

  7. Resolvin D1 prevents smoking-induced emphysema and promotes lung tissue regeneration.

    Science.gov (United States)

    Kim, Kang-Hyun; Park, Tai Sun; Kim, You-Sun; Lee, Jae Seung; Oh, Yeon-Mok; Lee, Sang-Do; Lee, Sei Won

    2016-01-01

    Emphysema is an irreversible disease that is characterized by destruction of lung tissue as a result of inflammation caused by smoking. Resolvin D1 (RvD1), derived from docosahexaenoic acid, is a novel lipid that resolves inflammation. The present study tested whether RvD1 prevents smoking-induced emphysema and promotes lung tissue regeneration. C57BL/6 mice, 8 weeks of age, were randomly divided into four groups: control, RvD1 only, smoking only, and smoking with RvD1 administration. Four different protocols were used to induce emphysema and administer RvD1: mice were exposed to smoking for 4 weeks with poly(I:C) or to smoking only for 24 weeks, and RvD1 was injected within the smoking exposure period to prevent regeneration or after completion of smoking exposure to assess regeneration. The mean linear intercept and inflammation scores were measured in the lung tissue, and inflammatory cells and cytokines were measured in the bronchoalveolar lavage fluid. Measurements of mean linear intercept showed that RvD1 significantly attenuated smoking-induced lung destruction in all emphysema models. RvD1 also reduced smoking-induced inflammatory cell infiltration, which causes the structural derangements observed in emphysema. In the 4-week prevention model, RvD1 reduced the smoking-induced increase in eosinophils and interleukin-6 in the bronchoalveolar lavage fluid. In the 24-week prevention model, RvD1 also reduced the increased neutrophils and total cell counts induced by smoking. RvD1 attenuated smoking-induced emphysema in vivo by reducing inflammation and promoting tissue regeneration. This result suggests that RvD1 may be useful in the prevention and treatment of emphysema.

  8. History of Mechanical Ventilation. From Vesalius to Ventilator-induced Lung Injury.

    Science.gov (United States)

    Slutsky, Arthur S

    2015-05-15

    Mechanical ventilation is a life-saving therapy that catalyzed the development of modern intensive care units. The origins of modern mechanical ventilation can be traced back about five centuries to the seminal work of Andreas Vesalius. This article is a short history of mechanical ventilation, tracing its origins over the centuries to the present day. One of the great advances in ventilatory support over the past few decades has been the development of lung-protective ventilatory strategies, based on our understanding of the iatrogenic consequences of mechanical ventilation such as ventilator-induced lung injury. These strategies have markedly improved clinical outcomes in patients with respiratory failure.

  9. [Protective effect of curcumin on oleic-induced acute lung injury in rats].

    Science.gov (United States)

    Zhu, Rui-fang; Zhou, Min; He, Jian-lin; Ding, Fu-yun; Yu, Shu-qin; Xu, Guang-lin

    2008-09-01

    To investigate the effect of curcumine on acute lung injury induced by oleic acid in rat and the possible mechanism of action. The rats were divided into 6 groups randomly: normal group, control group, curcumine groups (5, 10, 20 mg x kg(-1)) and dexamethasone group (1 mg x kg(-1)). During the experiment, acute lung injury was induced by oleic acid in rat. The changes of dynamic lung compliance were recorded by anrise 2005 pulmonary function test apparatus, light microscope was used to examine histological changes and lung index as well as wet to dry weight ratio was calculated by weighting method. Lung vascular permeability and protein level in BALF were detected by ultraviolet spectrophotometry, and the concentrations of TNF-alpha, IL-6 and IL-10 in BALF were measured by enzyme linked immunosorbent assay (ELISA). The result showed that the changes of pulmonary compliance were inhibited and pulmonary function was improved by curcumine. The OA-induced elevation of lung index was restrained, as well as wet to dry weight ratio, lung vascular permeability, protein level, TNF-alpha (250.4 +/- 21.6 vs. 172.53 +/- 14.88, 122.2 +/- 10.98, 108.69 +/- 3.39) ng x L(-1), IL-6 (763.6 +/- 88.33 vs. 207.41 +/- 15.55, 172.13 +/- 21.91, 142.92 +/- 4.32) ng x L(-1) in BALF in curcumine groups, IL-10 (98.90 +/- 2.99 vs. 208.44 +/- 16.30, 218.43 +/- 6.23, 252.70 +/- 20.58) ng x L(-1) in BALF was increased, respectively significantly. Light microscope findings shown that the impairment in curcumine groups was far less severe than that in model groups. Pretreatment of curcumine showed beneficial effect on acute lung injury induced by oleic acid in rats. The mediation of both proinflammatory factor and anti-inflammatory factor by curcumine may be involved in mechanism of action of curcumine effects.

  10. Role of TNFR1 in lung injury and altered lung function induced by the model sulfur mustard vesicant, 2-chloroethyl ethyl sulfide

    International Nuclear Information System (INIS)

    Sunil, Vasanthi R.; Patel-Vayas, Kinal; Shen, Jianliang; Gow, Andrew J.; Laskin, Jeffrey D.; Laskin, Debra L.

    2011-01-01

    Lung toxicity induced by sulfur mustard is associated with inflammation and oxidative stress. To elucidate mechanisms mediating pulmonary damage, we used 2-chloroethyl ethyl sulfide (CEES), a model sulfur mustard vesicant. Male mice (B6129) were treated intratracheally with CEES (3 or 6 mg/kg) or control. Animals were sacrificed 3, 7 or 14 days later and bronchoalveolar lavage (BAL) fluid and lung tissue collected. Treatment of mice with CEES resulted in an increase in BAL protein, an indication of alveolar epithelial damage, within 3 days. Expression of Ym1, an oxidative stress marker also increased in the lung, along with inducible nitric oxide synthase, and at 14 days, cyclooxygenase-2 and monocyte chemotactic protein-1, inflammatory proteins implicated in tissue injury. These responses were attenuated in mice lacking the p55 receptor for TNFα (TNFR1-/-), demonstrating that signaling via TNFR1 is key to CEES-induced injury, oxidative stress, and inflammation. CEES-induced upregulation of CuZn-superoxide dismutase (SOD) and MnSOD was delayed or absent in TNFR1-/- mice, relative to WT mice, suggesting that TNFα mediates early antioxidant responses to lung toxicants. Treatment of WT mice with CEES also resulted in functional alterations in the lung including decreases in compliance and increases in elastance. Additionally, methacholine-induced alterations in total lung resistance and central airway resistance were dampened by CEES. Loss of TNFR1 resulted in blunted functional responses to CEES. These effects were most notable in the airways. These data suggest that targeting TNFα signaling may be useful in mitigating lung injury, inflammation and functional alterations induced by vesicants.

  11. Dexmedetomidine Attenuates Oxidative Stress Induced Lung Alveolar Epithelial Cell Apoptosis In Vitro

    Directory of Open Access Journals (Sweden)

    Jian Cui

    2015-01-01

    Full Text Available Background. Oxidative stress plays a pivotal role in the lung injuries of critical ill patients. This study investigates the protection conferred by α2 adrenoceptor agonist dexmedetomidine (Dex from lung alveolar epithelial cell injury induced by hydrogen peroxide (H2O2 and the underlying mechanisms. Methods. The lung alveolar epithelial cell line, A549, was cultured and then treated with 500 μM H2O2 with or without Dex (1 nM or Dex in combination with atipamezole (10 nM, an antagonist of α2 receptors. Their effect on mitochondrial membrane potential (Δψm, reactive oxygen species (ROS, and the cell cycle was assessed by flow cytometry. Cleaved-caspases 3 and 9, BAX, Bcl-2, phospho-mTOR (p-mTOR, ERK1/2, and E-cadherin expression were also determined with immunocytochemistry. Results. Upregulation of cleaved-caspases 3 and 9 and BAX and downregulation of Bcl-2, p-mTOR, and E-cadherin were found following H2O2 treatment, and all of these were reversed by Dex. Dex also prevented the ROS generation, cytochrome C release, and cell cycle arrest induced by H2O2. The effects of Dex were partially reversed by atipamezole. Conclusion. Our study demonstrated that Dex protected lung alveolar epithelial cells from apoptotic injury, cell cycle arrest, and loss of cell adhesion induced by H2O2 through enhancing the cell survival and proliferation.

  12. Does granulocyte colony-stimulating factor exacerbate radiation-induced acute lung injury in rats?

    International Nuclear Information System (INIS)

    Miura, Gouji; Awaya, Hitomi; Matsumoto, Tsuneo; Tanaka, Nobuyuki; Matsunaga, Naofumi

    2000-01-01

    Radiation pneumonitis (RP) frequently occurs as a complication of thoracic irradiation. However, the mechanism of RP is not well known. Activated neutrophils are a possible pathogenesis of RP. Neutrophil activation induced by granulocyte colony-stimulating factor (G-CSF) may exacerbate RP. We studied the effects of recombinant human G-CSF on acute lung injury induced by thoracic irradiation using rats. Animals were divided into three groups: sham irradiation with saline control, irradiation alone, and irradiation with G-CSF. Actual irradiation was given as a single fraction of 16 Gy delivered to the right hemithorax. G-CSF at a dose of 12 μg/body was administered subcutaneously once a day from 14 to 18 days after actual irradiation. Lung injury was evaluated 21 days after irradiation by bronchoalveolar lavage (BAL) fluid findings and the lung wet/dry weight (W/D) ratio. Neutrophil and lymphocyte counts in BAL fluid and the W/D ratio were significantly increased in the irradiation alone and the irradiation with G-CSF groups compared with those of the sham irradiation+saline control group. However, there was no significant difference observed between the irradiation alone and irradiation with G-CSF groups. In conclusion, this study suggests that postradiation administration of G-CSF does not exacerbate acute lung injury induced by thoracic irradiation in rats. (author)

  13. Activation of PPARα by Wy-14643 ameliorates systemic lipopolysaccharide-induced acute lung injury

    Energy Technology Data Exchange (ETDEWEB)

    Yoo, Seong Ho, E-mail: yoosh@snu.ac.kr [Seoul National University Hospital, Biomedical Research Institute and Institute of Forensic Medicine, Seoul National University College of Medicine, Seoul (Korea, Republic of); Abdelmegeed, Mohamed A. [Laboratory of Membrane Biochemistry and Biophysics, National Institute on Alcohol Abuse and Alcoholism, Bethesda, MD (United States); Song, Byoung-Joon, E-mail: bj.song@nih.gov [Laboratory of Membrane Biochemistry and Biophysics, National Institute on Alcohol Abuse and Alcoholism, Bethesda, MD (United States)

    2013-07-05

    Highlights: •Activation of PPARα attenuated LPS-mediated acute lung injury. •Pretreatment with Wy-14643 decreased the levels of IFN-γ and IL-6 in ALI. •Nitrosative stress and lipid peroxidation were downregulated by PPARα activation. •PPARα agonists may be potential therapeutic targets for acute lung injury. -- Abstract: Acute lung injury (ALI) is a major cause of mortality and morbidity worldwide. The activation of peroxisome proliferator-activated receptor-α (PPARα) by its ligands, which include Wy-14643, has been implicated as a potential anti-inflammatory therapy. To address the beneficial efficacy of Wy-14643 for ALI along with systemic inflammation, the in vivo role of PPARα activation was investigated in a mouse model of lipopolysaccharide (LPS)-induced ALI. Using age-matched Ppara-null and wild-type mice, we demonstrate that the activation of PPARα by Wy-14643 attenuated LPS-mediated ALI. This was evidenced histologically by the significant alleviation of inflammatory manifestations and apoptosis observed in the lung tissues of wild-type mice, but not in the corresponding Ppara-null mice. This protective effect probably resulted from the inhibition of LPS-induced increases in pro-inflammatory cytokines and nitroxidative stress levels. These results suggest that the pharmacological activation of PPARα might have a therapeutic effect on LPS-induced ALI.

  14. Activation of PPARα by Wy-14643 ameliorates systemic lipopolysaccharide-induced acute lung injury

    International Nuclear Information System (INIS)

    Yoo, Seong Ho; Abdelmegeed, Mohamed A.; Song, Byoung-Joon

    2013-01-01

    Highlights: •Activation of PPARα attenuated LPS-mediated acute lung injury. •Pretreatment with Wy-14643 decreased the levels of IFN-γ and IL-6 in ALI. •Nitrosative stress and lipid peroxidation were downregulated by PPARα activation. •PPARα agonists may be potential therapeutic targets for acute lung injury. -- Abstract: Acute lung injury (ALI) is a major cause of mortality and morbidity worldwide. The activation of peroxisome proliferator-activated receptor-α (PPARα) by its ligands, which include Wy-14643, has been implicated as a potential anti-inflammatory therapy. To address the beneficial efficacy of Wy-14643 for ALI along with systemic inflammation, the in vivo role of PPARα activation was investigated in a mouse model of lipopolysaccharide (LPS)-induced ALI. Using age-matched Ppara-null and wild-type mice, we demonstrate that the activation of PPARα by Wy-14643 attenuated LPS-mediated ALI. This was evidenced histologically by the significant alleviation of inflammatory manifestations and apoptosis observed in the lung tissues of wild-type mice, but not in the corresponding Ppara-null mice. This protective effect probably resulted from the inhibition of LPS-induced increases in pro-inflammatory cytokines and nitroxidative stress levels. These results suggest that the pharmacological activation of PPARα might have a therapeutic effect on LPS-induced ALI

  15. Innate type 2 response to Alternaria extract enhances ryegrass-induced lung inflammation.

    Science.gov (United States)

    Kim, Hee-Kyoo; Lund, Sean; Baum, Rachel; Rosenthal, Peter; Khorram, Naseem; Doherty, Taylor A

    2014-01-01

    Exposure to the fungal allergen Alternaria alternata as well as ryegrass pollen has been implicated in severe asthma symptoms during thunderstorms. We have previously shown that Alternaria extract induces innate type 2 lung inflammation in mice. We hypothesized that the innate eosinophilic response to Alternaria extract may enhance lung inflammation induced by ryegrass. Mice were sensitized to ryegrass allergen and administered a single challenge with A. alternata extract before or after final ryegrass challenges. Levels of eosinophils, neutrophils, Th2 cells, innate lymphoid cells (ILC2), interleukin (IL)-5 and IL-13 in bronchoalveolar lavage (BAL) as well as inflammation and mucus were assessed. Mice receiving ryegrass sensitization and challenge developed an eosinophilic lung response. A single challenge with Alternaria extract given 3 days before or 3 days after ryegrass challenges resulted in increased eosinophils, peribronchial inflammation and mucus production in the airways compared with ryegrass-only challenges. Type 2 ILC2 and Th2 cell recruitment to the airways was increased after Alternaria extract exposure in ryegrass-challenged mice. Innate immune challenges with Alternaria extract induced BAL eosinophilia, Th2 cell recruitment as well as ILC2 expansion and proliferation. A single exposure to Alternaria extract in ryegrass-sensitized and -challenged mice enhances the type 2 lung inflammatory response, including airway eosinophilia, peribronchial infiltrate, and mucus production, possibly through Th2 cell recruitment and ILC2 expansion. If translated to humans, exposure to both grass pollen and Alternaria may be a potential cause of thunderstorm-related asthma.

  16. Innate Type-2 Response to Alternaria Extract Enhances Ryegrass-induced Lung Inflammation

    Science.gov (United States)

    Kim, Hee-Kyoo; Lund, Sean; Baum, Rachel; Rosenthal, Peter; Khorram, Naseem; Doherty, Taylor A.

    2014-01-01

    Background Exposure to the fungal allergen Alternaria alternata as well as ryegrass pollen has been implicated in severe asthma symptoms during thunderstorms. We have previously shown that Alternaria extract induces innate type 2 lung inflammation in mice. We hypothesized that the innate eosinophilic response to Alternaria extract may enhance lung inflammation induced by ryegrass. Methods Mice were sensitized to ryegrass allergen and administered a single challenge with Alternaria alternata extract before or after final ryegrass challenges. Levels of BAL eosinophils, neutrophils, Th2 cells, innate lymphoid cells (ILC2), IL-5 and IL-13 as well as inflammation and mucus were assessed. Results Mice receiving ryegrass sensitization and challenge developed an eosinophilic lung response. A single challenge with Alternaria extract given 3 days before or 3 days after ryegrass challenges resulted in increased eosinophils, peribronchial inflammation and mucus production in the airway compared with ryegrass only challenges. Type 2 innate lymphoid cell (ILC2) and Th2 cell recruitment to the airway was increased after Alternaria extract exposure in ryegrass challenged mice. Innate challenges with Alternaria extract induced BAL eosinophilia, Th2 cell recruitment as well as ILC2 expansion and proliferation. Conclusions A single exposure of Alternaria extract in ryegrass sensitized and challenged mice enhances the type-2 lung inflammatory response including airway eosinophilia, peribronchial infiltrate, and mucus production possibly through Th2 cell recruitment and ILC2 expansion. If translated to humans, exposures to both grass pollen and Alternaria may be a potential cause of thunderstorm-related asthma. PMID:24296722

  17. Detection of radiation-induced lung injury using hyperpolarized (13)C magnetic resonance spectroscopy and imaging.

    Science.gov (United States)

    Thind, K; Chen, A; Friesen-Waldner, L; Ouriadov, A; Scholl, T J; Fox, M; Wong, E; VanDyk, J; Hope, A; Santyr, G

    2013-09-01

    Radiation-induced lung injury limits radiotherapy of thoracic cancers. Detection of radiation pneumonitis associated with early radiation-induced lung injury (2-4 weeks postirradiation) may provide an opportunity to adjust treatment, before the onset of acute pneumonitis and/or irreversible fibrosis. In this study, localized magnetic resonance (MR) spectroscopy and imaging of hyperpolarized (13)C-pyruvate (pyruvate) and (13)C-lactate (lactate) were performed in the thorax and kidney regions of rats 2 weeks following whole-thorax irradiation (14 Gy). Lactate-to-pyruvate signal ratio was observed to increase by 110% (P radiated rats compared with healthy age-matched rats. This was consistent with lung inflammation confirmed using cell micrographs of bronchioalveolar lavage specimens and decreases in arterial oxygen partial pressure (paO2), indicative of hypoxia. No statistically significant difference was observed in either lactate-to-pyruvate signal ratios in the kidney region (P = 0.50) between the healthy (0.215 ± 0.100) and radiated cohorts (0.215 ± 0.054) or in blood lactate levels (P = 0.69) in the healthy (1.255 ± 0.247 mmol/L) and the radiated cohorts (1.325 ± 0.214 mmol/L), confirming that the injury is localized to the thorax. This work demonstrates the feasibility of hyperpolarized (13)C metabolic MR spectroscopy and imaging for detection of early radiation-induced lung injury. Copyright © 2012 Wiley Periodicals, Inc.

  18. Does granulocyte colony-stimulating factor exacerbate radiation-induced acute lung injury in rats?

    Energy Technology Data Exchange (ETDEWEB)

    Miura, Gouji; Awaya, Hitomi; Matsumoto, Tsuneo; Tanaka, Nobuyuki; Matsunaga, Naofumi [Yamaguchi Univ., Ube (Japan). School of Medicine

    2000-08-01

    Radiation pneumonitis (RP) frequently occurs as a complication of thoracic irradiation. However, the mechanism of RP is not well known. Activated neutrophils are a possible pathogenesis of RP. Neutrophil activation induced by granulocyte colony-stimulating factor (G-CSF) may exacerbate RP. We studied the effects of recombinant human G-CSF on acute lung injury induced by thoracic irradiation using rats. Animals were divided into three groups: sham irradiation with saline control, irradiation alone, and irradiation with G-CSF. Actual irradiation was given as a single fraction of 16 Gy delivered to the right hemithorax. G-CSF at a dose of 12 {mu}g/body was administered subcutaneously once a day from 14 to 18 days after actual irradiation. Lung injury was evaluated 21 days after irradiation by bronchoalveolar lavage (BAL) fluid findings and the lung wet/dry weight (W/D) ratio. Neutrophil and lymphocyte counts in BAL fluid and the W/D ratio were significantly increased in the irradiation alone and the irradiation with G-CSF groups compared with those of the sham irradiation+saline control group. However, there was no significant difference observed between the irradiation alone and irradiation with G-CSF groups. In conclusion, this study suggests that postradiation administration of G-CSF does not exacerbate acute lung injury induced by thoracic irradiation in rats. (author)

  19. Geranylgeranylacetone alleviates radiation-induced lung injury by inhibiting epithelial-to-mesenchymal transition signaling.

    Science.gov (United States)

    Kim, Joong-Sun; Son, Yeonghoon; Jung, Myung-Gu; Jeong, Ye Ji; Kim, Sung-Ho; Lee, Su-Jae; Lee, Yoon-Jin; Lee, Hae-June

    2016-06-01

    Radiation-induced lung injury (RILI) involves pneumonitis and fibrosis, and results in pulmonary dysfunction. Moreover, RILI can be a fatal complication of thoracic radiotherapy. The present study investigated the protective effect of geranylgeranlyacetone (GGA), an inducer of heat shock protein (HSP)70, on RILI using a C57BL/6 mouse model of RILI developing 6 months subsequent to exposure to 12.5 Gy thoracic radiation. GGA was administered 5 times orally prior and subsequent to radiation exposure, and the results were assessed by histological analysis and western blotting. The results show that late RILI was alleviated by GGA treatment, possibly through the suppression of epithelial‑to‑mesenchymal transition (EMT) marker expression. Based on histological examination, orally administered GGA during the acute phase of radiation injury not only significantly inhibited pro‑surfactant protein C (pro‑SPC) and vimentin expression, but also preserved E‑cadherin expression 6 months after irradiation‑induced injury of the lungs. GGA induced HSP70 and inhibited EMT marker expression in L132 human lung epithelial cells following IR. These data suggest that the prevention of EMT signaling is a key cytoprotective effect in the context of RILI. Thus, HSP70‑inducing drugs, such as GGA, could be beneficial for protection against RILI.

  20. Mechanisms of lung endothelial barrier disruption induced by cigarette smoke: role of oxidative stress and ceramides.

    Science.gov (United States)

    Schweitzer, Kelly S; Hatoum, Hadi; Brown, Mary Beth; Gupta, Mehak; Justice, Matthew J; Beteck, Besem; Van Demark, Mary; Gu, Yuan; Presson, Robert G; Hubbard, Walter C; Petrache, Irina

    2011-12-01

    The epithelial and endothelial cells lining the alveolus form a barrier essential for the preservation of the lung respiratory function, which is, however, vulnerable to excessive oxidative, inflammatory, and apoptotic insults. Whereas profound breaches in this barrier function cause pulmonary edema, more subtle changes may contribute to inflammation. The mechanisms by which cigarette smoke (CS) exposure induce lung inflammation are not fully understood, but an early alteration in the epithelial barrier function has been documented. We sought to investigate the occurrence and mechanisms by which soluble components of mainstream CS disrupt the lung endothelial cell barrier function. Using cultured primary rat microvascular cell monolayers, we report that CS induces endothelial cell barrier disruption in a dose- and time-dependent manner of similar magnitude to that of the epithelial cell barrier. CS exposure triggered a mechanism of neutral sphingomyelinase-mediated ceramide upregulation and p38 MAPK and JNK activation that were oxidative stress dependent and that, along with Rho kinase activation, mediated the endothelial barrier dysfunction. The morphological changes in endothelial cell monolayers induced by CS included actin cytoskeletal rearrangement, junctional protein zonula occludens-1 loss, and intercellular gap formation, which were abolished by the glutathione modulator N-acetylcysteine and ameliorated by neutral sphingomyelinase inhibition. The direct application of ceramide recapitulated the effects of CS, by disrupting both endothelial and epithelial cells barrier, by a mechanism that was redox and apoptosis independent and required Rho kinase activation. Furthermore, ceramide induced dose-dependent alterations of alveolar microcirculatory barrier in vivo, measured by two-photon excitation microscopy in the intact rat. In conclusion, soluble components of CS have direct endothelial barrier-disruptive effects that could be ameliorated by glutathione

  1. Diet-induced obesity reprograms the inflammatory response of the murine lung to inhaled endotoxin

    International Nuclear Information System (INIS)

    Tilton, Susan C.; Waters, Katrina M.; Karin, Norman J.; Webb-Robertson, Bobbie-Jo M.; Zangar, Richard C.; Lee, K. Monica; Bigelow, Diana J.; Pounds, Joel G.; Corley, Richard A.

    2013-01-01

    The co-occurrence of environmental factors is common in complex human diseases and, as such, understanding the molecular responses involved is essential to determine risk and susceptibility to disease. We have investigated the key biological pathways that define susceptibility for pulmonary infection during obesity in diet-induced obese (DIO) and regular weight (RW) C57BL/6 mice exposed to inhaled lipopolysaccharide (LPS). LPS induced a strong inflammatory response in all mice as indicated by elevated cell counts of macrophages and neutrophils and levels of proinflammatory cytokines (MDC, MIP-1γ, IL-12, RANTES) in the bronchoalveolar lavage fluid. Additionally, DIO mice exhibited 50% greater macrophage cell counts, but decreased levels of the cytokines, IL-6, TARC, TNF-α, and VEGF relative to RW mice. Microarray analysis of lung tissue showed over half of the LPS-induced expression in DIO mice consisted of genes unique for obese mice, suggesting that obesity reprograms how the lung responds to subsequent insult. In particular, we found that obese animals exposed to LPS have gene signatures showing increased inflammatory and oxidative stress response and decreased antioxidant capacity compared with RW. Because signaling pathways for these responses can be common to various sources of environmentally induced lung damage, we further identified biomarkers that are indicative of specific toxicant exposure by comparing gene signatures after LPS exposure to those from a parallel study with cigarette smoke. These data show obesity may increase sensitivity to further insult and that co-occurrence of environmental stressors result in complex biosignatures that are not predicted from analysis of individual exposures. - Highlights: ► Obesity modulates inflammatory markers in BAL fluid after LPS exposure. ► Obese animals have a unique transcriptional signature in lung after LPS exposure. ► Obesity elevates inflammatory stress and reduces antioxidant capacity in the lung

  2. Enhanced cough reflex in a model of bleomycin-induced lung fibrosis in guinea pigs.

    Science.gov (United States)

    Fernández-Blanco, Joan Antoni; Aguilera, Mònica; Domènech, Anna; Tarrasón, Gema; Prats, Neus; Miralpeix, Montse; De Alba, Jorge

    2015-12-01

    Fibrotic lung diseases, such as idiopathic pulmonary fibrosis, are associated with spontaneous dry cough and hypersensitivity to tussive agents. Understanding the pathophysiology driving enhanced cough may help us to define better therapies for patients. We hypothesized that lung fibrosis induced by intratracheal bleomycin would exacerbate the cough reflex induced by tussive agents in guinea pigs. Disease progression in the lungs was characterized at days 1, 7, 14, 21 and 28 after bleomycin administration. Inflammatory and fibrotic markers, as well as neurotrophin levels, were assessed in bronchoalveolar lavage fluid and/or lung tissue. Cough sensitivity to citric acid, capsaicin and allylisothiocyanate was evaluated in conscious animals at days 14 and 21 after bleomycin administration. Pulmonary lesions evolved from an early inflammatory phase (from day 1 to day 7) to a fibrotic stage (between days 14 and 28). Fibrosis was related to increased levels of matrix metalloproteinase-2 in bronchoalveolar lavage fluid (day 21: saline, 0.26 ng/ml; bleomycin, 0.49 ng/ml). At day 14, we also observed increased cough reflexes to citric acid (163%), capsaicin (125%) and allylisothiocyanate (178%). Cough exacerbation persisted, but at a lower extent, by day 21 for capsaicin (100%) and allylisothiocyanate (54%). Moreover, bronchoalveolar lavage fluid concentrations of brain-derived neurotrophic factor, suggested to induce nerve remodelling in chronic cough, were also enhanced (day 1: saline, 14.21 pg/ml; bleomycin, 30.09 pg/ml). In summary, our model of bleomycin-induced cough exacerbation may be a valuable tool to investigate cough hypersensitivity and develop antitussive therapies for fibrotic lung diseases. © 2015 Authors; published by Portland Press Limited.

  3. Diet-induced obesity reprograms the inflammatory response of the murine lung to inhaled endotoxin

    Energy Technology Data Exchange (ETDEWEB)

    Tilton, Susan C., E-mail: susan.tilton@pnnl.gov [Pacific Northwest National Laboratory, Richland, WA 99352 (United States); Waters, Katrina M.; Karin, Norman J.; Webb-Robertson, Bobbie-Jo M.; Zangar, Richard C. [Pacific Northwest National Laboratory, Richland, WA 99352 (United States); Lee, K. Monica [Battelle Toxicology Northwest, Richland, WA 99352 (United States); Bigelow, Diana J.; Pounds, Joel G.; Corley, Richard A. [Pacific Northwest National Laboratory, Richland, WA 99352 (United States)

    2013-03-01

    The co-occurrence of environmental factors is common in complex human diseases and, as such, understanding the molecular responses involved is essential to determine risk and susceptibility to disease. We have investigated the key biological pathways that define susceptibility for pulmonary infection during obesity in diet-induced obese (DIO) and regular weight (RW) C57BL/6 mice exposed to inhaled lipopolysaccharide (LPS). LPS induced a strong inflammatory response in all mice as indicated by elevated cell counts of macrophages and neutrophils and levels of proinflammatory cytokines (MDC, MIP-1γ, IL-12, RANTES) in the bronchoalveolar lavage fluid. Additionally, DIO mice exhibited 50% greater macrophage cell counts, but decreased levels of the cytokines, IL-6, TARC, TNF-α, and VEGF relative to RW mice. Microarray analysis of lung tissue showed over half of the LPS-induced expression in DIO mice consisted of genes unique for obese mice, suggesting that obesity reprograms how the lung responds to subsequent insult. In particular, we found that obese animals exposed to LPS have gene signatures showing increased inflammatory and oxidative stress response and decreased antioxidant capacity compared with RW. Because signaling pathways for these responses can be common to various sources of environmentally induced lung damage, we further identified biomarkers that are indicative of specific toxicant exposure by comparing gene signatures after LPS exposure to those from a parallel study with cigarette smoke. These data show obesity may increase sensitivity to further insult and that co-occurrence of environmental stressors result in complex biosignatures that are not predicted from analysis of individual exposures. - Highlights: ► Obesity modulates inflammatory markers in BAL fluid after LPS exposure. ► Obese animals have a unique transcriptional signature in lung after LPS exposure. ► Obesity elevates inflammatory stress and reduces antioxidant capacity in the lung

  4. Bile acids induce activation of alveolar epithelial cells and lung fibroblasts through farnesoid X receptor-dependent and independent pathways.

    Science.gov (United States)

    Chen, Bi; Cai, Hou-Rong; Xue, Shan; You, Wen-Jie; Liu, Bin; Jiang, Han-Dong

    2016-08-01

    The roles of bile acid microaspiration and bile acid-activated farnesoid X receptor (FXR) in the pathogenesis of idiopathic pulmonary fibrosis (IPF) remain unclear. We hypothesized that bile acids activate alveolar epithelial cells (AECs) and lung fibroblasts, which may be regulated by FXR activation. Human AECs and normal or IPF-derived lung fibroblast cells were incubated with the three major bile acids: lithocholic acid (LCA), deoxycholic acid (DCA) and chenodeoxycholic acid (CDCA). The AECs injury indices, epithelial-mesenchymal transition (EMT) and lung fibroblast activation were evaluated. FXR expression in IPF lungs and the roles of FXR and FXR-independent pathways in bile acid-induced profibrotic effects were also investigated. LCA, DCA and CDCA reduced cell viability and increased intracellular reactive oxygen species (ROS) production in A549 cells. They all induced EMT, as shown by enhanced α-SMA and vimentin and decreased E-cadherin levels. LCA directly induced differentiation of lung fibroblasts to myofibroblasts. All three bile acids promoted cellular migration but not proliferation of lung fibroblasts. FXR expression was upregulated in IPF lungs, and inhibition of FXR restrained the bile acid-induced EMT and lung fibroblast activation. Differentiation and proliferation were enhanced in lung fibroblasts exposed to conditioned medium from bile acid-stimulated A549 cells, which contained increased levels of profibrotic factors. TGF-β/Smad3 signaling was also involved in the bile acid-induced EMT and lung fibroblast differentiation. Bile acid microaspiration may promote the development of pulmonary fibrosis by inducing activation of AECs and lung fibroblasts via FXR-dependent and independent pathways. © 2016 Asian Pacific Society of Respirology.

  5. Ketamine attenuates sepsis-induced acute lung injury via regulation of HMGB1-RAGE pathways.

    Science.gov (United States)

    Li, Kehan; Yang, Jianxue; Han, Xuechang

    2016-05-01

    High mobility group box protein 1 (HMGB1) and receptor for the advanced glycation end product (RAGE) play important roles in the development of sepsis-induced acute lung injury (ALI). Ketamine is considered to confer protective effects on ALI during sepsis. In this study, we investigated the effects of ketamine on HMGB1-RAGE activation in a rat model of sepsis-induced ALI. ALI was induced in wild type (WT) and RAGE deficient (RAGE(-/-)) rats by cecal ligation and puncture (CLP) or HMGB1 to mimic sepsis-induced ALI. Rats were randomly divided to six groups: sham-operation+normal saline (NS, 10 mL/kg), sham-operation+ketamine (10 mg/kg), CLP/HMGB1+NS (10 mL/kg), CLP/HMGB1+ketamine (5 mg/kg), CLP/HMGB1+ketamine (7.5 mg/kg), and CLP/HMGB1+ketamine (10 mg/kg) groups. NS and ketamine were administered at 3 and 12 h after CLP/HMGB1 via intraperitoneal injection. Pathological changes of lung, inflammatory cell counts, expression of HMGB1 and RAGE, and concentrations of various inflammatory mediators in bronchoalveolar lavage fluids (BALF) and lung tissue were then assessed. Nuclear factor-kappa B (NF-κB) and mitogen-activated protein kinases (MAPK) signaling pathways in the lung were also evaluated. CLP/HMGB1 increased the wet to dry weight ratio and myeloperoxidase activity in lung, the number of total cells, neutrophils, and macrophages in the BALF, and inflammatory mediators in the BALF and lung tissues. Moreover, expression of HMGB1 and RAGE in lung tissues was increased after CLP. Ketamine inhibited all the above effects. It also inhibited the activation of IκB-α, NF-κB p65, and MAPK. Ketamine protects rats against HMGB1-RAGE activation in a rat model of sepsis-induced ALI. These effects may partially result from reductions in NF-κB and MAPK. Crown Copyright © 2016. Published by Elsevier B.V. All rights reserved.

