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Sample records for acute lung damage

  1. Cerium Oxide Nanoparticles in Lung Acutely Induce Oxidative Stress, Inflammation, and DNA Damage in Various Organs of Mice

    Abderrahim Nemmar

    2017-01-01

    Full Text Available CeO2 nanoparticles (CeO2 NPs which are used as a diesel fuel additive are emitted in the particulate phase in the exhaust, posing a health concern. However, limited information exists regarding the in vivo acute toxicity of CeO2 NPs on multiple organs. Presently, we investigated the acute (24 h effects of intratracheally instilled CeO2 NPs in mice (0.5 mg/kg on oxidative stress, inflammation, and DNA damage in major organs including lung, heart, liver, kidneys, spleen, and brain. Lipid peroxidation measured by malondialdehyde production was increased in the lungs only, and reactive oxygen species were increased in the lung, heart, kidney, and brain. Superoxide dismutase activity was decreased in the lung, liver, and kidney, whereas glutathione increased in lung but it decreased in the kidney. Total nitric oxide was increased in the lung and spleen but it decreased in the heart. Tumour necrosis factor-α increased in all organs studied. Interleukin- (IL- 6 increased in the lung, heart, liver, kidney, and spleen. IL-1β augmented in the lung, heart, kidney, and spleen. Moreover, CeO2 NPs induced DNA damage, assessed by COMET assay, in all organs studied. Collectively, these findings indicate that pulmonary exposure to CeO2 NPs causes oxidative stress, inflammation, and DNA damage in multiple organs.

  2. Human mesenchymal stem cells attenuate early damage in a ventilated pig model of acute lung injury

    Yuben Moodley

    2016-07-01

    Full Text Available Acute lung injury/acute respiratory distress syndrome (ALI/ARDS is a major cause of global morbidity and mortality. Mesenchymal stem cells (MSC have shown promise in treating inflammatory lung conditions. We hypothesised that human MSC (hMSC can improve ALI/ARDS through their anti-inflammatory actions. We subjected pigs (n = 6 to intravenous oleic acid (OA injury, ventilation and hMSC infusion, while the controls (n = 5 had intravenous OA, ventilation and an infusion vehicle control. hMSC were infused 1 h after the administration of OA. The animals were monitored for additional 4 h. Nuclear translocation of nuclear factor-light chain enhancer of activated B cells (NF-κB, a transcription factor that mediates several inflammatory pathways was reduced in hMSC treated pigs compared to controls (p = 0.04. There was no significant difference in lung injury, assessed by histological scoring in hMSC treated pigs versus controls (p = 0.063. There was no difference in neutrophil counts between hMSC-treated pigs and controls. Within 4 h, there was no difference in the levels of IL-10 and IL-8 pre- and post-treatment with hMSC. In addition, there was no difference in hemodynamics, lung mechanics or arterial blood gases between hMSC treated animals and controls. Subsequent studies are required to determine if the observed decrease in inflammatory transcription factors will translate into improvement in inflammation and in physiological parameters over the long term.

  3. Loss of extracellular superoxide dismutase leads to acute lung damage in the presence of ambient air: a potential mechanism underlying adult respiratory distress syndrome.

    Gongora, Maria Carolina; Lob, Heinrich E; Landmesser, Ulf; Guzik, Tomasz J; Martin, W David; Ozumi, Kiyoski; Wall, Susan M; Wilson, David Scott; Murthy, Niren; Gravanis, Michael; Fukai, Tohru; Harrison, David G

    2008-10-01

    The extracellular superoxide dismutase 3 (SOD3) is highly expressed in both blood vessels and lungs. In different models of pulmonary injury, SOD3 is reduced; however, it is unclear whether this contributes to lung injury. To study the role of acute SOD3 reduction in lung injury, the SOD3 gene was deleted in adult mice by using the Cre-Lox technology. Acute reduction of SOD3 led to a fivefold increase in lung superoxide, marked inflammatory cell infiltration, a threefold increase in the arterial-alveolar gradient, respiratory acidosis, histological changes similar to those observed in adult respiratory distress syndrome, and 85% mortality. Treatment with the SOD mimetic MnTBAP and intranasal administration of SOD-containing polyketal microparticles reduced mortality, prevented the histological alterations, and reduced lung superoxide levels. To understand how mice with the SOD3 embryonic deletion survived without lung injury, gene array analysis was performed. These data demonstrated the up-regulation of 37 genes and down-regulation of nine genes, including those involved in cell signaling, inflammation, and gene transcription in SOD3-/- mice compared with either mice with acute SOD3 reduction or wild-type controls. These studies show that SOD3 is essential for survival in the presence of ambient oxygen and that acute loss of this enzyme can lead to severe lung damage. Strategies either to prevent SOD3 inactivation or to augment its levels might prove useful in the treatment of acute lung injury.

  4. Spores of Aspergillus versicolor isolated from indoor air of a moisture-damaged building provoke acute inflammation in mouse lungs.

    Jussila, Juha; Komulainen, Hannu; Kosma, Veli-Matti; Nevalainen, Aino; Pelkonen, Jukka; Hirvonen, Maija-Riitta

    2002-12-01

    Microbial growth in moisture-damaged buildings has been associated with respiratory health effects, and the spores of the mycotoxin producing fungus Aspergillus versicolor are frequently present in the indoor air. To characterize the potential of these spores to cause harmful respiratory effects, mice were exposed via intratracheal instillation to a single dose of the spores of A. versicolor (1 x 10(5), 1 x 10(6), 5 x 10(6), 1 x 10(7), or 1 x 10(8) spores), isolated from the indoor air of a moisture-damaged building. Inflammation and toxicity in lungs were evaluated 24 h later by assessment of biochemical markers and histopathology. The time course of the effects was investigated with the dose of 5 x 10(6) spores for up to 28 days. The exposure to the spores increased transiently proinflammatory cytokine levels (tumor necrosis factor [TNF] alpha and interleukin [IL]-6) in bronchoalveolar lavage fluid (BALF). The cytokine responses were dose and time dependent. The highest cytokine concentrations were measured at 6 h after the dose, and they returned to the control level by 3 days. Moreover, the spores of A. versicolor recruited inflammatory cells into airways: Neutrophils peaked transiently at 24 h, macrophages at 3 days, and lymphocytes at 7 days after the dosing. The inflammatory cell response did not completely disappear during the subsequent 28 days, though no histopathological changes were seen at that time point. The spores did not induce expression of inducible nitric oxide synthase in lavaged cells. Only the highest spore dose (1 x 10(8)) markedly increased serum IL-6, increased vascular leakage, and caused cytotoxicity (i.e., increased levels of albumin, total protein, lactate dehydrogenase [LDH], and hemoglobin in BALF) in the airways. In summary, the spores of A. versicolor caused acute inflammation in mouse lungs. This indicates that they have potential to provoke adverse health effects in the occupants of moisture-damaged buildings.

  5. "Cromoglycate: A healing agent in acute Chlorine-induced lung damage "

    "Pipelzadeh MH

    2002-09-01

    Full Text Available In the present study the effectiveness of sodium cromoglycate in treatment of alveolar damage induced by chlorine gas in rats was investigated. Chlorine was generated by chemical interaction between potassium permanganate and concentrated hydrochloric acid. The rats were exposed to sublethal dose of chlorine gas. Treatment with 2.5 mg of 1 ml nebulized sodium cromoglycate solution over 5 minutes was initiated 30 minutes after exposure followed by twice daily treatment for 21 days. Results of this study show that cromoglycate reduced alveolar thickness, septal rupture, hemorrhage and detachment of the epithelial lining of the bronchioles induced by chlorine gas.

  6. Biomarkers in acute lung injury.

    Mokra, Daniela; Kosutova, Petra

    2015-04-01

    Acute respiratory distress syndrome (ARDS) and its milder form acute lung injury (ALI) may result from various diseases and situations including sepsis, pneumonia, trauma, acute pancreatitis, aspiration of gastric contents, near-drowning etc. ALI/ARDS is characterized by diffuse alveolar injury, lung edema formation, neutrophil-derived inflammation, and surfactant dysfunction. Clinically, ALI/ARDS is manifested by decreased lung compliance, severe hypoxemia, and bilateral pulmonary infiltrates. Severity and further characteristics of ALI/ARDS may be detected by biomarkers in the plasma and bronchoalveolar lavage fluid (or tracheal aspirate) of patients. Changed concentrations of individual markers may suggest injury or activation of the specific types of lung cells-epithelial or endothelial cells, neutrophils, macrophages, etc.), and thereby help in diagnostics and in evaluation of the patient's clinical status and the treatment efficacy. This chapter reviews various biomarkers of acute lung injury and evaluates their usefulness in diagnostics and prognostication of ALI/ARDS.

  7. Acute exacerbations of fibrotic interstitial lung disease.

    Churg, Andrew; Wright, Joanne L; Tazelaar, Henry D

    2011-03-01

    An acute exacerbation is the development of acute lung injury, usually resulting in acute respiratory distress syndrome, in a patient with a pre-existing fibrosing interstitial pneumonia. By definition, acute exacerbations are not caused by infection, heart failure, aspiration or drug reaction. Most patients with acute exacerbations have underlying usual interstitial pneumonia, either idiopathic or in association with a connective tissue disease, but the same process has been reported in patients with fibrotic non-specific interstitial pneumonia, fibrotic hypersensitivity pneumonitis, desquamative interstitial pneumonia and asbestosis. Occasionally an acute exacerbation is the initial manifestation of underlying interstitial lung disease. On biopsy, acute exacerbations appear as diffuse alveolar damage or bronchiolitis obliterans organizing pneumonia (BOOP) superimposed upon the fibrosing interstitial pneumonia. Biopsies may be extremely confusing, because the acute injury pattern can completely obscure the underlying disease; a useful clue is that diffuse alveolar damage and organizing pneumonia should not be associated with old dense fibrosis and peripheral honeycomb change. Consultation with radiology can also be extremely helpful, because the fibrosing disease may be evident on old or concurrent computed tomography scans. The aetiology of acute exacerbations is unknown, and the prognosis is poor; however, some patients survive with high-dose steroid therapy.

  8. Lung Oxidative Damage by Hypoxia

    O. F. Araneda

    2012-01-01

    Full Text Available One of the most important functions of lungs is to maintain an adequate oxygenation in the organism. This organ can be affected by hypoxia facing both physiological and pathological situations. Exposure to this condition favors the increase of reactive oxygen species from mitochondria, as from NADPH oxidase, xanthine oxidase/reductase, and nitric oxide synthase enzymes, as well as establishing an inflammatory process. In lungs, hypoxia also modifies the levels of antioxidant substances causing pulmonary oxidative damage. Imbalance of redox state in lungs induced by hypoxia has been suggested as a participant in the changes observed in lung function in the hypoxic context, such as hypoxic vasoconstriction and pulmonary edema, in addition to vascular remodeling and chronic pulmonary hypertension. In this work, experimental evidence that shows the implied mechanisms in pulmonary redox state by hypoxia is reviewed. Herein, studies of cultures of different lung cells and complete isolated lung and tests conducted in vivo in the different forms of hypoxia, conducted in both animal models and humans, are described.