  6. Capillary Pressure-induced Lung Injury: Fact or Fiction?

    African Journals Online (AJOL)

    QuickSilver

    2003-05-07

    May 7, 2003 ... initial safety factor, the low interstitial compliance, which coun- teracts the further progression of ... the release thromboxane A2 and by alveolar hypoxia following hydrostatic oedema. Promising clinical ... monary gene transfer of endothelial or inducible nitric oxide synthase. The rise in intra-cellular calcium ...

  7. Pyrrolidine Dithiocarbamate Attenuates Paraquat-Induced Lung Injury in Rats

    Directory of Open Access Journals (Sweden)

    Xiuli Chang

    2009-01-01

    PQ+PDTC-treated groups than that of PQ-treated groups (P<.05. The histopathological changes in the PQ+PDTC-treated groups were milder than those of PQ groups. Our results suggested that PDTC treatment significantly attenuated paraquat-induced pulmonary damage.

  8. Methylene Blue in Ventilator-Induced Lung Injury after Pneumonectomy: an Experimental Study

    Directory of Open Access Journals (Sweden)

    Ye. V Suborov

    2007-01-01

    Full Text Available Objective: to study the expediency and efficiency of using methylene blue (MB on a model of pneumectomy (PE and subsequent ventilator-induced lung injury (VILI in sheep. Materials and methods. The study was conducted at the Research Laboratory of University of Tromse. The experiment included 23 sheep weighing 41.0±4.9 kg. Thoracotomy and right-sided pneumonectomy were performed in the animals under general anesthesia and controlled artificial ventilation. After measurement of the parameters of systemic hemodynamics and extravascular water of the lung (EVWL, the animals were divided into 3 groups: 1 a control group (CG, n=7 with a tidal volume (TV of 6 ml/kg and an end-expiratory positive pressure (PEEP of 2 cm H2O; 2 a VILI group (n=9 with a TV of 12 ml/kg and a PEEP of 0 cm H2O; 3 a group of MB (n=7 that was given in parallel with a damaging ventilation mode. The thermodilution technique (using a Cold Z-021 monitor, (Pulsion, Germany was employed to measure volumetric parameters and EVWL. The parameters of pulmonary hemodynamics, respiratory mechanics, and blood gas composition were recorded. Results: After its reduction at PE, EVWL index increased during damaging ventilation in the VILI and MB groups. In addition, there was an increase in pulmonary artery wedge pressure after PE in the MB and VILI groups. In the latter group, arterial hypoxemia was observed at the end of the experiment. Along with this, after PE pulmonary compliance decreased and airway pressure elevated in the VILI and MB groups. Conclusion: In the presented model of VILI, MB does not prevent the development of postp-neumectomic edema of the lung. Key words: thermochromodilution, acute lung injury, pneumectomy, ventilator-induced lung injury, postpneumectomic edema of the lung, methylene blue.

  9. Sulforaphane-induced apoptosis in Xuanwei lung adenocarcinoma cell line XWLC-05.

    Science.gov (United States)

    Zhou, Lan; Yao, Qian; Li, Yan; Huang, Yun-Chao; Jiang, Hua; Wang, Chuan-Qiong; Fan, Lei

    2017-01-01

    Xuanwei district in Yunnan Province has the highest incidence of lung cancer in China, especially among non-smoking women. Cruciferous vegetables can reduce lung cancer risk by prompting a protective mechanism against respiratory tract inflammation caused by air pollution, and are rich in sulforaphane, which can induce changes in gene expression. We investigated the effect of sulforaphane-induced apoptosis in Xuanwei lung adenocarcinoma cell line (XWCL-05) to explore the value of sulforaphane in lung cancer prevention and treatment. Cell growth inhibition was determined by methyl thiazolyl tetrazolium assay; cell morphology and apoptosis were observed under transmission electron microscope; cell cycle and apoptosis rates were detected using flow cytometry; B-cell lymphoma 2 (Bcl-2) and Bcl-2-like protein 4 (Bax) messenger RNA expression were determined by quantitative PCR; and p53, p73, p53 upregulated modulator of apoptosis (PUMA), Bax, Bcl-2, and caspase-9 protein expression were detected by Western blotting. Sulforaphane inhibited XWLC-05 cell growth with inhibitory concentration (IC) 50 of 4.04, 3.38, and 3.02 μg/mL at 24, 48, and 72 hours, respectively. Sulforaphane affected the XWLC-05 cell cycle as cells accumulated in the G2/M phase. The proportion of apoptotic cells observed was 27.6%. Compared with the control, the sulforaphane group showed decreased Bcl-2 and p53 expression, and significantly increased p73, PUMA, Bax, and caspase-9 protein expression (P cell apoptosis. Its possible mechanism may involve the upregulation of p73 expression and its effector target genes PUMA and Bax in lung cancer cells, downregulation of the anti-apoptotic gene B cl -2, and activation of caspase-9. It may also involve downregulation of the mutant p53 protein. © 2016 The Authors. Thoracic Cancer published by China Lung Oncology Group and John Wiley & Sons Australia, Ltd.

  10. Multiple exposures to swine barn air induce lung inflammation and airway hyper-responsiveness

    Directory of Open Access Journals (Sweden)

    Willson Philip

    2005-06-01

    Full Text Available Abstract Background Swine farmers repeatedly exposed to the barn air suffer from respiratory diseases. However the mechanisms of lung dysfunction following repeated exposures to the barn air are still largely unknown. Therefore, we tested a hypothesis in a rat model that multiple interrupted exposures to the barn air will cause chronic lung inflammation and decline in lung function. Methods Rats were exposed either to swine barn (8 hours/day for either one or five or 20 days or ambient air. After the exposure periods, airway hyper-responsiveness (AHR to methacholine (Mch was measured and rats were euthanized to collect bronchoalveolar lavage fluid (BALF, blood and lung tissues. Barn air was sampled to determine endotoxin levels and microbial load. Results The air in the barn used in this study had a very high concentration of endotoxin (15361.75 ± 7712.16 EU/m3. Rats exposed to barn air for one and five days showed increase in AHR compared to the 20-day exposed and controls. Lungs from the exposed groups were inflamed as indicated by recruitment of neutrophils in all three exposed groups and eosinophils and an increase in numbers of airway epithelial goblet cells in 5- and 20-day exposure groups. Rats exposed to the barn air for one day or 20 days had more total leukocytes in the BALF and 20-day exposed rats had more airway epithelial goblet cells compared to the controls and those subjected to 1 and 5 exposures (P Conclusion We conclude that multiple exposures to endotoxin-containing swine barn air induce AHR, increase in mucus-containing airway epithelial cells and lung inflammation. The data also show that prolonged multiple exposures may also induce adaptation in AHR response in the exposed subjects.

  11. Targeted deletion of Nrf2 reduces urethane-induced lung tumor development in mice.

    Directory of Open Access Journals (Sweden)

    Alison K Bauer

    Full Text Available Nrf2 is a key transcription factor that regulates cellular redox and defense responses. However, permanent Nrf2 activation in human lung carcinomas promotes pulmonary malignancy and chemoresistance. We tested the hypothesis that Nrf2 has cell survival properties and lack of Nrf2 suppresses chemically-induced pulmonary neoplasia by treating Nrf2(+/+ and Nrf2(-/- mice with urethane. Airway inflammation and injury were assessed by bronchoalveolar lavage analyses and histopathology, and lung tumors were analyzed by gross and histologic analysis. We used transcriptomics to assess Nrf2-dependent changes in pulmonary gene transcripts at multiple stages of neoplasia. Lung hyperpermeability, cell death and apoptosis, and inflammatory cell infiltration were significantly higher in Nrf2(-/- mice compared to Nrf2(+/+ mice 9 and 11 wk after urethane. Significantly fewer lung adenomas were found in Nrf2(-/- mice than in Nrf2(+/+ mice at 12 and 22 wk. Nrf2 modulated expression of genes involved cell-cell signaling, glutathione metabolism and oxidative stress response, and immune responses during early stage neoplasia. In lung tumors, Nrf2-altered genes had roles in transcriptional regulation of cell cycle and proliferation, carcinogenesis, organismal injury and abnormalities, xenobiotic metabolism, and cell-cell signaling genes. Collectively, Nrf2 deficiency decreased susceptibility to urethane-induced lung tumorigenesis in mice. Cell survival properties of Nrf2 were supported, at least in part, by reduced early death of initiated cells and heightened advantage for tumor cell expansion in Nrf2(+/+ mice relative to Nrf2(-/- mice. Our results were consistent with the concept that Nrf2 over-activation is an adaptive response of cancer conferring resistance to anti-cancer drugs and promoting malignancy.

  12. Inflammation in lung after acute myocardial infarction is induced by dendritic cell-mediated immune response.

    Science.gov (United States)

    Hu, L J; Ren, W Y; Shen, Q J; Ji, H Y; Zhu, L

    2017-01-01

    The present study was performed to describe the changes of lung tissues in mice with acute myocardial infarction (AMI) and also explain the cell mechanism involved in inflammation in lung. AMI was established by left coronary ligation in mice. Then mice were divided into three groups: control group, MW1 group (sampling after surgery for one week) and MW2 group (sampling after surgery for two weeks). Afterwards, measurement of lung weight and lung histology, cell sorting in bronchoalveolar lavage (BAL) fluid and detection of several adhesive molecules, inflammatory molecules as well as enzyme associated with inflammation were performed. Moreover, dendritic cells (DCs) were isolated from bone marrow of C57B/L6 mice. After incubating with necrotic myocardium, the expression of antigen presenting molecules, co-stimulatory molecules and inflammatory molecules were detected by flow cytometry or immunohistochemistry in DCs. We also detected T-cell proliferation after incubating with necrotic myocardium-treated DCs. AMI induced pathological changes of lung tissue and increased inflammatory cell amount in BAL fluid. AMI also increased the expression of several inflammatory factors, adhesive molecules and enzymes associated with inflammation. CD11c and TLR9, which are DC surface markers, showed a significantly increased expression in mice with AMI. Additionally, necrotic myocardium significantly increased the expression of co-stimulatory factors including CD83 and CD80, inflammatory cytokines including TNF-α, IFN-γ and NF-κB in DCs. Furthermore, DCs treated with necrotic myocardium also significantly promoted T-cell proliferation. AMI induced inflammation in lung and these pathological changes were mediated by DC-associated immune response.

  13. Cigarette smoke induces an unfolded protein response in the human lung: a proteomic approach.

    Science.gov (United States)

    Kelsen, Steven G; Duan, Xunbao; Ji, Rong; Perez, Oscar; Liu, Chunli; Merali, Salim

    2008-05-01

    Cigarette smoking, which exposes the lung to high concentrations of reactive oxidant species (ROS) is the major risk factor for chronic obstructive pulmonary disease (COPD). Recent studies indicate that ROS interfere with protein folding in the endoplasmic reticulum and elicit a compensatory response termed the "unfolded protein response" (UPR). The importance of the UPR lies in its ability to alter expression of a variety of genes involved in antioxidant defense, inflammation, energy metabolism, protein synthesis, apoptosis, and cell cycle regulation. The present study used comparative proteomic technology to test the hypothesis that chronic cigarette smoking induces a UPR in the human lung. Studies were performed on lung tissue samples obtained from three groups of human subjects: nonsmokers, chronic cigarette smokers, and ex-smokers. Proteomes of lung samples from chronic cigarette smokers demonstrated 26 differentially expressed proteins (20 were up-regulated, 5 were down-regulated, and 1 was detected only in the smoking group) compared with nonsmokers. Several UPR proteins were up-regulated in smokers compared with nonsmokers and ex-smokers, including the chaperones, glucose-regulated protein 78 (GRP78) and calreticulin; a foldase, protein disulfide isomerase (PDI); and enzymes involved in antioxidant defense. In cultured human airway epithelial cells, GRP78 and the UPR-regulated basic leucine zipper, transcription factors, ATF4 and Nrf2, which enhance expression of important anti-oxidant genes, increased rapidly (< 24 h) with cigarette smoke extract. These data indicate that cigarette smoke induces a UPR response in the human lung that is rapid in onset, concentration dependent, and at least partially reversible with smoking cessation. We speculate that activation of a UPR by cigarette smoke may protect the lung from oxidant injury and the development of COPD.

  14. Using bosentan to treat paraquat poisoning-induced acute lung injury in rats.

    Directory of Open Access Journals (Sweden)

    Zhongchen Zhang

    Full Text Available BACKGROUND: Paraquat poisoning is well known for causing multiple organ function failure (MODS and high mortality. Acute lung injury and advanced pulmonary fibrosis are the most serious complications. Bosentan is a dual endothelin receptor antagonist. It plays an important role in treating PF. There is no related literature on the use of bosentan therapy for paraquat poisoning. OBJECTIVE: To study the use of bosentan to treat acute lung injury and pulmonary fibrosis as induced by paraquat. METHOD: A total of 120 adult Wister male rats were randomly assigned to three groups: the paraquat poisoning group (rats were intragastrically administered with paraquat at 50 mg/kg body weight once at the beginning; the bosentan therapy group (rats were administered bosentan at 100 mg/kg body weight by intragastric administration half an hour after paraquat was administered, then the same dose was administered once a day; and a control group (rats were administered intragastric physiological saline. On the 3rd, 7th, 14th, and 21st days following paraquat exposure, rats were sacrificed, and samples of lung tissue and venous blood were collected. The levels of transforming growth factor-β1 (TGF-β1, endothelin-1 (ET-1, and hydroxyproline (HYP in the plasma and lung homogenate were determined. Optical and electronic microscopes were used to examine pathological changes. RESULT: The TGF-β1, ET-1, and HYP of the paraquat poisoning group were significantly higher than in the control group, and they were significantly lower in the 21st day therapy group than in the paraquat poisoning group on the same day. Under the optical and electronic microscopes, lung tissue damage was observed to be more severe but was then reduced after bosentan was administered. CONCLUSION: Bosentan can reduce inflammation factor release. It has a therapeutic effect on acute lung injury as induced by paraquat.

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

    Science.gov (United States)

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

    2015-04-01

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

  16. The features of radiation induced lung fibrosis related with dosimetric parameters

    International Nuclear Information System (INIS)

    Oh, Young-Taek; Noh, O Kyu; Jang, Hyunsoo; Chun, Mison; Park, Kyung Joo; Park, Kwang Joo; Kim, Mi-Hwa; Park, Hae-Jin

    2012-01-01

    Background and purpose: Radiation induced lung fibrosis (RILF) is a major complication after lung irradiation and is very important for long term quality of life and could result in fatal respiratory insufficiency. However, there has been little information on dosimetric parameters for radiotherapy planning in the aspect of RILF. The features of RILF related with dosimetric parameters were evaluated. Methods and materials: Forty-eight patients with non-small cell lung carcinoma who underwent post-operative radiation therapy (PORT) without adjuvant chemotherapy were analyzed. The degree of lung fibrosis was estimated by fibrosis volume and the dosimetric parameters were calculated from the plan of 3-dimensional conformal radiotherapy. Results: The fibrosis volume and V-dose as dosimetric parameters showed significant correlation and the correlation coefficient ranged from 0.602 to 0.683 (P < 0.01). The degree of the correlation line was steeper as the dose increase and threshold dose was not found. Mean lung dose (MLD) showed strong correlation with fibrosis volume (correlation coefficient = 0.726, P < 0.01). Conclusions: The fibrosis volume is continuously increased with V-dose as the reference dose increases. MLD is useful as a single parameter for comparing rival plans in the aspect of RILF.

  17. Mitochondrial Targeted Endonuclease III DNA Repair Enzyme Protects against Ventilator Induced Lung Injury in Mice

    Directory of Open Access Journals (Sweden)

    Masahiro Hashizume

    2014-08-01

    Full Text Available The mitochondrial targeted DNA repair enzyme, 8-oxoguanine DNA glycosylase 1, was previously reported to protect against mitochondrial DNA (mtDNA damage and ventilator induced lung injury (VILI. In the present study we determined whether mitochondrial targeted endonuclease III (EndoIII which cleaves oxidized pyrimidines rather than purines from damaged DNA would also protect the lung. Minimal injury from 1 h ventilation at 40 cmH2O peak inflation pressure (PIP was reversed by EndoIII pretreatment. Moderate lung injury due to ventilation for 2 h at 40 cmH2O PIP produced a 25-fold increase in total extravascular albumin space, a 60% increase in W/D weight ratio, and marked increases in MIP-2 and IL-6. Oxidative mtDNA damage and decreases in the total tissue glutathione (GSH and the GSH/GSSH ratio also occurred. All of these indices of injury were attenuated by mitochondrial targeted EndoIII. Massive lung injury caused by 2 h ventilation at 50 cmH2O PIP was not attenuated by EndoIII pretreatment, but all untreated mice died prior to completing the two hour ventilation protocol, whereas all EndoIII-treated mice lived for the duration of ventilation. Thus, mitochondrial targeted DNA repair enzymes were protective against mild and moderate lung damage and they enhanced survival in the most severely injured group.

  18. Effect of commercial saccharin preparations on urethan-induced lung tumorigenesis in strain A mice.

    Science.gov (United States)

    Theiss, J C; Arnold, L J; Shimkin, M B

    1980-11-01

    The effect of commercial saccharin preparations on urethan-induced mouse lung tumorigenesis was assessed by gavaging groups of male strain A mice with 1-g/kg doses of each saccharin preparation on a daily basis 5 days/week. Gavage was initiated 1 week before i.p. injection of either a low (0.1 mg/g) or a high (1 mg/g) dose of urethan and continued until the mice were sacrificed 16 weeks after urethan administration. The average number of surface lung tumors per mouse for each group of mice was determined and was compared statistically with the appropriate control group. The commercial saccharin preparations did not produce an elevated lung tumor response when administered alone. One of the four saccharin preparations enhanced the lung tumor response to urethan when given in conjunction with the low dose of urethan, but this enhancement was not statistically significant. At the high urethan dose, all saccharin preparations produced a statistically significant enhancement of the lung tumor response to urethan.

  19. Propofol inhibits LPS-induced apoptosis in lung epithelial cell line, BEAS-2B.

    Science.gov (United States)

    Lv, Xiang; Zhou, Xuhui; Yan, Jia; Jiang, Jue; Jiang, Hong

    2017-03-01

    Lipopolysaccharide (LPS) plays an important role in lung endothelial apoptosis which is crucial for lung fibrogenesis in ARDS progression. Reactive oxygen species (ROS) has been reported to be involved in LPS-induced lung epithelial cell apoptosis. Propofol is a commonly used intravenous anesthetic agent in clinic and it could attenuate LPS-induced epithelial cells oxidation and apoptosis. However, the mechanisms are still obscure. In this study, we examined whether and how propofol attenuates LPS-induced oxidation and apoptosis in BEAS-2B cells. Compared with control group, LPS up-regulated Pin-1, phosphatase A2 (PP2A) expression, induced p66 Shc -Ser 36 phosphorylation, and facilitated p66 Shc mitochondrial translocation, thus leading to superoxide anion (O 2 - ) generation, mitochondrial cytochrome c release, active caspase 3 over-expression and cell viability inhibition. Importantly, propofol was shown to down-regulate LPS-induced PP2A expression, limit p66 Shc mitochondrial translocation, decrease O 2 - generation, inhibit mitochondrial cytochrome c release, reduce active caspase 3 expression, and recover cells viability, while propofol had no effects on LPS-induced Pin-1 expression and p66 Shc -Ser 36 phosphorylation. Moreover, the protective effects of propofol on LPS-induced BEAS-2B cells apoptosis were similar to that of calyculin A, which is an inhibitor of PP2A. We also found that FTY720, which is an activator of PP2A, can effectively reverse the protective function of propofol. Our data illustrated that propofol could alleviate LPS-induced BEAS-2B cells oxidation and apoptosis through down-regulating PP2A expression, limiting p66 Shc -Ser 36 dephosphorylation and p66 Shc mitochondrial translocation, decreasing O 2 - generation, mitochondrial cytochrome c release, activating caspase 3 expression. Copyright © 2016 Elsevier Masson SAS. All rights reserved.

  20. Erythropoietin Pretreatment Attenuates Seawater Aspiration-Induced Acute Lung Injury in Rats.

    Science.gov (United States)

    Ji, Mu-Huo; Tong, Jian-Hua; Tan, Yuan-Hui; Cao, Zhen-Yu; Ou, Cong-Yang; Li, Wei-Yan; Yang, Jian-Jun; Peng, Y G; Zhu, Si-Hai

    2016-02-01

    Seawater drowning-induced acute lung injury (ALI) is a serious clinical condition characterized by increased alveolar-capillary permeability, excessive inflammatory responses, and refractory hypoxemia. However, current therapeutic options are largely supportive; thus, it is of great interest to search for alternative agents to treat seawater aspiration-induced ALI. Erythropoietin (EPO) is a multifunctional agent with antiinflammatory, antioxidative, and antiapoptotic properties. However, the effects of EPO on seawater aspiration-induced ALI remain unclear. In the present study, male rats were randomly assigned to the naive group, normal saline group, seawater group, or seawater + EPO group. EPO was administered intraperitoneally at 48 and 24 h before seawater aspiration. Arterial blood gas analysis was performed with a gas analyzer at baseline, 30 min, 1 h, 4 h, and 24 h after seawater aspiration, respectively. Histological scores, computed tomography scan, nuclear factor kappa B p65, inducible nitric oxide synthase, caspase-3, tumor necrosis factor-alpha, interleukin (IL)-1β, IL-6, IL-10, wet-to-dry weight ratio, myeloperoxidase activity, malondialdehyde, and superoxide dismutase in the lung were determined 30 min after seawater aspiration. Our results showed that EPO pretreatment alleviated seawater aspiration-induced ALI, as indicated by increased arterial partial oxygen tension and decreased lung histological scores. Furthermore, EPO pretreatment attenuated seawater aspiration-induced increase in the expressions of pulmonary nuclear factor kappa B p65, inducible nitric oxide synthase, caspase-3, tumor necrosis factor-alpha, IL-1β, myeloperoxidase activity, and malondialdehyde when compared with the seawater group. Collectively, our study suggested that EPO pretreatment attenuates seawater aspiration-induced ALI by down-regulation of pulmonary pro-inflammatory cytokines, oxidative stress, and apoptosis.

  1. Oxidative Lung Injury in Virus-Induced Wheezing

    Science.gov (United States)

    2013-05-01

    flavonoids quercetin and EGCG, the nonflavonoids curcumin and re- sveratrol, and the phenolic acid and diterpens rosmarinic and carnosic (carnasol) acids... Curcumin has been tested in clinical trials for certain cancers and in degenerative neurological disease (18). Curcumin has been shown to induce Nrf2...and ARE-dependent genes in human cell lines and in mice fed with a diet containing curcumin (80). EGCG, as well as other catechins contained in green

  2. Cordycepin inhibits LPS-induced acute lung injury by inhibiting inflammation and oxidative stress.

    Science.gov (United States)

    Lei, Jiaji; Wei, Youlei; Song, Pengcheng; Li, Yongchao; Zhang, Tianze; Feng, Qingjiang; Xu, Guangquan

    2018-01-05

    Acute lung injury (ALI) is a common severe clinical syndrome in intensive care unit. Inflammation has been reported to play a critical role in the development of ALI. Cordycepin, an active component isolated from Cordyceps militaris, has been reported to have anti-inflammatory effects. However, the anti-inflammatory effects of cordycepin on LPS-induced ALI remain unclear. Therefore, in the present study, we assessed whether cordycepin could attenuate ALI induced by LPS. The mice were conditioned with cordycepin 1h before intranasal instillation of LPS. Lung wet/dry (W/D) ratio, MPO activity, MDA content, and inflammatory cytokines production were detected. The expression of NF-κB p65, I-κB, Nrf2, and HO-1 were detected by western blot analysis. We found that LPS significantly increased lung wet/dry (W/D) ratio, MPO activity, MDA content, and inflammatory cytokines production. However, the increases were significantly inhibited by treatment of cordycepin. LPS-induced NF-κB activation was also suppressed by cordycepin. In addition, cordycepin was found to up-regulate the expression of Nrf2 and HO-1 in a dose-dependent manner. In conclusion, our results demonstrated that cordycepin could attenuate LPS-induced ALI effectively, probably due to inhibition of inflammation and oxidative stress. Copyright © 2017 Elsevier B.V. All rights reserved.

  3. Angiotensin-Converting Enzyme 2 Attenuates Bleomycin-Induced Lung Fibrosis in Mice

    Directory of Open Access Journals (Sweden)

    Lifang Wang

    2015-05-01

    Full Text Available Background: Local renin-angiotensin system (RAS activation has been shown to play an important role in the pathogenesis of idiopathic pulmonary fibrosis (IPF. It has been reported that angiotensin-converting enzyme 2 (ACE2 could inhibit RAS-mediated epithelial injury and fibrogenesis and that ACE2 deficiency could aggravate acute and chronic lung injury. Through research, it could be deduced that ACE2 could protect against pulmonary fibrosis as a therapeutic target. Methods: Time-course analysis of the pathological characteristics of bleomycin-induced lung fibrosis was undertaken in a mouse model, and the effect of exogenous ACE2 on lung fibrosis was studied. Immunohistchemistry (IHC staining and western blot (WB testing for AGT and ACE2 were performed to evaluate the regulation of local RAS. TUNEL staining was used to observe epithelial apoptosis. Leukocyte common antigen (LCA and pulmonary surfactant-associated protein A (SP-A IHC staining and WB testing were performed to assess the inflammatory response and epithelial regeneration. Masson's staining and a hydroxyproline assay were performed to examine collagen deposition. IHC staining and WB testing for TGF-β1 and α-SMA were performed to investigate the regulation of pro-fibrotic cytokines and the activation of fibroblasts. Results: Exogenous ACE2 attenuated bleomycin-induced lung fibrosis by reversing the reduction of local ACE2 and by suppressing the elevation of AGT. ACE2 decreased the apoptosis index and LCA levels and ameliorated the dynamic change in SP-A level, thus protecting against epithelial injury. Reductions of TGF-β1 and α-SMA were also found in ACE2-treated mice, indicating the inhibition of fibrogenesis. Conclusion: ACE2 attenuated bleomycin-induced lung fibrosis as an anti-inflammatory anti-apoptotic and anti-fibrotic agent, and it might be a promising therapeutic target for IPF.

  4. Angiotensin-Converting Enzyme 2 Attenuates Bleomycin-Induced Lung Fibrosis in Mice.

    Science.gov (United States)

    Wang, Lifang; Wang, Yuxiang; Yang, Tuo; Guo, Yanfei; Sun, Tieying

    2015-01-01

    Local renin-angiotensin system (RAS) activation has been shown to play an important role in the pathogenesis of idiopathic pulmonary fibrosis (IPF). It has been reported that angiotensin-converting enzyme 2 (ACE2) could inhibit RAS-mediated epithelial injury and fibrogenesis and that ACE2 deficiency could aggravate acute and chronic lung injury. Through research, it could be deduced that ACE2 could protect against pulmonary fibrosis as a therapeutic target. Time-course analysis of the pathological characteristics of bleomycin-induced lung fibrosis was undertaken in a mouse model, and the effect of exogenous ACE2 on lung fibrosis was studied. Immunohistchemistry (IHC) staining and western blot (WB) testing for AGT and ACE2 were performed to evaluate the regulation of local RAS. TUNEL staining was used to observe epithelial apoptosis. Leukocyte common antigen (LCA) and pulmonary surfactant-associated protein A (SP-A) IHC staining and WB testing were performed to assess the inflammatory response and epithelial regeneration. Masson's staining and a hydroxyproline assay were performed to examine collagen deposition. IHC staining and WB testing for TGF-β1 and α-SMA were performed to investigate the regulation of pro-fibrotic cytokines and the activation of fibroblasts. Exogenous ACE2 attenuated bleomycin-induced lung fibrosis by reversing the reduction of local ACE2 and by suppressing the elevation of AGT. ACE2 decreased the apoptosis index and LCA levels and ameliorated the dynamic change in SP-A level, thus protecting against epithelial injury. Reductions of TGF-β1 and α-SMA were also found in ACE2-treated mice, indicating the inhibition of fibrogenesis. ACE2 attenuated bleomycin-induced lung fibrosis as an anti-inflammatory anti-apoptotic and anti-fibrotic agent, and it might be a promising therapeutic target for IPF. © 2015 S. Karger AG, Basel.

  5. Protective Effects of Erythropoietin and N-Acetylcysteine on Methotrexate-Induced Lung Injury in Rats

    Directory of Open Access Journals (Sweden)

    Hasan Kahraman

    2013-03-01

    Full Text Available Objective: Methotrexate (MTX is known to have deleterious side effects on lung tissue. We aimed to investigate the effects of erythropoietin (EPO and N-acetyl-cysteine (NAC on MTX-induced lung injury in rats. Study Design: Animal experiment. Material and Methods: Twenty-six female Sprague-Dawley rats were divided into 4 groups. Sham group, 0.3 mL saline; MTX group, 5 mg/kg MTX; EPO group, 5mg/kg MTX and 2000 IU/kg EPO; NAC group, 5 mg/kg MTX and 200 mg/kg NAC were administered once daily for 4 consecutive days. Malondialdehyde (MDA, superoxide dismutase (SOD, catalase (CAT and inflammation and congestion scores in lung tissues were evaluated. Results: In MTX group MDA were significantly higher, CAT and SOD were significantly lower than in sham, EPO and NAC groups (p0.005. In group MTX both scores were significantly higher than in sham (p<0.005. The congestion score of group MTX was significantly higher than those of group EPO and NAC (p<0.005. Conclusion: EPO and NAC have significant preventive effects on MTX-induced lung injury in rats. Decreased antioxidant capacity and increased MDA level may cause the oxidative damage in MTX group. Also, higher antioxidant capacity and lower MDA level may be a response to oxidative stress in EPO and NAC groups.

  6. Linalool attenuates lung inflammation induced by Pasteurella multocida via activating Nrf-2 signaling pathway.

    Science.gov (United States)

    Wu, Qianchao; Yu, Lijun; Qiu, Jiaming; Shen, Bingyu; Wang, Di; Soromou, Lanan Wassy; Feng, Haihua

    2014-08-01

    Pasteurellosis caused by Pasteurella multocida manifest often as respiratory infection in farmed small ruminants. Although the incidence of pasteurellosis due to P. multocida mainly takes the form of pneumonia, there is limited information on host factors that play a role in disease pathogenesis in the milieu of host-pathogen interactions. Nuclear factor-erythroid 2 related factor 2 (Nrf-2), a critical regulator for various inflammatory and immune responses by controlling oxidative stress, may play an important role in the processes of inflammation induced by P. multocida. In this study, linalool, a natural compound of the essential oils in several aromatic plant species, elevated nuclear Nrf-2 protein translocation in the A549 lung cell line and in vivo. The P. multocida-induced pro-inflammatory cytokines expression was abrogated by Nrf-2 siRNA. Postponed treatment with linalool decreased lung neutrophil accumulation and enhanced clearance of P. multocida. Furthermore, linalool significantly increased the expression of antioxidant enzymes regulated by Nrf-2 and diminished lung tissue levels of several pro-inflammatory cytokines, including tumor necrosis factor α (TNF-α) and interleukin (IL)-6. In addition, animals treated with linalool had a marked improvement in survival. These findings have uncovered that linalool acts as a novel Nrf-2 activator for a novel therapeutic strategy in pathogen-mediated lung inflammation. Copyright © 2014 Elsevier B.V. All rights reserved.

  7. Mechanical stretch induces MMP-2 release and activation in lung endothelium: role of EMMPRIN.

    Science.gov (United States)

    Haseneen, Nadia A; Vaday, Gayle G; Zucker, Stanley; Foda, Hussein D

    2003-03-01

    High-volume mechanical ventilation leads to ventilator-induced lung injury. This type of lung injury is accompanied by an increased release and activation of matrix metalloproteinases (MMPs). To investigate the mechanism leading to the increased MMP release, we systematically studied the effect of mechanical stretch on human microvascular endothelial cells isolated from the lung. We exposed cells grown on collagen 1 BioFlex plates to sinusoidal cyclic stretch at 0.5 Hz using the Flexercell system with 17-18% elongation of cells. After 4 days of cell stretching, conditioned media and cell lysate were collected and analyzed by gelatin, casein, and reverse zymograms as well as Western blotting. RT-PCR of mRNA extracted from stretched cells was performed. Our results show that 1) cyclic stretch led to increased release and activation of MMP-2 and MMP-1; 2) the activation of MMP-2 was accompanied by an increase in membrane type-1 MMP (MT1-MMP) and inhibited by a hydroxamic acid-derived inhibitor of MMPs (Prinomastat, AG3340); and 3) the MMP-2 release and activation were preceded by an increase in production of extracellular MMP inducer (EMMPRIN). These results suggest that cyclic mechanical stretch leads to MMP-2 activation through an MT1-MMP mechanism. EMMPRIN may play an important role in the release and activation of MMPs during lung injury.

  8. Characterization of a murine model of monocrotaline pyrrole-induced acute lung injury

    Directory of Open Access Journals (Sweden)

    Pullamsetti Soni S

    2008-12-01

    Full Text Available Abstract Background New animal models of chronic pulmonary hypertension in mice are needed. The injection of monocrotaline is an established model of pulmonary hypertension in rats. The aim of this study was to establish a murine model of pulmonary hypertension by injection of the active metabolite, monocrotaline pyrrole. Methods Survival studies, computed tomographic scanning, histology, bronchoalveolar lavage were performed, and arterial blood gases and hemodynamics were measured in animals which received an intravenous injection of different doses of monocrotaline pyrrole. Results Monocrotaline pyrrole induced pulmonary hypertension in Sprague Dawley rats. When injected into mice, monocrotaline pyrrole induced dose-dependant mortality in C57Bl6/N and BALB/c mice (dose range 6–15 mg/kg bodyweight. At a dose of 10 mg/kg bodyweight, mice developed a typical early-phase acute lung injury, characterized by lung edema, neutrophil influx, hypoxemia and reduced lung compliance. In the late phase, monocrotaline pyrrole injection resulted in limited lung fibrosis and no obvious pulmonary hypertension. Conclusion Monocrotaline and monocrotaline pyrrole pneumotoxicity substantially differs between the animal species.

  9. Beta-Cryptoxanthin supplementation prevents cigarette smoke-induced lung inflammation, oxidative damage and squamous metaplasia in ferrets

    Science.gov (United States)

    In epidemiologic studies, high intake of beta-cryptoxanthin has been associated with a decreased risk of lung cancer, particularly among current smokers. However, data are not available from well-controlled animal studies to examine the effects of beta-cryptoxanthin on cigarette smoke-induced lung ...

  10. Agmatine Protects against Zymosan-Induced Acute Lung Injury in Mice by Inhibiting NF-κB-Mediated Inflammatory Response

    Directory of Open Access Journals (Sweden)

    Xuanfei Li

    2014-01-01

    Full Text Available Acute lung injury (ALI is characterized by overwhelming lung inflammation and anti-inflammation treatment is proposed to be a therapeutic strategy for ALI. Agmatine, a cationic polyamine formed by decarboxylation of L-arginine, is an endogenous neuromodulator that plays protective roles in diverse central nervous system (CNS disorders. Consistent with its neuromodulatory and neuroprotective properties, agmatine has been reported to have beneficial effects on depression, anxiety, hypoxic ischemia, Parkinson’s disease, and gastric disorder. In this study, we tested the effect of agmatine on the lung inflammation induced by Zymosan (ZYM challenge in mice. We found that agmatine treatment relieved ZYM-induced acute lung injury, as evidenced by the reduced histological scores, wet/dry weight ratio, and myeloperoxidase activity in the lung tissue. This was accompanied by reduced levels of TNF-α, IL-1β, and IL-6 in lung and bronchoalveolar lavage fluid and decreased iNOS expression in lung. Furthermore, agmatine inhibited the phosphorylation and degradation of IκB and subsequently blocked the activation of nuclear factor (NF-κB induced by Zymosan. Taken together, our results showed that agmatine treatment inhibited NF-κB signaling in lungs and protected mice against ALI induced by Zymosan, suggesting agmatine may be a potential safe and effective approach for the treatment of ALI.

  11. Caryocar brasiliense camb protects against genomic and oxidative damage in urethane-induced lung carcinogenesis

    Directory of Open Access Journals (Sweden)

    N.B.R. Colombo

    2015-01-01

    Full Text Available The antioxidant effects of Caryocar brasiliense Camb, commonly known as the pequi fruit, have not been evaluated to determine their protective effects against oxidative damage in lung carcinogenesis. In the present study, we evaluated the role of pequi fruit against urethane-induced DNA damage and oxidative stress in forty 8-12 week old male BALB/C mice. An in vivo comet assay was performed to assess DNA damage in lung tissues and changes in lipid peroxidation and redox cycle antioxidants were monitored for oxidative stress. Prior supplementation with pequi oil or its extract (15 µL, 60 days significantly reduced urethane-induced oxidative stress. A protective effect against DNA damage was associated with the modulation of lipid peroxidation and low protein and gene expression of nitric oxide synthase. These findings suggest that the intake of pequi fruit might protect against in vivo genotoxicity and oxidative stress.

  12. Oleic Acid Induces Lung Injury in Mice through Activation of the ERK Pathway

    Directory of Open Access Journals (Sweden)

    Cassiano Felippe Gonçalves-de-Albuquerque

    2012-01-01

    Full Text Available Oleic acid (OA can induce acute lung injury in experimental models. In the present work, we used intratracheal OA injection to show augmented oedema formation, cell migration and activation, lipid mediator, and cytokine productions in the bronchoalveolar fluids of Swiss Webster mice. We also demonstrated that OA-induced pulmonary injury is dependent on ERK1/2 activation, since U0126, an inhibitor of ERK1/2 phosphorylation, blocked neutrophil migration, oedema, and lipid body formation as well as IL-6, but not IL-1β production. Using a mice strain carrying a null mutation for the TLR4 receptor, we proved that increased inflammatory parameters after OA challenges were not due to the activation of the TLR4 receptor. With OA being a Na/K-ATPase inhibitor, we suggest the possible involvement of this enzyme as an OA target triggering lung inflammation.

  13. Perillyl alcohol suppresses antigen-induced immune responses in the lung

    International Nuclear Information System (INIS)

    Imamura, Mitsuru; Sasaki, Oh; Okunishi, Katsuhide; Nakagome, Kazuyuki; Harada, Hiroaki; Kawahata, Kimito; Tanaka, Ryoichi; Yamamoto, Kazuhiko; Dohi, Makoto

    2014-01-01

    Highlights: •Perillyl alcohol (POH) is an isoprenoid which inhibits the mevalonate pathway. •We examined whether POH suppresses immune responses with a mouse model of asthma. •POH treatment during sensitization suppressed Ag-induced priming of CD4 + T cells. •POH suppressed airway eosinophila and cytokine production in thoracic lymph nodes. -- Abstract: Perillyl alcohol (POH) is an isoprenoid which inhibits farnesyl transferase and geranylgeranyl transferase, key enzymes that induce conformational and functional changes in small G proteins to conduct signal production for cell proliferation. Thus, it has been tried for the treatment of cancers. However, although it affects the proliferation of immunocytes, its influence on immune responses has been examined in only a few studies. Notably, its effect on antigen-induced immune responses has not been studied. In this study, we examined whether POH suppresses Ag-induced immune responses with a mouse model of allergic airway inflammation. POH treatment of sensitized mice suppressed proliferation and cytokine production in Ag-stimulated spleen cells or CD4 + T cells. Further, sensitized mice received aerosolized OVA to induce allergic airway inflammation, and some mice received POH treatment. POH significantly suppressed indicators of allergic airway inflammation such as airway eosinophilia. Cytokine production in thoracic lymph nodes was also significantly suppressed. These results demonstrate that POH suppresses antigen-induced immune responses in the lung. Considering that it exists naturally, POH could be a novel preventive or therapeutic option for immunologic lung disorders such as asthma with minimal side effects

  14. Prognostic value of chemotherapy-induced leukopenia in small-cell lung cancer

    OpenAIRE

    Liu, Wei; Zhang, Cui-Cui; Li, Kai

    2013-01-01

    Objective Chemotherapy is the standard treatment for small-cell lung cancer (SCLC), and leukopenia is a common side effect. This study assesses whether chemotherapy-induced leukopenia is a predictor of efficacy and whether it is associated with the survival of SCLC patients. Methods A retrospective analysis was conducted on data from 445 patients with SCLC who received standard chemotherapy for 4 to 10 cycles. The World Health Organization grading system classifies leukopenia during chemother...

  15. Ghrelin ameliorates acute lung injury induced by oleic acid via inhibition of endoplasmic reticulum stress.

    Science.gov (United States)

    Tian, Xiuli; Liu, Zhijun; Yu, Ting; Yang, Haitao; Feng, Linlin

    2018-03-01

    Acute lung injury (ALI) is associated with excessive mortality and lacks appropriate therapy. Ghrelin is a novel peptide that protects the lung against ALI. This study aimed to investigate whether endoplasmic reticulum stress (ERS) mediates the protective effect of ghrelin on ALI. We used a rat oleic acid (OA)-induced ALI model. Pulmonary impairment was detected by hematoxylin and eosin (HE) staining, lung mechanics, wet/dry weight ratio, and arterial blood gas analysis. Plasma and lung content of ghrelin was examined by ELISA, and mRNA expression was measured by quantitative real-time PCR. Protein levels were detected by western blot. Rats with OA treatment showed significant pulmonary injury, edema, inflammatory cellular infiltration, cytokine release, hypoxia and CO 2 retention as compared with controls. Plasma and pulmonary content of ghrelin was reduced in rats with ALI, and mRNA expression was downregulated. Ghrelin (10nmol/kg) treatment ameliorated the above symptoms, but treatment with the ghrelin antagonists D-Lys 3 GHRP-6 (1μmol/kg) and JMV 2959 (6mg/kg) exacerbated the symptoms. ERS induced by OA was prevented by ghrelin and augmented by ghrelin antagonist treatment. The ERS inducer, tunicamycin (Tm) prevented the ameliorative effect of ghrelin on ALI. The decreased ratio of p-Akt and Akt induced by OA was improved by ghrelin treatment, and was further exacerbated by ghrelin antagonists. Ghrelin protects against ALI by inhibiting ERS. These results provide a new target for prevention and therapy of ALI. Copyright © 2017 Elsevier Inc. All rights reserved.

  16. Role of Smac in apoptosis of lung cancer cells A549 induced by Taxol.

    Science.gov (United States)

    Zhang, Ying; Hao, Yingtao; Sun, Qifeng; Peng, Chuanliang

    2015-01-01

    A series of structurally unique second mitochondria-derived activators of caspase (Smac) that act as antagonists of inhibitor of apoptosis proteins (IAPs) directly have been discovered and have been shown to promote chemotherapy-induced apoptosis. In this study, we investigate the role of Smac in Taxol-induced apoptosis of lung cancer cell in vitro. PcDNA3.1/Smac recombinants were transfected into the non-small cell lung cancer cell line A549. Smac expression was detected by RT-PCR and Western blot. The invasive ability of cells was examined. Flow cytometry was used to analyze apoptosis of cells induced by Taxol with Annexin V/PI double staining technique. Smac expression was significantly higher in the PcDNA3.1/Smac recombinant group than in the untransfected group at mRNA and protein level (p Smac group. There were significant differences compared to the empty vector group and control group. The apoptosis rate was significantly higher in PcDNA3.1/Smac + Taxol group than in other groups (p Smac can enhance the chemosensitivity of the non-small cell lung cancer cell line A549 to Taxol.

  17. Bronchoconstriction Induces TGF-β Release and Airway Remodelling in Guinea Pig Lung Slices.

    Directory of Open Access Journals (Sweden)

    Tjitske A Oenema

    Full Text Available Airway remodelling, including smooth muscle remodelling, is a primary cause of airflow limitation in asthma. Recent evidence links bronchoconstriction to airway remodelling in asthma. The mechanisms involved are poorly understood. A possible player is the multifunctional cytokine TGF-β, which plays an important role in airway remodelling. Guinea pig lung slices were used as an in vitro model to investigate mechanisms involved in bronchoconstriction-induced airway remodelling. To address this aim, mechanical effects of bronchoconstricting stimuli on contractile protein expression and TGF-β release were investigated. Lung slices were viable for at least 48 h. Both methacholine and TGF-β1 augmented the expression of contractile proteins (sm-α-actin, sm-myosin, calponin after 48 h. Confocal fluorescence microscopy showed that increased sm-myosin expression was enhanced in the peripheral airways and the central airways. Mechanistic studies demonstrated that methacholine-induced bronchoconstriction mediated the release of biologically active TGF-β, which caused the increased contractile protein expression, as inhibition of actin polymerization (latrunculin A or TGF-β receptor kinase (SB431542 prevented the methacholine effects, whereas other bronchoconstricting agents (histamine and KCl mimicked the effects of methacholine. Collectively, bronchoconstriction promotes the release of TGF-β, which induces airway smooth muscle remodelling. This study shows that lung slices are a useful in vitro model to study mechanisms involved in airway remodelling.

  18. Drug-induced lung disease: High-resolution CT and histological findings

    International Nuclear Information System (INIS)

    Cleverley, Joanne R.; Screaton, Nicholas J.; Hiorns, Melanie P.; Flint, Julia D.A.; Mueller, Nestor L.

    2002-01-01

    AIM: To compare the parenchymal high-resolution computed tomography (HRCT) appearances with histological findings in patients with drug-induced lung disease and to determine the prognostic value of HRCT. MATERIALS AND METHODS: Drug history, HRCT features, histological findings and outcome at 3 months in 20 patients with drug induced-lung disease were reviewed retrospectively. The HRCT images were assessed for the pattern and distribution of abnormalities and classified as most suggestive of interstitial pneumonitis/fibrosis, diffuse alveolar damage (DAD), organizing pneumonia (OP) reaction, or a hypersensitivity reaction. RESULTS: On histopathological examination there were eight cases of interstitial pneumonitis/fibrosis, five of DAD, five of OP reactions, one of hypersensitivity reaction and one of pulmonary eosinophilia. The most common abnormalities on HRCT were ground-glass opacities (n = 17), consolidation (n = 14), interlobular septal thickening (n = 15) and centrilobular nodules (n 8). HRCT interpretation and histological diagnosis were concordant in only nine (45%) of 20 patients. The pattern, distribution, and extent of HRCT abnormalities were of limited prognostic value: all eight patients with histological findings of OP, hypersensitivity reaction, or eosinophilic infiltrate improved on follow-up compared to only five of 13 patients with interstitial pneumonitis/fibrosis or DAD. CONCLUSION: In many cases of drug-induced lung injury HRCT is of limited value in determining the histological pattern and prognosis. Cleverly, J.R. et al

  19. Cardiopulmonary bypass does not induce lung dysfunction after pulmonary thrombarterectomy: role of pulmonary compliance.

    Science.gov (United States)

    Sacuto, Thierry; Sacuto, Yann

    2017-12-01

    Pulmonary endarterectomy is a heavy surgical procedure that is performed under cardiopulmonary bypass (CPB) and aimed to cure postembolic pulmonary hypertension. Reperfusion oedema is both the hallmark of successful surgical procedure and the most frequent postoperative complication. Post-CPB lung dysfunction was not mentioned in any report. We undertook a study to determine whether post-CPB lung dysfunction was present in these patients. In a retrospective cohort study with matching on some baseline covariates, we selected 41 patients who had undergone pulmonary endarterectomy and in whom pre-, intra- and postoperative records were complete. The control group was composed of 39 patients operated on from elective cardiac surgery during the same period and matched with a study group for age, gender, body mass index, blood creatinine, diabetes and baseline partial pressure of oxygen/fraction of inspired oxygen ratio. Criteria for post-CPB lung dysfunction were partial pressure of oxygen/fraction of inspired oxygen ratio decrease and bilateral basal oedema. Explanatory variables for post-CPB lung dysfunction were coronary arterial bypass, pleura opening, static pulmonary compliance measured at the time of thorax closed then retracted, fluid infusion, transfusion and vasopressors. All patients operated on from pulmonary endarterectomy presented radiological oedema reperfusion in surgical unblocking areas. Among them, only 2 had bilateral basal oedema when compared to the 24 patients from the control group (P pulmonary compliance were at risk for post-CPB lung dysfunction. Patients operated on from pulmonary endarterectomy were saved from post-CPB lung dysfunction. The latter could be induced by a mechanical phenomenon. © The Author 2017. Published by Oxford University Press on behalf of the European Association for Cardio-Thoracic Surgery. All rights reserved.

  20. Impact of interleukin-6 on hypoxia-induced pulmonary hypertension and lung inflammation in mice

    Directory of Open Access Journals (Sweden)

    Izziki Mohamed

    2009-01-01

    Full Text Available Abstract Background Inflammation may contribute to the pathogenesis of various forms of pulmonary hypertension (PH. Recent studies in patients with idiopathic PH or PH associated with underlying diseases suggest a role for interleukin-6 (IL-6. Methods To determine whether endogenous IL-6 contributes to mediate hypoxic PH and lung inflammation, we studied IL-6-deficient (IL-6-/- and wild-type (IL-6+/+ mice exposed to hypoxia for 2 weeks. Results Right ventricular systolic pressure, right ventricle hypertrophy, and the number and media thickness of muscular pulmonary vessels were decreased in IL-6-/- mice compared to wild-type controls after 2 weeks' hypoxia, although the pressure response to acute hypoxia was similar in IL-6+/+ and IL-6-/- mice. Hypoxia exposure of IL-6+/+ mice led to marked increases in IL-6 mRNA and protein levels within the first week, with positive IL-6 immunostaining in the pulmonary vessel walls. Lung IL-6 receptor and gp 130 (the IL-6 signal transducer mRNA levels increased after 1 and 2 weeks' hypoxia. In vitro studies of cultured human pulmonary-artery smooth-muscle-cells (PA-SMCs and microvascular endothelial cells revealed prominent synthesis of IL-6 by PA-SMCs, with further stimulation by hypoxia. IL-6 also markedly stimulated PA-SMC migration without affecting proliferation. Hypoxic IL-6-/- mice showed less inflammatory cell recruitment in the lungs, compared to hypoxic wild-type mice, as assessed by lung protein levels and immunostaining for the specific macrophage marker F4/80, with no difference in lung expression of adhesion molecules or cytokines. Conclusion These data suggest that IL-6 may be actively involved in hypoxia-induced lung inflammation and pulmonary vascular remodeling in mice.

  1. Chronic cadmium exposure in vitro induces cancer cell characteristics in human lung cells

    Science.gov (United States)

    Person, Rachel J.; Tokar, Erik J.; Xu, Yuanyuan; Orihuela, Ruben; Olive Ngalame, Ntube N.; Waalkes, Michael P.

    2013-01-01

    Cadmium is a known human lung carcinogen. Here, we attempt to develop an in vitro model of cadmium-induced human lung carcinogenesis by chronically exposing the peripheral lung epithelia cell line, HPL-1D, to a low level of cadmium. Cells were chronically exposed to 5 μM cadmium, a noncytotoxic level, and monitored for acquired cancer characteristics. By 20 weeks of continuous cadmium exposure, these chronic cadmium treated lung (CCT-LC) cells showed marked increases in secreted MMP-2 activity (3.5-fold), invasion (3.4-fold), and colony formation in soft agar (2-fold). CCT-LC cells were hyperproliferative, grew well in serum-free media, and overexpressed cyclin D1. The CCT-LC cells also showed decreased expression of the tumor suppressor genes p16 and SLC38A3 at the protein levels. Also consistent with an acquired cancer cell phenotype, CCT-LC cells showed increased expression of the oncoproteins K-RAS and N-RAS as well as the epithelial-to-mesenchymal transition marker protein Vimentin. Metallothionein (MT) expression is increased by cadmium, and is typically overexpressed in human lung cancers. The major MT isoforms, MT-1A and MT-2A were elevated in CCT-LC cells. Oxidant adaptive response genes HO-1 and HIF-1A were also activated in CCT-LC cells. Expression of the metal transport genes ZNT-1, ZNT-5, and ZIP-8 increased in CCT-LC cells culminating in reduced cadmium accumulation, suggesting adaptation to the metal. Overall, these data suggest that exposure of human lung epithelial cells to cadmium causes acquisition of cancer cell characteristics. Furthermore, transformation occurs despite the cell’s ability to adapt to chronic cadmium exposure. PMID:23811327

  2. Triptolide potentiates lung cancer cells to cisplatin-induced apoptosis by selectively inhibiting the NER activity.

    Science.gov (United States)

    Wang, Gan; Wang, Xing; Xu, Xiaoxin

    2015-01-01

    Cisplatin and many other platinum-based compounds are important anticancer drugs that are used in treating many cancer types. The development of cisplatin-resistant cancer cells, however, quickly diminishes the effectiveness of these drugs and causes treatment failure. New strategies that reverse cancer cell drug resistance phenotype or sensitize cancer cells to these drugs, therefore, need to be explored in order to improve platinum drug-based cancer treatment. Triptolide is a bioactive ingredient isolated from Tripterygium wilfordii, a Chinese herbal medicine. Triptolide binds to the TFIIH basal transcription factor and is required for both transcription and nucleotide excision repair (NER), a DNA repair pathway involved in repairing DNA damage generated by the platinum-based anticancer drugs. Caspase-3 activation and cell growth inhibition assays were used to determine the effect of triptolide on cisplatin-induced apoptosis and cell growth in lung cancer cells. Real time PCR, immunoblotting, and expression of reef coral red protein were used to determine a mechanism through which the presence of triptolide increased cisplatin-induced apoptosis of the lung cancer cells. Our caspase-3 activation studies demonstrated that the presence of low-levels of triptolide greatly increased the cisplatin-induced apoptosis of HTB182, A549, CRL5810, and CRL5922 lung cancer cells. The results of our cell growth inhibition studies revealed that the presence of low-levels triptolide itself had little effect on cell growth but greatly enhanced cisplatin-induced cell growth inhibition in both A549 and HTB182 cells. The results of our reef coral-red protein reporter expression studies indicated that the presence of low-levels triptolide did not affect expression of the reef coral-red protein from pDsRed2-C1 plasmid but greatly inhibited expression of the reef coral-red protein from cisplatin-damaged pDsRed2-C1 plasmid DNA in A549 cells. In addition, the results of our protein

  3. Role of sphingolipids in murine radiation-induced lung injury: protection by sphingosine 1-phosphate analogs

    Science.gov (United States)

    Mathew, Biji; Jacobson, Jeffrey R.; Berdyshev, Evgeny; Huang, Yong; Sun, Xiaoguang; Zhao, Yutong; Gerhold, Lynnette M.; Siegler, Jessica; Evenoski, Carrie; Wang, Ting; Zhou, Tong; Zaidi, Rafe; Moreno-Vinasco, Liliana; Bittman, Robert; Chen, Chin Tu; LaRiviere, Patrick J.; Sammani, Saad; Lussier, Yves A.; Dudek, Steven M.; Natarajan, Viswanathan; Weichselbaum, Ralph R.; Garcia, Joe G. N.

    2011-01-01

    Clinically significant radiation-induced lung injury (RILI) is a common toxicity in patients administered thoracic radiotherapy. Although the molecular etiology is poorly understood, we previously characterized a murine model of RILI in which alterations in lung barrier integrity surfaced as a potentially important pathobiological event and genome-wide lung gene mRNA levels identified dysregulation of sphingolipid metabolic pathway genes. We hypothesized that sphingolipid signaling components serve as modulators and novel therapeutic targets of RILI. Sphingolipid involvement in murine RILI was confirmed by radiation-induced increases in lung expression of sphingosine kinase (SphK) isoforms 1 and 2 and increases in the ratio of ceramide to sphingosine 1-phosphate (S1P) and dihydro-S1P (DHS1P) levels in plasma, bronchoalveolar lavage fluid, and lung tissue. Mice with a targeted deletion of SphK1 (SphK1−/−) or with reduced expression of S1P receptors (S1PR1+/−, S1PR2−/−, and S1PR3−/−) exhibited marked RILI susceptibility. Finally, studies of 3 potent vascular barrier-protective S1P analogs, FTY720, (S)-FTY720-phosphonate (fTyS), and SEW-2871, identified significant RILI attenuation and radiation-induced gene dysregulation by the phosphonate analog, fTyS (0.1 and 1 mg/kg i.p., 2×/wk) and to a lesser degree by SEW-2871 (1 mg/kg i.p., 2×/wk), compared with those in controls. These results support the targeting of S1P signaling as a novel therapeutic strategy in RILI.—Mathew, B., Jacobson, J. R., Berdyshev, E., Huang, Y., Sun, X., Zhao, Y., Gerhold, L. M., Siegler, J., Evenoski, C., Wang, T., Zhou, T., Zaidi, R., Moreno-Vinasco, L., Bittman, R., Chen, C. T., LaRiviere, P. J., Sammani, S., Lussier, Y. A., Dudek, S. M., Natarajan, V., Weichselbaum, R. R., Garcia, J. G. N. Role of sphingolipids in murine radiation-induced lung injury: protection by sphingosine 1-phosphate analogs. PMID:21712494

  4. Beta-cryptoxanthin protection against cigarette smoke-induced inflammatory responses in the lung is due to the action of its own molecule

    Science.gov (United States)

    Higher intake of the dietary xanthophyll, beta-cryptoxanthin (BCX), has been associated with a lower risk of lung cancer death in smokers. We have previously shown that BCX feeding was effective in reducing both cigarette smoke (CS)-induced lung inflammation in ferrets and carcinogen-induced lung tu...

  5. Enhancement of the Acrolein-Induced Production of Reactive Oxygen Species and Lung Injury by GADD34

    OpenAIRE

    Sun, Yang; Ito, Sachiko; Nishio, Naomi; Tanaka, Yuriko; Chen, Nana; Liu, Lintao; Isobe, Ken-ichi

    2015-01-01

    Chronic obstructive pulmonary disease (COPD) is characterized by lung destruction and inflammation. As a major compound of cigarette smoke, acrolein plays a critical role in the induction of respiratory diseases. GADD34 is known as a growth arrest and DNA damage-related gene, which can be overexpressed in adverse environmental conditions. Here we investigated the effects of GADD34 on acrolein-induced lung injury. The intranasal exposure of acrolein induced the expression of GADD34, developing...

  6. Lysophosphatidic Acid Receptor–2 Deficiency Confers Protection against Bleomycin-Induced Lung Injury and Fibrosis in Mice

    Science.gov (United States)

    Huang, Long Shuang; Fu, Panfeng; Patel, Priya; Harijith, Anantha; Sun, Tianjiao; Zhao, Yutong; Garcia, Joe G. N.; Chun, Jerold

    2013-01-01

    Idiopathic pulmonary fibrosis is a devastating disease characterized by alveolar epithelial cell injury, the accumulation of fibroblasts/myofibroblasts, and the deposition of extracellular matrix proteins. Lysophosphatidic acid (LPA) signaling through its G protein–coupled receptors is critical for its various biological functions. Recently, LPA and LPA receptor 1 were implicated in lung fibrogenesis. However, the role of other LPA receptors in fibrosis remains unclear. Here, we use a bleomycin-induced pulmonary fibrosis model to investigate the roles of LPA2 in pulmonary fibrogenesis. In the present study, we found that LPA2 knockout (Lpar2−/−) mice were protected against bleomycin-induced lung injury, fibrosis, and mortality, compared with wild-type control mice. Furthermore, LPA2 deficiency attenuated the bleomycin-induced expression of fibronectin (FN), α–smooth muscle actin (α-SMA), and collagen in lung tissue, as well as levels of IL-6, transforming growth factor–β (TGF-β), and total protein in bronchoalveolar lavage fluid. In human lung fibroblasts, the knockdown of LPA2 attenuated the LPA-induced expression of TGF-β1 and the differentiation of lung fibroblasts to myofibroblasts, resulting in the decreased expression of FN, α-SMA, and collagen, as well as decreased activation of extracellular regulated kinase 1/2, Akt, Smad3, and p38 mitogen-activated protein kinase. Moreover, the knockdown of LPA2 with small interfering RNA also mitigated the TGF-β1–induced differentiation of lung fibroblasts. In addition, LPA2 deficiency significantly attenuated the bleomycin-induced apoptosis of alveolar and bronchial epithelial cells in the mouse lung. Together, our data indicate that the knockdown of LPA2 attenuated bleomycin-induced lung injury and pulmonary fibrosis, and this may be related to an inhibition of the LPA-induced expression of TGF-β and the activation and differentiation of fibroblasts. PMID:23808384

  7. Adenovirus-mediated Foxp3 expression in lung epithelial cells ameliorates acute radiation-induced pneumonitis in mice.

    Science.gov (United States)

    Shin, D; Lee, G; Lee, S; Park, S; Jung, K-H; Lee, J H; Lee, J M; Kim, J-Y; Cho, J; Bae, H

    2017-02-01

    Forkhead transcription factor 3 (Foxp3) has a critical role in regulatory T cells (Treg). There are an increasing number of researches concerning the functions of Foxp3 in other cells, including lung epithelial cells besides Treg. However, the roles of Foxp3 in lung epithelial cells remain poorly understood. To examine the potential therapeutic benefits of Foxp3 for lung inflammation, this study investigates the effect of adenovirus-mediated Foxp3 overexpression in a radiation-induced lung damage model. Foxp3-EGFP expressing adenovirus was administered by intratracheal injection three times over 14 days after focal X-ray irradiation. To evaluate effects of Foxp3 overexpression in radiation-induced lung inflammation, immune cell profiles of bronchoalveolar lavage (BAL) fluid were analyzed. Foxp3 gene-delivered mice showed significant inhibition of immune cell infiltration, such as eosinophils, lymphocytes, macrophages and neutrophils in BAL fluid. Histopathological analysis also showed that Foxp3 overexpression inhibits inflammatory cell recruitment and collagen deposition in lung tissues. In addition, expression of inflammatory and fibrosis-related genes was decreased in the Foxp3 expression adenovirus-infected group. These results suggest that Foxp3 expression in lungs holds considerable therapeutic potential for attenuating inflammation and fibrosis in radiation-induced lung injury.

  8. Mesenchymal stromal cell treatment prevents H9N2 avian influenza virus-induced acute lung injury in mice.

    Science.gov (United States)

    Li, Yan; Xu, Jun; Shi, Weiqing; Chen, Cheng; Shao, Yan; Zhu, Limei; Lu, Wei; Han, XiaoDong

    2016-10-28

    The avian influenza virus (AIV) can cross species barriers and expand its host range from birds to mammals, even humans. Avian influenza is characterized by pronounced activation of the proinflammatory cytokine cascade, which perpetuates the inflammatory response, leading to persistent systemic inflammatory response syndrome and pulmonary infection in animals and humans. There are currently no specific treatment strategies for avian influenza. We hypothesized that mesenchymal stromal cells (MSCs) would have beneficial effects in the treatment of H9N2 AIV-induced acute lung injury in mice. Six- to 8-week-old C57BL/6 mice were infected intranasally with 1 × 10 4 MID 50 of A/HONG KONG/2108/2003 [H9N2 (HK)] H9N2 virus to induce acute lung injury. After 30 min, syngeneic MSCs were delivered through the caudal vein. Three days after infection, we measured the survival rate, lung weight, arterial blood gas, and cytokines in both bronchoalveolar lavage fluid (BALF) and serum, and assessed pathological changes to the lungs. MSC administration significantly palliated H9N2 AIV-induced pulmonary inflammation by reducing chemokines and proinflammatory cytokines levels, as well as reducing inflammatory cell recruit into the lungs. Thus, H9N2 AIV-induced lung injury was markedly alleviated in mice treated with MSCs. Lung histopathology and arterial blood gas analysis were improved in mice with H9N2 AIV-induced lung injury following MSC treatment. MSC treatment significantly reduces H9N2 AIV-induced acute lung injury in mice and is associated with reduced pulmonary inflammation. These results indicate a potential role for MSC therapy in the treatment of clinical avian influenza.

  9. Low-Dose Radiation Induces Cell Proliferation in Human Embryonic Lung Fibroblasts but not in Lung Cancer Cells

    Directory of Open Access Journals (Sweden)

    Xinyue Liang

    2016-01-01

    Full Text Available Hormesis and adaptive responses are 2 important biological effects of low-dose ionizing radiation (LDR. In normal tissue, LDR induces hormesis as evinced by increased cell proliferation; however, whether LDR also increases tumor cell proliferation needs to be investigated. In this study, cell proliferation was assayed by total cell numbers and the Cell Counting Kit 8 assay. Mitogen-activated protein kinases (MAPK/extracellular signal-regulated kinase (ERK and phosphatidylinositol 3′ -kinase(PI3K-Akt (PI3K/AKT phosphorylation were determined by Western blot analysis. Human embryonic lung fibroblast 2BS and lung cancer NCI-H446 cell lines were irradiated with LDR at different doses (20-100 mGy. In response to 20 to 75 mGy X-rays, cell proliferation was significantly increased in 2BS but not in NCI-H446 cells. In 2BS cells, LDR at 20 to 75 mGy also stimulated phosphorylation of MAPK/ERK pathway proteins including ERK, MEK, and Raf and of the PI3K/AKT pathway protein AKT. To test whether ERK1/2 and AKT pathway activation was involved in the stimulation of cell proliferation in 2BS cells, the MAPK/ERK and PI3K/AKT pathways were inhibited using their specific inhibitors, U0126 and LY294002. U0126 decreased the phosphorylation of ERK1/2, and LY294002 decreased the phosphorylation of AKT; each could significantly inhibit LDR-induced 2BS cell proliferation. However, LDR did not stimulate these kinases, and kinase inhibitors also did not affect cell proliferation in the NCI-H446 cells. These results suggest that LDR stimulates cell proliferation via the activation of both MAPK/ERK and PI3K/AKT signaling pathways in 2BS but not in NCI-H446 cells. This finding implies the potential for applying LDR to protect normal tissues from radiotherapy without diminishing the efficacy of tumor therapy.