  9. A novel Respiratory Health Score (RHS supports a role of acute lung damage and pig breed in the course of an Actinobacillus pleuropneumoniae infection

    Gerlach Gerald F

    2009-04-01

    Full Text Available Abstract Background Bacterial lung infections are a major cause of economic losses in the pig industry; they are responsible for approximately 50% of the antibiotics used in pigs and, therefore, also present an increasing concern to consumer protection agencies. In response to this changing market we investigated the feasibility of an old approach aimed at the breeding selection of more resistant pigs. As a first step in this direction we applied a new respiratory health score system to study the susceptibility of four different pig breeding lines (German Landrace, Piétrain, Hampshire, Large White towards the respiratory tract pathogen Actinobacillus (A. pleuropneumoniae. Results A controlled experimental aerosol infection with an A. pleuropneumoniae serotype 7 isolate was performed using 106 weaning pigs of defined breeding lines from the breeds German Landrace, Piétrain, Hamphire, and Large White. Pigs were clinically assessed on days 4 and 20 post infection following a novel scoring system, the Respiratory Health Score (RHS, which combines clinical, sonographic and radiographic examination results. The ranking on day 4 was significantly correlated with the ranking based on the pathomorphological Lung Lesion Score (LLS; Spearman Rank Correlation Coefficient of 0.86 [p Conclusion These results demonstrate that the RHS obtained from live pigs shows a highly significant correlation to the lung lesion score considered as a "gold standard". The correlation of the ranking at days 4 and 20 post infection implies that the course of disease is highly dependent on the acute lung damage. The different severity of signs among the tested pig breeding lines clearly suggests a genetic difference in the susceptibility of pigs to A. pleuropneumoniae infection.

  10. Acute lung injury and ARDS in acute pancreatitis: Mechanisms and potential intervention

    Roland; Andersson

    2010-01-01

    Acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) in acute pancreatitis still represents a substantial problem,with a mortality rate in the range of 30%-40%.The present review evaluates underlying pathophysiological mechanisms in both ALI and ARDS and potential clinical implications.Several mediators and pathophysiological pathways are involved during the different phases of ALI and ARDS.The initial exudative phase is characterized by diffuse alveolar damage,microvascular injury and inf...

  11. Pathogenesis of acute lung injury in severe acute pancreatitis

    SHI Lei; YUE Yuan; ZHANG Mei; PAN Cheng-en

    2005-01-01

    Objective:To study the pathogenesis of acute lung injury in severe acute pancreatitis (SAP). Methods:Rats were sacrificed at 1, 3, 5, 6, 9 and 12 h after establishment of inducing model. Pancreas and lung tissues were obtained for pathological study, microvascular permeability and MPO examination. Gene expressions of TNF-α and ICAM-1 in pancreas and lung tissues were detected by RT-PCR. Results:After inducing SAP model, the injury degree of the pancreas and the lung increased gradually, accompanied with gradually increased MPO activity and microvascular permeability. Gene expressions of TNF-α and ICAM-1 in pancreas rose at 1 h and reached peak at 7 h. Relatively, their gene expressions in the lungs only rose slightly at 1 h and reached peak at 9-12 h gradually. Conclusion:There is an obvious time window between SAP and lung injury, when earlier protection is beneficial to prevent development of acute lung injury.

  12. ICAM-1 and Acute Pancreatitis Complicated by Acute Lung Injury

    XiPing Zhang

    2009-01-01

    Full Text Available One of the most common complications of acute pancreatitis is acute lung injury, during which intercellular adhesion molecule-1 (ICAM-1 plays an important role by participating in leukocyte adhesion and activation as well as by inducing the “cascade effect” of inflammatory mediators, pulmonary microcirculation dysfunction and even acute respiratory distress syndrome, multiple organ failure or death. Although it is generally believed that the modulatory mechanism of ICAM-1 during this process is associated with the activation of nuclear transcription factor kappa B which is mediated by IL-1, IL-6, IL-18 and oxygen free radical, etc., further studies are still required to clarify it. Since the upregulation of ICAM-1 expression in the lung during acute lung injury is one of main pathogeneses, the early detection of the ICAM-1 expression level may contribute to the prevention and treatment of acute lung injury. Moreover, reducing pulmonary ICAM-1 expression levels through treatment with anti-ICAM-1 monoclonal antibody (aICAM-1 and antagonists of the neurokinin 1 receptor, etc., should have a positive effect on protecting the lungs during acute pancreatitis. This review aims to further clarify the relationship between ICAM-1 and acute pancreatitis complicated by acute lung injury, and therefore provides a theoretical basis for the formulation of corresponding therapeutic measures in clinical practice for acute pancreatitis.

  13. Acute interstitial pneumonia (AIP): relationship to Hamman-Rich syndrome, diffuse alveolar damage (DAD), and acute respiratory distress syndrome (ARDS).

    Mukhopadhyay, Sanjay; Parambil, Joseph G

    2012-10-01

    Acute interstitial pneumonia (AIP) is a term used for an idiopathic form of acute lung injury characterized clinically by acute respiratory failure with bilateral lung infiltrates and histologically by diffuse alveolar damage (DAD), a combination of findings previously known as the Hamman-Rich syndrome. This review aims to clarify the diagnostic criteria of AIP, its relationship with DAD and acute respiratory distress syndrome (ARDS), key etiologies that need to be excluded before making the diagnosis, and the salient clinical features. Cases that meet clinical and pathologic criteria for AIP overlap substantially with those that fulfill clinical criteria for ARDS. The main differences between AIP and ARDS are that AIP requires a histologic diagnosis of DAD and exclusion of known etiologies. AIP should also be distinguished from "acute exacerbation of IPF," a condition in which acute lung injury (usually DAD) supervenes on underlying usual interstitial pneumonia (UIP)/idiopathic pulmonary fibrosis (IPF).

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

    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.

  15. Surfactant for pediatric acute lung injury.

    Willson, Douglas F; Chess, Patricia R; Notter, Robert H

    2008-06-01

    This article reviews exogenous surfactant therapy and its use in mitigating acute lung injury (ALI) and the acute respiratory distress syndrome (ARDS) in infants, children, and adults. Biophysical and animal research documenting surfactant dysfunction in ALI/ARDS is described, and the scientific rationale for treatment with exogenous surfactant is discussed. Major emphasis is placed on reviewing clinical studies of surfactant therapy in pediatric and adult patients who have ALI/ARDS. Particular advantages from surfactant therapy in direct pulmonary forms of these syndromes are described. Also discussed are additional factors affecting the efficacy of exogenous surfactants in ALI/ARDS.

  16. Human models of acute lung injury

    Alastair G. Proudfoot

    2011-03-01

    Full Text Available Acute lung injury (ALI is a syndrome that is characterised by acute inflammation and tissue injury that affects normal gas exchange in the lungs. Hallmarks of ALI include dysfunction of the alveolar-capillary membrane resulting in increased vascular permeability, an influx of inflammatory cells into the lung and a local pro-coagulant state. Patients with ALI present with severe hypoxaemia and radiological evidence of bilateral pulmonary oedema. The syndrome has a mortality rate of approximately 35% and usually requires invasive mechanical ventilation. ALI can follow direct pulmonary insults, such as pneumonia, or occur indirectly as a result of blood-borne insults, commonly severe bacterial sepsis. Although animal models of ALI have been developed, none of them fully recapitulate the human disease. The differences between the human syndrome and the phenotype observed in animal models might, in part, explain why interventions that are successful in models have failed to translate into novel therapies. Improved animal models and the development of human in vivo and ex vivo models are therefore required. In this article, we consider the clinical features of ALI, discuss the limitations of current animal models and highlight how emerging human models of ALI might help to answer outstanding questions about this syndrome.

  17. Bleomycin and radiation-induced lung damage in mice

    Collis, C.H.; Down, J.D.; Pearson, A.E.; Steel, G.G. (Institute of Cancer Research, Sutton (UK). Surrey Branch)

    1983-01-01

    Bleomycin-induced lung damage was assessed using both a functional end-point and mortality. The extent of lung damage was found to depend on the schedule, mode of administration and dose of the drug. Greater damage occurred following twice-weekly administration than when the same dose was given as a single injection. Intravenous administration resulted in greater damage than intraperitoneal administration. When bleomycin was given with thoracic irradiation lung damage occurred earlier and at lower radiation doses than with radiation alone. Similar responses were obtained whether bleomycin was given four weeks before, with or four weeks after irradiation. Thus although there was enhanced damage from the combined treatment, there was no evidence of a time-dependent interaction.

  18. Desferrioxamine attenuates minor lung injury following surgical acute liver failure.

    Kostopanagiotou, G G; Kalimeris, K A; Arkadopoulos, N P; Pafiti, A; Panagopoulos, D; Smyrniotis, V; Vlahakos, D; Routsi, C; Lekka, M E; Nakos, G

    2009-06-01

    Acute liver failure (ALF) can be complicated by lung dysfunction. The aim of this study was to test the hypothesis that inhibition of oxidative stress through iron chelation with desferrioxamine (DFX) attenuates pulmonary injury caused by ALF. 14 adult female domestic pigs were subjected to surgical devascularisation of the liver and were randomised to a study group (DFX group, n = 7), which received post-operative intravenous infusion of DFX (14.5 mg x kg(-1) x h(-1) for the first 6 h post-operatively and 2.4 mg x kg(-1) x h(-1) until completion of 24 h), and a control group (n = 7). Post-operative lung damage was evaluated by histological and bronchoalveolar lavage fluid (BALF) analysis. DFX resulted in reduced BALF protein levels and tissue phospholipase (PL)A(2) activity. Plasma malondialdehyde and BALF nitrate and nitrite concentrations were lower, while catalase activity in the lung was higher after DFX treatment. PLA(2), platelet-activating factor acetylhydrolase and total cell counts in BALF did not differ between groups. Histological examination revealed reduced alveolar collapse, pneumonocyte necrosis and total lung injury in the DFX-treated animals. DFX reduced systemic and pulmonary oxidative stress during ALF. The limited activity of PLA(2) and the attenuation of pneumonocyte necrosis could represent beneficial mechanisms by which DFX improves alveolar-capillary membrane permeability and prevents alveolar space collapse.

  19. [Acute damage to the myocardium and left lung is a complication of high-frequency percutaneous thermoablation of solitary metastasis of renal cancer into the liver (a clinical observation)].

    Tipisev, D A; Gorobets, E S; Agapov, A A; Zotov, A V; Kosyrev, V Iu

    2005-01-01

    The paper describes a case of severe complication of radio-frequency percutaneous thermoablation of renal metastasis into the liver, which occurred in a young woman with the intact cardiovascular system and manifested itself in the development of alveolar edema of the lung and acute dilation of the stomach. Pulmonary edema resulted from left ventricular myocardial and pulmonary parenchymal lesions and acute mitral valvular insufficiency. The authors' considerations as to the possible cause and mechanisms of development of this life-threatening complication first described in the literature are also given.

  20. QUANTIFYING LOCAL RADIATION-INDUCED LUNG DAMAGE FROM COMPUTED TOMOGRAPHY

    Ghobadi, Ghazaleh; Hogeweg, Laurens E.; Faber, Hette; Tukker, Wim G. J.; Schippers, Jacobus M.; Brandenburg, Sytze; Langendijk, Johannes A.; Coppes, Robert P.; van Luijk, Peter

    2010-01-01

    Purpose: Optimal implementation of new radiotherapy techniques requires accurate predictive models for normal tissue complications. Since clinically used dose distributions are nonuniform, local tissue damage needs to be measured and related to local tissue dose. In lung, radiation-induced damage re

  1. A review of pulmonary coagulopathy in acute lung injury, acute respiratory distress syndrome and pneumonia

    Nieuwenhuizen, Laurens; de Groot, Philip G.; Grutters, Jan C.; Biesma, Douwe H.