  10. Protective effect of salvianolate on lung injury induced by ischemia reperfusion injury of liver in mice

    Directory of Open Access Journals (Sweden)

    Zheng-xin WANG

    2011-11-01

    Full Text Available Objective To evaluate the protective effect of salvianolate on lung injury induced by hepatic ischemia reperfusion(IR injury in mice and its underlying mechanisms.Methods A hepatic IR model of mice was reproduced,and 24 animals were assigned into 3 groups(8 each: sham operation(SO group,control group and salvianolate(SV group.Just before ischemia induction,animals in SV group received salvianolate injection at a dose of 60 mg/kg via tail vein,while in control group the mice received normal saline with an equal volume,and in SO group the mice received the same operation as in SV group but without producing liver ischemia.Four hours after reperfusion,the serum,liver and lung tissue were collected.The alanine aminotransferase(ALT and aspartate aminotransferase(AST levels in serum were detected and the histological changes in liver and lung were examined.The wet-to-dry weight ratio of pulmonary tissue was measured.The contents of tumor necrosis factor α(TNF-α,interleukin(IL-6,IL-1β and IL-10 in bronchoalveolar lavage fluid(BALF were detected by enzyme linked immunosorbent assay(ELISA,and the relative mRNA levels of TNF-α,IL-6,IL-1β and IL-10 in pulmonary tissue were analyzed by real-time reverse transcription PCR(RT-PCR.The activaty of transcription factor NF-κB was measured with Western blotting analysis.Results No significant pathologic change was found in mice of SO group.Compared with the mice in control group,those in SV group exhibited lower levels of ALT and AST(P < 0.01,lighter histological changes in liver and lung(P < 0.05,lower levels of wet-to-dry weight ratio of lung tissue(P < 0.05,lower expression levels of TNF-α,IL-6,IL-1β and IL-10 in BALF and lung tissue(P < 0.05 or P < 0.01.Further examination demonstrated that the activity of NF-κB in SV group was significantly down-regulated as compared with that in control group.Conclusion Salvianolate can attenuate lung injury induced by hepatic IR in mice,the mechanism may inclade

  11. Lung injury via oxidative stress in mice induced by inhalation exposure to rocket kerosene.

    Science.gov (United States)

    Xu, Bingxin; Li, Chenglin; Wang, Jianying; Wu, Jihua; Si, Shaoyan; Liu, Zhiguo; Li, Jianzhong; Zhang, Jianzhong; Cui, Yan

    2015-01-01

    Rocket kerosene (RK) is a new rocket propellant. Toxicity occurs if a high level of RK is inhaled. To study the toxicity of RK in lung and the mechanisms of RK-induced lung jury, a total of 72 male ICR mice (1.5 months, adult) were randomly assigned to the RK exposure group (RKEG) and normal control group (NCG). Mice were whole-body exposed to room air or aerosol of 18000 mg/m3 RK for 4 hours. Histopathological analysis was performed to evaluate the pulmonary lesions. Oxidative stress was assessed by assay of MDA, SOD, GSH-PX and TAOC. Inflammatory response was estimated by detecting inflammatory cell counts, TNF-α and IL-6 protein levels in serum. The results showed that after 2 to 6 hours of RK exposure, pulmonary vascular dilatation, congestion and edematous widening of the alveolar septum were noted. After 12 to 24 hours post-exposure, diffuse hemorrhage in alveolar space were found, along with the progressive pulmonary vascular dilatation and edematous widening of alveolar septum. During 3 to 7 days of RK-exposure, inflammatory cells were scattered in the lung tissue. The pathological alterations of the lung were alleviated after 14 days post-exposure, and showed significant improvement after 21 days post-exposure. After 30 days of RK exposure, the pathological changes in the lung tissue were nearly recovered except the local thickening of the alveolar wall. Compared with NCG, RK inhalation produced a significant increase of MDA levels and a significant decrease of SOD, GSH-Px and TAOC activity in the lung after 2 hours post-exposure (P<0.05). There were significant increases of TNF-α and IL-6 protein levels in serum of mice in RKEG after 2, 6 and 12 hours and 1, 4 and 7 days post-exposure compared with NCG (P<0.05). TNF-α protein levels had a sharp increase after 4 days of exposure. IL-6 protein level was increased at early phase of experiment and then gradually decreased along with the prolonged course of exposure. Considering that the RK-induced lung

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

    Directory of Open Access Journals (Sweden)

    Takeo Nakanishi

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

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

    Science.gov (United States)

    Nakanishi, Takeo; Hasegawa, Yoshitaka; Mimura, Reo; Wakayama, Tomohiko; Uetoko, Yuka; Komori, Hisakazu; Akanuma, Shin-Ichi; Hosoya, Ken-Ichi; Tamai, Ikumi

    2015-01-01

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

  14. Aerosolized human extracellular superoxide dismutase prevents hyperoxia-induced lung injury.

    Directory of Open Access Journals (Sweden)

    Chih-Ching Yen

    Full Text Available An important issue in critical care medicine is the identification of ways to protect the lungs from oxygen toxicity and reduce systemic oxidative stress in conditions requiring mechanical ventilation and high levels of oxygen. One way to prevent oxygen toxicity is to augment antioxidant enzyme activity in the respiratory system. The current study investigated the ability of aerosolized extracellular superoxide dismutase (EC-SOD to protect the lungs from hyperoxic injury. Recombinant human EC-SOD (rhEC-SOD was produced from a synthetic cassette constructed in the methylotrophic yeast Pichia pastoris. Female CD-1 mice were exposed in hyperoxia (FiO2>95% to induce lung injury. The therapeutic effects of EC-SOD and copper-zinc SOD (CuZn-SOD via an aerosol delivery system for lung injury and systemic oxidative stress at 24, 48, 72 and 96 h of hyperoxia were measured by bronchoalveolar lavage, wet/dry ratio, lung histology, and 8-oxo-2'-deoxyguanosine (8-oxo-dG in lung and liver tissues. After exposure to hyperoxia, the wet/dry weight ratio remained stable before day 2 but increased significantly after day 3. The levels of oxidative biomarker 8-oxo-dG in the lung and liver were significantly decreased on day 2 (P<0.01 but the marker in the liver increased abruptly after day 3 of hyperoxia when the mortality increased. Treatment with aerosolized rhEC-SOD increased the survival rate at day 3 under hyperoxia to 95.8%, which was significantly higher than that of the control group (57.1%, albumin treated group (33.3%, and CuZn-SOD treated group (75%. The protective effects of EC-SOD against hyperoxia were further confirmed by reduced lung edema and systemic oxidative stress. Aerosolized EC-SOD protected mice against oxygen toxicity and reduced mortality in a hyperoxic model. The results encourage the use of an aerosol therapy with EC-SOD in intensive care units to reduce oxidative injury in patients with severe hypoxemic respiratory failure, including

  15. Cthrc1 lowers pulmonary collagen associated with bleomycin-induced fibrosis and protects lung function.

    Science.gov (United States)

    Binks, Andrew P; Beyer, Megyn; Miller, Ryan; LeClair, Renee J

    2017-03-01

    Idiopathic pulmonary fibrosis (IPF) involves collagen deposition that results in a progressive decline in lung function. This process involves activation of Smad2/3 by transforming growth factor (TGF)- β and Wnt signaling pathways. Collagen Triple Helix Repeat-Containing-1 (Cthrc1) protein inhibits Smad2/3 activation. To test the hypothesis that Cthrc1 limits collagen deposition and the decline of lung function, Cthrc1 knockout (Cthrc1 -/- ) and wild-type mice (WT) received intratracheal injections of 2.5 U/kg bleomycin or saline. Lungs were harvested after 14 days and Bronchoalveolar lavage (BAL) TGF- β , IL1- β , hydroxyproline and lung compliance were assessed. TGF- β was significantly higher in Cthrc1 -/- compared to WT (53.45 ± 6.15 ng/mL vs. 34.48 ± 11.05) after saline injection. Bleomycin injection increased TGF- β in both Cthrc1 -/- (66.37 ± 8.54 ng/mL) and WT (63.64 ± 8.09 ng/mL). Hydroxyproline was significantly higher in Cthrc1 -/- compared to WT after bleomycin-injection (2.676 ± 0.527  μ g/mg vs. 1.889 ± 0.520, P  = 0.028). Immunohistochemistry of Cthrc1 -/- lung sections showed intracellular localization and activation of β -catenin Y654 in areas of tissue remodeling that was not evident in WT Lung compliance was significantly reduced by bleomycin in Cthrc1 -/- but there was no effect in WT animals. These data suggest Cthrc1 reduces fibrotic tissue formation in bleomycin-induced lung fibrosis and the effect is potent enough to limit the decline in lung function. We conclude that Cthrc1 plays a protective role, limiting collagen deposition and could form the basis of a novel therapy for pulmonary fibrosis. © 2017 The Authors. Physiological Reports published by Wiley Periodicals, Inc. on behalf of The Physiological Society and the American Physiological Society.

  16. Histamine induces human lung fibroblast-mediated collagen gel contraction via histamine H1 receptor.

    Science.gov (United States)

    Horie, Masafumi; Saito, Akira; Yamauchi, Yasuhiro; Mikami, Yu; Sakamoto, Makiko; Jo, Taisuke; Nakajima, Jun; Takizawa, Hajime; Nagase, Takahide; Kohyama, Tadashi

    2014-06-01

    Airway remodeling is implicated in irreversible airflow limitation of refractory asthma, which includes increased smooth muscle mass and subepithelial fibrosis. Activated fibroblasts acquire contractile phenotype to participate in tissue contraction and structural alteration of extracellular matrices. Histamine is a potent mediator of allergic inflammation, substantially involved in asthmatic pathophysiology. We hypothesized that histamine might play a role in airway remodeling, and investigated its effect on fibroblast-mediated collagen gel contraction. Fibroblast-mediated collagen gel contraction was studied. Histamine's regulation of collagen gel contraction was characterized by using specific histamine-receptor antagonists, an IP3 receptor antagonist and a PKC inhibitor. Histamine induced contraction of collagen gels embedded with human lung fibroblasts, in a time-dependent manner, and at the concentration more than 10(-6) M, both in four primary cultured adult lung fibroblasts and three fetal lung fibroblast cell lines. This effect was attenuated by H1 receptor antagonist, whereas those for H2 to H4 receptors failed to show an inhibitory effect. Furthermore, IP3 receptor-mediated Ca(2+) mobilization was implicated in histamine's action on collagen gel contraction. Our results suggest that histamine is involved in airway remodeling through its action on lung fibroblasts, and antihistamine drugs, especially H1 receptor antagonists, might be potentially beneficial for a subset of asthmatic patients.

  17. Acrolein induced both pulmonary inflammation and the death of lung epithelial cells.

    Science.gov (United States)

    Sun, Yang; Ito, Sachiko; Nishio, Naomi; Tanaka, Yuriko; Chen, Nana; Isobe, Ken-Ichi

    2014-09-02

    Acrolein, a compound found in cigarette smoke, is a major risk factor for respiratory diseases. Previous research determined that both acrolein and cigarette smoke produced reactive oxygen species (ROS). As many types of pulmonary injuries are associated with inflammation, this study sought to ascertain the extent to which exposure to acrolein advanced inflammatory state in the lungs. Our results showed that intranasal exposure of mice to acrolein increased CD11c(+)F4/80(high) macrophages in the lungs and increased ROS formation via induction of NF-κB signaling. Treatment with acrolein activated macrophages and led to their increased production of ROS and expression of several key pro-inflammatory cytokines. In in vitro studies, acrolein treatment of bone marrow-derived GM-CSF-dependent immature macrophages (GM-IMs), activated the cells and led to their increased production of ROS and expression of several key pro-inflammatory cytokines. Acrolein treatment of macrophages induced apoptosis of lung epithelial cells. Inclusion of an inhibitor of ROS formation markedly decreased acrolein-mediated macrophage activation and reduced the extent of epithelial cell death. These results indicate that acrolein can cause lung damage, in great part by mediating the increased release of pro-inflammatory cytokines/factors by macrophages. Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.

  18. Targeted Metabolomics Identifies Pharmacodynamic Biomarkers for BIO 300 Mitigation of Radiation-Induced Lung Injury.

    Science.gov (United States)

    Jones, Jace W; Jackson, Isabel L; Vujaskovic, Zeljko; Kaytor, Michael D; Kane, Maureen A

    2017-12-01

    Biomarkers serve a number of purposes during drug development including defining the natural history of injury/disease, serving as a secondary endpoint or trigger for intervention, and/or aiding in the selection of an effective dose in humans. BIO 300 is a patent-protected pharmaceutical formulation of nanoparticles of synthetic genistein being developed by Humanetics Corporation. The primary goal of this metabolomic discovery experiment was to identify biomarkers that correlate with radiation-induced lung injury and BIO 300 efficacy for mitigating tissue damage based upon the primary endpoint of survival. High-throughput targeted metabolomics of lung tissue from male C57L/J mice exposed to 12.5 Gy whole thorax lung irradiation, treated daily with 400 mg/kg BIO 300 for either 2 weeks or 6 weeks starting 24 h post radiation exposure, were assayed at 180 d post-radiation to identify potential biomarkers. A panel of lung metabolites that are responsive to radiation and able to distinguish an efficacious treatment schedule of BIO 300 from a non-efficacious treatment schedule in terms of 180 d survival were identified. These metabolites represent potential biomarkers that could be further validated for use in drug development of BIO 300 and in the translation of dose from animal to human.

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

    Directory of Open Access Journals (Sweden)

    Satish K. Madala

    2011-01-01

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

  20. Toona Sinensis Extracts Induced Cell Cycle Arrest and Apoptosis in the Human Lung Large Cell Carcinoma

    Directory of Open Access Journals (Sweden)

    Cheng-Yuan Wang

    2010-02-01

    Full Text Available Toona sinensis extracts have been shown to exhibit anti-cancer effects in human ovarian cancer cell lines, human promyelocytic leukemia cells and human lung adenocarcinoma. Its safety has also been confirmed in animal studies. However, its anti-cancer properties in human lung large cell carcinoma have not been studied. Here, we used a powder obtained by freeze-drying the super-natant of centrifuged crude extract from Toona sinensis leaves (TSL-1 to treat the human lung carcinoma cell line H661. Cell viability was evaluated by the 3-(4-,5-dimethylthiazol-2-yl-2,5-diphenyl tetrazolium bromide assay. Flow cytometry analysis revealed that TSL-1 blocked H661 cell cycle progression. Western blot analysis showed decreased expression of cell cycle proteins that promote cell cycle progression, including cyclin-dependent kinase 4 and cyclin D1, and increased the expression of proteins that inhibit cell cycle progression, including p27. Furthermore, flow cytometry analysis showed that TSL-1 induced H661 cell apoptosis. Western blot analysis showed that TSL-1 reduced the expression of the anti-apoptotic protein B-cell lymphoma 2, and degraded the DNA repair protein, poly(ADP-ribose polymerase. TSL-1 shows potential as a novel therapeutic agent or for use as an adjuvant for treating human lung large cell carcinoma.

  1. Beclin1-induced autophagy abrogates radioresistance of lung cancer cells by suppressing osteopontin

    International Nuclear Information System (INIS)

    Chang, Seung-Hee; Minai-Tehrani, Arash; Shin, Ji-Young

    2012-01-01

    Osteopontin (OPN) serves as an indicator of resistance to radiotherapy. However, the role of OPN in the development of acquired radioresistance in human lung cancer cells has not yet been fully elucidated. Therefore, the potential importance of OPN as a marker of lung cancer with a potential significant role in the development of radioresistance against repeated radiotherapy has prompted us to define the pathways by which OPN regulates lung cancer cell growth. In addition, autophagy has been reported to play a key role in the radiosensitization of cancer cells. Here, we report that increased OPN expression through induction of nuclear p53 following irradiation was inhibited by exogenous beclin-1 (BECN1). Our results clearly show that BECN1 gene expression led to induction of autophagy and inhibition of cancer cell growth and angiogenesis. Our results suggest that the induction of autophagy abrogated the radioresistance of the cancer cells. Interestingly, we showed that knockdown of OPN by lentivirus-mediated shRNA induced the autophagy of human lung cancer cell. Taken together, these results suggest that OPN and BECN1 can be molecular targets for overcoming radioresistance by controlling autophagy. (author)

  2. Pistacia chinensis: A Potent Ameliorator of CCl4 Induced Lung and Thyroid Toxicity in Rat Model

    Directory of Open Access Journals (Sweden)

    Kiran Naz

    2014-01-01

    Full Text Available In the current study protective effect of ethanol extract of Pistacia chinensis bark (PCEB was investigated in rats against CCl4 induced lung and thyroid injuries. PCEB dose dependently inhibited the rise of thiobarbituric acid-reactive substances, hydrogen peroxide, nitrite, and protein content and restored the levels of antioxidant enzymes, that is, catalase, peroxidase, superoxide dismutase, glutathione-S-transferase, glutathione reductase, glutathione peroxidase, γ-glutamyl transpeptidase, and quinone reductase in both lung and thyroid tissues of CCl4 treated rats. Decrease in number of leukocytes, neutrophils, and hemoglobin and T3 and T4 content as well as increase in monocytes, eosinophils, and lymphocytes count with CCl4 were restored to normal level with PCEB treatment. Histological study of CCl4 treated rats showed various lung injuries like rupture of alveolar walls and bronchioles, aggregation of fibroblasts, and disorganized Clara cells. Similarly, histology of CCl4 treated thyroid tissues displayed damaged thyroid follicles, hypertrophy, and colloidal depletion. However, PCEB exhibited protective behaviour for lungs and thyroid, with improved histological structure in a dose dependant manner. Presence of three known phenolic compounds, that is, rutin, tannin, and gallic acid, and three unknown compounds was verified in thin layer chromatographic assessment of PCEB. In conclusion, P. chinensis exhibited antioxidant activity by the presence of free radical quenching constituents.

  3. Immunosuppressive effects of Pteridium aquilinum enhance susceptibility to urethane-induced lung carcinogenesis.

    Science.gov (United States)

    Caniceiro, Beatriz D; Latorre, Andreia O; Fukumasu, Heidge; Sanches, Daniel S; Haraguchi, Mitsue; Górniak, Silvana L

    2015-01-01

    Pteridium aquilinum (bracken fern), one of the most important toxic plants in the world, contains the toxic norsequiterpene ptaquiloside that induces cancers in humans and farm animals. Previous studies in the laboratory demonstrated immunotoxic effects produced by ptaquiloside, which are characterized by suppression of natural killer (NK) cell activity (i.e. cytotoxicity and interferon [IFN]-γ production). However, it is unknown whether these immunosuppressive effects could contribute to carcinogenesis in situ in general because of the important function of NK cells in innate killing of tumor cells. This study assessed the impact of P. aquilinum-induced immunosuppression on urethane-induced lung cancer in C57BL/6 mice. Adult mice were treated with an extract of P. aquilinum (30 g/kg/day) by gavage once daily for 14 days, followed by gavage (5 days/week) during an 11-week period that was accompanied by treatment with urethane (1 g/kg) via once-weekly intraperitoneal injection; 20 weeks after the end of the treatment period, all lungs were evaluated. The results indicated there was a significant increase in lung nodule number as well as in multiplicity of lesions in mice treated with both P. aquilinum and urethane (PU group) compared to values in mice treated only with the urethane (U group). In addition, histologic evaluation revealed a 76% increase in the rate of lung adenomas and a 41% increase in rate of bronchiolization of alveoli in the mice from the PU group compared to levels seen in mice within the U group. Taken together, the results here show for the first time that immunosuppressive effects of P. aquilinum could increase the risk of cancer formation in exposed hosts.

  4. The role of lymphocytes in radiotherapy-induced adverse late effects in the lung

    Directory of Open Access Journals (Sweden)

    Florian Wirsdörfer

    2016-12-01

    Full Text Available Radiation-induced pneumonitis and fibrosis are dose-limiting side effects of thoracic irradiation. Thoracic irradiation triggers acute and chronic environmental lung changes that are shaped by the damage response of resident cells, by the resulting reaction of the immune system, and by repair processes. Although considerable progress has been made during the last decade in defining involved effector cells and soluble mediators, the network of pathophysiological events and the cellular cross-talk linking acute tissue damage to chronic inflammation and fibrosis still require further definition. Infiltration of cells from the innate and adaptive immune systems is a common response of normal tissues to ionizing radiation. Herein lymphocytes represent a versatile and wide-ranged group of cells of the adaptive immune system that can react under specific conditions in various ways and participate in modulating the lung environment by adopting pro-inflammatory, anti-inflammatory or even pro- or anti-fibrotic phenotypes. The present review provides an overview on published data about the role of lymphocytes in radiation-induced lung disease and related damage-associated pulmonary diseases with a focus on T-lymphocytes and B-lymphocytes. We also discuss the suspected dual role of specific lymphocyte subsets during the pneumonitic phase and fibrotic phase that is shaped by the environmental conditions and the interaction and the intercellular cross-talk between cells from the innate and adaptive immune systems and (damaged resident epithelial cells and stromal cells (e.g. endothelial cells, mesenchymal stem cells (MSC, fibroblasts. Finally, we highlight potential therapeutic targets suited to counteract pathological lymphocyte responses to prevent or treat radiation-induced lung disease.

  5. The Role of Lymphocytes in Radiotherapy-Induced Adverse Late Effects in the Lung

    Science.gov (United States)

    Wirsdörfer, Florian; Jendrossek, Verena

    2016-01-01

    Radiation-induced pneumonitis and fibrosis are dose-limiting side effects of thoracic irradiation. Thoracic irradiation triggers acute and chronic environmental lung changes that are shaped by the damage response of resident cells, by the resulting reaction of the immune system, and by repair processes. Although considerable progress has been made during the last decade in defining involved effector cells and soluble mediators, the network of pathophysiological events and the cellular cross talk linking acute tissue damage to chronic inflammation and fibrosis still require further definition. Infiltration of cells from the innate and adaptive immune systems is a common response of normal tissues to ionizing radiation. Herein, lymphocytes represent a versatile and wide-ranged group of cells of the immune system that can react under specific conditions in various ways and participate in modulating the lung environment by adopting pro-inflammatory, anti-inflammatory, or even pro- or anti-fibrotic phenotypes. The present review provides an overview on published data about the role of lymphocytes in radiation-induced lung disease and related damage-associated pulmonary diseases with a focus on T lymphocytes and B lymphocytes. We also discuss the suspected dual role of specific lymphocyte subsets during the pneumonitic phase and fibrotic phase that is shaped by the environmental conditions as well as the interaction and the intercellular cross talk between cells from the innate and adaptive immune systems and (damaged) resident epithelial cells and stromal cells (e.g., endothelial cells, mesenchymal stem cells, and fibroblasts). Finally, we highlight potential therapeutic targets suited to counteract pathological lymphocyte responses to prevent or treat radiation-induced lung disease. PMID:28018357

  6. Oxidative injury induced by cadmium sulfide nanoparticles in A549 cells and rat lungs.

    Science.gov (United States)

    Wang, Junfeng; Jiang, Chunyang; Alattar, Mohamed; Hu, Xiaoli; Ma, Dong; Liu, Huibin; Meng, Chunyan; Cao, Fuyuan; Li, Weihong; Li, Qingzhao

    2015-01-01

    Rod-shaped cadmium sulfide nanoparticles (CdS NPs) are becoming increasingly important in many industrial fields, but their potential hazards remain unknown. This study aimed to explore the patterns and mechanisms of lung injury induced by CdS NPs. A549 cells and rats were exposed to two types of CdS NPs with a same diameter of 20-30 nm but different lengths, CdS1 (80-100 nm) and CdS2 (110-130 nm). The using doses were included 10 μg/ml and 20 μg/ml two types of CdS NPs for cellular experiments and five times dose of 20 mg/kg body weight for rats' exposure. Methylthiazolyldiphenyl-tetrazolium bromide (MTT) and trypan blue staining were used to detect the A549 cell mortality percentage. The levels of reactive oxygen species (ROS) were determined in A549 cell. The vigor of superoxide dismutase (SOD) and the contents of catalase (CAT) and malondialdehyde (MDA) were detected both in A549 cells and in rats' serum and lung tissues. The cellular morphological changes were observed under transmission electron microscopy (TEM) and the pathological changes were observed in rats' lung tissue. CdS NPs significantly increased A549 cell mortality percentage. The CdS NPs also increased the levels of ROS and MDA content, whereas they decreased SOD and CAT activities. In parallel, similar changes of the contents of MDA, SOD and CAT were also observed in the sera and lung tissues of CdS NP-treated rats. The cellular TEM detection revealed that two types of CdS nanorods appeared as orderly arranged rounded fat droplets separately and leading to nucleus condensation (CdS1). These cellular and rats' tissues changes in the group treated with CdS1 were more significant than the CdS2 groups. Furthermore, CdS NPs induced many pathological changes, including emphysematous changes in rat lung tissue. Especially visible lung consolidation can be observed in the CdS1 group. CdS NPs induce oxidative injury in the respiratory system, and their toxic effects may be related to grain length.

  7. Hypoxia-induced pulmonary arterial hypertension augments lung injury and airway reactivity caused by ozone exposure

    International Nuclear Information System (INIS)

    Zychowski, Katherine E.; Lucas, Selita N.; Sanchez, Bethany; Herbert, Guy; Campen, Matthew J.

    2016-01-01

    Ozone (O 3 )-related cardiorespiratory effects are a growing public health concern. Ground level O 3 can exacerbate pre-existing respiratory conditions; however, research regarding therapeutic interventions to reduce O 3 -induced lung injury is limited. In patients with chronic obstructive pulmonary disease, hypoxia-associated pulmonary hypertension (HPH) is a frequent comorbidity that is difficult to treat clinically, yet associated with increased mortality and frequency of exacerbations. In this study, we hypothesized that established HPH would confer vulnerability to acute O 3 pulmonary toxicity. Additionally, we tested whether improvement of pulmonary endothelial barrier integrity via rho-kinase inhibition could mitigate pulmonary inflammation and injury. To determine if O 3 exacerbated HPH, male C57BL/6 mice were subject to either 3 weeks continuous normoxia (20.9% O 2 ) or hypoxia (10.0% O 2 ), followed by a 4-h exposure to either 1 ppm O 3 or filtered air (FA). As an additional experimental intervention fasudil (20 mg/kg) was administered intraperitoneally prior to and after O 3 exposures. As expected, hypoxia significantly increased right ventricular pressure and hypertrophy. O 3 exposure in normoxic mice caused lung inflammation but not injury, as indicated by increased cellularity and edema in the lung. However, in hypoxic mice, O 3 exposure led to increased inflammation and edema, along with a profound increase in airway hyperresponsiveness to methacholine. Fasudil administration resulted in reduced O 3 -induced lung injury via the enhancement of pulmonary endothelial barrier integrity. These results indicate that increased pulmonary vascular pressure may enhance lung injury, inflammation and edema when exposed to pollutants, and that enhancement of pulmonary endothelial barrier integrity may alleviate such vulnerability. - Highlights: • Environmental exposures can exacerbate chronic obstructive pulmonary disease (COPD). • It is unknown if comorbid

  8. No association between TGF-β1 polymorphisms and radiation-induced lung toxicity in a European cohort of lung cancer patients

    International Nuclear Information System (INIS)

    Voets, An M.; Oberije, Cary; Struijk, Robin B.; Reymen, Bart; Ruyck, Kim De; Thierens, Hubert; Vandecasteele, Katrien; Neve, Wilfried De; Houben, Ruud; Ruysscher, Dirk De; Smeets, Hubert J.M.; Lambin, Philippe

    2012-01-01

    This study aimed at validating the previously published association between TGF-β1 single nucleotide polymorphisms and a reduced risk for radiation-induced lung toxicity. We were not able to confirm the reported association, neither using maximum dyspnea score nor after correction for baseline dyspnea score.

  9. Gene expression of the concentration-sensitive sodium channel is suppressed in lipopolysaccharide-induced acute lung injury in mice.

    Science.gov (United States)

    Hagiwara, Teruki; Yoshida, Shigeru; Hidaka, Yuji

    2017-04-01

    The concentration-sensitive sodium channel (Na C ) is expressed in alveolar type II epithelial cells and pulmonary microvascular endothelial cells in mouse lungs. We recently reported that Na C contributes to amiloride-insensitive sodium transport in mouse lungs (Respiratory Physiology & Neurobiology, 2016). However, details regarding its physiological role in the lung remain unknown. To examine whether Na C is involved in alveolar fluid clearance during an acute lung injury (ALI), we analyzed the relationship between Na C gene expression in the lung and the development of pulmonary edema in lipopolysaccharide (LPS)-induced ALI mice. LPS-induced ALI mice were prepared by the intratracheal administration of LPS. Bronchoalveolar lavage (BAL) neutrophils and lung water content (LWCs) were used as a marker of ALI and pulmonary edema, respectively. Na C protein production in the lung was detected by immunoblotting and immunofluorescence. The gene expressions of Na C and the epithelial sodium channel (ENaC) of LPS-induced ALI mice were examined by quantitative RT-PCR over a time course of 14 days. The BAL neutrophil count increased until day 2 after LPS administration and had nearly recovered by day 6. LWCs in LPS-induced mice gradually increased until day 8 and had recovered by day 14. The expression of the Na C protein in the lungs of LPS-induced mice dramatically decreased from day 2 to day 6, but recovered by day 8. The mRNA expression of Na C decreased in the lung, as well as those for α-, β-, and γ-ENaC during ALI. Thus, Na C expression is suppressed during the development stage of pulmonary edema and then recovers in the convalescent phase. Our results suggest that suppression of the gene expression of Na C is involved in the development of pulmonary edema in ALI.

  10. An Uncaria tomentosa (cat's claw) extract protects mice against ozone-induced lung inflammation.

    Science.gov (United States)

    Cisneros, Francisco J; Jayo, Manuel; Niedziela, Linda

    2005-01-15

    Ozone (O(3)) inhalation has been associated with respiratory tract inflammation and lung functional alterations. To characterize the O(3)-induced lung inflammation in mice, the effective dose and exposure time were determined. Total protein levels of bronchoalveolar lavage fluid (BALF), cytological smears, and lung histopathology and morphometry were used to assess and measure the degree of pulmonary inflammation in the mouse model. Ozone inhalation caused acute pneumonitis that was characterized by a high number of infiltrating neutrophils (PMNs) immediately after exposure and increased levels of protein in BALF in mice killed 8h after O(3) exposure. The anti-inflammatory properties of Uncaria tomentosa (UT) have been documented previously. To evaluate the anti-inflammatory effects of UT, male mice were given an UT extract for 8 days, exposed to O(3), and killed 0 or 8 h after O(3) exposure. When compared to untreated controls, UT-treated mice had significantly (p < 0.05) lower levels of protein in BALF, lower degree of epithelial necrosis, higher number of intact epithelial cell nuclei in bronchial wall, and decreased number of PMNs in the bronchiolar lumen. Therefore, UT extract appeared to prevent O(3)-induced respiratory inflammation in male mice.

  11. MicroRNA-203 induces apoptosis by upregulating Puma expression in colon and lung cancer cells.

    Science.gov (United States)

    Funamizu, Naotake; Lacy, Curtis R; Kamada, Minori; Yanaga, Katsuhiko; Manome, Yoshinobu

    2015-11-01

    The present study investigated the relationship between microRNA-203 (miR-203) and the p53 upregulated modulator of apoptosis (Puma) in colon (HCT116) and lung cancer (A549) cells. Colon and lung cancer cell lines were selected for this study since a relationship between p53/miR-203 and p53/Puma has been established in both cancers. In the present study, adriamycin and nutlin-3 were used to activate p53, which induced both miR-203 and Puma expression in HCT116 cells. In contrast, HCT 116 cells with downregulated p53 showed decreased miR-203 and Puma expression. Importantly, we found that overexpressed miR-203 in HCT116 cells resulted in significantly increased Puma expression (PPuma axis depends on miR-203 expression. To further validate this relationship, we used lung cancer cells (A549) and found that activated p53 increased both miR-203 and Puma expression. In addition, we found that Puma expression remained elevated in cells with overexpressed miR-203 in the presence of p53 downregulation. Cumulatively, our data purport that p53 not only increased Puma expression directly, but that it may also do so through miR-203. Additionally, functional studies revealed that miR-203 overexpression induced apoptosis and inhibited cell invasiveness.

  12. Gene alterations in radiation-induced F344 rat lung tumors

    International Nuclear Information System (INIS)

    Kelly, G.; Hahn, F.F.

    1994-01-01

    The p53 tumor suppressor gene is frequently altered in all major histopathologic types of human lung tumors. Reported p53 mutations include base substitutions, allelic loss, rearrangements, and deletions. Point mutations resulting in base substitutions are clustered within a highly conserved region of the gene encoding exons 508, and mutations in this region substantially extend the half-life of the p53 protein. In addition to its prominent importance in lung carcinogenesis, the p53 gene plays a critical role in the cellular response to genetic damage caused by radiation. Specifically, the protein product of p53 induces a pause or block at the G 1 to S boundary of the cell cycle following radiation-caused DNA damage. This G 1 block may allow the cell time to repair the damaged DNA prior to replication. Cells lacking a functional p53 protein fail to pause for repair and consequently accumulate mutations in the genome at an accelerated rate. p53 has also been implicated as a controlling factor in apoptosis or in programmed cell death induced by DNA-damaging agents, such as ionizing radiation. The p53 gene is mutated in approximately 50% of squamous cell carcinomas from uranium miners who inhaled high doses of radon daughters. The purpose of the present study was to determine if a similar percentage of squamous cell carcinomas with p53 mutations developed in the lungs of rats exposed to aerosols of 239 PuO 2

  13. Toll-like receptor 4 promotes fibrosis in bleomycin-induced lung injury in mice.

    Science.gov (United States)

    Li, X X; Jiang, D Y; Huang, X X; Guo, S L; Yuan, W; Dai, H P

    2015-12-21

    The specific role of Toll-like receptor 4 (TLR4) in bleomycin-induced lung fibrosis of mice, a model of human idiopathic pulmonary fibrosis, has not been characterized. We injected bleomycin intratracheally into TLR4 knockout (TLR4(-/-)) and wild-type (WT) mice. Twenty-one days after injection, mice were sacrificed and their lungs were harvested for pathological, hydroxyproline, mRNA expression, and collagen I analyses. Body weight changes and mortality were observed. Light microscopy showed that lung fibrosis was minimal in TLR4(-/-) compared to that in WT mice on day 21 after bleomycin instillation. The Ashcroft score was significantly lower in TLR4(-/-) than in WT mice (3.667 ± 0.730 vs 4.945 ± 0.880, P bleomycin injection (0.281 ± 0.022 vs 0.371 ± 0.047, P bleomycin-treated TLR4(-/-) mice expressed significantly lower type I collagen mRNA levels (mesenchymal marker; 11.069 ± 2.627 vs 4.589 ± 1.440, P Bleomycin-treated TLR4(-/-) mice had a significantly lower mortality rate on day 21 than WT mice (33 vs 75%, P 0.05). Thus, bleomycin-induced pulmonary fibrosis is TLR4-dependent and TLR4 promoted fibrosis in bleomycin-challenged mice.

  14. Hypermethylation of CCND2 May Reflect a Smoking-Induced Precancerous Change in the Lung

    Directory of Open Access Journals (Sweden)

    Alexander Salskov

    2011-01-01

    Full Text Available It remains unknown whether tobacco smoke induces DNA hypermethylation as an early event in carcinogenesis or as a late event, specific to overt cancer tissue. Using MethyLight assays, we analyzed 316 lung tissue samples from 151 cancer-free subjects (121 ever-smokers and 30 never-smokers for hypermethylation of 19 genes previously observed to be hypermethylated in nonsmall cell lung cancers. Only APC (39%, CCND2 (21%, CDH1 (7%, and RARB (4% were hypermethylated in >2% of these cancer-free subjects. CCND2 was hypermethylated more frequently in ever-smokers (26% than in never-smokers (3%. CCND2 hypermethylation was also associated with increased age and upper lobe sample location. APC was frequently hypermethylated in both ever-smokers (41% and never-smokers (30%. BVES, CDH13, CDKN2A (p16, CDKN2B, DAPK1, IGFBP3, IGSF4, KCNH5, KCNH8, MGMT, OPCML, PCSK6, RASSF1, RUNX, and TMS1 were rarely hypermethylated (<2% in all subjects. Hypermethylation of CCND2 may reflect a smoking-induced precancerous change in the lung.

  15. Clozapine Induces Autophagic Cell Death in Non-Small Cell Lung Cancer Cells

    Directory of Open Access Journals (Sweden)

    Yu-Chun Yin

    2015-02-01

    Full Text Available Background/Aims: Previous studies have shown that patients with schizophrenia have a lower incidence of cancer than the general population, and several antipsychotics have been demonstrated to have cytotoxic effects on cancer cells. However, the mechanisms underlying these results remain unclear. The present study aimed to investigate the effect of clozapine, which is often used to treat patients with refractory schizophrenia, on the growth of non-small cell lung carcinoma cell lines and to examine whether autophagy contributes to its effects. Methods: A549 and H1299 cells were treated with clozapine, and cell cytotoxicity, cell cycle and autophagy were then assessed. The autophagy inhibitor bafilomycin A1 and siRNA-targeted Atg7 were used to determine the role of autophagy in the effect of clozapine. Results: Clozapine inhibited A549 and H1299 proliferation and increased p21 and p27 expression levels, leading to cell cycle arrest. Clozapine also induced a high level of autophagy, but not apoptosis, in both cell lines, and the growth inhibitory effect of clozapine was blunted by treatment with the autophagy inhibitor bafilomycin A1 or with an siRNA targeting atg7. Conclusions: Clozapine inhibits cell proliferation by inducing autophagic cell death in two non-small cell lung carcinoma cell lines. These findings may provide insights into the relationship between clozapine use and the lower incidence of lung cancer among patients with schizophrenia.

  16. The role of Src & ERK1/2 kinases in inspiratory resistive breathing induced acute lung injury and inflammation.

    Science.gov (United States)

    Toumpanakis, Dimitrios; Vassilakopoulou, Vyronia; Sigala, Ioanna; Zacharatos, Panagiotis; Vraila, Ioanna; Karavana, Vassiliki; Theocharis, Stamatios; Vassilakopoulos, Theodoros

    2017-12-13

    Inspiratory resistive breathing (IRB), a hallmark of obstructive airway diseases, is associated with large negative intrathoracic pressures, due to strenuous contractions of the inspiratory muscles. IRB is shown to induce lung injury in previously healthy animals. Src is a multifunctional kinase that is activated in the lung by mechanical stress. ERK1/2 kinase is a downstream target of Src. We hypothesized that Src is activated in the lung during IRB, mediates ERK1/2 activation and IRB-induced lung injury. Anaesthetized, tracheostomized adult rats breathed spontaneously through a 2-way non-rebreathing valve. Resistance was added to the inspiratory port to provide a peak tidal inspiratory pressure of 50% of maximum (inspiratory resistive breathing). Activation of Src and ERK1/2 in the lung was estimated during IRB. Following 6 h of IRB, respiratory system mechanics were measured by the forced oscillation technique and bronchoalveolar lavage (BAL) was performed to measure total and differential cell count and total protein levels. IL-1b and MIP-2a protein levels were measured in lung tissue samples. Wet lung weight to total body weight was measured and Evans blue dye extravasation was estimated to measure lung permeability. Lung injury was evaluated by histology. The Src inhibitor, PP-2 or the inhibitor of ERK1/2 activation, PD98059 was administrated 30 min prior to IRB. Src kinase was activated 30 min after the initiation of IRB. Src inhibition ameliorated the increase in BAL cellularity after 6 h IRB, but not the increase of IL-1β and MIP-2a in the lung. The increase in BAL total protein and lung injury score were not affected. The increase in tissue elasticity was partly inhibited. Src inhibition blocked ERK1/2 activation at 3 but not at 6 h of IRB. ERK1/2 inhibition ameliorated the increase in BAL cellularity after 6 h of IRB, blocked the increase of IL-1β and returned Evans blue extravasation and wet lung weight to control values. BAL total protein and

  17. Classical and alternative macrophage activation in the lung following ozone-induced oxidative stress

    Energy Technology Data Exchange (ETDEWEB)

    Sunil, Vasanthi R., E-mail: sunilva@pharmacy.rutgers.edu [Department of Pharmacology and Toxicology, Rutgers University, Ernest Mario School of Pharmacy, Piscataway, NJ 08854 (United States); Patel-Vayas, Kinal; Shen, Jianliang [Department of Pharmacology and Toxicology, Rutgers University, Ernest Mario School of Pharmacy, Piscataway, NJ 08854 (United States); Laskin, Jeffrey D. [Department of Environmental and Occupational Medicine, University of Medicine and Dentistry of New Jersey, Robert Wood Johnson Medical School, Piscataway, NJ (United States); Laskin, Debra L. [Department of Pharmacology and Toxicology, Rutgers University, Ernest Mario School of Pharmacy, Piscataway, NJ 08854 (United States)

    2012-09-01

    Ozone is a pulmonary irritant known to cause oxidative stress, inflammation and tissue injury. Evidence suggests that macrophages play a role in the pathogenic response; however, their contribution depends on the mediators they encounter in the lung which dictate their function. In these studies we analyzed the effects of ozone-induced oxidative stress on the phenotype of alveolar macrophages (AM). Exposure of rats to ozone (2 ppm, 3 h) resulted in increased expression of 8-hydroxy-2′-deoxyguanosine (8-OHdG), as well as heme oxygenase-1 (HO-1) in AM. Whereas 8-OHdG was maximum at 24 h, expression of HO-1 was biphasic increasing after 3 h and 48–72 h. Cleaved caspase-9 and beclin-1, markers of apoptosis and autophagy, were also induced in AM 24 h post-ozone. This was associated with increased bronchoalveolar lavage protein and cells, as well as matrix metalloproteinase (MMP)-2 and MMP-9, demonstrating alveolar epithelial injury. Ozone intoxication resulted in biphasic activation of the transcription factor, NFκB. This correlated with expression of monocyte chemotactic protein‐1, inducible nitric oxide synthase and cyclooxygenase‐2, markers of proinflammatory macrophages. Increases in arginase-1, Ym1 and galectin-3 positive anti-inflammatory/wound repair macrophages were also observed in the lung after ozone inhalation, beginning at 24 h (arginase-1, Ym1), and persisting for 72 h (galectin-3). This was associated with increased expression of pro-surfactant protein-C, a marker of Type II cell proliferation and activation, important steps in wound repair. These data suggest that both proinflammatory/cytotoxic and anti-inflammatory/wound repair macrophages are activated early in the response to ozone-induced oxidative stress and tissue injury. -- Highlights: ► Lung macrophages are highly sensitive to ozone induced oxidative stress. ► Ozone induces autophagy and apoptosis in lung macrophages. ► Proinflammatory and wound repair macrophages are activated

  18. Rac2 is involved in bleomycin-induced lung inflammation leading to pulmonary fibrosis.

    Science.gov (United States)

    Arizmendi, Narcy; Puttagunta, Lakshmi; Chung, Kerri L; Davidson, Courtney; Rey-Parra, Juliana; Chao, Danny V; Thebaud, Bernard; Lacy, Paige; Vliagoftis, Harissios

    2014-06-27

    Pulmonary fibrotic diseases induce significant morbidity and mortality, for which there are limited therapeutic options available. Rac2, a ras-related guanosine triphosphatase expressed mainly in hematopoietic cells, is a crucial molecule regulating a diversity of mast cell, macrophage, and neutrophil functions. All these cell types have been implicated in the development of pulmonary fibrosis in a variety of animal models. For the studies described here we hypothesized that Rac2 deficiency protects mice from bleomycin-induced pulmonary fibrosis. To determine the role of Rac2 in pulmonary fibrosis we used a bleomycin-induced mouse model. Anesthetized C57BL/6 wild type and rac2-/- mice were instilled intratracheally with bleomycin sulphate (1.25 U/Kg) or saline as control. Bronchoalveolar lavage (BAL) samples were collected at days 3 and 7 of treatment and analyzed for matrix metalloproteinases (MMPs). On day 21 after bleomycin treatment, we measured airway resistance and elastance in tracheotomized animals. Lung sections were stained for histological analysis, while homogenates were analyzed for hydroxyproline and total collagen content. BLM-treated rac2-/- mice had reduced MMP-9 levels in the BAL on day 3 and reduced neutrophilia and TNF and CCL3/MIP-1α levels in the BAL on day 7 compared to BLM-treated WT mice. We also showed that rac2-/- mice had significantly lower mortality (30%) than WT mice (70%) at day 21 of bleomycin treatment. Lung function was diminished in bleomycin-treated WT mice, while it was unaffected in bleomycin-treated rac2-/- mice. Histological analysis of inflammation and fibrosis as well as collagen and hydroxyproline content in the lungs did not show significant differences between BLM-treated rac2-/- and WT and mice that survived to day 21. Rac2 plays an important role in bleomycin-induced lung injury. It is an important signaling molecule leading to BLM-induced mortality and it also mediates the physiological changes seen in the airways

  19. Carvacrol and Pomegranate Extract in Treating Methotrexate-Induced Lung Oxidative Injury in Rats

    Science.gov (United States)

    Şen, Hadice Selimoğlu; Şen, Velat; Bozkurt, Mehtap; Türkçü, Gül; Güzel, Abdulmenap; Sezgi, Cengizhan; Abakay, Özlem; Kaplan, Ibrahim

    2014-01-01

    Background This study was designed to evaluate the effects of carvacrol (CRV) and pomegranate extract (PE) on methotrexate (MTX)-induced lung injury in rats. Material/Methods A total of 32 male rats were subdivided into 4 groups: control (group I), MTX treated (group II), MTX+CRV treated (group III), and MTX+PE treated (group IV). A single dose of 73 mg/kg CRV was administered intraperitoneally to rats in group III on Day 1 of the investigation. To group IV, a dose of 225 mg/kg of PE was administered via orogastric gavage once daily over 7 days. A single dose of 20 mg/kg of MTX was given intraperitoneally to groups II, III, and IV on Day 2. The total duration of experiment was 8 days. Malondialdehyde (MDA), total oxidant status (TOS), total antioxidant capacity (TAC), and oxidative stress index (OSI) were measured from rat lung tissues and cardiac blood samples. Results Serum and lung specimen analyses demonstrated that MDA, TOS, and OSI levels were significantly greater in group II relative to controls. Conversely, the TAC level was significantly reduced in group II when compared to the control group. Pre-administering either CRV or PE was associated with decreased MDA, TOS, and OSI levels and increased TAC levels compared to rats treated with MTX alone. Histopathological examination revealed that lung injury was less severe in group III and IV relative to group II. Conclusions MTX treatment results in rat lung oxidative damage that is partially counteracted by pretreatment with either CRV or PE. PMID:25326861

  20. [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.

  1. Poor Baseline Pulmonary Function May Not Increase the Risk of Radiation-Induced Lung Toxicity

    Energy Technology Data Exchange (ETDEWEB)

    Wang, Jingbo [Department of Radiation Oncology, University of Michigan/Ann Arbor Veterans Health System, Ann Arbor, Michigan (United States); Department of Radiation Oncology, Cancer Hospital, Chinese Academic Medical Sciences and Peking Union Medical College, Beijing (China); Cao, Jianzhong [Department of Radiation Oncology, Cancer Hospital, Chinese Academic Medical Sciences and Peking Union Medical College, Beijing (China); Yuan, Shuanghu [Department of Radiation Oncology, University of Michigan/Ann Arbor Veterans Health System, Ann Arbor, Michigan (United States); Ji, Wei [Department of Radiation Oncology, Cancer Hospital, Chinese Academic Medical Sciences and Peking Union Medical College, Beijing (China); Arenberg, Douglas [Department of Internal Medicine, University of Michigan/Ann Arbor Veterans Health System, Ann Arbor, Michigan (United States); Dai, Jianrong [Department of Radiation Oncology, Cancer Hospital, Chinese Academic Medical Sciences and Peking Union Medical College, Beijing (China); Stanton, Paul; Tatro, Daniel; Ten Haken, Randall K. [Department of Radiation Oncology, University of Michigan/Ann Arbor Veterans Health System, Ann Arbor, Michigan (United States); Wang, Luhua, E-mail: wlhwq@yahoo.com [Department of Radiation Oncology, Cancer Hospital, Chinese Academic Medical Sciences and Peking Union Medical College, Beijing (China); Kong, Feng-Ming, E-mail: fengkong@med.umich.edu [Department of Radiation Oncology, University of Michigan/Ann Arbor Veterans Health System, Ann Arbor, Michigan (United States)

    2013-03-01

    Purpose: Poor pulmonary function (PF) is often considered a contraindication to definitive radiation therapy for lung cancer. This study investigated whether baseline PF was associated with radiation-induced lung toxicity (RILT) in patients with non-small cell lung cancer (NSCLC) receiving conformal radiation therapy (CRT). Methods and Materials: NSCLC patients treated with CRT and tested for PF at baseline were eligible. Baseline predicted values of forced expiratory volume in 1 sec (FEV1), forced vital capacity (FVC), and diffusion capacity of lung for carbon monoxide (DLCO) were analyzed. Additional factors included age, gender, smoking status, Karnofsky performance status, coexisting chronic obstructive pulmonary disease (COPD), tumor location, histology, concurrent chemotherapy, radiation dose, and mean lung dose (MLD) were evaluated for RILT. The primary endpoint was symptomatic RILT (SRILT), including grade ≥2 radiation pneumonitis and fibrosis. Results: There was a total of 260 patients, and SRILT occurred in 58 (22.3%) of them. Mean FEV1 values for SRILT and non-SRILT patients were 71.7% and 65.9% (P=.077). Under univariate analysis, risk of SRILT increased with MLD (P=.008), the absence of COPD (P=.047), and FEV1 (P=.077). Age (65 split) and MLD were significantly associated with SRILT in multivariate analysis. The addition of FEV1 and age with the MLD-based model slightly improved the predictability of SRILT (area under curve from 0.63-0.70, P=.088). Conclusions: Poor baseline PF does not increase the risk of SRILT, and combining FEV1, age, and MLD may improve the predictive ability.

  2. Poor Baseline Pulmonary Function May Not Increase the Risk of Radiation-Induced Lung Toxicity

    International Nuclear Information System (INIS)

    Wang, Jingbo; Cao, Jianzhong; Yuan, Shuanghu; Ji, Wei; Arenberg, Douglas; Dai, Jianrong; Stanton, Paul; Tatro, Daniel; Ten Haken, Randall K.; Wang, Luhua; Kong, Feng-Ming

    2013-01-01

    Purpose: Poor pulmonary function (PF) is often considered a contraindication to definitive radiation therapy for lung cancer. This study investigated whether baseline PF was associated with radiation-induced lung toxicity (RILT) in patients with non-small cell lung cancer (NSCLC) receiving conformal radiation therapy (CRT). Methods and Materials: NSCLC patients treated with CRT and tested for PF at baseline were eligible. Baseline predicted values of forced expiratory volume in 1 sec (FEV1), forced vital capacity (FVC), and diffusion capacity of lung for carbon monoxide (DLCO) were analyzed. Additional factors included age, gender, smoking status, Karnofsky performance status, coexisting chronic obstructive pulmonary disease (COPD), tumor location, histology, concurrent chemotherapy, radiation dose, and mean lung dose (MLD) were evaluated for RILT. The primary endpoint was symptomatic RILT (SRILT), including grade ≥2 radiation pneumonitis and fibrosis. Results: There was a total of 260 patients, and SRILT occurred in 58 (22.3%) of them. Mean FEV1 values for SRILT and non-SRILT patients were 71.7% and 65.9% (P=.077). Under univariate analysis, risk of SRILT increased with MLD (P=.008), the absence of COPD (P=.047), and FEV1 (P=.077). Age (65 split) and MLD were significantly associated with SRILT in multivariate analysis. The addition of FEV1 and age with the MLD-based model slightly improved the predictability of SRILT (area under curve from 0.63-0.70, P=.088). Conclusions: Poor baseline PF does not increase the risk of SRILT, and combining FEV1, age, and MLD may improve the predictive ability

  3. Effect of the endothelin receptor antagonist tezosentan on alpha-naphthylthiourea-induced lung injury in rats

    Directory of Open Access Journals (Sweden)

    Figen Atalay

    2012-02-01

    Full Text Available Acute lung injury is an inflammatory syndrome that increases the permeability of the blood-gas barrier, resulting in high morbidity and mortality. Despite intensive research, treatment options remain limited. We investigated the protective efficacy of tezosentan, a novel, dual endothelin receptor antagonist, in an experimental model of alpha-naphthylthiourea (ANTU-induced acute lung injury in rats. ANTU was intraperitoneally (i.p. injected into rats at a dose of 10 mg/kg. Tezosentan was injected 30 minutes before ANTU was subcutaneously (s.c. injected at doses of 2, 10, or 30 mg/kg, 60 minutes before ANTU was injected at doses of 2, 10, or 30 mg/kg (i.p., and 90 minutes before ANTU at a dose of 10 mg/kg (i.p.. Four hours later, the lung weight/body weight (LW/BW ratio and pleural effusion (PE were measured. When injected 30 minutes before ANTU at doses of 2, 10, or 30 mg/kg (s.c., tezosentan had no effect on lung pathology. When injected 60 minutes before ANTU at doses of 2, 10, or 30 mg/kg (i.p. or 90 minutes before ANTU (10 mg/kg, i.p., tezosentan significantly decreased the PE/BW ratio and had a prophylactic effect on PE formation at all doses. Therefore, tezosentan may attenuate lung injury. Furthermore, its acute and inhibitory effects on fluid accumulation were more effective in the pleural cavity than in the interstitial compartment in this experimental model.

  4. Isoliquiritigenin protects against sepsis-induced lung and liver injury by reducing inflammatory responses.

    Science.gov (United States)

    Chen, Xiong; Cai, Xueding; Le, Rongrong; Zhang, Man; Gu, Xuemei; Shen, Feixia; Hong, Guangliang; Chen, Zimiao

    2018-02-05

    Sepsis, one of the most fatal diseases worldwide, often leads to multiple organ failure, mainly due to uncontrolled inflammatory responses. Despite accumulating knowledge obtained in recent years, effective drugs to treat sepsis in the clinic are still urgently needed. Isoliquiritigenin (ISL), a chalcone compound, has been reported to exert anti-inflammatory properties. However, little is known about the effects of ISL on sepsis and its related complications. In this study, we investigated the potential protective effects of ISL on lipopolysaccharide (LPS)-induced injuries and identified the mechanisms underlying these effects. ISL inhibited inflammatory cytokine expression in mouse primary peritoneal macrophages (MPMs) exposed to LPS. In an acute lung injury (ALI) mouse model, ISL prevented LPS-induced structural damage and inflammatory cell infiltration. Additionally, pretreatment with ISL attenuated sepsis-induced lung and liver injury, accompanied by a reduction in inflammatory responses. Moreover, these protective effects were mediated by the nuclear factor kappa B (NF-κB) pathway-mediated inhibition of inflammatory responses in vitro and in vivo. Our study suggests that ISL may be a potential therapeutic agent for sepsis-induced injuries. Copyright © 2017. Published by Elsevier Inc.

  5. Bioinformatics Methods for Learning Radiation-Induced Lung Inflammation from Heterogeneous Retrospective and Prospective Data

    Science.gov (United States)

    Spencer, Sarah J.; Almiron Bonnin, Damian; Deasy, Joseph O.; Bradley, Jeffrey D.; El Naqa, Issam

    2009-01-01

    Radiotherapy outcomes are determined by complex interactions between physical and biological factors, reflecting both treatment conditions and underlying genetics. Recent advances in radiotherapy and biotechnology provide new opportunities and challenges for predicting radiation-induced toxicities, particularly radiation pneumonitis (RP), in lung cancer patients. In this work, we utilize datamining methods based on machine learning to build a predictive model of lung injury by retrospective analysis of treatment planning archives. In addition, biomarkers for this model are extracted from a prospective clinical trial that collects blood serum samples at multiple time points. We utilize a 3-way proteomics methodology to screen for differentially expressed proteins that are related to RP. Our preliminary results demonstrate that kernel methods can capture nonlinear dose-volume interactions, but fail to address missing biological factors. Our proteomics strategy yielded promising protein candidates, but their role in RP as well as their interactions with dose-volume metrics remain to be determined. PMID:19704920

  6. Adrenaline stimulates the proliferation and migration of mesenchymal stem cells towards the LPS-induced lung injury.

    Science.gov (United States)

    Wu, Xiaodan; Wang, Zhiming; Qian, Mengjia; Wang, Lingyan; Bai, Chunxue; Wang, Xiangdong

    2014-08-01

    Bone marrow-derived mesenchymal stem cells (BMSCs) could modulate inflammation in experimental lung injury. On the other hand, adrenergic receptor agonists could increase DNA synthesis of stem cells. Therefore, we investigated the therapeutic role of adrenaline-stimulated BMSCs on lipopolysaccharide (LPS)-induced lung injury. BMSCs were cultured with adrenergic receptor agonists or antagonists. Suspensions of lung cells or sliced lung tissue from animals with or without LPS-induced injury were co-cultured with BMSCs. LPS-stimulated alveolar macrophages were co-cultured with BMSCs (with adrenaline stimulation or not) in Transwell for 6 hrs. A preliminary animal experiment was conducted to validate the findings in ex vivo study. We found that adrenaline at 10 μM enhanced proliferation of BMSCs through both α- and β-adrenergic receptors. Adrenaline promoted the migration of BMSCs towards LPS-injured lung cells or lung tissue. Adrenaline-stimulated BMSCs decreased the inflammation of LPS-stimulated macrophages, probably through the expression and secretion of several paracrine factors. Adrenaline reduced the extent of injury in LPS-injured rats. Our data indicate that adrenaline-stimulated BMSCs might contribute to the prevention from acute lung injury through the activation of adrenergic receptors, promotion of proliferation and migration towards injured lung, and modulation of inflammation. © 2014 The Authors. Journal of Cellular and Molecular Medicine published by John Wiley & Sons Ltd and Foundation for Cellular and Molecular Medicine.

  7. Attenuation of acute nitrogen mustard-induced lung injury, inflammation and fibrogenesis by a nitric oxide synthase inhibitor

    Energy Technology Data Exchange (ETDEWEB)

    Malaviya, Rama; Venosa, Alessandro [Department of Pharmacology and Toxicology, Ernest Mario School of Pharmacy, Rutgers University, Piscataway, NJ 08854 (United States); Hall, LeRoy [Drug Safety Sciences, Johnson and Johnson, Raritan, NJ 08869 (United States); Gow, Andrew J. [Department of Pharmacology and Toxicology, Ernest Mario School of Pharmacy, Rutgers University, Piscataway, NJ 08854 (United States); Sinko, Patrick J. [Department of Pharmaceutics, Ernest Mario School of Pharmacy, Rutgers University, Piscataway, NJ 08854 (United States); Laskin, Jeffrey D. [Department of Environmental and Occupational Medicine, UMDNJ-Robert Wood Johnson Medical School, Piscataway, NJ 08854 (United States); Laskin, Debra L., E-mail: laskin@eohsi.rutgers.edu [Department of Pharmacology and Toxicology, Ernest Mario School of Pharmacy, Rutgers University, Piscataway, NJ 08854 (United States)

    2012-12-15

    Nitrogen mustard (NM) is a toxic vesicant known to cause damage to the respiratory tract. Injury is associated with increased expression of inducible nitric oxide synthase (iNOS). In these studies we analyzed the effects of transient inhibition of iNOS using aminoguanidine (AG) on NM-induced pulmonary toxicity. Rats were treated intratracheally with 0.125 mg/kg NM or control. Bronchoalveolar lavage fluid (BAL) and lung tissue were collected 1 d–28 d later and lung injury, oxidative stress and fibrosis assessed. NM exposure resulted in progressive histopathological changes in the lung including multifocal lesions, perivascular and peribronchial edema, inflammatory cell accumulation, alveolar fibrin deposition, bronchiolization of alveolar septal walls, and fibrosis. This was correlated with trichrome staining and expression of proliferating cell nuclear antigen (PCNA). Expression of heme oxygenase (HO)-1 and manganese superoxide dismutase (Mn-SOD) was also increased in the lung following NM exposure, along with levels of protein and inflammatory cells in BAL, consistent with oxidative stress and alveolar-epithelial injury. Both classically activated proinflammatory (iNOS{sup +} and cyclooxygenase-2{sup +}) and alternatively activated profibrotic (YM-1{sup +} and galectin-3{sup +}) macrophages appeared in the lung following NM administration; this was evident within 1 d, and persisted for 28 d. AG administration (50 mg/kg, 2 ×/day, 1 d–3 d) abrogated NM-induced injury, oxidative stress and inflammation at 1 d and 3 d post exposure, with no effects at 7 d or 28 d. These findings indicate that nitric oxide generated via iNOS contributes to acute NM-induced lung toxicity, however, transient inhibition of iNOS is not sufficient to protect against pulmonary fibrosis. -- Highlights: ► Nitrogen mustard (NM) induces acute lung injury and fibrosis. ► Pulmonary toxicity is associated with increased expression of iNOS. ► Transient inhibition of iNOS attenuates acute

  8. Diet-Induced Obesity Reprograms the Inflammatory Response of the Murine Lung to Inhaled Endotoxin

    Energy Technology Data Exchange (ETDEWEB)

    Tilton, Susan C.; Waters, Katrina M.; Karin, Norman J.; Webb-Robertson, Bobbie-Jo M.; Zangar, Richard C.; Lee, Monika K.; Bigelow, Diana J.; Pounds, Joel G.; Corley, Richard A.

    2013-03-01

    The co-occurrence of environmental factors is common in complex human diseases and, as such, understanding the molecular responses involved is essential to determine risk and susceptibility to disease. We have investigated the key biological pathways that define susceptibility for pulmonary infection during obesity in diet-induced obese (DIO) and regular weight (RW) C57BL/6 mice exposed to inhaled lipopolysaccharide (LPS). LPS induced a strong inflammatory response in all mice as indicated by elevated cell counts of macrophages and neutrophils and levels of proinflammatory cytokines (MDC, MIP-1γ, IL-12, RANTES) in the bronchoalveolar lavage fluid. Additionally, DIO mice exhibited 50% greater macrophage cell counts, but decreased levels of the cytokines, IL-6, TARC, TNF-α, and VEGF relative to RW mice. Microarray analysis of lung tissue showed over half of the LPS-induced expression in DIO mice consisted of genes unique for obese mice, suggesting that obesity reprograms how the lung responds to subsequent insult. In particular, we found that obese animals exposed to LPS have gene signatures showing increased inflammatory and oxidative stress response and decreased antioxidant capacity compared with RW. Because signaling pathways for these responses can be common to various sources of environmentally induced lung damage, we further identified biomarkers that are indicative of specific toxicant exposure by comparing gene signatures after LPS exposure to those from a parallel study with cigarette smoke. These data show obesity may increase sensitivity to further insult and that co-occurrence of environmental stressors result in complex biosignatures that are not predicted from analysis of individual exposures.

  9. Comparative functional genomics analysis of NNK tobacco-carcinogen induced lung adenocarcinoma development in Gprc5a-knockout mice.

    Directory of Open Access Journals (Sweden)

    Junya Fujimoto

    2010-07-01

    Full Text Available Improved understanding of lung cancer development and progression, including insights from studies of animal models, are needed to combat this fatal disease. Previously, we found that mice with a knockout (KO of G-protein coupled receptor 5A (Gprc5a develop lung tumors after a long latent period (12 to 24 months.To determine whether a tobacco carcinogen will enhance tumorigenesis in this model, we administered 4-(methylnitrosamino-1-(3-pyridyl-1-butanone (NNK i.p. to 2-months old Gprc5a-KO mice and sacrificed groups (n=5 of mice at 6, 9, 12, and 18 months later. Compared to control Gprc5a-KO mice, NNK-treated mice developed lung tumors at least 6 months earlier, exhibited 2- to 4-fold increased tumor incidence and multiplicity, and showed a dramatic increase in lesion size. A gene expression signature, NNK-ADC, of differentially expressed genes derived by transcriptome analysis of epithelial cell lines from normal lungs of Gprc5a-KO mice and from NNK-induced adenocarcinoma was highly similar to differential expression patterns observed between normal and tumorigenic human lung cells. The NNK-ADC expression signature also separated both mouse and human adenocarcinomas from adjacent normal lung tissues based on publicly available microarray datasets. A key feature of the signature, up-regulation of Ube2c, Mcm2, and Fen1, was validated in mouse normal lung and adenocarcinoma tissues and cells by immunohistochemistry and western blotting, respectively.Our findings demonstrate that lung tumorigenesis in the Gprc5a-KO mouse model is augmented by NNK and that gene expression changes induced by tobacco carcinogen(s may be conserved between mouse and human lung epithelial cells. Further experimentation to prove the reliability of the Gprc5a knockout mouse model for the study of tobacco-induced lung carcinogenesis is warranted.

  10. Activation of Epac alleviates inflammation and vascular leakage in LPS-induced acute murine lung injury.

    Science.gov (United States)

    Wang, Xuefeng; Song, Shunde; Hu, Zhengqiang; Zhang, Zhewen; Li, Yajun; Yan, Chunguang; Li, Zigang; Tang, Huifang

    2017-12-01

    Exchange protein directly activated by cAMP (Epac) is an important molecule in cAMP signal transduction, but the effect of Epac on lipopolysaccharide (LPS)-induced acute lung injury (ALI) is unclear. In this study, we treated in vitro and in vivo models with the Epac activator 8CPT to determine the effect and related mechanisms of Epac. The in vitro results indicate that 8CPT inhibits lipopolysaccharide (LPS)-induced tumor necrosis factor-α (TNF-α) release from mouse macrophages (MH-S), whereas the protein kinase A (PKA) activator 6BnZ has no effect. Furthermore, Epac over-expression can significantly suppress TNF-α release from LPS induced MH-S cell, while Epac siRNA can slightly increase TNF-α release. Moreover, 8CPT reduces LPS-induced microvascular permeability in human pulmonary microvascular endothelial cells (HPMVECs), whereas the PKA activator 6BnZ has no effect. In mice with LPS-induced ALI, 8CPT significantly reduces LPS-induced inflammatory cytokine release, neutrophil recruitment, and albumin leakage. LPS simultaneously decreases the Epac but not the PKA levels. However, 8CPT reverses the decreased Epac levels. Furthermore, the mechanism involves the small GTPase Rac1/2 but not the mitogen-activated protein kinase (MAPK) pathway. Thus, Epac activation reduces inflammation and microvascular permeability in LPS-induced lung injury and an Epac activator represents a novel choice for the early therapy of ALI. Copyright © 2017 Elsevier Masson SAS. All rights reserved.

  11. Adiponectin attenuates lung fibroblasts activation and pulmonary fibrosis induced by paraquat.

    Directory of Open Access Journals (Sweden)

    Rong Yao

    Full Text Available Pulmonary fibrosis is one of the most common complications of paraquat (PQ poisoning, which demands for more effective therapies. Accumulating evidence suggests adiponectin (APN may be a promising therapy against fibrotic diseases. In the current study, we determine whether the exogenous globular APN isoform protects against pulmonary fibrosis in PQ-treated mice and human lung fibroblasts, and dissect the responsible underlying mechanisms. BALB/C mice were divided into control group, PQ group, PQ + low-dose APN group, and PQ + high-dose APN group. Mice were sacrificed 3, 7, 14, and 21 days after PQ treatment. We compared pulmonary histopathological changes among different groups on the basis of fibrosis scores, TGF-β1, CTGF and α-SMA pulmonary content via Western blot and real-time quantitative fluorescence-PCR (RT-PCR. Blood levels of MMP-9 and TIMP-1 were determined by ELISA. Human lung fibroblasts WI-38 were divided into control group, PQ group, APN group, and APN receptor (AdipoR 1 small-interfering RNA (siRNA group. Fibroblasts were collected 24, 48, and 72 hours after PQ exposure for assay. Cell viability and apoptosis were determined via Kit-8 (CCK-8 and fluorescein Annexin V-FITC/PI double labeling. The protein and mRNA expression level of collagen type III, AdipoR1, and AdipoR2 were measured by Western blot and RT-PCR. APN treatment significantly decreased the lung fibrosis scores, protein and mRNA expression of pulmonary TGF-β1, CTGF and α-SMA content, and blood MMP-9 and TIMP-1 in a dose-dependent manner (p<0.05. Pretreatment with APN significantly attenuated the reduced cell viability and up-regulated collagen type III expression induced by PQ in lung fibroblasts, (p<0.05. APN pretreatment up-regulated AdipoR1, but not AdipoR2, expression in WI-38 fibroblasts. AdipoR1 siRNA abrogated APN-mediated protective effects in PQ-exposed fibroblasts. Taken together, our data suggests APN protects against PQ-induced pulmonary fibrosis in a

  12. 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

  13. An experimentally induced fat embolism in the rabbit lung; high-resolution CT and pathologic findings

    International Nuclear Information System (INIS)

    Ha, Dong-Ho; Lee, Ki-Nam; Jeong, Jin Sook

    2001-01-01

    To assess the high-resolution CT and pathologic findings of fat embolism experimentally induced in rabbit lung. Twelve rabbits were divided into four groups, namely control, 2-hour, 24-hour, and 72-hour, with three rabbits in each, and closed tibiofibular fractures were induced. After the rabbits were sacrificed, high-resolution CT scanning of the artificially inflated lungs was performed, and the CT findings were analyzed by two radiologists. They determined the presence or absence of ground glass opacity or consolidation, the extent of the lesions (using a 10% grading scale), and their distribution, reaching a consensus. The pathologic findings were analyzed using the specimens prepared by H and E and Oil-red O staining. Although the high-resolution CT findings of pulmonary fat embolism were nonspecific, bilateral patchy ground glass opacity (100%), and focal air-space consolidation surrounding the bronchovascular bundle (89%) were most common. In all groups, the occlusion of vessels by fat globules was confirmed by Oil-red O staining. The microscopic findings included focal pulmonary hemorrhage, edema, alveolar collapse, and extensive infiltration of inflammatory cells in the lung parenchyma. The 24-hour group showed more extensive change in high-resolution CT and pathologic findings than did the others. Fat embolism in rabbit lung may occur after closed tibio-fibular fracture. The extent of the lesion revealed by high-resolution CT correlated closely with the pathologic findings. High-resolution CT may thus be helpful for the detection of pulmonary fat embolism and evaluation of its extent

  14. Pulmonary microvascular hyperpermeability and expression of vascular endothelial growth factor in smoke inhalation- and pneumonia-induced acute lung injury.

    Science.gov (United States)

    Lange, Matthias; Hamahata, Atsumori; Traber, Daniel L; Connelly, Rhykka; Nakano, Yoshimitsu; Traber, Lillian D; Schmalstieg, Frank C; Herndon, David N; Enkhbaatar, Perenlei

    2012-11-01

    Acute lung injury (ALI) and sepsis are major contributors to the morbidity and mortality of critically ill patients. The current study was designed further evaluate the mechanism of pulmonary vascular hyperpermeability in sheep with these injuries. Sheep were randomized to a sham-injured control group (n=6) or ALI/sepsis group (n=7). The sheep in the ALI/sepsis group received inhalation injury followed by instillation of Pseudomonas aeruginosa into the lungs. These groups were monitored for 24 h. Additional sheep (n=16) received the injury and lung tissue was harvested at different time points to measure lung wet/dry weight ratio, vascular endothelial growth factor (VEGF) mRNA and protein expression as well as 3-nitrotyrosine protein expression in lung homogenates. The injury induced severe deterioration in pulmonary gas exchange, increases in lung lymph flow and protein content, and lung water content (P<0.01 each). These alterations were associated with elevated lung and plasma nitrite/nitrate concentrations, increased tracheal blood flow, and enhanced VEGF mRNA and protein expression in lung tissue as well as enhanced 3-nitrotyrosine protein expression (P<0.05 each). This study describes the time course of pulmonary microvascular hyperpermeability in a clinical relevant large animal model and may improve the experimental design of future studies. Copyright © 2012 Elsevier Ltd and ISBI. All rights reserved.