    2009-01-01

    Enhanced bronchoalveolar coagulation is a hallmark of many acute inflammatory lung diseases such as acute lung injury, acute respiratory distress syndrome and pneumonia. Intervention with natural anticoagulants in these diseases has therefore become a topic of interest. Recently, new data on the rol

  2. Kinetic model for the pathogenesis of radiation lung damage

    Collis, C.H. (Institute of Cancer Research, Sutton (UK). Surrey Branch)

    1982-09-01

    The development of radiation-induced lung damage can be explained by a kinetic model, based on the assumption that this damage becomes manifest only when a critical proportion (K) of essential cells have ceased to function, and that the rate of loss of these cells following irradiation is linear and dose-dependent. The kinetic model relates the surviving fraction to the time to manifestation of radiation-induced lung damage and to constants, K and the cell cycle time, T. Predictions made from the model about the nature of the response to irradiation are, for the most part, fulfilled. The model can also be used to interpret the response to combined treatment with irradiation and cytotoxic drugs, including the much earlier manifestation of lung damage sometimes seen with such treatment.

  3. The mean lung dose (MLD). Predictive criterion for lung damage

    Geyer, Peter; Appold, Steffen [Dresden University of Technology (TU Dresden), Clinic and Polyclinic for Radiotherapy and Radiation Oncology, Carl Gustav Carus Medical Faculty, Dresden (Germany); Herrmann, Thomas

    2015-07-15

    The purpose of this work was to prove the validity of the mean lung dose (MLD), widely used in clinical practice to estimate the lung toxicity of a treatment plan, by reevaluating experimental data from mini pigs. A total of 43 mini pigs were irradiated in one of four dose groups (25, 29, 33, and 37 Gy). Two regimens were applied: homogeneous irradiation of the right lung or partial irradiation of both lungs - including parts with lower dose - but with similar mean lung doses. The animals were treated with five fractions with a linear accelerator applying a CT-based treatment plan. The clinical lung reaction (breathing frequency) and morphological changes in CT scans were examined frequently during the 48 weeks after irradiation. A clear dose-effect relationship was found for both regimens of the trial. However, a straightforward relationship between the MLD and the relative number of responders with respect to different grades of increased breathing frequency for both regimens was not found. A morphologically based parameter NTCP{sub lung} was found to be more suitable for this purpose. The dependence of this parameter on the MLD is markedly different for the two regimens. In clinical practice, the MLD can be used to predict lung toxicity of a treatment plan, except for dose values that could lead to severe side effects. In the latter mentioned case, limitations to the predictive value of the MLD are possible. Such severe developments of a radiation-induced pneumopathy are better predicted by the NTCP{sub lung} formalism. The predictive advantage of this parameter compared to the MLD seems to remain in the evaluation and comparison of widely differing dose distributions, like in the investigated trial. (orig.) [German] Es soll unter Reevaluation von Tierversuchsdaten am Minischwein geprueft werden, ob die in der klinischen Praxis zur Beurteilung der Lungentoxizitaet eines Bestrahlungsregims regelhaft verwendete mittlere Lungendosis (MLD) eine zuverlaessige

  4. Transfusion-related acute lung injury:A case report

    Emmanouil Petrou; Vasiliki Karali; Vasiliki Vartela

    2015-01-01

    Transfusion-related acute lung injury is the most common cause of serious morbidity and mortality associated with the transfusion of plasma-containing blood components. The syndrome can be confused with other causes of acute respiratory failure. Herein, we describe a 71-year-old man who was transfused with fresh frozen plasma due to prolonged INR, and died of what was considered as transfusion-related acute lung injury, despite treatment.

  5. High mobility group box 1 protein as a late-acting mediator of acute lung inflammation.

    Lutz, Waldemar; Stetkiewicz, Jan

    2004-01-01

    Acute inflammatory lung injury is often a delayed complication of critical illness and is associated with increased mortality. High mobility group box 1 (HMGB1) protein, in addition to its role as a transcriptional regulator factor, has been identified as a late mediator of endotoxin lethality and might be also involved in the development and progression of acute lung injury. HMGB1 protein itself can cause an acute inflammatory response manifested by increased production of proinflammatory cytokines and neutrophil accumulation. The delayed kinetics of HMGB1 protein release indicate that this protein is a distal mediator of acute inflamatory lung injury. Anti-HMGB1 protein antibodies attenuated endotoxin-induced lung injury, but not the early release of TNF-alpha and IL-1beta, indicating that HMGB1 protein is a late mediator of endotoxin-induced acute lung injury. HMGB1 protein is not released by apoptotic cells but is passively released by necrotic or damaged somatic and immune cells and it functions as a major stimulus of necrosis-induced inflammation. HMGB1 protein is also released by activated monocytes/macrophages and induces delayed and biphasic release of proinflammatory mediators from these cells. HMGB1 protein failed to stimulate cytokines release in lymphocytes, indicating that cellular stimulation is specific. We would like to suggest that HMGB1 protein may be also a primary mediator of the inflammatory responses to lung cells injury caused by toxic environmental chemicals.

  6. Transfusion-related acute lung injury.

    Federico, Anne

    2009-02-01

    Approximately one person in 5,000 will experience an episode of transfusion-related acute lung injury (TRALI) in conjunction with the transfusion of whole blood or blood components. Its hallmarks include hypoxemia, dyspnea, fever, hypotension, and bilateral pulmonary edema (noncardiogenic). The mortality for reported cases is 16.3%. The incidence and mortality may be even higher than estimated because of under-recognition and under-reporting. Although TRALI was identified as a clinical entity in the 1980s, a lack of consensus regarding a definition was present until 2004. An exact cause has yet to be identified; however, there are two theories regarding the etiology: the "antibody" and the "two-hit" theories. These theories involve both donor and recipient factors. Further education and research are needed to assist in the development of strategies for the prevention and treatment of TRALI.

  7. Acute lung injury induces cardiovascular dysfunction

    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...... these impairments (vasodilatory responses to acetylcholine, P = 0.005; cardiac output, P = 0.025). Pretreatment with the combination of budesonide and formoterol, but not either alone, ameliorated the vasodilatory responses to acetylcholine (P = 0.018) and cardiac output (P drugs also attenuated...

  8. Therapeutic Strategies for Severe Acute Lung Injury

    Diaz, Janet. V.; Brower, Roy; Calfee, Carolyn S.; Matthay, Michael A.

    2015-01-01

    Objective In the management of patients with severe Acute Lung Injury and the Acute Respiratory Distress Syndrome (ALI/ARDS), clinicians are sometimes challenged to maintain acceptable gas exchange while avoiding harmful mechanical ventilation practices. In some of these patients, physicians may consider the use of “rescue therapies” to sustain life. Our goal is to provide a practical, evidence-based review to assist critical care physicians’ care for patients with severe ALI/ARDS. Data Sources and Study Selection We searched the Pub Med database for clinical trials examining the use of the following therapies in ALI/ARDS: recruitment maneuvers, high positive end expiratory pressure, prone position, high frequency oscillatory ventilation, glucocorticoids, inhaled nitric oxide, buffer therapy and extracorporeal life support. Study selection All clinical trials that included patients with severe ALI/ARDS were included in the review. Data Synthesis The primary author reviewed the aforementioned trials in depth and then disputed findings and conclusions with other authors until consensus was achieved. Conclusions This article is designed to: a) provide clinicians with a simple, bedside definition for the diagnosis of severe ARDS; b) describe several therapies that can be used in severe ARDS with an emphasis on the potential risks as well as the indications and benefits; and c) to offer practical guidelines for implementation of these therapies. PMID:20562704

  9. Aerosolized prostacyclin for acute lung injury (ALI) and acute respiratory distress syndrome (ARDS)

    Afshari, Arash; Brok, Jesper; Møller, Ann

    2010-01-01

    Acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) are critical conditions that are associated with high mortality and morbidity. Aerosolized prostacyclin has been used to improve oxygenation despite the limited evidence available so far.......Acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) are critical conditions that are associated with high mortality and morbidity. Aerosolized prostacyclin has been used to improve oxygenation despite the limited evidence available so far....

  10. Lung injury in acute pancreatitis: mechanisms, prevention, and therapy.

    Shields, Conor J

    2012-02-03

    Lung injury is the most pertinent manifestation of extra-abdominal organ dysfunction in pancreatitis. The propensity of this retroperitoneal inflammatory condition to engender a diffuse and life-threatening lung injury is significant. Approximately one third of patients will develop acute lung injury and acute respiratory distress syndrome, which account for 60% of all deaths within the first week. The variability in the clinical course of pancreatitis renders it a vexing entity and makes demonstration of the efficacy of any specific intervention difficult. The distinct pathologic entity of pancreatitis-associated lung injury is reviewed with a focus on etiology and potential therapeutic maneuvers.

  11. Acute lung injury probably associated with infusion of propofol emulsion.

    Chondrogiannis, K D; Siontis, G C M; Koulouras, V P; Lekka, M E; Nakos, G

    2007-08-01

    We present a case of acute lung injury associated with propofol infusion in a mechanically ventilated patient with intracerebral haemorrhage. Diagnosis was based on the exclusion of other risk factors inducing acute lung injury and on the clinical improvement after discontinuation of the propofol emulsion. Laboratory data such as the increase in total phospholipids, neutral lipids and free fatty acids in the broncho-alveolar lavage fluid, the remarkably high percentage of alveolar macrophages including fat droplets and the similar lipid composition of propofol and broncho-alveolar lavage fluid support the relationship between propofol and acute lung injury.

  12. beta2 adrenergic agonists in acute lung injury? The heart of the matter.

    Lee, Jae W

    2009-01-01

    Despite extensive research into its pathophysiology, acute lung injury/acute respiratory distress syndrome (ALI/ARDS) remains a devastating syndrome with mortality approaching 40%. Pharmacologic therapies that reduce the severity of lung injury in vivo and in vitro have not yet been translated to effective clinical treatment options, and innovative therapies are needed. Recently, the use of beta2 adrenergic agonists as potential therapy has gained considerable interest due to their ability to increase the resolution of pulmonary edema. However, the results of clinical trials of beta agonist therapy for ALI/ARDS have been conflicting in terms of benefit. In the previous issue of Critical Care, Briot and colleagues present evidence that may help clarify the inconsistent results. The authors demonstrate that, in oleic acid lung injury in dogs, the inotropic effect of beta agonists may recruit damaged pulmonary capillaries, leading to increased lung endothelial permeability.

  13. [Positive end-expiratory pressure : adjustment in acute lung injury].

    Bruells, C S; Dembinski, R

    2012-04-01

    Treatment of patients suffering from acute lung injury is a challenge for the treating physician. In recent years ventilation of patients with acute hypoxic lung injury has changed fundamentally. Besides the use of low tidal volumes, the most beneficial setting of positive end-expiratory pressure (PEEP) has been in the focus of researchers. The findings allow adaption of treatment to milder forms of acute lung injury and severe forms. Additionally computed tomography techniques to assess the pulmonary situation and recruitment potential as well as bed-side techniques to adjust PEEP on the ward have been modified and improved. This review gives an outline of recent developments in PEEP adjustment for patients suffering from acute hypoxic and hypercapnic lung injury and explains the fundamental pathophysiology necessary as a basis for correct treatment.