  15. Characterization of lung stem cell niches in a mouse model of bleomycin-induced fibrosis

    Science.gov (United States)

    2012-01-01

    Introduction In lung fibrosis, alveolar epithelium degenerates progressively. The goal of regenerative medicine is to aid repair and regeneration of the lost tissues in parenchyma and airways for which mobilization of tissue-resident endogenous or bone marrow-derived exogenous stem cells niches is a critical step. We used a lung injury model in mice to identify and characterize functional lung stem cells to clarify how stem cell niches counteract this degenerative process. Methods Short term assay (STA) - Bleomycin-induced lung inflammation and fibrosis were assessed in a model of idiopathic pulmonary fibrosis in wild-type (WT), gp91phox-/- (NOX-/-), and gp91phoxMMP-12 double knockout (DKO) mice on C57Bl/6 background and Hoechst 33322 dye effluxing side population (SP) cells characterized. Long term assay (LTA) - In a bleomycin induced lung fibrosis model in C57Bl6 mice, the number of mature cells were quantified over 7, 14, and 21 days in bone marrow (BM), peripheral blood (PB), lung parenchyma (LP) and brochoalveolar lavage (BAL) fluid by FACS. BrdU pulse chase experiment (10 weeks) was used to identify label retaining cells (LRC). BrdU+ and BrdU- cells were characterized by hematopoietic (CD45+), pluripotency (TTF1+, Oct3/4+, SSEA-3+, SSEA-4+, Sca1+, Lin-, CD34+, CD31+), and lung lineage-specific (SPC+, AQP-5+, CC-10+) markers. Clonogenic potential of LRCs were measured by CFU-c assays. Results STA- In lung, cellularity increased by 5-fold in WT and 6-fold in NOX-/- by d7. Lung epithelial markers were very low in expression in all SP flow sorted from lung of all three genotypes cultured ex vivo. (p bleomycin, the SP in NOX-/- lung increased by 3.6-fold over WT where it increased by 20-fold over controls. Type I and II alveolar epithelial cells progressively diminished in all three genotypes by d21 post-bleomycin. D7 post-bleomycin, CD45+ cells in BALf in NOX-/- was 1.7-fold > WT, 57% of which were Mf that decreased by 67% in WT and 83% in NOX-/- by d21.LTA

  16. Extensive Analysis of Elastase-Induced Pulmonary Emphysema in Rats: ALP in the Lung, a New Biomarker for Disease Progression?

    Science.gov (United States)

    Inoue, Ken-ichiro; Koike, Eiko; Yanagisawa, Rie; Takano, Hirohisa

    2010-01-01

    It is accepted that pulmonary exposure of rodents to porcine pancreatic elastase (ELT) induces lesions that morphologically resemble human emphysema. Nonetheless, extensive analysis of this model has rarely been conducted. The present study was designed to extensively examine the effects of ELT on lung inflammation, cell damage, emphysematous change, and cholinergic reactivity in rats. Intratracheal administration of two doses of ELT induced 1) a proinflammatory response in the lung that was characterized by significant infiltration of macrophages and an increased level of interleukin-1β in lung homogenates, 2) lung cell damage as indicated by higher levels of total protein, lactate dehydrogenase, and alkaline phosphatase (ALP) in lung homogenates, 3) emphysema-related morphological changes including airspace enlargement and progressive destruction of alveolar wall structures, and 4) airway responsiveness to methacholine including an augmented Rn value. In addition, ELT at a high dose was more effective than that at a low dose. This is the novel study to extensively analyze ELT-induced lung emphysema, and the analysis might be applied to future investigations that evaluate new therapeutic agents or risk factors for pulmonary emphysema. In particular, ALP in lung homogenates might be a new biomarker for the disease progression/exacerbation. PMID:20216950

  17. A Subanesthetic Dose of Isoflurane during Postconditioning Ameliorates Zymosan-Induced Neutrophil Inflammation Lung Injury and Mortality in Mice

    Directory of Open Access Journals (Sweden)

    Hui Wang

    2013-01-01

    Full Text Available Anesthetic isoflurane (ISO has immunomodulatory effects. In the present study, we investigated whether a subanesthetic dose of ISO (0.7% protected against zymosan (ZY induced inflammatory responses in the murine lung and isolated neutrophils. At 1 and 6 hrs after ZY administration intraperitoneally, ISO was inhaled for 1 hr, and 24 hrs later, lung inflammation and injury were assessed. We found that ISO improved the survival rate of mice and mitigated lung injury as characterized by the histopathology, wet-to-dry weight ratio, protein leakage, and lung function index. ISO significantly attenuated ZY-induced lung neutrophil recruitment and inflammation. This was suggested by the downregulation of (a endothelial adhesion molecule expression and myeloperoxidase (MPO activity in lung tissue and polymorphonuclear neutrophils (b chemokines, and (c proinflammatory cytokines in BALF. Furthermore, ZY-induced nuclear translocation and DNA-binding activity of NF-κB p65 were also reduced by ISO. ISO treatment inhibited iNOS expression and activity, as well as subsequent nitric oxide generation. Consistent with these in vivo observations, in vitro studies confirmed that ISO blocked NF-κB and iNOS activation in primary mouse neutrophils challenged by ZY. These results provide evidence that 0.7% ISO ameliorates inflammatory responses in ZY-treated mouse lung and primary neutrophils.

  18. Hydrogen Gas Inhalation Attenuates Seawater Instillation-Induced Acute Lung Injury via the Nrf2 Pathway in Rabbits.

    Science.gov (United States)

    Diao, Mengyuan; Zhang, Sheng; Wu, Lifeng; Huan, Le; Huang, Fenglou; Cui, Yunliang; Lin, Zhaofen

    2016-12-01

    Seawater instillation-induced acute lung injury involves oxidative stress and apoptosis. Although hydrogen gas inhalation is reportedly protective in multiple types of lung injury, the effect of hydrogen gas inhalation on seawater instillation-induced acute lung injury remains unknown. This study investigated the effect of hydrogen gas on seawater instillation-induced acute lung injury and explored the mechanisms involved. Rabbits were randomly assigned to control, hydrogen (2 % hydrogen gas inhalation), seawater (3 mL/kg seawater instillation), and seawater + hydrogen (3 mL/kg seawater instillation + 2 % hydrogen gas inhalation) groups. Arterial partial oxygen pressure and lung wet/dry weight ratio were detected. Protein content in bronchoalveolar lavage fluid (BALF) and serum as well as tumor necrosis factor (TNF)-α, interleukin (IL)-1β, and IL-6 levels were determined. Hematoxylin-eosin staining was used to monitor changes in lung specimens, and malondialdehyde (MDA) content and myeloperoxidase (MPO) activity were assayed. In addition, NF-E2-related factor (Nrf) 2 and heme oxygenase (HO)-1 mRNA and protein expression were measured, and apoptosis was assessed by measuring caspase-3 expression and using terminal deoxy-nucleotidyl transferase dUTP nick end-labeling (TUNEL) staining. Hydrogen gas inhalation markedly improved lung endothelial permeability and decreased both MDA content and MPO activity in lung tissue; these changes were associated with decreases in TNF-α, IL-1β, and IL-6 in BALF. Hydrogen gas also alleviated histopathological changes and cell apoptosis. Moreover, Nrf2 and HO-1 expressions were significantly activated and caspase-3 expression was inhibited. These results demonstrate that hydrogen gas inhalation attenuates seawater instillation-induced acute lung injury in rabbits and that the protective effects observed may be related to the activation of the Nrf2 pathway.

  19. Extent and computed tomography appearance of early radiation induced lung injury for non-small cell lung cancer

    DEFF Research Database (Denmark)

    Bernchou, Uffe; Lübeck Christiansen, Rasmus; Asmussen, Jon Thor

    2017-01-01

    BACKGROUND AND PURPOSE: The present study investigates the extent and appearance of radiologic injury in the lung after radiotherapy for non-small cell lung cancer (NSCLC) patients and correlates radiologic response with clinical and dosimetric factors. METHODS AND MATERIALS: Eligible follow-up CT...... and time to follow-up predicted lung injury of all categories. Older age increased the risk of interstitial changes and current smoking reduced the risk of consolidation in the lung. CONCLUSION: Radiologic injuries were frequently found in follow-up CT scans after radiotherapy for NSCLC patients. The risk...... of a radiologic response increased with increasing time and lung dose metrics, and depended on patient age and smoking status....

  20. Caffeine modulates glucocorticoid-induced expression of CTGF in lung epithelial cells and fibroblasts.

    Science.gov (United States)

    Fehrholz, Markus; Glaser, Kirsten; Speer, Christian P; Seidenspinner, Silvia; Ottensmeier, Barbara; Kunzmann, Steffen

    2017-03-23

    Although caffeine and glucocorticoids are frequently used to treat chronic lung disease in preterm neonates, potential interactions are largely unknown. While anti-inflammatory effects of glucocorticoids are well defined, their impact on airway remodeling is less characterized. Caffeine has been ascribed to positive effects on airway inflammation as well as remodeling. Connective tissue growth factor (CTGF, CCN2) plays a key role in airway remodeling and has been implicated in the pathogenesis of chronic lung diseases such as bronchopulmonary dysplasia (BPD) in preterm infants. The current study addressed the impact of glucocorticoids on the regulation of CTGF in the presence of caffeine using human lung epithelial and fibroblast cells. The human airway epithelial cell line H441 and the fetal lung fibroblast strain IMR-90 were exposed to different glucocorticoids (dexamethasone, budesonide, betamethasone, prednisolone, hydrocortisone) and caffeine. mRNA and protein expression of CTGF, TGF-β1-3, and TNF-α were determined by means of quantitative real-time PCR and immunoblotting. H441 cells were additionally treated with cAMP, the adenylyl cyclase activator forskolin, and the selective phosphodiesterase (PDE)-4 inhibitor cilomilast to mimic caffeine-mediated PDE inhibition. Treatment with different glucocorticoids (1 μM) significantly increased CTGF mRNA levels in H441 (p caffeine (10 mM), both glucocorticoid-induced mRNA and protein expression were significantly reduced in IMR-90 cells (p caffeine alone significantly suppressed basal expression of CTGF mRNA and protein in IMR-90 cells. Caffeine-induced reduction of CTGF mRNA expression seemed to be independent of cAMP levels, adenylyl cyclase activation, or PDE-4 inhibition. While dexamethasone or caffeine treatment did not affect TGF-β1 mRNA in H441 cells, increased expression of TGF-β2 and TGF-β3 mRNA was detected upon exposure to dexamethasone or dexamethasone and caffeine, respectively. Moreover

  1. Reproduction of a model of lung injury induced by depleted uranium inhalation in canine

    Directory of Open Access Journals (Sweden)

    Bin ZHANG

    2011-02-01

    Full Text Available Objective To reproduce a canine model of subacute lung injury induced by depleted uranium inhalation.Methods Twenty-six dogs were randomized into the control group(CG,n=6,low-dose group(LG,n=10.and high-dose group(HG,n=10.All of them underwent tracheal intubation.In control group,0.2ml/kg of normal saline was intratracheally given.In low dosage group,10mg/kg of depleted uranium(LG,and in high dose group 100mg/ml of depleted uranium(HG was introduced.The survival time of animals was observed in one month after intratracheal introduction of various agents,and chest CT scan was performed in the survived animals.They were sacrificed for pathological examination of lung tissues on the 31st day post of them intratracheal introduction of various agents.Results During the observation period,no animal died in CG,one dog in LG died on the 22nd day and 9 of them survived longer than 30 days.All the animals in HG group died within 30 days with a mean survival time of 11.2±8.9 days(median=12d.In comparison with the HG,significant difference on survival time was found between LG and CG,while no significant difference was found between the latter 2 groups(P=0.439.Pathologically,changes were noted in lung tissue of LG,such as escape of inflammatory cells into alveoli,hemorrhage and hyaline membrane formation in alveolar space,dilatation and congestion of alveolar capillaries,and infiltration of inflammatory cells in interstitial tissue.CT scanning revealed patchy effusion and solid consolidation in the left lung.Conclusion The canine model of subacute lung injury induced by a dose of 2mg/kg depleted uranium introduced through tracheal intubation is suitable for the study of subacute toxicity induced by depleted uranium.

  2. How respiratory system mechanics may help in minimising ventilator-induced lung injury in ARDS patients.

    Science.gov (United States)

    Terragni, P P; Rosboch, G L; Lisi, A; Viale, A G; Ranieri, V M

    2003-08-01

    The main supportive therapy in acute respiratory distress syndrome patients is mechanical ventilation. As with any therapy, mechanical ventilation has side-effects, and may induce lung injury (ventilator-induced lung injury (VILI)/ventilator-associated lung injury). The mechanical factors responsible for VILI are thought to be related to tidal recruitment/derecruitment of previously collapsed alveoli and/or pulmonary overdistension. The volume/pressure (V/P) curve of the respiratory system in patients as well as in animal models of acute lung injury (ALI) has a characteristic sigmoid shape, with a lower inflection point (LIP) corresponding to the pressure/end-expiratory volume required to initiate recruitment of collapsed alveoli, and an upper inflection point (UIP) corresponding to the pressure/end inspiratory volume at which alveolar overdistension occurs. "Protective" ventilatory approaches have therefore set out to minimise mechanical injury by using the V/P curve to individualise positive end-expiratory pressure (PEEP) (PEEP above the LIP) and tidal volume (by setting end-inspiratory V/P below the UIP) since a large number of experimental studies correlate P/V curves to histological and biological manifestations of VILI and two randomised trials showed that protective ventilatory strategy individually tailored to the P/V curve minimised pulmonary and systemic inflammation and decreased mortality in patients with ALI. However, despite the fact that several studies have: 1) proposed new techniques to perform pressure/volume curves at the bedside, 2) confirmed that the lower inflection point and upper inflection point correspond to computed tomography scan evidence of atelectasis and overdistension, and 3) demonstrated the ability of the pressure/volume curve to estimate alveolar recruitment with positive end-expiratory pressure, no large studies have assessed whether such measurement can be performed in all intensive care units as a monitoring tool to orient

  3. MiR-122 Induces Radiosensitization in Non-Small Cell Lung Cancer Cell Line

    Directory of Open Access Journals (Sweden)

    Debin Ma

    2015-09-01

    Full Text Available MiR-122 is a novel tumor suppresser and its expression induces cell cycle arrest, or apoptosis, and inhibits cell proliferation in multiple cancer cells, including non-small cell lung cancer (NSCLC cells. Radioresistance of cancer cell leads to the major drawback of radiotherapy for NSCLC and the induction of radiosensitization could be a useful strategy to fix this problem. The present work investigates the function of miR-122 in inducing radiosensitization in A549 cell, a type of NSCLC cells. MiR-122 induces the radiosensitization of A549 cells. MiR-122 also boosts the inhibitory activity of ionizing radiation (IR on cancer cell anchor-independent growth and invasion. Moreover, miR-122 reduced the expression of its targeted genes related to tumor-survival or cellular stress response. These results indicate that miR-122 would be a novel strategy for NSCLC radiation-therapy.

  4. Radiation Mitigating Properties of Intranasally Administered KL4Surfactant in a Murine Model of Radiation-Induced Lung Damage.

    Science.gov (United States)

    Christofidou-Solomidou, Melpo; Pietrofesa, Ralph A; Arguiri, Evguenia; Koumenis, Constantinos; Segal, Robert

    2017-11-01

    The threat of exposure to ionizing radiation from a nuclear reactor accident or deliberate terrorist actions is a significant public health concern. The lung is particularly susceptible to radiation-induced injury from external sources or inhalation of radioactive particles from radioactive fallout. Radiation-induced lung disease can manifest with an acute radiation pneumonitis and/or delayed effects leading to pulmonary fibrosis. As prior warning of radiation exposure is unlikely, medical countermeasures (MCMs) to mitigate radiation-induced lung disease that can be given in mass-casualty situations many hours or days postirradiation are needed to prevent both early and late lung damage. In this study, KL 4 surfactant (lucinactant) was evaluated as a radiation mitigator in a well-characterized mouse model of targeted thoracic radiation exposure, for its effect on both early (several weeks) and late (18 weeks) lung damage. Here, 120 mg/kg total phospholipid of KL 4 surfactant was administered twice daily intranasally, (enabling intrapulmonary inhalation of drug) to C57BL/6 mice 24 h after a single 13.5 Gy dose of thoracic irradiation (LD 50 dose). Both early and chronic phase (2 and 4 weeks and 18 weeks postirradiation, respectively) assessments were performed. Mice were evaluated for evidence of reduced arterial blood oxygenation and early and chronic lung and systemic inflammation, lung fibrosis and oxidative stress. Analysis was done by performing lung function/respiration dynamics and measuring cellular protein content of bronchoalveolar lavage fluid (BALF), and levels of cytokines, 8-iso-prostaglandin F2α, hydroxyproline in lung and plasma, along with evaluating lung histology. The results of this study showed that intranasal delivery of KL 4 surfactant was able to preserve lung function as evidenced by adequate arterial oxygen saturation and reduced lung inflammation and oxidative stress; total white count and absolute neutrophil count was decreased in BALF

  5. Chronic inorganic arsenic exposure in vitro induces a cancer cell phenotype in human peripheral lung epithelial cells

    Energy Technology Data Exchange (ETDEWEB)

    Person, Rachel J.; Olive Ngalame, Ntube N.; Makia, Ngome L.; Bell, Matthew W.; Waalkes, Michael P.; Tokar, Erik J., E-mail: tokare@niehs.nih.gov

    2015-07-01

    Inorganic arsenic is a human lung carcinogen. We studied the ability of chronic inorganic arsenic (2 μM; as sodium arsenite) exposure to induce a cancer phenotype in the immortalized, non-tumorigenic human lung peripheral epithelial cell line, HPL-1D. After 38 weeks of continuous arsenic exposure, secreted matrix metalloproteinase-2 (MMP2) activity increased to over 200% of control, levels linked to arsenic-induced cancer phenotypes in other cell lines. The invasive capacity of these chronic arsenic-treated lung epithelial (CATLE) cells increased to 320% of control and colony formation increased to 280% of control. CATLE cells showed enhanced proliferation in serum-free media indicative of autonomous growth. Compared to control cells, CATLE cells showed reduced protein expression of the tumor suppressor gene PTEN (decreased to 26% of control) and the putative tumor suppressor gene SLC38A3 (14% of control). Morphological evidence of epithelial-to-mesenchymal transition (EMT) occurred in CATLE cells together with appropriate changes in expression of the EMT markers vimentin (VIM; increased to 300% of control) and e-cadherin (CDH1; decreased to 16% of control). EMT is common in carcinogenic transformation of epithelial cells. CATLE cells showed increased KRAS (291%), ERK1/2 (274%), phosphorylated ERK (p-ERK; 152%), and phosphorylated AKT1 (p-AKT1; 170%) protein expression. Increased transcript expression of metallothioneins, MT1A and MT2A and the stress response genes HMOX1 (690%) and HIF1A (247%) occurred in CATLE cells possibly in adaptation to chronic arsenic exposure. Thus, arsenic induced multiple cancer cell characteristics in human peripheral lung epithelial cells. This model may be useful to assess mechanisms of arsenic-induced lung cancer. - Highlights: • Chronic arsenic exposure transforms a human peripheral lung epithelia cell line. • Cells acquire characteristics in common with human lung adenocarcinoma cells. • These transformed cells provide a

  6. Perillyl alcohol suppresses antigen-induced immune responses in the lung

    Energy Technology Data Exchange (ETDEWEB)

    Imamura, Mitsuru; Sasaki, Oh; Okunishi, Katsuhide; Nakagome, Kazuyuki; Harada, Hiroaki; Kawahata, Kimito; Tanaka, Ryoichi; Yamamoto, Kazuhiko [Department of Allergy and Rheumatology, Graduate School of Medicine, The University of Tokyo, Tokyo (Japan); Dohi, Makoto, E-mail: mdohi-tky@umin.ac.jp [Department of Allergy and Rheumatology, Graduate School of Medicine, The University of Tokyo, Tokyo (Japan); Institute of Respiratory Immunology, Shibuya Clinic for Respiratory Diseases and Allergology, Tokyo (Japan)

    2014-01-03

    Highlights: •Perillyl alcohol (POH) is an isoprenoid which inhibits the mevalonate pathway. •We examined whether POH suppresses immune responses with a mouse model of asthma. •POH treatment during sensitization suppressed Ag-induced priming of CD4{sup +} T cells. •POH suppressed airway eosinophila and cytokine production in thoracic lymph nodes. -- Abstract: Perillyl alcohol (POH) is an isoprenoid which inhibits farnesyl transferase and geranylgeranyl transferase, key enzymes that induce conformational and functional changes in small G proteins to conduct signal production for cell proliferation. Thus, it has been tried for the treatment of cancers. However, although it affects the proliferation of immunocytes, its influence on immune responses has been examined in only a few studies. Notably, its effect on antigen-induced immune responses has not been studied. In this study, we examined whether POH suppresses Ag-induced immune responses with a mouse model of allergic airway inflammation. POH treatment of sensitized mice suppressed proliferation and cytokine production in Ag-stimulated spleen cells or CD4{sup +} T cells. Further, sensitized mice received aerosolized OVA to induce allergic airway inflammation, and some mice received POH treatment. POH significantly suppressed indicators of allergic airway inflammation such as airway eosinophilia. Cytokine production in thoracic lymph nodes was also significantly suppressed. These results demonstrate that POH suppresses antigen-induced immune responses in the lung. Considering that it exists naturally, POH could be a novel preventive or therapeutic option for immunologic lung disorders such as asthma with minimal side effects.

  7. Lipopolysaccharide triggers nuclear import of Lpcat1 to regulate inducible gene expression in lung epithelia.

    Science.gov (United States)

    Ellis, Bryon; Kaercher, Leah; Snavely, Courtney; Zhao, Yutong; Zou, Chunbin

    2012-07-26

    To report that Lpcat1 plays an important role in regulating lipopolysaccharide (LPS) inducible gene transcription. Gene expression in Murine Lung Epithelial MLE-12 cells with LPS treatment or Haemophilus influenza and Escherichia coli infection was analyzed by employing quantitative Reverse Transcription Polymerase Chain Reaction techniques. Nucleofection was used to deliver Lenti-viral system to express or knock down Lpcat1 in MLE cells. Subcellular protein fractionation and Western blotting were utilized to study Lpcat1 nuclear relocation. Lpcat1 translocates into the nucleus from the cytoplasm in murine lung epithelia (MLE) after LPS treatment. Haemophilus influenza and Escherichia coli, two LPS-containing pathogens that cause pneumonia, triggered Lpcat1 nuclear translocation from the cytoplasm. The LPS inducible gene expression profile was determined by quantitative reverse transcription polymerase chain reaction after silencing Lpcat1 or overexpression of the enzyme in MLE cells. We detected that 17 out of a total 38 screened genes were upregulated, 14 genes were suppressed, and 7 genes remained unchanged in LPS treated cells in comparison to controls. Knockdown of Lpcat1 by shRNA dramatically changed the spectrum of the LPS inducible gene transcription, as 18 genes out of 38 genes were upregulated, of which 20 genes were suppressed or unchanged. Notably, in Lpcat1 overexpressed cells, 25 genes out of 38 genes were reduced in the setting of LPS treatment. These observations suggest that Lpcat1 relocates into the nucleus in response to bacterial infection to differentially regulate gene transcriptional repression.

  8. Rabdosia japonica var. glaucocalyx Flavonoids Fraction Attenuates Lipopolysaccharide-Induced Acute Lung Injury in Mice

    Directory of Open Access Journals (Sweden)

    Chun-jun Chu

    2014-01-01

    Full Text Available Rabdosia japonica var. glaucocalyx (Maxim. Hara, belonging to the Labiatae family, is widely used as an anti-inflammatory and antitumor drug for the treatment of different inflammations and cancers. Aim of the Study. To investigate therapeutic effects and possible mechanism of the flavonoids fraction of Rabdosia japonica var. glaucocalyx (Maxim. Hara (RJFs in acute lung injury (ALI mice induced by lipopolysaccharide (LPS. Materials and Methods. Mice were orally administrated with RJFs (6.4, 12.8, and 25.6 mg/kg per day for 7 days, consecutively, before LPS challenge. Lung specimens and the bronchoalveolar lavage fluid (BALF were isolated for histopathological examinations and biochemical analysis. The level of complement 3 (C3 in serum was quantified by a sandwich ELISA kit. Results. RJFs significantly attenuated LPS-induced ALI via reducing productions of the level of inflammatory mediators (TNF-α, IL-6, and IL-1β, and significantly reduced complement deposition with decreasing the level of C3 in serum, which was exhibited together with the lowered myeloperoxidase (MPO activity and nitric oxide (NO and protein concentration in BALF. Conclusions. RJFs significantly attenuate LPS-induced ALI via reducing productions of proinflammatory mediators, decreasing the level of complement, and reducing radicals.

  9. Activation of TRPV1-dependent calcium oscillation exacerbates seawater inhalation-induced acute lung injury.

    Science.gov (United States)

    Li, Congcong; Bo, Liyan; Liu, Qingqing; Liu, Wei; Chen, Xiangjun; Xu, Dunquan; Jin, Faguang

    2016-03-01

    Calcium is an important second messenger and it is widely recognized that acute lung injury (ALI) is often caused by oscillations of cytosolic free Ca2+. Previous studies have indicated that the activation of transient receptor potential‑vanilloid (TRPV) channels and subsequent Ca2+ entry initiates an acute calcium‑dependent permeability increase during ALI. However, whether seawater exposure induces such an effect through the activation of TRPV channels remains unknown. In the current study, the effect of calcium, a component of seawater, on the inflammatory reactions that occur during seawater drowning‑induced ALI, was examined. The results demonstrated that a high concentration of calcium ions in seawater increased lung tissue myeloperoxidase activity and the secretion of inflammatory mediators, such as tumor necrosis factor‑α (TNF‑α) and interleukin (IL)‑1β and IL‑6. Further study demonstrated that the seawater challenge elevated cytosolic Ca2+ concentration, indicated by [Ca2+]c, by inducing calcium influx from the extracellular medium via TRPV1 channels. The elevated [Ca2+c] may have resulted in the increased release of TNF‑α and IL‑1β via increased phosphorylation of nuclear factor‑κB (NF‑κB). It was concluded that a high concentration of calcium in seawater exacerbated lung injury, and TRPV1 channels were notable mediators of the calcium increase initiated by the seawater challenge. Calcium influx through TRPV1 may have led to greater phosphorylation of NF‑κB and increased release of TNF‑α and IL‑1β.

  10. Enhancement of the Acrolein-Induced Production of Reactive Oxygen Species and Lung Injury by GADD34

    Directory of Open Access Journals (Sweden)

    Yang Sun

    2015-01-01

    Full Text Available Chronic obstructive pulmonary disease (COPD is characterized by lung destruction and inflammation. As a major compound of cigarette smoke, acrolein plays a critical role in the induction of respiratory diseases. GADD34 is known as a growth arrest and DNA damage-related gene, which can be overexpressed in adverse environmental conditions. Here we investigated the effects of GADD34 on acrolein-induced lung injury. The intranasal exposure of acrolein induced the expression of GADD34, developing the pulmonary damage with inflammation and increase of reactive oxygen species (ROS. Conversely, the integrality of pulmonary structure was preserved and the generation of ROS was reduced in GADD34-knockout mice. Acrolein-induced phosphorylation of eIF2α in GADD34-knockout epithelial cells by shRNA protected cell death by reducing misfolded protein-caused oxidative stress. These data indicate that GADD34 participates in the development of acrolein-induced lung injury.

  11. Enhancement of the acrolein-induced production of reactive oxygen species and lung injury by GADD34.

    Science.gov (United States)

    Sun, Yang; Ito, Sachiko; Nishio, Naomi; Tanaka, Yuriko; Chen, Nana; Liu, Lintao; Isobe, Ken-ichi

    2015-01-01

    Chronic obstructive pulmonary disease (COPD) is characterized by lung destruction and inflammation. As a major compound of cigarette smoke, acrolein plays a critical role in the induction of respiratory diseases. GADD34 is known as a growth arrest and DNA damage-related gene, which can be overexpressed in adverse environmental conditions. Here we investigated the effects of GADD34 on acrolein-induced lung injury. The intranasal exposure of acrolein induced the expression of GADD34, developing the pulmonary damage with inflammation and increase of reactive oxygen species (ROS). Conversely, the integrality of pulmonary structure was preserved and the generation of ROS was reduced in GADD34-knockout mice. Acrolein-induced phosphorylation of eIF2α in GADD34-knockout epithelial cells by shRNA protected cell death by reducing misfolded protein-caused oxidative stress. These data indicate that GADD34 participates in the development of acrolein-induced lung injury.

  12. Enhancement of the Acrolein-Induced Production of Reactive Oxygen Species and Lung Injury by GADD34

    Science.gov (United States)

    Sun, Yang; Ito, Sachiko; Nishio, Naomi; Tanaka, Yuriko; Chen, Nana; Isobe, Ken-ichi

    2015-01-01

    Chronic obstructive pulmonary disease (COPD) is characterized by lung destruction and inflammation. As a major compound of cigarette smoke, acrolein plays a critical role in the induction of respiratory diseases. GADD34 is known as a growth arrest and DNA damage-related gene, which can be overexpressed in adverse environmental conditions. Here we investigated the effects of GADD34 on acrolein-induced lung injury. The intranasal exposure of acrolein induced the expression of GADD34, developing the pulmonary damage with inflammation and increase of reactive oxygen species (ROS). Conversely, the integrality of pulmonary structure was preserved and the generation of ROS was reduced in GADD34-knockout mice. Acrolein-induced phosphorylation of eIF2α in GADD34-knockout epithelial cells by shRNA protected cell death by reducing misfolded protein-caused oxidative stress. These data indicate that GADD34 participates in the development of acrolein-induced lung injury. PMID:25821552

  13. Netrin-1 regulates fibrocyte accumulation in the decellularized fibrotic scleroderma lung microenvironment and in bleomycin induced pulmonary fibrosis

    Science.gov (United States)

    Sun, Huanxing; Zhu, Yangyang; Pan, Hongyi; Chen, Xiaosong; Balestrini, Jenna L.; Lam, TuKiet T.; Kanyo, Jean E.; Eichmann, Anne; Gulati, Mridu; Fares, Wassim H.; Bai, Hanwen; Feghali-Bostwick, Carol A.; Gan, Ye; Peng, Xueyan; Moore, Meagan W.; White, Eric S.; Sava, Parid; Gonzalez, Anjelica L.; Cheng, Yuwei; Niklason, Laura E.; Herzog, Erica L.

    2017-01-01

    Objectives Fibrocytes are collagen-producing leukocytes that accumulate in Scleroderma-associated interstitial lung disease (SSc-ILD) via unknown mechanisms. The extracellular matrix (ECM) influences cellular phenotypes. However, a relationship between the lung ECM and fibrocytes in Scleroderma has not been explored. This study uses a novel translational platform based on decellularized human lungs to determine whether the scleroderma lung ECM controls fibrocyte development from peripheral blood mononuclear cells. Methods Decellularized scaffolds prepared from healthy and fibrotic Scleroderma lung explants underwent biomechanical evaluation using tensile testing and biochemical analysis using proteomics. Cells from healthy and SSc-ILD subjects were cultured on these scaffolds, and CD45+Pro-ColIα1+ cells meeting criteria for fibrocytes were quantified. The contribution of Netrin-1 to fibrosis was assessed using neutralizing antibodies in this system and via the inhalational administration of bleomycin to Netrin-1+/− mice. Results Compared to control lung scaffold, SSc-ILD lung scaffolds showed aberrant anatomy, enhanced stiffness, and abnormal extracellular matrix composition. Culture of control cells in Scleroderma scaffolds increased Pro-ColIα1+ production, which was stimulated by enhanced stiffness and abnormal ECM composition. SSc-ILD cells demonstrated increased Pro-ColIα1 responsiveness to Scleroderma lung scaffolds, but not enhanced stiffness. Enhanced Netrin-1 expression was seen on CD14lo SSc-ILD cells and antibody mediated Netrin-1 neutralization attenuated CD45+Pro-ColIα1+ detection in all settings. Netrin-1+/− mice were protected from bleomycin induced lung fibrosis and fibrocyte accumulation. Conclusion Factors present in Scleroderma lung matrices regulate fibrocyte accumulation via a Netrin-1-dependent pathway. Netrin-1 regulates bleomycin induced murine pulmonary fibrosis. Netrin-1 might be a novel therapeutic target in SSc-ILD. PMID:26749424

  14. Overexpression of IL-38 protein in anticancer drug-induced lung injury and acute exacerbation of idiopathic pulmonary fibrosis.

    Science.gov (United States)

    Tominaga, Masaki; Okamoto, Masaki; Kawayama, Tomotaka; Matsuoka, Masanobu; Kaieda, Shinjiro; Sakazaki, Yuki; Kinoshita, Takashi; Mori, Daisuke; Inoue, Akira; Hoshino, Tomoaki

    2017-09-01

    Interleukin (IL)-38, a member of the IL-1 family, shows high homology to IL-1 receptor antagonist (IL-1Ra) and IL-36 receptor antagonist (IL-36Ra). Its function in interstitial lung disease (ILD) is still unknown. To determine the expression pattern of IL-38 mRNA, a panel of cDNAs derived from various tissues was analyzed by quantitative real-time PCR. Immunohistochemical reactivity with anti-human IL-38 monoclonal antibody (clone H127C) was evaluated semi-quantitatively in lung tissue samples from 12 patients with idiopathic pulmonary fibrosis/usual interstitial pneumonia (IPF/UIP), 5 with acute exacerbation of IPF, and 10 with anticancer drug-induced ILD (bleomycin in 5 and epidermal growth factor receptor-tyrosine kinase inhibitor in 5). Control lung tissues were obtained from areas of normal lung in 22 lung cancer patients who underwent extirpation surgery. IL-38 transcripts were strongly expressed in the lung, spleen, synoviocytes, and peripheral blood mononuclear cells, and at a lower level in pancreas and muscle. IL-38 protein was not strongly expressed in normal pulmonary alveolar tissues in all 22 control lungs. In contrast, IL-38 was overexpressed in the lungs of 4 of 5 (80%) patients with acute IPF exacerbation and 100% (10/10) of the patients with drug-induced ILD. IL-38 overexpression was limited to hyperplastic type II pneumocytes, which are considered to reflect regenerative change following diffuse alveolar damage in ILD. IL-38 may play an important role in acute and/or chronic inflammation in anticancer drug-induced lung injury and acute exacerbation of IPF. Copyright © 2017 The Japanese Respiratory Society. Published by Elsevier B.V. All rights reserved.