  14. Transfusion related acute lung injury presenting with acute dyspnoea: a case report

    Haji Altaf

    2008-10-01

    Full Text Available Abstract Introduction Transfusion-related acute lung injury is emerging as a common cause of transfusion-related adverse events. However, awareness about this entity in the medical fraternity is low and it, consequently, remains a very under-reported and often an under-diagnosed complication of transfusion therapy. Case presentation We report a case of a 46-year old woman who developed acute respiratory and hemodynamic instability following a single unit blood transfusion in the postoperative period. Investigation results were non-specific and a diagnosis of transfusion-related acute lung injury was made after excluding other possible causes of acute lung injury. She responded to symptomatic management with ventilatory and vasopressor support and recovered completely over the next 72 hours. Conclusion The diagnosis of transfusion-related acute lung injury relies on excluding other causes of acute pulmonary edema following transfusion, such as sepsis, volume overload, and cardiogenic pulmonary edema. All plasma containing blood products have been implicated in transfusion-related acute lung injury, with the majority being linked to whole blood, packed red blood cells, platelets, and fresh-frozen plasma. The pathogenesis of transfusion-related acute lung injury may be explained by a "two-hit" hypothesis, involving priming of the inflammatory machinery and then activation of this primed mechanism. Treatment is supportive, with prognosis being substantially better than for most other causes of acute lung injury.

  15. Ligustrazine alleviates acute lung injury in a rat model of acute necrotizing pancreatitis

    Jian-Xin Zhang; Sheng-Chun Dang

    2006-01-01

    BACKGROUND:Acute necrotizing pancreatitis leads to a systemic inlfammatory response characterized by widespread leukocyte activation and, as a consequence, distant lung injury. The aim of this study was to evaluate the effect of ligustrazine, extracted from Ligusticum wallichii a traditional Chinese medicine, on lung injury in a rat model of acute necrotizing pancreatitis (ANP). METHODS:A total of 192 rats were randomly divided into three groups: control (C group); ANP without treatment (P group); and ANP treated with ligustrazine (T group). Each group was further divided into 0.5, 2, 6 and 12 hours subgroups. All rats were anesthetized with an intraperitoneal injection of sodium pentobarbital. Sodium taurocholate was infused through the pancreatic membrane to induce ANP. For the T group, sodium taurocholate was infused as above, then 0.6%ligustrazine was administered via the femoral vein. The effects of ligustrazine on the severity of lung injury were assessed by lung wet/dry weight ratio, myeloperoxidase (MPO) activity and histopathological changes. Pulmonary blood lfow was determined by the radioactive microsphere technique (RMT). RESULTS:The blood lfow in the P group was signiifcantly lower than that of the C group, while the blood lfow in the T group was signiifcantly higher than that of the P group but showed no signiifcant difference from the C group. Compared with C group, the lung wet/dry ratios in both the P and T groups were signiifcantly increased, but there was no signiifcant difference between them. The MPO activity in the P group was greatly increased over that of the C group. In the T group, although the MPO activity was also higher than in the C group, it much less increased than in the P group. Moreover, the difference between P and T groups was signiifcant after 0.5 to 12 hours. After induction of the ANP model, the pancreas showed mild edema and congestion;the longer the time, the more severe this became. The pulmonary pathological changes were

  16. Ticagrelor reduces neutrophil recruitment and lung damage in abdominal sepsis.

    Rahman, Milladur; Gustafsson, David; Wang, Yongzhi; Thorlacius, Henrik; Braun, Oscar Ö

    2014-01-01

    Abstract Platelets play an important role in abdominal sepsis and P2Y12 receptor antagonists have been reported to exert anti-inflammatory effects. Herein, we assessed the impact of platelet inhibition with the P2Y12 receptor antagonist ticagrelor on pulmonary neutrophil recruitment and tissue damage in a model of abdominal sepsis. Wild-type C57BL/6 mice were subjected to cecal ligation and puncture (CLP). Animals were treated with ticagrelor (100 mg/kg) or vehicle prior to CLP induction. Edema formation and bronchoalveolar neutrophils as well as lung damage were quantified. Flow cytometry was used to determine expression of platelet-neutrophil aggregates, neutrophil activation and CD40L expression on platelets. CLP-induced pulmonary infiltration of neutrophils at 24 hours was reduced by 50% in ticagrelor-treated animals. Moreover, ticagrelor abolished CLP-provoked lung edema and decreased lung damage score by 41%. Notably, ticagrelor completely inhibited formation of platelet-neutrophil aggregates and markedly reduced thrombocytopenia in CLP animals. In addition, ticagrelor reduced platelet shedding of CD40L in septic mice. Our data indicate that ticagrelor can reduce CLP-induced pulmonary neutrophil recruitment and lung damage suggesting a potential role for platelet antagonists, such as ticagrelor, in the management of patients with abdominal sepsis.

  17. EXPRESSION OF INTERCELLULAR ADHESION MOLECULE IN LUNG TISSUES OF EXPERIMENTAL ACUTE LUNG INJURY AND THE AFFECT OF RHUBARB ON IT

    李春盛; 桂培春; 何新华

    2000-01-01

    Objeaive. To approach the relation and the possible mechanism between the expression of intercellular adhesion molecule (ICAM-1) mRNA and acute lung injury (ALI) and the mechanisms of rhubarb in the prevention and treatment of the lung injury. Methods. Lipopolysaeeharide (LPS) was injected into the sublingual vein of male Wistar rats to perform ALI animal model. The rats were divided into 4 groups: LPS group, control group, rhubarb group and dexamethasoue group.Macroscopic and histopathological e~aminatiom were performed and biological markers were measured for the lung specimem. The markers included lung wet/dry weight, the rate of neutrophils and protein content in the pulmonary alveolar lavage fluid, pulmonary vascular permeability and pulmonary alveolar permeability index. Molecular hybridization method was used to determine the expression of ICAM-1 mRNA. Results. In the lung tissues, the ICAM-1 mRNA expression was increased in the endothelial cells of pulmonary veins and capillaries, rhubarb and dexamethasone had the action of decreasing the expression. The light reflex value in the gray scale scanning showed that in the comparison between the LPS and the control group, the gray scale value of the lung tissues in ALI was significantly increased, thus the light reflex value was markedly decreased (P < 0.01),demonstrating the expression of ICAM-1 mRNA was increased. In comparison with the LPS group, dexamethasoue and rhubarb emfld decrease the gray scale value of the lung tissue significantly, thus the light reflex value was elevated (P< 0.01, P < 0.05) ; the correslxmding pathologic changes of lung tissues and the biological markers of the lung injury were simifieantlv decreased or ameliorated. Conclusions. The increase of the expression d ICAM-1 mRNA in the lung tissues of ALI plays the roles in ALI.The application of rhubarb and dexamethasone can decrease the expression and ameliorate the lung damage; its mechanism is possibly via the inhibition of ICAM-1 m

  18. EXPRESSION OF INTERCELLULAR ADHESION MOLECULE IN LUNG TISSUES OF EXPERIMENTAL ACUTE LUNG INJURY AND THE AFFECT OF RHUBARB ON IT

    2000-01-01

    Objective. To approach the relation and the possible mechanism between the expression of intercellular adhesion molecule (ICAM-1) mRNA and acute lung injury (ALI) and the mechanisms of rhubarb in the prevention and treatment of the lung injury.Methods. Lipopolysaccharide (LPS) was injected into the sublingual vein of male Wistar rats to perform ALI animal model. The rats were divided into 4 groups: LPS group, control group, rhubarb group and dexamethasone group. Macroscopic and histopathological examinations were performed and biological markers were measured for the lung specimens. The markers included lung wet/dry weight, the rate of neutrophils and protein content in the pulmonary alveolar lavage fluid, pulmonary vascular permeability and pulmonary alveolar permeability index. Molecular hybridization method was used to determine the expression of ICAM-1 mRNA.Results. In the lung tissues, the ICAM-1 mRNA expression was increased in the endothelial cells of pulmonary veins and capillaries, rhubarb and dexamethasone had the action of decreasing the expression. The light reflex value in the gray scale scanning showed that in the comparison between the LPS and the control group, the gray scale value of the lung tissues in ALI was significantly increased, thus the light reflex value was markedly decreased (P<0.01), demonstrating the expression of ICAM-1 mRNA was increased. In comparison with the LPS group, dexamethasone and rhubarb could decrease the gray scale value of the lung tissue significantly, thus the light reflex value was elevated (P<0.01, P<0.05); the corresponding pathologic changes of lung tissues and the biological markers of the lung injury were significantly decreased or ameliorated.Conclusions. The increase of the expression of ICAM-1 mRNA in the lung tissues of ALI plays the roles in ALI. The application of rhubarb and dexamethasone can decrease the expression and ameliorate the lung damage; its mechanism is possibly via the inhibition of ICAM

  19. B-lines quantify the lung water content: a lung ultrasound versus lung gravimetry study in acute lung injury.

    Jambrik, Zoltán; Gargani, Luna; Adamicza, Agnes; Kaszaki, József; Varga, Albert; Forster, Tamás; Boros, Mihály; Picano, Eugenio

    2010-12-01

    B-lines (also termed ultrasound lung comets) obtained with lung ultrasound detect experimental acute lung injury (ALI) very early and before hemogasanalytic changes, with a simple, noninvasive, nonionizing and real-time method. Our aim was to estimate the correlation between B-lines number and the wet/dry ratio of the lung tissue, measured by gravimetry, in an experimental model of ALI. Seventeen Na-pentobarbital anesthetized, cannulated (central vein and carotid artery) minipigs were studied: five sham-operated animals served as controls and, in 12 animals, ALI was induced by injection of oleic acid (0.1 mL/kg) via the central venous catheter. B-lines were measured by echographic scanner in four predetermined chest scanning sites in each animal. At the end of each experiment, both lungs were dissected, weighed and dried to determine wet/dry weight ratio by gravimetry. After the injection of oleic acid, B-lines number increased over time. A significant correlation was found between the wet/dry ratio and B-lines number (r = 0.91, p < 0.001). These data suggest that in an experimental pig model of ALI/ARDS, B-lines assessed by lung ultrasound provide a simple, semiquantitative, noninvasive index of lung water accumulation, strongly correlated to invasive gravimetric assessment.

  20. DISTINCT PHENOTYPES OF INFILTRATING CELLS DURING ACUTE AND CHRONIC LUNG REJECTION IN HUMAN HEART-LUNG TRANSPLANTS

    WINTER, JB; CLELLAND, C; GOUW, ASH; PROP, J

    1995-01-01

    To differentiate between acute and chronic lung rejection in an early stage, phenotypes of infiltrating inflammatory cells were analyzed in 34 transbronchial biopsies (TBBs) of 24 patients after heart-lung transplantation. TBBs were taken during during acute lung rejection and chronic lung rejection

  1. Dihydro-Resveratrol Ameliorates Lung Injury in Rats with Cerulein-Induced Acute Pancreatitis.

    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.

  2. DIETARY FLAXSEED PREVENTS RADIATION-INDUCED OXIDATIVE LUNG DAMAGE, INFLAMMATION AND FIBROSIS IN A MOUSE MODEL OF THORACIC RADIATION INJURY

    Lee, James C.; Krochak, Ryan; Blouin, Aaron; Kanterakis, Stathis; Chatterjee, Shampa; Arguiri, Evguenia; Vachani, Anil; Solomides, Charalambos C.; Cengel, Keith A.; Christofidou-Solomidou, Melpo

    2009-01-01

    Flaxseed (FS) has high contents of omega-3 fatty acids and lignans with antioxidant properties. Its use in preventing thoracic X-ray radiation therapy (XRT)-induced pneumonopathy has never been evaluated. We evaluated FS supplementation given to mice given before and post-XRT. FS-derived lignans, known for their direct antioxidant properties, were evaluated in abrogating ROS generation in cultured endothelial cells following gamma radiation exposure. Mice were fed 10% FS or isocaloric control diet for three weeks and given 13.5 Gy thoracic XRT. Lungs were evaluated at 24 hours for markers of radiation-induced injury, three weeks for acute lung damage (lipid peroxidation, lung edema and inflammation), and at four months for late lung damage (inflammation and fibrosis). FS-Lignans blunted ROS generation in vitro, resulting from radiation in a dose-dependent manner. FS-fed mice had reduced expression of lung injury biomarkers (Bax, p21, and TGF-beta1) at 24 hours following XRT and reduced oxidative lung damage as measured by malondialdehyde (MDA) levels at 3 weeks following XRT. In addition, FS-fed mice had decreased lung fibrosis as determined by hydroxyproline content and decreased inflammatory cell influx into lungs at 4 months post XRT. Importantly, when Lewis Lung carcinoma cells were injected systemically in mice, FS dietary supplementation did not appear to protect lung tumors from responding to thoracic XRT. Dietary FS is protective against pulmonary fibrosis, inflammation and oxidative lung damage in a murine model. Moreover, in this model, tumor radioprotection was not observed. FS lignans exhibited potent radiation-induced ROS scavenging action. Taken together, these data suggest that dietary flaxseed may be clinically useful as an agent to increase the therapeutic index of thoracic XRT by increasing the radiation tolerance of lung tissues. PMID:18981722

  3. Lung tissue remodeling in the acute respiratory distress syndrome

    Souza Alba Barros de

    2003-01-01

    Full Text Available Acute respiratory distress syndrome (ARDS is characterized by diffuse alveolar damage, and evolves progressively with three phases: exsudative, fibroproliferative, and fibrotic. In the exudative phase, there are interstitial and alveolar edemas with hyaline membrane. The fibropro­liferative phase is characterized by exudate organization and fibroelastogenesis. There is proliferation of type II pneumocytes to cover the damaged epithelial surface, followed by differentiation into type I pneumocytes. The fibroproliferative phase starts early, and its severity is related to the patient?s prognosis. The alterations observed in the phenotype of the pulmonary parenchyma cells steer the tissue remodeling towards either progressive fibrosis or the restoration of normal alveolar architecture. The fibrotic phase is characterized by abnormal and excessive deposition of extracellular matrix proteins, mainly collagen. The dynamic control of collagen deposition and degradation is regulated by metalloproteinases and their tissular regulators. The deposition of proteoglycans in the extracellular matrix of ARDS patients needs better study. The regulation of extracellular matrix remodeling, in normal conditions or in several pulmonary diseases, such as ARDS, results from a complex mechanism that integrate the transcription of elements that destroy the matrix protein and produce activation/inhibition of several cellular types of lung tissue. This review article will analyze the ECM organization in ARDS, the different pulmonary parenchyma remodeling mechanisms, and the role of cytokines in the regulation of the different matrix components during the remodeling process.

  4. Supplementation of parenteral nutrition with fish oil attenuates acute lung injury in a rat model

    Kohama, Keisuke; Nakao, Atsunori; Terashima, Mariko; Aoyama-Ishikawa, Michiko; Shimizu, Takayuki; Harada, Daisuke; Nakayama, Mitsuo; Yamashita, Hayato; Fujiwara, Mayu; Kotani, Joji

    2014-01-01

    Fish oil rich in n-3 polyunsaturated fatty acids has diverse immunomodulatory properties and attenuates acute lung injury when administered in enternal nutrition. However, enteral nutrition is not always feasible. Therefore, we investigated the ability of parenteral nutrition supplemented with fish oil to ameliorate acute lung injury. Rats were infused with parenteral nutrition solutions (without lipids, with soybean oil, or with soybean oil and fish oil) for three days. Lipopolysaccharide (15 mg/kg) was then administered intratracheally to induce acute lung injury, characterized by impaired lung function, polymorphonuclear leukocyte recruitment, parenchymal tissue damage, and upregulation of mRNAs for inflammatory mediators. Administration of parenteral nutrition supplemented with fish oil prior to lung insult improved gas exchange and inhibited neutrophil recruitment and upregulation of mRNAs for inflammatory mediators. Parenteral nutrition supplemented with fish oil also prolonged survival. To investigate the underlying mechanisms, leukotriene B4 and leukotriene B5 secretion was measured in neutrophils from the peritoneal cavity. The neutrophils from rats treated with fish oil-rich parenteral nutrition released significantly more leukotriene B5, an anti-inflammatory eicosanoid, than neutrophils isolated from rats given standard parenteral nutrition. Parenteral nutrition with fish oil significantly reduced lipopolysaccharide-induced lung injury in rats in part by promoting the synthesis of anti-inflammatory eicosanoids. PMID:24688221

  5. Melatonin reduces acute lung injury in endotoxemic rats

    SHANG You; XU San-peng; WU Yan; JIANG Yuan-xu; WU Zhou-yang; YUAN Shi-ying; YAO Shang-long

    2009-01-01

    Background Treatment with melatonin significantly reduces lung injury induced by bleomycin, paraquat and ischemia reperfusion. In the present study, we investigated the possible protective roles of melatonin in pulmonary inflammation and lung injury during acute endotoxemia.Methods Thirty-two male Sprague-Dawley rats were randomly assigned to four groups: vehicle + saline group, melatonin + saline group, vehicle + lipopolysaccharide group, melatonin + lipopolysaccharide group. The rats were treated with melatonin (10 mg/kg, intraperitoneal injection (I.p.)) or vehicle (1% ethanol saline), 30 minutes prior to lipopolysaccharide administration (6 mg/kg, intravenous injection). Four hours after lipopolysaccharide injection, samples of pulmonary tissue were collected. Blood gas analysis was carried out. Optical microscopy was performed to examine pathological changes in lungs and lung injury score was assessed. Wet/dry ratios (W/D), myeloperoxidase activity, malondialdehyde concentrations and tumor necrosis factor-alpha (TNF-a) and interleukin-10 (IL-10) levels in lungs were measured. The pulmonary expression of nuclear factor-kappa B (NF-KB) p65 was evaluated by Western blotting. Results PaO2 in the vehicle + lipopolysaccharide group decreased compared with that in the vehicle + saline group. This decrease was significantly reduced in the melatonin + lipopolysaccharide group. The lung tissues from the saline + lipopolysaccharide group were significantly damaged, which were less pronounced in the melatonin + lipopolysaccharide group. The W/D ratio increased significantly in the vehicle + lipopolysaccharide group (6.1±0.18) as compared with that in the vehicle + saline group (3.611±0.3) (P <0.01), which was significantly reduced in the melatonin + lipopolysaccharide group (4.8±0.25) (P <0.01). Myeloperoxidase activity and malondialdehyde levels increased significantly in the vehicle + lipopolysaccharide group compared with that in the vehicle + saline group, which

  6. Expression of Prothrombinase/fibroleukin Gene fg12 in Lung Impairment in a Murine Severe Acute Respiratory Syndrome Model

    Wei-ming YAN; Jia-quan HUANG; Xiao-ping LUO; Qin NING

    2007-01-01

    To evaluate the role of murine fibrinogen like protein 2 (mfgl2) /fibroleukin in lung impairment in Severe acute respiratory syndrome (SARS), a murine SARS model induced by Murine hepatitis virus strain 3 (MHV-3) through trachea was established. Impressively, all the animals developed interstitial pneumonia with extensive hyaline membranes formation within alveoli, and presence of micro-vascular thrombosis in the pulmonary vessels. MHV-3 nucleocapsid gene transcripts were identified in multiple organs including lungs, spleen etc. As a representative proinflammatory gene, mfgl2 prothrombinase expression was evident in terminal and respiratory bronchioles, alveolar epithelia and infiltrated cells in the lungs associated with fibrin deposition and micro-vascular thrombosis. In summary, the established murine SARS model could mimic the pathologic characteristics of lungs in patients with SARS. Besides the physical damages due to virus replication in organs, the up-regulation of novel gene mfgl2 in lungs may play a vital role in the development of SARS associated lung damage.

  7. Glutamine Attenuates Acute Lung Injury Caused by Acid Aspiration

    Chih-Cheng Lai

    2014-08-01

    Full Text Available Inadequate ventilator settings may cause overwhelming inflammatory responses associated with ventilator-induced lung injury (VILI in patients with acute respiratory distress syndrome (ARDS. Here, we examined potential benefits of glutamine (GLN on a two-hit model for VILI after acid aspiration-induced lung injury in rats. Rats were intratracheally challenged with hydrochloric acid as a first hit to induce lung inflammation, then randomly received intravenous GLN or lactated Ringer’s solution (vehicle control thirty min before different ventilator strategies. Rats were then randomized to receive mechanical ventilation as a second hit with a high tidal volume (TV of 15 mL/kg and zero positive end-expiratory pressure (PEEP or a low TV of 6 mL/kg with PEEP of 5 cm H2O. We evaluated lung oxygenation, inflammation, mechanics, and histology. After ventilator use for 4 h, high TV resulted in greater lung injury physiologic and biologic indices. Compared with vehicle treated rats, GLN administration attenuated lung injury, with improved oxygenation and static compliance, and decreased respiratory elastance, lung edema, extended lung destruction (lung injury scores and lung histology, neutrophil recruitment in the lung, and cytokine production. Thus, GLN administration improved the physiologic and biologic profiles of this experimental model of VILI based on the two-hit theory.

  8. Lung Transplantation in Acute Respiratory Distress Syndrome Caused by Influenza Pneumonia

    Youjin Chang

    2015-08-01

    Full Text Available Severe acute respiratory distress syndrome (ARDS is a life-threatening disease with a high mortality rate. Although many therapeutic trials have been performed for improving the mortality of severe ARDS, limited strategies have demonstrated better outcomes. Recently, advanced rescue therapies such as extracorporeal membrane oxygenation (ECMO made it possible to consider lung transplantation (LTPL in patients with ARDS, but data is insufficient. We report a 62-year-old man who underwent LTPL due to ARDS with no underlying lung disease. He was admitted to the hospital due to influenza A pneumonia-induced ARDS. Although he was supported by ECMO, he progressively deteriorated. We judged that his lungs were irreversibly damaged and decided he needed to undergo LTPL. Finally, bilateral sequential double-lung transplantation was successfully performed. He has since been alive for three years. Conclusively, we demonstrate that LTPL can be a therapeutic option in patients with severe ARDS refractory to conventional therapies.

  9. Acute lung injury and the acute respiratory distress syndrome in the injured patient

    Bakowitz Magdalena

    2012-08-01

    Full Text Available Abstract Acute lung injury and acute respiratory distress syndrome are clinical entities of multi-factorial origin frequently seen in traumatically injured patients requiring intensive care. We performed an unsystematic search using PubMed and the Cochrane Database of Systematic Reviews up to January 2012. The purpose of this article is to review recent evidence for the pathophysiology and the management of acute lung injury/acute respiratory distress syndrome in the critically injured patient. Lung protective ventilation remains the most beneficial therapy. Future trials should compare intervention groups to controls receiving lung protective ventilation, and focus on relevant outcome measures such as duration of mechanical ventilation, length of intensive care unit stay, and mortality.

  10. Acute Lung Injury during Antithymocyte Globulin Therapy for Aplastic Anemia

    Ewan Christopher Goligher

    2009-01-01

    Full Text Available The case of a 33-year-old man with aplastic anemia who experienced recurrent episodes of hypoxemia and pulmonary infiltrates during infusions of antithymocyte globulin (ATG is described. With the use of high-dose corticosteroids, the patient’s original episodes resolved, and were subsequently prevented before additional administrations of ATG. Rare reports of an association between ATG and acute lung injury are found in the literature, but this is the first report of successful steroid-supported re-exposure. Although the mechanism of ATG-related acute lung injury remains uncertain, it may be parallel to the mechanism of transfusion-related acute lung injury because the pathogenesis of the latter relies, in part, on antileukocyte antibodies. ATG-related toxicity should be included in the differential diagnosis of new, infusion-associated pulmonary infiltrates, and corticosteroids may be a useful therapeutic consideration in the management.