  15. Effects of SDF-1/CXCR4 on Acute Lung Injury Induced by Cardiopulmonary Bypass.

    Science.gov (United States)

    Shi, Hai; Lu, Rujian; Wang, Shuo; Chen, Honglin; Wang, Fei; Liu, Kun

    2017-06-01

    Acute lung injury (ALI) is one of the most important complications after cardiopulmonary bypass (CPB) and the complex pathophysiology remains to be resolved incomplete. SDF-1/CXCR4 chemokine axis can chemotactically accumulate inflammatory cell to local tissue and regulate the release of inflammatory factors, and SDF-1 has a strong chemotaxis effect on neutrophils with CXCR4. Since CPB animal model was difficult to establish, there was still no report about the effect of SDF-1/CXCR4 on neutrophil chemotaxis in ALI after CPB. Here, a stable CPB rat model was constructed to clarify the role of SDF-1/CXCR4 axis in the CPB-induced ALI. Real-time quantitative PCR (RT-qPCR), Western blot analysis, and enzyme-linked immunosorbent assay (ELISA) were used to detect the changes of SDF-1 and CXCR4 in lung tissues, blood, bronchoalveolar lavage (BALF), and/or isolated neutrophils. SDF-1/CXCR4 was increased after CPB, both of that were increased in blood; CXCR4 was increased in neutrophils; SDF-1/CXCR4 was also increased in BALF of CPB model. Results indicated that SDF-1/CXCR4 axis played a key role in the process of early ALI after CPB, also showed that lung injury was significantly reduce after blocking SDF-1/CXCR4 axis, suggest that CXCR4 might be a new target for ALI treatment.

  16. First-Breath-Induced Type 2 Pathways Shape the Lung Immune Environment

    Directory of Open Access Journals (Sweden)

    Simona Saluzzo

    2017-02-01

    Full Text Available From birth onward, the lungs are exposed to the external environment and therefore harbor a complex immunological milieu to protect this organ from damage and infection. We investigated the homeostatic role of the epithelium-derived alarmin interleukin-33 (IL-33 in newborn mice and discovered the immediate upregulation of IL-33 from the first day of life, closely followed by a wave of IL-13-producing type 2 innate lymphoid cells (ILC2s, which coincided with the appearance of alveolar macrophages (AMs and their early polarization to an IL-13-dependent anti-inflammatory M2 phenotype. ILC2s contributed to lung quiescence in homeostasis by polarizing tissue resident AMs and induced an M2 phenotype in transplanted macrophage progenitors. ILC2s continued to maintain the M2 AM phenotype during adult life at the cost of a delayed response to Streptococcus pneumoniae infection in mice. These data highlight the homeostatic role of ILC2s in setting the activation threshold in the lung and underline their implications in anti-bacterial defenses.

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

    Directory of Open Access Journals (Sweden)

    Abdulaleem Alnajar

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

  18. Mucosal BCG Vaccination Induces Protective Lung-Resident Memory T Cell Populations against Tuberculosis

    Science.gov (United States)

    Perdomo, Carolina; Zedler, Ulrike; Kühl, Anja A.; Lozza, Laura; Saikali, Philippe; Sander, Leif E.; Vogelzang, Alexis; Kupz, Andreas

    2016-01-01

    ABSTRACT Mycobacterium bovis Bacille Calmette-Guérin (BCG) is the only licensed vaccine against tuberculosis (TB), yet its moderate efficacy against pulmonary TB calls for improved vaccination strategies. Mucosal BCG vaccination generates superior protection against TB in animal models; however, the mechanisms of protection remain elusive. Tissue-resident memory T (TRM) cells have been implicated in protective immune responses against viral infections, but the role of TRM cells following mycobacterial infection is unknown. Using a mouse model of TB, we compared protection and lung cellular infiltrates of parenteral and mucosal BCG vaccination. Adoptive transfer and gene expression analyses of lung airway cells were performed to determine the protective capacities and phenotypes of different memory T cell subsets. In comparison to subcutaneous vaccination, intratracheal and intranasal BCG vaccination generated T effector memory and TRM cells in the lung, as defined by surface marker phenotype. Adoptive mucosal transfer of these airway-resident memory T cells into naive mice mediated protection against TB. Whereas airway-resident memory CD4+ T cells displayed a mixture of effector and regulatory phenotype, airway-resident memory CD8+ T cells displayed prototypical TRM features. Our data demonstrate a key role for mucosal vaccination-induced airway-resident T cells in the host defense against pulmonary TB. These results have direct implications for the design of refined vaccination strategies. PMID:27879332

  19. A CD36 synthetic peptide inhibits silica-induced lung fibrosis in the mice.

    Science.gov (United States)

    Wang, Xin; Lv, Lina; Chen, Ying; Chen, Jie

    2010-02-01

    Silicosis is a kind of pneumoconiosis caused by inhalation of silica dust, which is characterized by lung fibrosis. The biologically active form of transforming growth factor-beta1 (TGF-beta1) plays a key role in the development of lung fibrosis. CD36 is involved in the transformation of latent TGF-beta1 (L-TGF-beta1) to active TGF-beta1. The antagonistic effect of the synthetic peptide was analyzed by the administration of CD36 (93-110) synthetic peptide to the silicosis model of mice. The hydroxyproline content of the silica + CD36 (93-110) synthetic peptide group was significantly lower than that of the other experimental groups [silica and silica + CD36 (208-225) synthetic peptide groups] (p synthetic peptide group were less than those of the other experimental groups. The expressions of collagen I and III of the silica + CD36 (93-110) synthetic peptide group were significantly lower than those of the other experimental groups (p synthetic peptide reduced the tissue fibrotic pathologies and collagen accumulation in the silicosis model of mice, resulting in the decreased severity of silica-induced lung fibrosis.

  20. Dihydro-Resveratrol Ameliorates Lung Injury in Rats with Cerulein-Induced Acute Pancreatitis.

    Science.gov (United States)

    Lin, Ze-Si; Ku, Chuen Fai; Guan, Yi-Fu; Xiao, Hai-Tao; Shi, Xiao-Ke; Wang, Hong-Qi; Bian, Zhao-Xiang; Tsang, Siu Wai; Zhang, Hong-Jie

    2016-04-01

    Acute pancreatitis is an inflammatory process originated in the pancreas; however, it often leads to systemic complications that affect distant organs. Acute respiratory distress syndrome is indeed the predominant cause of death in patients with severe acute pancreatitis. In this study, we aimed to delineate the ameliorative effect of dihydro-resveratrol, a prominent analog of trans-resveratrol, against acute pancreatitis-associated lung injury and the underlying molecular actions. Acute pancreatitis was induced in rats with repetitive injections of cerulein (50 µg/kg/h) and a shot of lipopolysaccharide (7.5 mg/kg). By means of histological examination and biochemical assays, the severity of lung injury was assessed in the aspects of tissue damages, myeloperoxidase activity, and levels of pro-inflammatory cytokines. When treated with dihydro-resveratrol, pulmonary architectural distortion, hemorrhage, interstitial edema, and alveolar thickening were significantly reduced in rats with acute pancreatitis. In addition, the production of pro-inflammatory cytokines and the activity of myeloperoxidase in pulmonary tissues were notably repressed. Importantly, nuclear factor-kappaB (NF-κB) activation was attenuated. This study is the first to report the oral administration of dihydro-resveratrol ameliorated acute pancreatitis-associated lung injury via an inhibitory modulation of pro-inflammatory response, which was associated with a suppression of the NF-κB signaling pathway. Copyright © 2016 John Wiley & Sons, Ltd.

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

    Directory of Open Access Journals (Sweden)

    Evgenii Germanovich Skurikhin

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

  2. Up-Regulation of Claudin-6 in the Distal Lung Impacts Secondhand Smoke-Induced Inflammation

    Directory of Open Access Journals (Sweden)

    Joshua B. Lewis

    2016-10-01

    Full Text Available It has long been understood that increased epithelial permeability contributes to inflammation observed in many respiratory diseases. Recently, evidence has revealed that environmental exposure to noxious material such as cigarette smoke reduces tight junction barrier integrity, thus enhancing inflammatory conditions. Claudin-6 (Cldn6 is a tetraspanin transmembrane protein found within the tight junctional complex and is implicated in maintaining lung epithelial barriers. To test the hypothesis that increased Cldn6 ameliorates inflammation at the respiratory barrier, we utilized the Tet-On inducible transgenic system to conditionally over-express Clnd6 in the distal lung. Cldn6 transgenic (TG and control mice were continuously provided doxycycline from postnatal day (PN 30 until euthanasia date at PN90. A subset of Cldn6 TG and control mice were also subjected to daily secondhand tobacco smoke (SHS via a nose only inhalation system from PN30-90 and compared to room air (RA controls. Animals were euthanized on PN90 and lungs were harvested for histological and molecular characterization. Bronchoalveolar lavage fluid (BALF was procured for the assessment of inflammatory cells and molecules. Quantitative RT-PCR and immunoblotting revealed increased Cldn6 expression in TG vs. control animals and SHS decreased Cldn6 expression regardless of genetic up-regulation. Histological evaluations revealed no adverse pulmonary remodeling via Hematoxylin and Eosin (H&E staining or any qualitative alterations in the abundance of type II pneumocytes or proximal non-ciliated epithelial cells via staining for cell specific propeptide of Surfactant Protein-C (proSP-C or Club Cell Secretory Protein (CCSP, respectively. Immunoblotting and qRT-PCR confirmed the differential expression of Cldn6 and the pro-inflammatory cytokines TNF-α and IL-1β. As a general theme, inflammation induced by SHS exposure was influenced by the availability of Cldn6. These data reveal

  3. Up-Regulation of Claudin-6 in the Distal Lung Impacts Secondhand Smoke-Induced Inflammation.

    Science.gov (United States)

    Lewis, Joshua B; Milner, Dallin C; Lewis, Adam L; Dunaway, Todd M; Egbert, Kaleb M; Albright, Scott C; Merrell, Brigham J; Monson, Troy D; Broberg, Dallin S; Gassman, Jason R; Thomas, Daniel B; Arroyo, Juan A; Reynolds, Paul R

    2016-10-17

    It has long been understood that increased epithelial permeability contributes to inflammation observed in many respiratory diseases. Recently, evidence has revealed that environmental exposure to noxious material such as cigarette smoke reduces tight junction barrier integrity, thus enhancing inflammatory conditions. Claudin-6 (Cldn6) is a tetraspanin transmembrane protein found within the tight junctional complex and is implicated in maintaining lung epithelial barriers. To test the hypothesis that increased Cldn6 ameliorates inflammation at the respiratory barrier, we utilized the Tet-On inducible transgenic system to conditionally over-express Clnd6 in the distal lung. Cldn6 transgenic (TG) and control mice were continuously provided doxycycline from postnatal day (PN) 30 until euthanasia date at PN90. A subset of Cldn6 TG and control mice were also subjected to daily secondhand tobacco smoke (SHS) via a nose only inhalation system from PN30-90 and compared to room air (RA) controls. Animals were euthanized on PN90 and lungs were harvested for histological and molecular characterization. Bronchoalveolar lavage fluid (BALF) was procured for the assessment of inflammatory cells and molecules. Quantitative RT-PCR and immunoblotting revealed increased Cldn6 expression in TG vs. control animals and SHS decreased Cldn6 expression regardless of genetic up-regulation. Histological evaluations revealed no adverse pulmonary remodeling via Hematoxylin and Eosin (H&E) staining or any qualitative alterations in the abundance of type II pneumocytes or proximal non-ciliated epithelial cells via staining for cell specific propeptide of Surfactant Protein-C (proSP-C) or Club Cell Secretory Protein (CCSP), respectively. Immunoblotting and qRT-PCR confirmed the differential expression of Cldn6 and the pro-inflammatory cytokines TNF-α and IL-1β. As a general theme, inflammation induced by SHS exposure was influenced by the availability of Cldn6. These data reveal captivating

  4. The Nitrated Fatty Acid 10-Nitro-oleate Diminishes Severity of LPS-Induced Acute Lung Injury in Mice

    Directory of Open Access Journals (Sweden)

    Aravind T. Reddy

    2012-01-01

    Full Text Available Acute lung injury (ALI is an inflammatory condition culminating in respiratory failure. There is currently no effective pharmacological treatment. Nitrated fatty acids (NFAs have been shown to exert anti-inflammatory effects. We therefore hypothesized that delivery of NFAs directly to the site of inflammation would reduce the severity of ALI. Pulmonary delivery of 10-nitro-oleate following endotoxin-induced ALI in mice reduced markers of lung inflammation and injury, including capillary leakage, lung edema, infiltration of neutrophils into the lung, and oxidant stress, as well as plasma levels of proinflammatory cytokines. Nitro-oleate delivery likewise downregulated expression of proinflammatory genes by alveolar macrophages, key cells in regulation of lung inflammation. These effects may be accounted for by the observed increases in the activity of PPAR-γ and the PPAR-γ-induced antioxidant transcription factor Nrf2, together with the decreased activity of NF-κB. Our results demonstrate that pulmonary delivery of NFAs reduces severity of acute lung injury and suggest potential utility of these molecules in other inflammatory lung diseases.

  5. Longitudinal follow-up study of smoking-induced emphysema progression in low-dose CT screening of lung cancer

    Science.gov (United States)

    Suzuki, H.; Matsuhiro, M.; Kawata, Y.; Niki, N.; Nakano, Y.; Ohmatsu, H.; Kusumoto, M.; Tsuchida, T.; Eguchi, K.; Kaneko, Masahiro; Moriyama, N.

    2014-03-01

    Chronic obstructive pulmonary disease is a major public health problem that is predicted to be third leading cause of death in 2030. Although spirometry is traditionally used to quantify emphysema progression, it is difficult to detect the loss of pulmonary function by emphysema in early stage, and to assess the susceptibility to smoking. This study presents quantification method of smoking-induced emphysema progression based on annual changes of low attenuation volume (LAV) by each lung lobe acquired from low-dose CT images in lung cancer screening. The method consists of three steps. First, lung lobes are segmented using extracted interlobar fissures by enhancement filter based on fourdimensional curvature. Second, LAV of each lung lobe is segmented. Finally, smoking-induced emphysema progression is assessed by statistical analysis of the annual changes represented by linear regression of LAV percentage in each lung lobe. This method was applied to 140 participants in lung cancer CT screening for six years. The results showed that LAV progressions of nonsmokers, past smokers, and current smokers are different in terms of pack-year and smoking cessation duration. This study demonstrates effectiveness in diagnosis and prognosis of early emphysema in lung cancer CT screening.

  6. Effect of hypertonic saline treatment on the inflammatory response after hydrochloric acid-induced lung injury in pigs.

    Science.gov (United States)

    Holms, Carla Augusto; Otsuki, Denise Aya; Kahvegian, Marcia; Massoco, Cristina Oliveira; Fantoni, Denise Tabacchi; Gutierrez, Paulo Sampaio; Auler Junior, Jose Otavio Costa

    2015-08-01

    Hypertonic saline has been proposed to modulate the inflammatory cascade in certain experimental conditions, including pulmonary inflammation caused by inhaled gastric contents. The present study aimed to assess the potential anti-inflammatory effects of administering a single intravenous dose of 7.5% hypertonic saline in an experimental model of acute lung injury induced by hydrochloric acid. Thirty-two pigs were anesthetized and randomly allocated into the following four groups: Sham, which received anesthesia and were observed; HS, which received intravenous 7.5% hypertonic saline solution (4 ml/kg); acute lung injury, which were subjected to acute lung injury with intratracheal hydrochloric acid; and acute lung injury + hypertonic saline, which were subjected to acute lung injury with hydrochloric acid and treated with hypertonic saline. Hemodynamic and ventilatory parameters were recorded over four hours. Subsequently, bronchoalveolar lavage samples were collected at the end of the observation period to measure cytokine levels using an oxidative burst analysis, and lung tissue was collected for a histological analysis. Hydrochloric acid instillation caused marked changes in respiratory mechanics as well as blood gas and lung parenchyma parameters. Despite the absence of a significant difference between the acute lung injury and acute lung injury + hypertonic saline groups, the acute lung injury animals presented higher neutrophil and tumor necrosis factor alpha (TNF-α), interleukin (IL)-6 and IL-8 levels in the bronchoalveolar lavage analysis. The histopathological analysis revealed pulmonary edema, congestion and alveolar collapse in both groups; however, the differences between groups were not significant. Despite the lower cytokine and neutrophil levels observed in the acute lung injury + hypertonic saline group, significant differences were not observed among the treated and non-treated groups. Hypertonic saline infusion after intratracheal hydrochloric

  7. Prevention of chinese green tea on 3,4-benzopyrene-induced lung cancer and its mechanism in animal model

    Directory of Open Access Journals (Sweden)

    Qihua GU

    2008-08-01

    Full Text Available Background and objective Chinese green tea is one of the daily consumption beverages in the world and is considered a promising cancer chemopreventive agent. In the present study, we investigate the role of lung cancer prevention by green tea and its mechanism. Methods Three groups of female SD rats were kept with the same feed. Rats in group A were administrated with 1% green tea drinking, while in group B and group C with water only. Animals in group A and group B were given 3,4-benzopyrene-corn oil mixture pulmonary injection fortnightly for 4 times, while in group C corn oil only. Rats were sacrificed 1 year after the first injection under narcotism. Lung tumors and lung tissues were performed H&E staining for cancer identification. Each case of lung cancer was examined for expression of p53 and Bcl-2 with in situ hybridization analysis and immunohistochemistry staining. Results No cancer was found in rats in group C. However, in group B, 15 out of 20 rats were found generating lung cancer, and in group A, 6 out of 20 rats inducing lung cancer were recorded. The rate of lung carcinogenesis in rats was decreased from 75% to 30% by 1% chinese green tea oral administration (χ2=8.12, P0.05. However, significantly lower level of Bcl-2 expression was found in lung cancer tissues of group A than that of group B (P<0.05. Conclusion The results indicate that chinese green tea inhibits lung carcinogenesis. Chinese green tea can slightly upregulate expression of p53, but significantly downregulate expression of Bcl-2 in lung cancer, and this may be related to the mechanism of lung cancer prevention.

  8. Ursolic acid improves survival and attenuates lung injury in septic rats induced by cecal ligation and puncture.

    Science.gov (United States)

    Hu, Zhansheng; Gu, Zhilong; Sun, Meina; Zhang, Ke; Gao, Penghui; Yang, Qinwu; Yuan, Yuan

    2015-04-01

    Sepsis is characterized as a systemic inflammatory response syndrome during infection, which can result in multiple organ dysfunction and death. Ursolic acid (UA), a pentacyclic triterpene acid, has been reported to have potent anti-inflammatory and antioxidant properties. The aim of this study was to detect the possible protective effects of UA on sepsis-evoked acute lung injury. A rat model of sepsis induced by cecal ligation and puncture (CLP) was used. Rats were injected intraperitoneally with UA (10 mg/kg) after CLP, and then the survival was determined twice a day for 4 d. The protective effects of UA on CLP-induced acute lung injury were assayed at 24 h after CLP. The results revealed that UA treatment markedly improved the survival of septic rats, and attenuated CLP-induced lung injury, including reduction of lung wet/dry weight ratio, infiltration of leukocytes and proteins, myeloperoxidase activity, and malondialdehyde content. In addition, UA significantly decreased the serum levels of tumor necrosis factor-α, interleukin-6, and interleukin-1β, inhibited the expression of inducible nitric oxide synthase and cyclooxygenase-2 in the lung, which are involved in the productions of nitric oxide and prostaglandin E2. These findings indicate that UA exerts protective effects on CLP-induced septic rats. UA may be a potential therapeutic agent against sepsis. Copyright © 2015 Elsevier Inc. All rights reserved.

  9. Effect of anti-podoplanin antibody administration during lipopolysaccharide-induced lung injury in mice.

    Science.gov (United States)

    Lax, Sian; Rayes, Julie; Thickett, David R; Watson, Steve P

    2017-01-01

    Acute respiratory distress syndrome (ARDS) is a devastating pulmonary condition in the critically ill patient. A therapeutic intervention is yet to be found that can prevent progression to ARDS. We recently demonstrated that the interaction between podoplanin expressed on inflammatory alveolar macrophages (iAMs) and its endogenous ligand, platelet C-type lectin-like 2 (CLEC-2), protects against exaggerated lung inflammation during a mouse model of ARDS. In this study, we aim to investigate the therapeutic use of a crosslinking/activating anti-podoplanin antibody (α-PDPN, clone 8.1.1) during lipopolysaccharide (LPS)-induced lung inflammation in mice. Intravenous administration of α-PDPN was performed 6 hours after intratracheal LPS in wildtype, C57Bl/6 mice. Lung function decline was measured by pulse oximetry as well as markers of local inflammation including bronchoalveolar lavage neutrophilia and cytokine/chemokine expression. In parallel, alveolar macrophages were isolated and cultured in vitro from haematopoietic-specific podoplanin-deficient mice (Pdpn fl/fl VAV1cre + ) and floxed-only controls treated with or without LPS in the presence or absence of α-PDPN. Lung function decline as well as alveolar neutrophil recruitment was significantly decreased in mice treated with the crosslinking/activating α-PDPN in vivo. Furthermore, we demonstrate that, in vitro, activation of podoplanin on iAMs regulates their secretion of proinflammatory cytokines and chemokines. These data confirm the importance of the CLEC-2-podoplanin pathway during intratracheal (IT)-LPS and demonstrate the beneficial effect of targeting podoplanin during IT-LPS in mice possibly via modulation of local cytokine/chemokine expression. Moreover, these data suggest that podoplanin-targeted therapies may have a beneficial effect in patients at risk of developing ARDS.

  10. Radiation-induced organizing pneumonia after stereotactic body radiotherapy for lung tumor

    International Nuclear Information System (INIS)

    Ochiai, Satoru; Yamashita, Yasufumi; Nomoto, Yoshihito

    2015-01-01

    The aim of this retrospective study was to investigate characteristics of organizing pneumonia (OP) after stereotactic body radiotherapy (SBRT) for lung tumor. Between September 2010 and June 2014, patients who were diagnosed as Stage I lung cancer and treated with SBRT at our institution were included in this study. A total of 78 patients (47 males with a median age of 80 years) were analyzed. The median follow-up period was 23 months. Five patients (6.4%) developed OP at 6–18 months after SBRT. The cumulative incidence of OP was 4.3% (95% confidence interval [CI], 1.1–11.0) and 8.2% (95% CI, 2.9–17.0) at 1 and 2 years, respectively. Tumor location (superior and middle lobe vs inferior lobe) was shown to be a borderline significant factor for the occurrence of OP (P = 0.069). In the subgroup analysis of patients with a radiographic follow-up period at least 6 months, or who died within 6 months after SBRT, 7 of 72 patients (9.7%) developed Grade 2 or 3 radiation pneumonitis (G2/3 RP) at 2–4 months after SBRT. A statistically significant association between G2/3 RP in the subacute phase and OP was shown (P = 0.040). In two of the five patients who developed OP, the symptoms and radiographic change were improved rapidly by corticosteroid administration. One patient had relapsed OP after suspending the treatment and re-administration was required. Three patients with minor symptoms were managed without corticosteroid administration and OP resolved without any relapse. The radiation-induced OP should be considered as one of the late lung injuries after SBRT for lung tumors. (author)

  11. Milan PM1 induces adverse effects on mice lungs and cardiovascular system.

    Science.gov (United States)

    Farina, Francesca; Sancini, Giulio; Longhin, Eleonora; Mantecca, Paride; Camatini, Marina; Palestini, Paola

    2013-01-01

    Recent studies have suggested a link between inhaled particulate matter (PM) exposure and increased mortality and morbidity associated with cardiorespiratory diseases. Since the response to PM1 has not yet been deeply investigated, its impact on mice lungs and cardiovascular system is here examined. A repeated exposure to Milan PM1 was performed on BALB/c mice. The bronchoalveolar lavage fluid (BALf) and the lung parenchyma were screened for markers of inflammation (cell counts, tumor necrosis factor-α (TNF-α); macrophage inflammatory protein-2 (MIP-2); heme oxygenase-1 (HO-1); nuclear factor kappa-light-chain-enhancer of activated B cells p50 subunit (NFκB-p50); inducible nitric oxide synthetase (iNOS); endothelial-selectin (E-selectin)), cytotoxicity (lactate dehydrogenase (LDH); alkaline phosphatase (ALP); heat shock protein 70 (Hsp70); caspase-8-p18), and a putative pro-carcinogenic marker (cytochrome 1B1 (Cyp1B1)). Heart tissue was tested for HO-1, caspase-8-p18, NFκB-p50, iNOS, E-selectin, and myeloperoxidase (MPO); plasma was screened for markers of platelet activation and clot formation (soluble platelet-selectin (sP-selectin); fibrinogen; plasminogen activator inhibitor 1 (PAI-1)). PM1 triggers inflammation and cytotoxicity in lungs. A similar cytotoxic effect was observed on heart tissues, while plasma analyses suggest blood-endothelium interface activation. These data highlight the importance of lung inflammation in mediating adverse cardiovascular events following increase in ambient PM1 levels, providing evidences of a positive correlation between PM1 exposure and cardiovascular morbidity.

  12. Milan PM1 Induces Adverse Effects on Mice Lungs and Cardiovascular System

    Directory of Open Access Journals (Sweden)

    Francesca Farina

    2013-01-01

    Full Text Available Recent studies have suggested a link between inhaled particulate matter (PM exposure and increased mortality and morbidity associated with cardiorespiratory diseases. Since the response to PM1 has not yet been deeply investigated, its impact on mice lungs and cardiovascular system is here examined. A repeated exposure to Milan PM1 was performed on BALB/c mice. The bronchoalveolar lavage fluid (BALf and the lung parenchyma were screened for markers of inflammation (cell counts, tumor necrosis factor-α (TNF-α; macrophage inflammatory protein-2 (MIP-2; heme oxygenase-1 (HO-1; nuclear factor kappa-light-chain-enhancer of activated B cells p50 subunit (NFκB-p50; inducible nitric oxide synthetase (iNOS; endothelial-selectin (E-selectin, cytotoxicity (lactate dehydrogenase (LDH; alkaline phosphatase (ALP; heat shock protein 70 (Hsp70; caspase-8-p18, and a putative pro-carcinogenic marker (cytochrome 1B1 (Cyp1B1. Heart tissue was tested for HO-1, caspase-8-p18, NFκB-p50, iNOS, E-selectin, and myeloperoxidase (MPO; plasma was screened for markers of platelet activation and clot formation (soluble platelet-selectin (sP-selectin; fibrinogen; plasminogen activator inhibitor 1 (PAI-1. PM1 triggers inflammation and cytotoxicity in lungs. A similar cytotoxic effect was observed on heart tissues, while plasma analyses suggest blood-endothelium interface activation. These data highlight the importance of lung inflammation in mediating adverse cardiovascular events following increase in ambient PM1 levels, providing evidences of a positive correlation between PM1 exposure and cardiovascular morbidity.

  13. The role of the acute phase protein PTX3 in the ventilator-induced lung injury

    Directory of Open Access Journals (Sweden)

    JM Real

    2008-06-01

    Full Text Available The pentraxin 3 (PTX3 is an acute phase proinflammatory protein produced by fibroblasts and alveolar epithelial cells. We have previously demonstrated that PTX3 is a key modulator of inflammation. Mechanical ventilation (MV is a life saving therapeutic approach for patients with acute lung injury that, nevertheless could lead to an inflammatory response and tissue injury (ventilator-induced lung injury: VILI, representing a major cause of iatrogenic lung damage in intensive units. Our objective was to investigate the role of PTX3 in VILI. PTX3 transgenic, knockout and Wt control mice (n = 12/group were ventilated (45ml·kg–1 until respiratory system Elastance increased 50% (Ers150%, an indicator of VILI. Histological analysis demonstrated that using a Ers150% was appropriate for our analysis since identical degrees of inflammation were observed in Tg, KO and Wt mice as assessed by leukocyte infiltration, oedema, alveolar collapse and number of breaks in alveolar septa. However, Tg mice reached Ers150% faster than Wt controls (p = 0.0225. We also showed that the lack of PTX3 does not abolish the occurrence of VILI in KOs. Gene expression profile of PTX3, IL-1beta, IL-6, KC, IFNgamma, TGFbeta and PCIII were investigated by QPCR. MV drastically up modulated PTX3 as well as IL-1beta, IL-6, IFNgamma and KC. Alternatively, mice were ventilated for 20, 40 and 60 min. The faster kinetics of Tg mice to reach Ers150% was accompanied by an earlier augmentation of IL-1b and PTX3 expression. The kinetics of local PTX3 expression in the lungs of ventilated mice strongly suggests the involvement of this pentraxin in the pathogenesis of VILI.

  14. Heme Attenuation Ameliorates Irritant Gas Inhalation-Induced Acute Lung Injury

    Science.gov (United States)

    Aggarwal, Saurabh; Lam, Adam; Bolisetty, Subhashini; Carlisle, Matthew A.; Traylor, Amie; Agarwal, Anupam

    2016-01-01

    Abstract Aims: Exposure to irritant gases, such as bromine (Br2), poses an environmental and occupational hazard that results in severe lung and systemic injury. However, the mechanism(s) of Br2 toxicity and the therapeutic responses required to mitigate lung damage are not known. Previously, it was demonstrated that Br2 upregulates the heme degrading enzyme, heme oxygenase-1 (HO-1). Since heme is a major inducer of HO-1, we determined whether an increase in heme and heme-dependent oxidative injury underlies the pathogenesis of Br2 toxicity. Results: C57BL/6 mice were exposed to Br2 gas (600 ppm, 30 min) and returned to room air. Thirty minutes postexposure, mice were injected intraperitoneally with a single dose of the heme scavenging protein, hemopexin (Hx) (3 μg/gm body weight), or saline. Twenty-four hours postexposure, saline-treated mice had elevated total heme in bronchoalveolar lavage fluid (BALF) and plasma and acute lung injury (ALI) culminating in 80% mortality after 10 days. Hx treatment significantly lowered heme, decreased evidence of ALI (lower protein and inflammatory cells in BALF, lower lung wet-to-dry weight ratios, and decreased airway hyperreactivity to methacholine), and reduced mortality. In addition, Br2 caused more severe ALI and mortality in mice with HO-1 gene deletion (HO-1−/−) compared to wild-type controls, while transgenic mice overexpressing the human HO-1 gene (hHO-1) showed significant protection. Innovation: This is the first study delineating the role of heme in ALI caused by Br2. Conclusion: The data suggest that attenuating heme may prove to be a useful adjuvant therapy to treat patients with ALI. Antioxid. Redox Signal. 24, 99–112. PMID:26376667

  15. Drug-induced interstitial lung diseases. Often forgotten; Medikamenteninduzierte interstitielle Lungenerkrankungen. Haeufig vergessen

    Energy Technology Data Exchange (ETDEWEB)

    Poschenrieder, F.; Stroszczynski, C. [Universitaetsklinikum Regensburg, Institut fuer Roentgendiagnostik, Regensburg (Germany); Hamer, O.W. [Universitaetsklinikum Regensburg, Institut fuer Roentgendiagnostik, Regensburg (Germany); Lungenfachklinik Donaustauf, Donaustauf (Germany)

    2014-12-15

    Drug-induced interstitial lung diseases (DILD) are probably more common than diagnosed. Due to their potential reversibility, increased vigilance towards DILD is appropriate also from the radiologist's point of view, particularly as these diseases regularly exhibit radiological correlates in high-resolution computed tomography (HRCT) of the lungs. Based on personal experience typical relatively common manifestations of DILD are diffuse alveolar damage (DAD), eosinophilic pneumonia (EP), hypersensitivity pneumonitis (HP), organizing pneumonia (OP), non-specific interstitial pneumonia (NSIP) and usual interstitial pneumonia (UIP). These patterns are presented based on case studies, whereby emphasis is placed on the clinical context. This is to highlight the relevance of interdisciplinary communication and discussion in the diagnostic field of DILD as it is a diagnosis of exclusion or of probability in most cases. Helpful differential diagnostic indications for the presence of DILD, such as an accompanying eosinophilia or increased attenuation of pulmonary consolidations in amiodarone-induced pneumopathy are mentioned and the freely available online database http://www.pneumotox.com is presented. (orig.) [German] Medikamenteninduzierte interstitielle Lungenerkrankungen (engl. ''drug-induced interstitial lung diseases'', DILD) sind wahrscheinlich haeufiger, als sie diagnostiziert werden. Aufgrund ihrer potenziellen Reversibilitaet ist eine erhoehte Vigilanz gegenueber DILD auch seitens der Radiologie angebracht, da diese regelmaessig ein radiomorphologisches Korrelat in der hochaufloesenden Computertomographie (''high-resolution CT'', HRCT) der Lunge aufweisen. Typische, nach eigener Erfahrung relativ haeufige Manifestationsformen von DILD sind der diffuse Alveolarschaden (engl. ''diffuse alveolar damage'', DAD), die eosinophile Pneumonie (EP), die Hypersensitivitaetspneumonitis (HP), die organisierende

  16. High levels of S100A8/A9 proteins aggravate ventilator-induced lung injury via TLR4 signaling.

    Directory of Open Access Journals (Sweden)

    Maria T Kuipers

    Full Text Available BACKGROUND: Bacterial products add to mechanical ventilation in enhancing lung injury. The role of endogenous triggers of innate immunity herein is less well understood. S100A8/A9 proteins are released by phagocytes during inflammation. The present study investigates the role of S100A8/A9 proteins in ventilator-induced lung injury. METHODS: Pulmonary S100A8/A9 levels were measured in samples obtained from patients with and without lung injury. Furthermore, wild-type and S100A9 knock-out mice, naive and with lipopolysaccharide-induced injured lungs, were randomized to 5 hours of spontaneously breathing or mechanical ventilation with low or high tidal volume (VT. In addition, healthy spontaneously breathing and high VT ventilated mice received S100A8/A9, S100A8 or vehicle intratracheal. Furthermore, the role of Toll-like receptor 4 herein was investigated. RESULTS: S100A8/A9 protein levels were elevated in patients and mice with lung injury. S100A8/A9 levels synergistically increased upon the lipopolysaccharide/high VT MV double hit. Markers of alveolar barrier dysfunction, cytokine and chemokine levels, and histology scores were attenuated in S100A9 knockout mice undergoing the double-hit. Exogenous S100A8/A9 and S100A8 induced neutrophil influx in spontaneously breathing mice. In ventilated mice, these proteins clearly amplified inflammation: neutrophil influx, cytokine, and chemokine levels were increased compared to ventilated vehicle-treated mice. In contrast, administration of S100A8/A9 to ventilated Toll-like receptor 4 mutant mice did not augment inflammation. CONCLUSION: S100A8/A9 proteins increase during lung injury and contribute to inflammation induced by HVT MV combined with lipopolysaccharide. In the absence of lipopolysaccharide, high levels of extracellular S100A8/A9 still amplify ventilator-induced lung injury via Toll-like receptor 4.