  11. Transfusion-related acute lung injury: report of two cases.

    Čermáková, Z; Kořískta, M; Blahutová, Š; Dvořáčková, J; Brát, R; Valkovský, I; Hrdličková, R

    2012-01-01

    Transfusion-related acute lung injury (TRALI) is a severe life-threatening complication of blood transfusion, characterized by acute lung injury developing within 2-6 h of transfusion. However, TRALI is difficult to diagnose, and the initial report or suspicion of TRALI depends on close collaboration between clinical departments and transfusion centres. A total of 17 adverse post-transfusion reactions were reported to the Blood Centre of the University Hospital Ostrava as suspected TRALI between 2005 and 2010. We report two cases of serious TRALI with different pathogenetic mechanisms.

  12. Neutrophils contain cholesterol crystals in transfusion-related acute lung injury (TRALI)

    Van Ness, Michael; Jensen, Hanne; Adamson, Grete N

    2013-01-01

    Intracellular components of transfusion-related acute lung injury (TRALI) were investigated by transmission electron microscopy.......Intracellular components of transfusion-related acute lung injury (TRALI) were investigated by transmission electron microscopy....

  13. Effects of acute hypercapnia with and without acidosis on lung inflammation and apoptosis in experimental acute lung injury.

    Nardelli, L M; Rzezinski, A; Silva, J D; Maron-Gutierrez, T; Ornellas, D S; Henriques, I; Capelozzi, V L; Teodoro, W; Morales, M M; Silva, P L; Pelosi, P; Garcia, C S N B; Rocco, P R M

    2015-01-01

    We investigated the effects of acute hypercapnic acidosis and buffered hypercapnia on lung inflammation and apoptosis in experimental acute lung injury (ALI). Twenty-four hours after paraquat injection, 28 Wistar rats were randomized into four groups (n=7/group): (1) normocapnia (NC, PaCO2=35-45 mmHg), ventilated with 0.03%CO2+21%O2+balancedN2; (2) hypercapnic acidosis (HC, PaCO2=60-70 mmHg), ventilated with 5%CO2+21%O2+balancedN2; and (3) buffered hypercapnic acidosis (BHC), ventilated with 5%CO2+21%O2+balancedN2 and treated with sodium bicarbonate (8.4%). The remaining seven animals were not mechanically ventilated (NV). The mRNA expression of interleukin (IL)-6 (p=0.003), IL-1β (pacidosis, reduced lung inflammation and lung and kidney cell apoptosis.

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

    Sepehr, Reyhaneh; Audi, Said H; Maleki, Sepideh; Staniszewski, Kevin; Eis, Annie L; Konduri, Girija G; Ranji, Mahsa

    2013-07-01

    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.

  15. Protective Effect of Genistein on Lipopolysaccharide-induced Acute Lung Injury in Rats

    LI Xingwang; XU Tao; LIAN Qingquan; ZENG Bangxiong; ZHANG Bing; XIE Yubo

    2005-01-01

    To investigate the protective effect of genistein on endotoxin-induced acute lung injury in rats, and explore the underlying mechanisms, 32 male Sprague-Dawley rats were randomly divided into 4 experimental groups: saline control, genistein alone, lipopolysaccaride alone, and genistein pretreatment. Each treatment group consisted of eight animals. Animals were observed for 6 h after LPS challenge, and the wet/dry (W/D) weight ratio of the lung and bronchoalveolar lavage fluid(BALF) protein content were used as a measure of lung injury. Neutrophil recruitment and activation were evaluated by BALF cellularity and myeloperoxidase (MPO) activity. RT-PCR analysis was performed in lung tissue to assess gene expression of ICAM-1. The histopathological changes were also observed using the HE staining of lung tissue. Our results showed that lung injury parameters, including the wet/dry weight ratio and protein content in BALF, were significantly higher in the LPS alone group than in the saline control group (P<0.01). In the LPS alone group, a larger number of neutrophils and greater MPO activity in cell-free BAL and lung homogenates were observed when compared with the saline control group (P<0.01). There was a significant increase in lung ICAM-1 mRNA in response to LPS challenge (P< 0. 01, group L versus group S).Genistein pretreatment significantly attenuated LPS-induced changes in these indices. LPS caused extensive lung damage, which was also lessened after genistein pretreatment. All above-mentioned parameters in the genistein alone group were not significantly different from those of the saline control group. It is concluded that genistein pretreatment attenuated LPS-induced lung injury in rats.This beneficial effect of genistein may involves, in part, an inhibition of neutrophilic recruitment and activity, possibly through an inhibition of lung ICAM-1 expression.

  16. Acute respiratory distress syndrome and lung fibrosis after ingestion of a high dose of ortho-phenylphenol.

    Cheng, Shih-Lung; Wang, Hao-Chien; Yang, Pan-Chyr

    2005-08-01

    Ortho-phenylphenol (OPP) and its sodium salt are used as fungicides and antibacterial agents, ingestion of which has been found to cause liver toxicity, renal toxicity and carcinomas in the urinary tract of rats. Lung damage due to OPP ingestion has not been reported in humans. We report a suicidal 39-year-old woman with stage II cervical cancer who drank a potentially lethal dose of OPP in the form of a commercial antiseptic, which led to the complication of liver and renal function impairment, severe lung damage with acute respiratory distress syndrome and subsequent severe lung fibrosis. Open lung biopsy showed diffuse alveolar damage. She was discharged after 34 days of hospitalization with continuing domiciliary oxygen therapy.

  17. Activated protein C in the treatment of acute lung injury and acute respiratory distress syndrome

    A.D. Cornet; G.P. van Nieuw Amerongen; A. Beishuizen; M.J. Schultz; A.R.J. Girbes; A.B.J. Groeneveld

    2009-01-01

    Background: Acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) frequently necessitate mechanical ventilation in the intensive care unit. The syndromes have a high mortality rate and there is at present no treatment specifically directed at the underlying pathogenesis. Central in

  18. Epidemiology of acute lung injury and acute respiratory distress syndrome in The Netherlands : A survey

    Wind, Jan; Versteegt, Jens; Twisk, Jos; van der Werf, Tjip S.; Bindels, Alexander J. G. H.; Spijkstra, Jan-Jaap; Girbes, Armand R. J.; Groeneveld, A. B. Johan

    2007-01-01

    Background: The characteristics, incidence and risk factors for acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) may depend on definitions and geography. Methods: A prospective, 3-day point-prevalence study was performed by a survey of all intensive care units (ICU) in the Neth

  19. Strategies to improve oxygenation in experimental acute lung injury

    A. Hartog (Arthur)

    2000-01-01

    textabstractOne of the most important clinical syndromes, in which failure of oxygen uptake in the lung leads to severe hypoxia, is the so-called acute respiratory distress syndrome (ARDS). ARDS is a complex of clinical signs and symptoms which occur following diverse pulmonary or systemic insults,

  20. Life-threatening acute lung injury after gamma butyrolactone ingestion

    van Gerwen, M.; Scheper, H.; Touw, D. J.; van Nieuwkoop, C.

    2015-01-01

    We describe a case of a 44-year-old woman with a borderline personality disorder and chronic gamma-butyrolactone (GBL) use who presented with progressive dyspnoea and an altered mental status. A high anion gap metabolic acidosis and acute lung injury was diagnosed. We hypothesise this was caused by

  1. Endotoxin-induced lung alveolar cell injury causes brain cell damage

    Rodríguez-González, Raquel; Ramos-Nuez, Ángela; Martín-Barrasa, José Luis; López-Aguilar, Josefina; Baluja, Aurora; Álvarez, Julián; Rocco, Patricia RM; Pelosi, Paolo

    2015-01-01

    Sepsis is the most common cause of acute respiratory distress syndrome, a severe lung inflammatory disorder with an elevated morbidity and mortality. Sepsis and acute respiratory distress syndrome involve the release of inflammatory mediators to the systemic circulation, propagating the cellular and molecular response and affecting distal organs, including the brain. Since it has been reported that sepsis and acute respiratory distress syndrome contribute to brain dysfunction, we investigated the brain-lung crosstalk using a combined experimental in vitro airway epithelial and brain cell injury model. Conditioned medium collected from an in vitro lipopolysaccharide-induced airway epithelial cell injury model using human A549 alveolar cells was subsequently added at increasing concentrations (no conditioned, 2%, 5%, 10%, 15%, 25%, and 50%) to a rat mixed brain cell culture containing both astrocytes and neurons. Samples from culture media and cells from mixed brain cultures were collected before treatment, and at 6 and 24 h for analysis. Conditioned medium at 15% significantly increased apoptosis in brain cell cultures 24 h after treatment, whereas 25% and 50% significantly increased both necrosis and apoptosis. Levels of brain damage markers S100 calcium binding protein B and neuron-specific enolase, interleukin-6, macrophage inflammatory protein-2, as well as matrix metalloproteinase-9 increased significantly after treating brain cells with ≥2% conditioned medium. Our findings demonstrated that human epithelial pulmonary cells stimulated with bacterial lipopolysaccharide release inflammatory mediators that are able to induce a translational clinically relevant and harmful response in brain cells. These results support a brain-lung crosstalk during sepsis and sepsis-induced acute respiratory distress syndrome. PMID:25135986

  2. The Role of Neutrophil Collagenase in Endotoxic Acute Lung Injury

    徐涛; 曾邦雄; 李兴旺

    2004-01-01

    The aim of this study was to determine the role of neutrophil collagenase in the pathogenesis of acute lung injury induced by endotoxin. 28 Sprague-Dawley were randomized into control group and LPS-enduced groups. Samples of left lung were obtained in 2 h (group L1 ), 6 h (group L2), 12 h (group L3 ) after intravenous LPS. Immunohistochemsitry was employed for detection of expression of neutrophil collagenase. Pathological scores, lung wet/dry weight ratio and the number of neutrophils were measured. The results showed that the concentration of neutrophil collagenase in LPS-enduced groups (group L1, L2, L3 ) were significantly higher than that of control group (P<0.01). Pathological scores, lung wet/dry weight ratio and the number of neutrophils in LPS-enduced groups (group L1, L2, L3 ) were also significantly higher than that of control group (P<0.01).Moreover, among group L1, L2 and L3, there were significant correlations in concentration of neutrophil collagenase and pathological scores, lung wet/dry weight ratio, the number of neutrophils (P<0.05). The present study showed that neutrophil collagenase play an important role in the pathogenesis and progress of endotoxic acute lung injury.

  3. Could erlotinib treatment lead to acute cardiovascular events in patients with lung adenocarcinoma after chemotherapy failure?

    Kus T

    2015-06-01

    Full Text Available Tulay Kus, Gokmen Aktas, Alper Sevinc, Mehmet Emin Kalender, Celaletdin Camci Department of Internal Medicine, Division of Medical Oncology, Gaziantep University, Gaziantep, Turkey Abstract: Erlotinib, an epidermal growth factor receptor and tyrosine kinase inhibitor, is a targeted drug that was approved for the treatment of non-small-cell lung cancers and pancreatic cancers. Targeted tyrosine kinase inhibitors are known to have cardiotoxic effects. However, erlotinib does not have a statistically proven effect of increasing acute cardiovascular event (ACE risk. Preclinical studies showed that beta agonist stimulation among rats that were administered erlotinib led to cardiovascular damage. Thus, there would be an aggregate effect of erlotinib on ACE, although it is not thought to be a cardiotoxic drug itself. In this paper, we present two non-small-cell lung cancer cases that developed ACE under erlotinib treatment. Keywords: erlotinib, lung cancer, myocardial infarction, EGFR

  4. Effects of biliverdin administration on acute lung injury induced by hemorrhagic shock and resuscitation in rats.

    Junko Kosaka

    Full Text Available Hemorrhagic shock and resuscitation induces pulmonary inflammation that leads to acute lung injury. Biliverdin, a metabolite of heme catabolism, has been shown to have potent cytoprotective, anti-inflammatory, and anti-oxidant effects. This study aimed to examine the effects of intravenous biliverdin administration on lung injury induced by hemorrhagic shock and resuscitation in rats. Biliverdin or vehicle was administered to the rats 1 h before sham or hemorrhagic shock-inducing surgery. The sham-operated rats underwent all surgical procedures except bleeding. To induce hemorrhagic shock, rats were bled to achieve a mean arterial pressure of 30 mmHg that was maintained for 60 min, followed by resuscitation with shed blood. Histopathological changes in the lungs were evaluated by histopathological scoring analysis. Inflammatory gene expression was determined by Northern blot analysis, and oxidative DNA damage was assessed by measuring 8-hydroxy-2' deoxyguanosine levels in the lungs. Hemorrhagic shock and resuscitation resulted in prominent histopathological damage, including congestion, edema, cellular infiltration, and hemorrhage. Biliverdin administration prior to hemorrhagic shock and resuscitation significantly ameliorated these lung injuries as judged by histopathological improvement. After hemorrhagic shock and resuscitation, inflammatory gene expression of tumor necrosis factor-α and inducible nitric oxide synthase were increased by 18- and 8-fold, respectively. Inflammatory gene expression significantly decreased when biliverdin was administered prior to hemorrhagic shock and resuscitation. Moreover, after hemorrhagic shock and resuscitation, lung 8-hydroxy-2' deoxyguanosine levels in mitochondrial DNA expressed in the pulmonary interstitium increased by 1.5-fold. Biliverdin administration prior to hemorrhagic shock and resuscitation decreased mitochondrial 8-hydroxy-2' deoxyguanosine levels to almost the same level as that in the

  5. Chronic Exposure to Water-Pipe Smoke Induces Alveolar Enlargement, DNA Damage and Impairment of Lung Function

    Abderrahim Nemmar

    2016-03-01

    Full Text Available Background/Aim: Epidemiological evidence indicates that water-pipe smoking (WPS adversely affects the respiratory system. However, the mechanisms underlying its effects are not well understood. Recent experimental studies reported the occurrence of lung inflammation and oxidative stress following acute and subacute exposure to WPS. Here, we wanted to verify the extent of inflammation and oxidative stress in mice chronically-exposed to WPS and to evaluate, for the first time, its effect on alveolar injury and DNA damage and their association with impairment of lung function. Methods: Mice were nose-only exposed to mainstream WPS (30 min/day; 5 days/week for 6 consecutive months. Control mice were exposed using the same protocol to atmospheric air only. At the end of the exposure period, several respiratory parameters were assessed. Results: In bronchoalveolar lavage fluid, WPS increased neutrophil and lymphocyte numbers, lactate dehydrogenase, myeloperoxidase and matrix metallopeptidase 9 activities, as well as several proinflammatory cytokines. In lung tissue, lipid peroxidation, reactive oxygen species, superoxide dismutase activity and reduced glutathione were all increased by WPS exposure. Along with oxidative stress, WPS exposure significantly increased lung DNA damage index. Histologically the lungs of WPS-exposed mice had foci of mixed inflammatory cells infiltration in the interalveolar interstitium which consisted of neutrophils, lymphocytes and macrophages. Interestingly, we found dilated alveolar spaces and alveolar ducts with damaged interalveolar septae, and impairment of lung function following WPS exposure. Conclusion: We show the persistence of lung inflammation and oxidative stress in mice chronically-exposed to WPS and demonstrate, for the first time, the occurrence of DNA damage and enlargement of alveolar spaces and ducts associated with impairment of lung function. Our findings provide novel mechanistic elucidation for the

  6. Crocin attenuates lipopolysacchride-induced acute lung injury in mice

    Wang, Jian; Kuai, Jianke; Luo, Zhonghua; Wang, Wuping; Wang, Lei; Ke, Changkang; Li, Xiaofei; Ni, Yunfeng

    2015-01-01

    Crocin, a representative of carotenoid compounds, exerts a spectrum of activities including radical scavenger, anti-microbial and anti-inflammatory properties. To investigate the protective effect of crocin on lipopolysaccharide (LPS)-induced acute lung injury (ALI) in mice. ALI was induced in mice by intratracheal instillation of LPS (1 mg/kg). The mice received intragastric injection of crocin (50 mg/kg) 1 h before LPS administration. Pulmonary histological changes were evaluated by hematoxylineosin stain and lung wet/dry weight ratios were observed. Concentrations of tumor necrosis factor (TNF)-α, interleukin (IL)-1β and nitric oxide (NO), and myeloperoxidase (MPO) activity were measured by enzymelinked immunosorbent assay. Expression of inducible nitric oxide synthase (iNOS) in lung tissues was determined by Western blot analysis. Crocin pretreatment significantly alleviated the severity of lung injury and inhibited the production of TNF-α and IL-1β in mice with ALI. After LPS administration, the lung wet/dry weight ratios, as an index of lung edema, and MPO activity were also markedly reduced by crocin pretreatment. Crocin pretreatment also reduced the concentrations of NO in lung tissues. Furthermore, the expression of iNOS was significantly suppressed by crocin pretreatment. Croncin potently protected against LPS-induced ALI and the protective effects of crocin may attribute partly to the suppression of iNOS expression. PMID:26191176

  7. Treatment for sulfur mustard lung injuries; new therapeutic approaches from acute to chronic phase

    Poursaleh Zohreh

    2012-09-01

    Full Text Available Abstract Objective Sulfur mustard (SM is one of the major potent chemical warfare and attractive weapons for terrorists. It has caused deaths to hundreds of thousands of victims in World War I and more recently during the Iran-Iraq war (1980–1988. It has ability to develop severe acute and chronic damage to the respiratory tract, eyes and skin. Understanding the acute and chronic biologic consequences of SM exposure may be quite essential for developing efficient prophylactic/therapeutic measures. One of the systems majorly affected by SM is the respiratory tract that numerous clinical studies have detailed processes of injury, diagnosis and treatments of lung. The low mortality rate has been contributed to high prevalence of victims and high lifetime morbidity burden. However, there are no curative modalities available in such patients. In this review, we collected and discussed the related articles on the preventive and therapeutic approaches to SM-induced respiratory injury and summarized what is currently known about the management and therapeutic strategies of acute and long-term consequences of SM lung injuries. Method This review was done by reviewing all papers found by searching following key words sulfur mustard; lung; chronic; acute; COPD; treatment. Results Mustard lung has an ongoing pathological process and is active disorder even years after exposure to SM. Different drug classes have been studied, nevertheless there are no curative modalities for mustard lung. Conclusion Complementary studies on one hand regarding pharmacokinetic of drugs and molecular investigations are mandatory to obtain more effective treatments.

  8. Treatment for Sulfur Mustard Lung Injuries; New Therapeutic Approaches from Acute to Chronic Phase

    Zohreh Poursaleh

    2012-09-01

    Full Text Available Objective: Sulfur mustard (SM is one of the major potent chemical warfare and attractive weapons for terrorists. It has caused deaths to hundreds of thousands of victims in World War I and more recently during the Iran-Iraq war (1980-1988. It has ability to develop severe acute and chronic damage to the respiratory tract, eyes and skin. Understanding the acute and chronic biologic consequences of SM exposure may be quite essential for developing efficient prophylactic/therapeutic measures. One of the systems majorly affected by SM is the respiratory tract that numerous clinical studies have detailed processes of injury, diagnosis and treatments of lung. The low mortality rate has been contributed to high prevalence of victims and high lifetime morbidity burden. However, there are no curative modalities available in such patients. In this review, we collected and discussed the related articles on the preventive and therapeutic approaches to SM-induced respiratory injury and summarized what is currently known about the management and therapeutic strategies of acute and long-term consequences of SM lung injuries.Method:This review was done by reviewing all papers found by searching following key words sulfur mustard; lung; chronic; acute; COPD; treatment.Results:Mustard lung has an ongoing pathological process and is active disorder even years after exposure to SM. Different drug classes have been studied, nevertheless there are no curative modalities for mustard lung. Conclusion:Complementary studies on one hand regarding pharmacokinetic of drugs and molecular investigations are mandatory to obtain more effective treatments.

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

    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.

  10. Inhaled hydrogen sulfide protects against lipopolysaccharide-induced acute lung injury in mice

    Faller Simone

    2012-10-01

    Full Text Available Abstract Background Local pulmonary and systemic infections can lead to acute lung injury (ALI. The resulting lung damage can evoke lung failure and multiple organ dysfunction associated with increased mortality. Hydrogen sulfide (H2S appears to represent a new therapeutic approach to ALI. The gas has been shown to mediate potent anti-inflammatory and organ protective effects in vivo. This study was designed to define its potentially protective role in sepsis-induced lung injury. Methods C57BL/6 N mice received lipopolysaccharide (LPS intranasally in the absence or presence of 80 parts per million H2S. After 6 h, acute lung injury was determined by comparative histology. Bronchoalveolar lavage (BAL fluid was analyzed for total protein content and differential cell counting. BAL and serum were further analyzed for interleukin-1β, macrophage inflammatory protein-2, and/or myeloperoxidase glycoprotein levels by enzyme-linked immunosorbent assays. Differences between groups were analyzed by one way analysis of variance. Results Histological analysis revealed that LPS instillation led to increased alveolar wall thickening, cellular infiltration, and to an elevated ALI score. In the presence of H2S these changes were not observed despite LPS treatment. Moreover, neutrophil influx, and pro-inflammatory cytokine release were enhanced in BAL fluid of LPS-treated mice, but comparable to control levels in H2S treated mice. In addition, myeloperoxidase levels were increased in serum after LPS challenge and this was prevented by H2S inhalation. Conclusion Inhalation of hydrogen sulfide protects against LPS-induced acute lung injury by attenuating pro-inflammatory responses.

  11. Niacinamide abrogates the organ dysfunction and acute lung injury caused by endotoxin.

    Kao, Shang-Jyh; Liu, Demeral David; Su, Chain-Fa; Chen, Hsing I

    2007-09-01

    Poly (ADP-ribose) synthabse (PARS) or polymerase (PARP) is a cytotoxic enzyme causing cellular damage. Niacinamide inhibits PARS or PARP. The present experiment tests the effects of niacinamide (NCA) on organ dysfunction and acute lung injury (ALI) following lipopolysaccharide (LPS). LPS was administered to anesthetized rats and to isolated rat lungs. In anesthetized rats, LPS caused systemic hypotension and increased biochemical factors, nitrate/nitrite (NOx), methyl guanidine (MG), tumor necrosis factoralpha (TNFalpha), and interleukin-1beta (IL-1beta). In isolated lungs, LPS increased lung weight (LW) to body weight ratio, LW gain, protein and dye tracer leakage, and capillary permeability. The insult also increased NOx, MG, TNFalpha, and IL-1beta in lung perfusate, while decreased adenosine triphosphate (ATP) content with an increase in PARP activity in lung tissue. Pathological examination revealed pulmonary edema with inflammatory cell infiltration. These changes were abrogated by posttreatment (30 min after LPS) with NCA. Following LPS, the inducible NO synthase (iNOS) mRNA expression was increased. NCA reduced the iNOS expression. Niacinamide exerts protective effects on the organ dysfunction and ALI caused by endotoxin. The mechanisms may be mediated through the inhibition on the PARP activity, iNOS expression and the subsequent suppression of NO, free radicals, and proinflammatory cytokines with restoration of ATP.