  17. Risk of radiation-induced pneumonitis after helical and static-port tomotherapy in lung cancer patients and experimental rats

    International Nuclear Information System (INIS)

    Zhang, Xianglan; Shin, You Keun; Zheng, Zhenlong; Zhu, Lianhua; Lee, Ik Jae

    2015-01-01

    Radiotherapy (RT) is one of the major non-operative treatment modalities for treating lung cancer. Tomotherapy is an advanced type of intensity-modulated radiotherapy (IMRT) in which radiation may be delivered in a helical fashion. However, unexpected pneumonitis may occur in patients treated with tomotherapy, especially in combination with chemotherapy, as a result of extensive low-dose radiation of large lung volumes. The aim of our study was to investigate the risk of radiation-induced pneumonitis after helical-mode and static-mode tomotherapy in patients with lung cancer and in an animal model. A total of 63 patients with primary lung cancer who were treated with static or helical tomotherapy with or without concurrent chemoradiotherapy (CCRT) were analyzed. Additionally, rats with radiation-induced pulmonary toxicity, which was induced by the application of helical or static tomography with or without CCRT, were evaluated. Helical-mode tomotherapy resulted in a significantly higher rate of late radiation pneumonitis in lung cancer patients than static-mode tomotherapy when evaluated by the Radiation Therapy Oncology Group (RTOG) and National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE) scoring system. In the animal model, helical tomotherapy alone induced significantly higher expression of interleukin (IL)-1α, IL-1β, IL-6, and transforming growth factor (TGF)-β in lung specimens, especially on the untreated side, compared to static tomotherapy alone. Additionally, rats treated with helical tomotherapy and CCRT demonstrated significantly higher expression of inflammatory cytokines compared to those treated with static tomotherapy and CCRT. Rat models treated with tomotherapy with or without CCRT could present similar patterns of pulmonary toxicity to those shown in lung cancer patients. The models can be used in further investigations of radiation induced pulmonary toxicity

  18. Genetic Phagocyte NADPH Oxidase Deficiency Enhances Nonviable Candida albicans-Induced Inflammation in Mouse Lungs.

    Science.gov (United States)

    Endo, Daiki; Fujimoto, Kenta; Hirose, Rika; Yamanaka, Hiroko; Homme, Mizuki; Ishibashi, Ken-Ichi; Miura, Noriko; Ohno, Naohito; Aratani, Yasuaki

    2017-02-01

    Patients with chronic granulomatous disease (CGD) have mutated phagocyte NADPH oxidase, resulting in reduced production of reactive oxygen species (ROS). While the mechanism underlying hyperinfection in CGD is well understood, the basis for inflammatory disorders that arise in the absence of evident infection has not been fully explained. This study aimed to evaluate the effect of phagocyte NADPH oxidase deficiency on lung inflammation induced by nonviable Candida albicans (nCA). Mice deficient in this enzyme (CGD mice) showed more severe neutrophilic pneumonia than nCA-treated wild-type mice, which exhibited significantly higher lung concentrations of interleukin (IL)-1β, tumor necrosis factor (TNF)-α, and keratinocyte-derived chemokine (KC). Neutralization of these proinflammatory mediators significantly reduced neutrophil infiltration. In vitro, production of IL-1β and TNF-α from neutrophils and that of KC from macrophages was enhanced in nCA-stimulated neutrophils from CGD mice. Expression of IL-1β mRNA was higher in the stimulated CGD neutrophils than in the stimulated wild-type cells, concomitant with upregulation of nuclear factor (NF)-κB and its upstream regulator extracellular-signal regulated kinase (ERK) 1/2. Pretreatment with an NADPH oxidase inhibitor significantly enhanced IL-1β production in the wild-type neutrophils stimulated with nCA. These results suggest that lack of ROS production because of NADPH oxidase deficiency results in the production of higher levels of proinflammatory mediators from neutrophils and macrophages, which may at least partly contribute to the exacerbation of nCA-induced lung inflammation in CGD mice.

  19. Mast cells modulate acute ozone-induced inflammation of the murine lung

    Energy Technology Data Exchange (ETDEWEB)

    Kleeberger, S.R.; Seiden, J.E.; Levitt, R.C.; Zhang, L.Y. (Johns Hopkins School of Public Health, Baltimore, MD (United States))

    1993-11-01

    We hypothesized that mast cells modulate lung inflammation that develops after acute ozone (O3) exposure. Two tests were done: (1) genetically mast-cell-deficient (WBB6F1-W/Wv, WCB6F1-SI/SId) and bone-marrow-transplanted W/Wv mice were exposed to O3 or filtered air, and the inflammatory responses were compared with those of mast-cell-sufficient congenic mice (WBB6F1-(+)/+, WCB6F1-(+)/+); (2) genetically O3-susceptible C57BL/6J mice were treated pharmacologically with putative mast-cell modulators or vehicle, and the O3-induced inflammatory responses were compared. Mice were exposed to 1.75 ppm O3 or air for 3 h, and lung inflammation was assessed by bronchoalveolar lavage (BAL) 6 and 24 h after exposure. Relative to O3-exposed W/Wv and SI/SId mice, the mean numbers of lavageable polymorphonuclear leukocytes (PMNs) and total BAL protein concentration (a marker of permeability) were significantly greater in the respective O3-exposed normal congenic +/+ mice (p < 0.05). Mast cells were reconstituted in W/Wv mice by transplantation of bone marrow cells from congenic +/+ mice, and O3-induced lung inflammation was assessed in the mast-cell-replete W/Wv mice. After O3 exposure, the changes in lavageable PMNs and total protein of mast-cell-replete W/Wv mice were not different from age-matched normal +/+ control mice, and they were significantly greater than those of sham-transplanted W/Wv mice (p < 0.05). Genetically susceptible C57BL/6J mice were pretreated with a mast-cell stabilizer (nedocromil sodium), secretagogue (compound 48/80), or vehicle, and the mice were exposed to O3.

  20. Andrographolide protects against cigarette smoke-induced oxidative lung injury via augmentation of Nrf2 activity

    Science.gov (United States)

    Guan, SP; Tee, W; Ng, DSW; Chan, TK; Peh, HY; Ho, WE; Cheng, C; Mak, JC; Wong, WSF

    2013-01-01

    Background and Purpose Cigarette smoke is a major cause for chronic obstructive pulmonary disease (COPD). Andrographolide is an active biomolecule isolated from the plant Andrographis paniculata. Andrographolide has been shown to activate nuclear factor erythroid-2-related factor 2 (Nrf2), a redox-sensitive antioxidant transcription factor. As Nrf2 activity is reduced in COPD, we hypothesize that andrographolide may have therapeutic value for COPD. Experimental Approach Andrographolide was given i.p. to BALB/c mice daily 2 h before 4% cigarette smoke exposure for 1 h over five consecutive days. Bronchoalveolar lavage fluid and lungs were collected for analyses of cytokines, oxidative damage markers and antioxidant activities. BEAS-2B bronchial epithelial cells were exposed to cigarette smoke extract (CSE) and used to study the antioxidant mechanism of action of andrographolide. Key Results Andrographolide suppressed cigarette smoke-induced increases in lavage fluid cell counts; levels of IL-1β, MCP-1, IP-10 and KC; and levels of oxidative biomarkers 8-isoprostane, 8-OHdG and 3-nitrotyrosine in a dose-dependent manner. Andrographolide promoted inductions of glutathione peroxidase (GPx) and glutathione reductase (GR) activities in lungs from cigarette smoke-exposed mice. In BEAS-2B cells, andrographolide markedly increased nuclear Nrf2 accumulation, promoted binding to antioxidant response element (ARE) and total cellular glutathione level in response to CSE. Andrographolide up-regulated ARE-regulated gene targets including glutamate-cysteine ligase catalytic (GCLC) subunit, GCL modifier (GCLM) subunit, GPx, GR and heme oxygenase-1 in BEAS-2B cells in response to CSE. Conclusions Andrographolide possesses antioxidative properties against cigarette smoke-induced lung injury probably via augmentation of Nrf2 activity and may have therapeutic potential for treating COPD. PMID:23146110

  1. Pathological studies on carcinoma of the lung in rats induced by external x-ray irradiation

    International Nuclear Information System (INIS)

    Kodama, Tetsuro

    1978-01-01

    Lung tumors in Wistar rats were induced by administration of various doses of external irradiation through the anterior chest wall. Pulmonary fibrosis following external irradiation was observed in 13 of 17 rats (76.4%) in Group I (800R/day for 5 days), in 26 of 36 rats (78.8%) in Group II (800R/WK for 5 WKs), and in 6 of 18 rats (35.3%) in Group III (500R/WK for 4 WKs). The degree of pulmonary fibrosis was greater each time in the rats given 4,000R than in the rats given 2,000R. In Groups I and II 5 pulmonary tumors (2 squamous cell carcinomas, 1 adenocarcinoma, and 2 adenomas) were observed in 3 of 16 rats (17.6%), and 10 pulmonary tumors (4 squamous cell carcinomas, 1 adenocarcinoma, 4 adenomas, and 1 fibrosarcoma) were observed in 9 of 33 rats (24.2%), respectively. In Group III only 1 case of pulmonary adenoma was observed among 17 rats (6.8%). The first case of epithelial tumor of the lung was found in a rat in Group I. Histological findings during the course of the experiment revealed that the earliest changes following irradiation were those of radiation pneuminitis, characterized by engorged capillaries and edema in collapsed alveoli, with lymphocytic and plasma cell infiltrations. In addition, the nuclei of the lining cells of the alveoli and bronchioles were enlarged and atypical. From the 10th through the 20th experimental week, fibrosis of the alveolar septum and adenomatous hyperplasia of the alveolar lining became extensive, particularly in the bronchiolo-alveolar areas of the periphery of the lung. Atypical adenomatous hyperplasia occurred within the fibrotic lesion or in proximity to it. It was frequently followed by carcinoma, suggesting that carcinoma in the present experiment arose in atypical epithelium, induced by irradiation of the bronchiolo-alveolar epithelial lining

  2. Xylitol induces cell death in lung cancer A549 cells by autophagy.

    Science.gov (United States)

    Park, Eunjoo; Park, Mi Hee; Na, Hee Sam; Chung, Jin

    2015-05-01

    Xylitol is a widely used anti-caries agent that has anti-inflammatory effects. We have evaluated the potential of xylitol in cancer treatment. It's effects on cell proliferation and cytotoxicity were measured by MTT assay and LDH assay. Cell morphology and autophagy were examined by immunostaining and immunoblotting. Xylitol inhibited cell proliferation in a dose-dependent manner in these cancer cells: A549, Caki, NCI-H23, HCT-15, HL-60, K562, and SK MEL-2. The IC50 of xylitol in human gingival fibroblast cells was higher than in cancer cells, indicating that it is more specific for cancer cells. Moreover, xylitol induced autophagy in A549 cells that was inhibited by 3-methyladenine, an autophagy inhibitor. These results indicate that xylitol has potential in therapy against lung cancer by inhibiting cell proliferation and inducing autophagy of A549 cells.

  3. Acid-induced autophagy protects human lung cancer cells from apoptosis by activating ER stress.

    Science.gov (United States)

    Xie, Wen-Yue; Zhou, Xiang-Dong; Li, Qi; Chen, Ling-Xiu; Ran, Dan-Hua

    2015-12-10

    An acidic tumor microenvironment exists widely in solid tumors. However, the detailed mechanism of cell survival under acidic stress remains unclear. The aim of this study is to clarify whether acid-induced autophagy exists and to determine the function and mechanism of autophagy in lung cancer cells. We have found that acute low pH stimulated autophagy by increasing LC3-positive punctate vesicles, increasing LC3 II expression levels and reducing p62 protein levels. Additionally, autophagy was inhibited by the addition of Baf or knockdown of Beclin 1, and cell apoptosis was increased markedly. In mouse tumors, the expression of cleaved caspase3 and p62 was enhanced by oral treatment with sodium bicarbonate, which can raise the intratumoral pH. Furthermore, the protein levels of ER stress markers, including p-PERK, p-eIF2α, CHOP, XBP-1s and GRP78, were also increased in response to acidic pH. The antioxidant NAC, which reduces ROS accumulation, alleviated acid-mediated ER stress and autophagy, and knocking down GRP78 reduced autophagy activation under acidic conditions, which suggests that autophagy was induced by acidic pH through ER stress. Taken together, these results indicate that the acidic microenvironment in non-small cell lung cancer cells promotes autophagy by increasing ROS-ER stress, which serves as a survival adaption in this setting. Copyright © 2015 Elsevier Inc. All rights reserved.

  4. Seawater-drowning-induced acute lung injury: From molecular mechanisms to potential treatments.

    Science.gov (United States)

    Jin, Faguang; Li, Congcong

    2017-06-01

    Drowning is a crucial public safety problem and is the third leading cause of accidental fatality, claiming ~372,000 lives annually, worldwide. In near-drowning patients, acute lung injury (ALI) or acute respiratory distress syndrome (ARDS) is one of the most common complications. Approximately 1/3 of near-drowning patients fulfill the criteria for ALI or ARDS. In the present article, the current literature of near-drowning, pathophysiologic changes and the molecular mechanisms of seawater-drowning-induced ALI and ARDS was reviewed. Seawater is three times more hyperosmolar than plasma, and following inhalation of seawater the hyperosmotic seawater may cause serious injury in the lung and alveoli. The perturbing effects of seawater may be primarily categorized into insufficiency of pulmonary surfactant, blood-air barrier disruption, formation of pulmonary edema, inflammation, oxidative stress, autophagy, apoptosis and various other hypertonic stimulation. Potential treatments for seawater-induced ALI/ARDS were also presented, in addition to suggestions for further studies. A total of nine therapeutic strategies had been tested and all had focused on modulating the over-activated immunoreactions. In conclusion, seawater drowning is a complex injury process and the exact mechanisms and potential treatments require further exploration.

  5. Arctigenin represses TGF-β-induced epithelial mesenchymal transition in human lung cancer cells.

    Science.gov (United States)

    Xu, Yanrui; Lou, Zhiyuan; Lee, Seong-Ho

    2017-11-18

    Arctigenin (ARC) is a lignan that is abundant in Asteraceae plants, which show anti-inflammatory and anti-cancer activities. The current study investigated whether ARC affects cancer progression and metastasis, focusing on EMT using invasive human non-small cell lung cancer (NSCLC) cells. No toxicity was observed in the cells treated with different doses of ARC (12-100 μM). The treatment of ARC repressed TGF-β-stimulated changes of metastatic morphology and cell invasion and migration. ARC inhibited TGF-β-induced phosphorylation and transcriptional activity of smad2/3, and expression of snail. ARC also decreased expression of N-cadherin and increased expression of E-cadherin in dose-dependent and time-dependent manners. These changes were accompanied by decreased amount of phospho-smad2/3 in nucleus and nuclear translocation of smad2/3. Moreover, ARC repressed TGF-β-induced phosphorylation of ERK and transcriptional activity of β-catenin. Our data demonstrate anti-metastatic activity of ARC in lung cancer model. Copyright © 2017 Elsevier Inc. All rights reserved.

  6. COX-2 and PPAR-γ confer cannabidiol-induced apoptosis of human lung cancer cells.

    Science.gov (United States)

    Ramer, Robert; Heinemann, Katharina; Merkord, Jutta; Rohde, Helga; Salamon, Achim; Linnebacher, Michael; Hinz, Burkhard

    2013-01-01

    The antitumorigenic mechanism of cannabidiol is still controversial. This study investigates the role of COX-2 and PPAR-γ in cannabidiol's proapoptotic and tumor-regressive action. In lung cancer cell lines (A549, H460) and primary cells from a patient with lung cancer, cannabidiol elicited decreased viability associated with apoptosis. Apoptotic cell death by cannabidiol was suppressed by NS-398 (COX-2 inhibitor), GW9662 (PPAR-γ antagonist), and siRNA targeting COX-2 and PPAR-γ. Cannabidiol-induced apoptosis was paralleled by upregulation of COX-2 and PPAR-γ mRNA and protein expression with a maximum induction of COX-2 mRNA after 8 hours and continuous increases of PPAR-γ mRNA when compared with vehicle. In response to cannabidiol, tumor cell lines exhibited increased levels of COX-2-dependent prostaglandins (PG) among which PGD(2) and 15-deoxy-Δ(12,14)-PGJ(2) (15d-PGJ(2)) caused a translocation of PPAR-γ to the nucleus and induced a PPAR-γ-dependent apoptotic cell death. Moreover, in A549-xenografted nude mice, cannabidiol caused upregulation of COX-2 and PPAR-γ in tumor tissue and tumor regression that was reversible by GW9662. Together, our data show a novel proapoptotic mechanism of cannabidiol involving initial upregulation of COX-2 and PPAR-γ and a subsequent nuclear translocation of PPAR-γ by COX-2-dependent PGs.

  7. Chlorobenzene induces oxidative stress in human lung epithelial cells in vitro

    International Nuclear Information System (INIS)

    Feltens, Ralph; Moegel, Iljana; Roeder-Stolinski, Carmen; Simon, Jan-Christoph; Herberth, Gunda; Lehmann, Irina

    2010-01-01

    Chlorobenzene is a volatile organic compound (VOC) that is widely used as a solvent, degreasing agent and chemical intermediate in many industrial settings. Occupational studies have shown that acute and chronic exposure to chlorobenzene can cause irritation of the mucosa of the upper respiratory tract and eyes. Using in vitro assays, we have shown in a previous study that human bronchial epithelial cells release inflammatory mediators such as the cytokine monocyte chemoattractant protein-1 (MCP-1) in response to chlorobenzene. This response is mediated through the NF-κB signaling pathway. Here, we investigated the effects of monochlorobenzene on human lung cells, with emphasis on potential alterations of the redox equilibrium to clarify whether the chlorobenzene-induced inflammatory response in lung epithelial cells is caused via an oxidative stress-dependent mechanism. We found that expression of cellular markers for oxidative stress, such as heme oxygenase 1 (HO-1), glutathione S-transferase π1 (GSTP1), superoxide dismutase 1 (SOD1), prostaglandin-endoperoxide synthase 2 (PTGS2) and dual specificity phosphatase 1 (DUSP1), were elevated in the presence of monochlorobenzene. Likewise, intracellular reactive oxygen species (ROS) were increased in response to exposure. However, in the presence of the antioxidants N-(2-mercaptopropionyl)-glycine (MPG) or bucillamine, chlorobenzene-induced upregulation of marker proteins and release of the inflammatory mediator MCP-1 are suppressed. These results complement our previous findings and point to an oxidative stress-mediated inflammatory response following chlorobenzene exposure.

  8. A DISCUSSION ON DIFFERENT APPROACHES FOR ASSESSING LIFETIME RISKS OF RADON-INDUCED LUNG CANCER.

    Science.gov (United States)

    Chen, Jing; Murith, Christophe; Palacios, Martha; Wang, Chunhong; Liu, Senlin

    2017-11-01

    Lifetime risks of radon induced lung cancer were assessed based on epidemiological approaches for Canadian, Swiss and Chinese populations, using the most recent vital statistic data and radon distribution characteristics available for each country. In the risk calculation, the North America residential radon risk model was used for the Canadian population, the European residential radon risk model for the Swiss population, the Chinese residential radon risk model for the Chinese population, and the EPA/BEIR-VI radon risk model for all three populations. The results were compared with the risk calculated from the International Commission on Radiological Protection (ICRP)'s exposure-to-risk conversion coefficients. In view of the fact that the ICRP coefficients were recommended for radiation protection of all populations, it was concluded that, generally speaking, lifetime absolute risks calculated with ICRP-recommended coefficients agree reasonably well with the range of radon induced lung cancer risk predicted by risk models derived from epidemiological pooling analyses. © The Author 2017. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

  9. Bioactive Components from Qingwen Baidu Decoction against LPS-Induced Acute Lung Injury in Rats

    Directory of Open Access Journals (Sweden)

    Qi Zhang

    2017-04-01

    Full Text Available Qingwen Baidu Decoction (QBD is an extraordinarily “cold” formula. It was traditionally used to cure epidemic hemorrhagic fever, intestinal typhoid fever, influenza, sepsis and so on. The purpose of this study was to discover relationships between the change of the constituents in different extracts of QBD and the pharmacological effect in a rat model of acute lung injury (ALI induced by lipopolysaccharide (LPS. The study aimed to discover the changes in constituents of different QBD extracts and the pharmacological effects on acute lung injury (ALI induced by LPS. The results demonstrated that high dose and middle dose of QBD had significantly potent anti-inflammatory effects and reduced pulmonary edema caused by ALI in rats (p < 0.05. To explore the underlying constituents of QBD, we assessed its influence of six different QBD extracts on ALI and analyzed the different constituents in the corresponding HPLC chromatograms by a Principal Component Analysis (PCA method. The results showed that the pharmacological effect of QBD was related to the polarity of its extracts, and the medium polarity extracts E2 and E5 in particular displayed much better protective effects against ALI than other groups. Moreover, HPLC-DAD-ESI-MSn and PCA analysis showed that verbascoside and angoroside C played a key role in reducing pulmonary edema. In addition, the current study revealed that ethyl gallate, pentagalloylglucose, galloyl paeoniflorin, mudanpioside C and harpagoside can treat ALI mainly by reducing the total cells and infiltration of activated polymorphonuclear leukocytes (PMNs.

  10. Paraquat induced lung injury: long-term follow-up of HRCT

    International Nuclear Information System (INIS)

    Kim, Young Tong; Kim, Hyun Cheol; Bae, Won Kyung; Kim, Il Young; Im, Han Hyek

    2004-01-01

    To determine the long-term follow-up CT findings of paraquat-induced lung injury. Six patients who ingested paraquat underwent sequential follow-up CT scanning during a period of at least six months, and the results were analysed. Scans were obtained 1-6 (mean, 3.3) time during a 7-84 (mean, 25.7) months period, and the findings at 1-2 months, 3-12 months, 1-2 years, 2-3 years and more than above 7 years after poisoning were analyzed. We observed irregular-shaped areas of consolidation with traction bronchiectasis at 1-2 months (5/5), irregular-shaped consolidation and ground-glass opacity (5/5) at 3-12 months, and irregular-shaped consolidations/ground-glass opacity (4/5) and focal honeycombing (1/5) one year later. In the same patients, follow-up CT scans showed that some areas of focal consolidation could not be visualized and the radio-opacity of the lesions had decreased. The HRCT findings of paraquat-induced lung injury were irregular shaped areas of consolidation 1-2 months after ingestion, and irregular-shaped consolidation and ground-glass opacity or focal honeycombing 3-12 months later. At this thim slight improvement was observed

  11. Paraquat induced lung injury: long-term follow-up of HRCT

    Energy Technology Data Exchange (ETDEWEB)

    Kim, Young Tong; Kim, Hyun Cheol; Bae, Won Kyung; Kim, Il Young; Im, Han Hyek [Soonchunhyang Univ., Chunan (Korea, Republic of)

    2004-03-01

    To determine the long-term follow-up CT findings of paraquat-induced lung injury. Six patients who ingested paraquat underwent sequential follow-up CT scanning during a period of at least six months, and the results were analysed. Scans were obtained 1-6 (mean, 3.3) time during a 7-84 (mean, 25.7) months period, and the findings at 1-2 months, 3-12 months, 1-2 years, 2-3 years and more than above 7 years after poisoning were analyzed. We observed irregular-shaped areas of consolidation with traction bronchiectasis at 1-2 months (5/5), irregular-shaped consolidation and ground-glass opacity (5/5) at 3-12 months, and irregular-shaped consolidations/ground-glass opacity (4/5) and focal honeycombing (1/5) one year later. In the same patients, follow-up CT scans showed that some areas of focal consolidation could not be visualized and the radio-opacity of the lesions had decreased. The HRCT findings of paraquat-induced lung injury were irregular shaped areas of consolidation 1-2 months after ingestion, and irregular-shaped consolidation and ground-glass opacity or focal honeycombing 3-12 months later. At this thim slight improvement was observed.

  12. Seawater-drowning-induced acute lung injury: From molecular mechanisms to potential treatments

    Science.gov (United States)

    Jin, Faguang; Li, Congcong

    2017-01-01

    Drowning is a crucial public safety problem and is the third leading cause of accidental fatality, claiming ~372,000 lives annually, worldwide. In near-drowning patients, acute lung injury (ALI) or acute respiratory distress syndrome (ARDS) is one of the most common complications. Approximately 1/3 of near-drowning patients fulfill the criteria for ALI or ARDS. In the present article, the current literature of near-drowning, pathophysiologic changes and the molecular mechanisms of seawater-drowning-induced ALI and ARDS was reviewed. Seawater is three times more hyperosmolar than plasma, and following inhalation of seawater the hyperosmotic seawater may cause serious injury in the lung and alveoli. The perturbing effects of seawater may be primarily categorized into insufficiency of pulmonary surfactant, blood-air barrier disruption, formation of pulmonary edema, inflammation, oxidative stress, autophagy, apoptosis and various other hypertonic stimulation. Potential treatments for seawater-induced ALI/ARDS were also presented, in addition to suggestions for further studies. A total of nine therapeutic strategies had been tested and all had focused on modulating the over-activated immunoreactions. In conclusion, seawater drowning is a complex injury process and the exact mechanisms and potential treatments require further exploration. PMID:28587319

  13. Apoptosis signal-regulating kinase 1 mediates denbinobin-induced apoptosis in human lung adenocarcinoma cells

    Directory of Open Access Journals (Sweden)

    Pan Shiow-Lin

    2009-05-01

    Full Text Available Abstract In the present study, we explore the role of apoptosis signal-regulating kinase 1 (ASK1 in denbinobin-induced apoptosis in human lung adenocarcinoma (A549 cells. Denbinobin-induced cell apoptosis was attenuated by an ASK1 dominant-negative mutant (ASK1DN, two antioxidants (N-acetyl-L-cysteine (NAC and glutathione (GSH, a c-Jun N-terminal kinase (JNK inhibitor (SP600125, and an activator protein-1 (AP-1 inhibitor (curcumin. Treatment of A549 cells with denbinobin caused increases in ASK1 activity and reactive oxygen species (ROS production, and these effects were inhibited by NAC and GSH. Stimulation of A549 cells with denbinobin caused JNK activation; this effect was markedly inhibited by NAC, GSH, and ASK1DN. Denbinobin induced c-Jun phosphorylation, the formation of an AP-1-specific DNA-protein complex, and Bim expression. Bim knockdown using a bim short interfering RNA strategy also reduced denbinobin-induced A549 cell apoptosis. The denbinobin-mediated increases in c-Jun phosphorylation and Bim expression were inhibited by NAC, GSH, SP600125, ASK1DN, JNK1DN, and JNK2DN. These results suggest that denbinobin might activate ASK1 through ROS production to cause JNK/AP-1 activation, which in turn induces Bim expression, and ultimately results in A549 cell apoptosis.

  14. Suppression of RAGE and TLR9 by Ketamine Contributes to Attenuation of Lipopolysaccharide-Induced Acute Lung Injury.

    Science.gov (United States)

    Yang, Chunyan; Song, Yulong; Wang, Hui

    2017-06-01

    The present study aimed to investigate the protective role of ketamine in lipopolysaccharide (LPS)-induced acute lung injury (ALI) by the inhibition of the receptor for advanced glycation end products (RAGE) and toll-like receptor 9 (TLR9). ALI was induced in rats by intratracheal instillation of LPS (5 mg/kg), and ketamine (5, 7.5, and 10 mg/kg) was injected intraperitoneally 1 h after LPS administration. Meanwhile, A549 alveolar epithelial cells were incubated with LPS in the presence or absence of ketamine. After 24 h, bronchoalveolar lavage fluid (BALF) and lung tissue were collected. Ketamine posttreatment at doses of 5, 7.5, and 10 mg/kg decreased LPS-induced evident lung histopathological changes, lung wet-to-dry weight ratio, and lung myeloperoxidase activity. In addition, posttreatment with ketamine-inhibited inflammatory cells and inflammatory mediators including tumor necrosis factor-α, interleukin-6, and high-mobility group box 1 in BALF. Furthermore, we demonstrated that ketamine-inhibited LPS-induced RAGE and TLR9 protein up-expressions and the phosphorylation of I-κB-α and nuclear factor-κB (NF-κB) p65 in vivo and in vitro. The results presented here suggest that the protective mechanism of ketamine may be attributed partly to decreased production of inflammatory mediators through the inhibition of RAGE/TLR9-NF-κB pathway.

  15. Heme Oxygenase-1/CO as protective mediators in cigarette smoke- induced lung cell injury and chronic obstructive pulmonary disease.

    Science.gov (United States)

    Dolinay, Tamás; Choi, Augustine M K; Ryter, Stefan W

    2012-05-01

    Chronic obstructive pulmonary disease (COPD) is a disease involving airways restriction, alveolar destruction, and loss of lung function, primarily due to cigarette smoke (CS) exposure. The inducible stress protein heme oxygenase-1 (HO-1) has been implicated in cytoprotection against the toxic action of many xenobiotics, including CS. HO-1 also protects against elastase-induced emphysema. Differential expression of HO-1 in epithelial cells and macrophages may contribute to COPD susceptibility. Genetic polymorphisms in the HO-1 gene, which may account for variations in HO-1 expression among subpopulations, may be associated with COPD pathogenesis. Carbon monoxide (CO), a primary reaction product of HO-1 has been implicated in cytoprotection in many acute lung injury models, though it's precise role in chronic CS-induced lung injury remains unclear. CO is a potential biomarker of CS exposure and of inflammatory lung conditions. To date, a single clinical trial has addressed the possible therapeutic potential of CO in COPD patients. The implications of the cytoprotective potential of HO-1/CO system in CS-induced lung injury and COPD are discussed.

  16. Different imaging methods in the assessment of radiation-induced lung injury following hemithorax irradiation for pleural mesothelioma

    International Nuclear Information System (INIS)

    Maasilta, P.; Kivisaari, L.; Mattson, K.

    1990-01-01

    The authors have characterized the radiation-induced lung-injury on serial chest X-rays, CTs and ultralow field MRs and evaluated the clinical value and cost/benefit ratio of the different imaging methods in 30 patients receiving high-dose hemithorax irradiation for pleural mesothelioma. Lung injury was severe in all patients, but non-specific and essentially as described in text-books. CT provided no clinically relevant, cost effective diagnostic advantage over conventional X-rays in the detection of early or late radiation-induced lung injury, but it was necessary for the evaluation of the disease status of the mesothelioma. The possible advantage of MR over CT could not be evaluated and needs further studies. Optimal time-points for imaging CTs or MRs to detect early radiation-induced lung injury following high dose hemithorax irradiation were during the latter part of the treatment or very shortly after the end of the irradiation. Late injury or irreversible fibrosis develop rapidly after 6 months and was clearly documented by chest X-rays. The authors recommend serial chest X-rays at 1-2, 6 and 12 months following radiotherapy as a cost-effective method for the detection of radiation-induced lung injury with additional CTs to document the stage of mesothelioma, when needed. (author). 31 refs.; 4 figs

  17. Identification of crucial microRNAs and genes in hypoxia-induced human lung adenocarcinoma cells

    Directory of Open Access Journals (Sweden)

    Geng Y

    2016-07-01

    Full Text Available Ying Geng,1,* Lili Deng,2,* Dongju Su,1 Jinling Xiao,1 Dongjie Ge,3 Yongxia Bao,1 Hui Jing4 1Department of Respiratory, 2Department of Oncology, The Second Affiliated Hospital of Harbin Medical University, 3Department of Respiratory, The First Hospital of Harbin, 4Department of Emergency, The Second Affiliated Hospital of Harbin Medical University Harbin, Heilongjiang, People’s Republic of China *These authors contributed equally to this work Background: Variations of microRNA (miRNA expression profile in hypoxic lung cancer cells have not been studied so far. Therefore, using miRNA microarray technology, this study aimed to study the miRNA expression profile and investigate the potential crucial miRNAs and their target genes in hypoxia-induced human lung adenocarcinoma cells.Materials and methods: Based on miRNA microarray, miRNA expression profiling of hypoxia-induced lung adenocarcinoma A549 cells was obtained. After identification of differentially expressed miRNAs (DE-miRNAs in hypoxic cells, target genes of DE-miRNAs were predicted, and functional enrichment analysis of targets was conducted. Furthermore, the expression levels of DE-miRNAs and their target genes were validated by real-time quantitative polymerase chain reaction. In addition, using miRNA mimics, the effect of overexpressed DE-miRNAs on A549 cell behaviors (cell proliferation, cell cycle, and apoptosis was evaluated.Results: In total, 14 DE-miRNAs (nine upregulated miRNAs and five downregulated miRNAs were identified in hypoxic cells, compared with normoxic cells. Target genes of both upregulated and downregulated miRNAs were enriched in the functions such as chromatin modification, and pathways such as Wnt signaling pathway and transforming growth factor (TGF-β signaling pathway. The expression levels of several miRNAs and their target genes were confirmed, including hsa-miR-301b/FOXF2, hsa-miR-148b-3p/WNT10B, hsa-miR-769-5p/(SMAD2, ARID1A, and hsa-miR-622. Among them

  18. Choriodecidual group B streptococcal inoculation induces fetal lung injury without intra-amniotic infection and preterm labor in Macaca nemestrina.

    Directory of Open Access Journals (Sweden)

    Kristina M Adams Waldorf

    Full Text Available BACKGROUND: Early events leading to intrauterine infection and fetal lung injury remain poorly defined, but may hold the key to preventing neonatal and adult chronic lung disease. Our objective was to establish a nonhuman primate model of an early stage of chorioamnionitis in order to determine the time course and mechanisms of fetal lung injury in utero. METHODOLOGY/PRINCIPAL FINDINGS: Ten chronically catheterized pregnant monkeys (Macaca nemestrina at 118-125 days gestation (term=172 days received one of two treatments: 1 choriodecidual and intra-amniotic saline (n=5, or 2 choriodecidual inoculation of Group B Streptococcus (GBS 1×10(6 colony forming units (n=5. Cesarean section was performed regardless of labor 4 days after GBS or 7 days after saline infusion to collect fetal and placental tissues. Only two GBS animals developed early labor with no cervical change in the remaining animals. Despite uterine quiescence in most cases, blinded review found histopathological evidence of fetal lung injury in four GBS animals characterized by intra-alveolar neutrophils and interstitial thickening, which was absent in controls. Significant elevations of cytokines in amniotic fluid (TNF-α, IL-8, IL-1β, IL-6 and fetal plasma (IL-8 were detected in GBS animals and correlated with lung injury (p<0.05. Lung injury was not directly caused by GBS, because GBS was undetectable in amniotic fluid (~10 samples tested/animal, maternal and fetal blood by culture and polymerase chain reaction. In only two cases was GBS cultured from the inoculation site in low numbers. Chorioamnionitis occurred in two GBS animals with lung injury, but two others with lung injury had normal placental histology. CONCLUSIONS/SIGNIFICANCE: A transient choriodecidual infection can induce cytokine production, which is associated with fetal lung injury without overt infection of amniotic fluid, chorioamnionitis or preterm labor. Fetal lung injury may, thus, occur silently without

  19. Can mesenchymal stem cells reverse chronic stress-induced impairment of lung healing following traumatic injury?

    Science.gov (United States)

    Gore, Amy V; Bible, Letit