  12. Independent lung ventilation in a newborn with asymmetric acute lung injury due to respiratory syncytial virus: a case report

    Di Nardo Matteo

    2008-06-01

    Full Text Available Abstract Introduction Independent lung ventilation is a form of protective ventilation strategy used in adult asymmetric acute lung injury, where the application of conventional mechanical ventilation can produce ventilator-induced lung injury and ventilation-perfusion mismatch. Only a few experiences have been published on the use of independent lung ventilation in newborn patients. Case presentation We present a case of independent lung ventilation in a 16-day-old infant of 3.5 kg body weight who had an asymmetric lung injury due to respiratory syncytial virus bronchiolitis. We used independent lung ventilation applying conventional protective pressure controlled ventilation to the less-compromised lung, with a respiratory frequency proportional to the age of the patient, and a pressure controlled high-frequency ventilation to the atelectatic lung. This was done because a single tube conventional ventilation protective strategy would have exposed the less-compromised lung to a high mean airways pressure. The target of independent lung ventilation is to provide adequate gas exchange at a safe mean airways pressure level and to expand the atelectatic lung. Independent lung ventilation was accomplished for 24 hours. Daily chest radiograph and gas exchange were used to evaluate the efficacy of independent lung ventilation. Extubation was performed after 48 hours of conventional single-tube mechanical ventilation following independent lung ventilation. Conclusion This case report demonstrates the feasibility of independent lung ventilation with two separate tubes in neonates as a treatment of an asymmetric acute lung injury.

  13. Prone positioning ventilation for treatment of acute lung injury and acute respiratory distress syndrome

    LAN Mei-juan; HE Xiao-di

    2009-01-01

    Patients who are diagnosed with acute lung injury/acute respiratory distress syndrome (ALI/ARDS) usually have ventilation-perfusion mismatch, severe decrease in lung capacity, and gas exchange abnormalities. Health care work-ers have implemented various strategies in an attempt to compensate for these pathological alterations. By rotating patients with ALI/ARDS between the supine and prone position, it is possible to achieve a significant improvement in PaO2/FiO2, decrease shunting and therefore improve oxy-genation without use of expensive, invasive and experimen-tal procedures.

  14. Microcirculation disturbance affects rats with acute severe pancreatitis following lung injury

    Xue-Min Liu; Qing-Guang Liu; Jun Xu; Cheng-En Pan

    2005-01-01

    AIM: To study the effects of microcirculation disturbance(MD) on rats with acute severe pancreatitis (ASP).METHODS: We developed ASP rat models, and anatomized separately after 1, 3, 5, 7, and 9 h. We took out blood and did hemorrheologic examination and erythrocyte osmotic fragility test, checked up the water content, capillary permeability, and genetic expression of intercellular adhesion molecule-1 (ICAM-1) in lung tissues, examined the apoptosis degree of blood vessel endothelium while we tested related gene expression of Bax and Bcl-2in lung tissues. We did the same examination in control group.RESULTS: The viscosity of total blood and plasma, the hematocrit, and the erythrocyte osmotic fragility were all increased. Fibrinogen was decreased. The water content in lung tissues and capillary permeability were increased.Apoptosis degree of blood vessel endothelium was increased too. ICAM-1 genetic expression moved up after1 h and reached its peak value after 9 h.CONCLUSION: MD plays an important role in ASP following acute lung injury (ALI). The functional damage of blood vessel endothelium, the apoptosis of capillary vessel endothelium, WBC edging-concentration and the increasing of erythrocyte fragility are the main reasons of ALI.

  15. Galangin dampens mice lipopolysaccharide-induced acute lung injury.

    Shu, Yu-Sheng; Tao, Wei; Miao, Qian-Bing; Lu, Shi-Chun; Zhu, Ya-Bing

    2014-10-01

    Galangin, an active ingredient of Alpinia galangal, has been shown to possess anti-inflammatory and antioxidant activities. Inflammation and oxidative stress are known to play vital effect in the pathogenesis of acute lung injury (ALI). In this study, we determined whether galangin exerts lung protection in lipopolysaccharide (LPS)-induced ALI. Male BALB/c mice were randomized to receive galangin or vehicle intraperitoneal injection 3 h after LPS challenge. Samples were harvested 24 h post LPS administration. Galangin administration decreased biochemical parameters of oxidative stress and inflammation, and improved oxygenation and lung edema in a dose-dependent manner. These protective effects of galangin were associated with inhibition of nuclear factor (NF)-κB and upregulation of heme oxygenase (HO)-1. Galangin reduces LPS-induced ALI by inhibition of inflammation and oxidative stress.

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

    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.

  17. RESPIRATORY VIRAL-INFECTIONS AGGRAVATE AIRWAY DAMAGE CAUSED BY CHRONIC REJECTION IN RAT LUNG ALLOGRAFTS

    WINTER, JB; GOUW, ASH; GROEN, M; WILDEVUUR, C; PROP, J

    1994-01-01

    Airway damage resulting in bronchiolitis obliterans occurs frequently in patients after heart-lung and lung transplantation. Generally, chronic rejection is assumed to be the most important cause of bronchiolitis obliterans. However, viral infections might also be potential causes of airway damage a

  18. Intravenous immunoglobulin prevents murine antibody-mediated acute lung injury at the level of neutrophil reactive oxygen species (ROS production.

    John W Semple

    Full Text Available Transfusion-related acute lung injury (TRALI is a leading cause of transfusion-associated mortality that can occur with any type of transfusion and is thought to be primarily due to donor antibodies activating pulmonary neutrophils in recipients. Recently, a large prospective case controlled clinical study of cardiac surgery patients demonstrated that despite implementation of male donors, a high incidence of TRALI still occurred and suggested a need for additional interventions in susceptible patient populations. To examine if intravenous immunoglobulin (IVIg may be effective, a murine model of antibody-mediated acute lung injury that approximates human TRALI was examined. When BALB/c mice were injected with the anti-major histocompatibility complex class I antibody 34-1-2s, mild shock (reduced rectal temperature and respiratory distress (dyspnea were observed and pre-treatment of the mice with 2 g/kg IVIg completely prevented these symptoms. To determine IVIg's usefulness to affect severe lung damage, SCID mice, previously shown to be hypersensitive to 34-1-2s were used. SCID mice treated with 34-1-2s underwent severe shock, lung damage (increased wet/dry ratios and 40% mortality within 2 hours. Treatment with 2 g/kg IVIg 18 hours before 34-1-2s administration completely protected the mice from all adverse events. Treatment with IVIg after symptoms began also reduced lung damage and mortality. While the prophylactic IVIg administration did not affect 34-1-2s-induced pulmonary neutrophil accumulation, bone marrow-derived neutrophils from the IVIg-treated mice displayed no spontaneous ROS production nor could they be stimulated in vitro with fMLP or 34-1-2s. These results suggest that IVIg prevents murine antibody-mediated acute lung injury at the level of neutrophil ROS production and thus, alleviating tissue damage.

  19. Paraquat poisoning: an experimental model of dose-dependent acute lung injury due to surfactant dysfunction

    M.F.R. Silva

    1998-03-01

    Full Text Available Since the most characteristic feature of paraquat poisoning is lung damage, a prospective controlled study was performed on excised rat lungs in order to estimate the intensity of lesion after different doses. Twenty-five male, 2-3-month-old non-SPF Wistar rats, divided into 5 groups, received paraquat dichloride in a single intraperitoneal injection (0, 1, 5, 25, or 50 mg/kg body weight 24 h before the experiment. Static pressure-volume (PV curves were performed in air- and saline-filled lungs; an estimator of surface tension and tissue works was computed by integrating the area of both curves and reported as work/ml of volume displacement. Paraquat induced a dose-dependent increase of inspiratory surface tension work that reached a significant two-fold order of magnitude for 25 and 50 mg/kg body weight (P<0.05, ANOVA, sparing lung tissue. This kind of lesion was probably due to functional abnormalities of the surfactant system, as was shown by the increase in the hysteresis of the paraquat groups at the highest doses. Hence, paraquat poisoning provides a suitable model of acute lung injury with alveolar instability that can be easily used in experimental protocols of mechanical ventilation

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

    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

  1. Dose-dependence of the time of appearance of lung damage in mice given thoracic irradiation

    Collis, C.H.; Steel, G.G. (Institute of Cancer Research, Sutton (UK). Surrey Branch)

    1982-09-01

    Male CBA mice were given X-radiation to the thorax in the range 7 to 23 Gy and their response was quantified by measuring ventilation rate and carbon monoxide uptake at intervals up to 2 years thereafter; their survival was also documented. The two functional end-points were similarly sensitive indicators of lung damage. Radiation damage was not observed below 10 Gy. As radiation dose was raised above this level there was a rapid shortening of the time to the appearance of damage and subsequent death. At a dose of 15 Gy the median survival time was 14 weeks but raising the dose above this level only slightly reduced the survival time. The way in which the time of survival after lung damage depends on dose is an important characteristic of the development of radiation-induced lung damage which should be considered when examining factors that may influence the development of radiation-induced lung damage.

  2. Unilateral Hydronephrosis and Renal Damage after Acute Leukemia

    Egle Simanauskiene

    2012-01-01

    Full Text Available A 14-year-old boy presented with asymptomatic right hydronephrosis detected on routine yearly ultrasound examination. Previously, he had at least two normal renal ultrasonograms, 4 years after remission of acute myeloblastic leukemia, treated by AML-BFM-93 protocol. A function of the right kidney and no damage on the left was confirmed by a DMSA scan. Right retroperitoneoscopic nephrectomy revealed 3 renal arteries with the lower pole artery lying on the pelviureteric junction. Histologically chronic tubulointerstitial nephritis was detected. In the pathogenesis of this severe unilateral renal damage, we suspect the exacerbation of deleterious effects of cytostatic therapy on kidneys with intermittent hydronephrosis.

  3. Resveratrol ameliorates LPS-induced acute lung injury via NLRP3 inflammasome modulation.

    Jiang, Lei; Zhang, Lei; Kang, Kai; Fei, Dongsheng; Gong, Rui; Cao, Yanhui; Pan, Shangha; Zhao, Mingran; Zhao, Mingyan

    2016-12-01

    NLRP3 inflammasome plays a pivotal role in the development of acute lung injury (ALI), accelerating IL-1β and IL-18 release and inducing lung inflammation. Resveratrol, a natural phytoalexin, has anti-inflammatory properties via inhibition of oxidation, leukocyte priming, and production of inflammatory mediators. In this study, we aimed to investigate the effect of resveratrol on NLRP3 inflammasome in lipopolysaccharide-induced ALI. Mice were intratracheally instilled with 3mg/kg lipopolysaccharide (LPS) to induce ALI. Resveratrol treatment alleviated the LPS-induced lung pathological damage, lung edema and neutrophil infiltration. In addition, resveratrol reversed the LPS-mediated elevation of IL-1β and IL-18 level in the BAL fluids. In lung tissue, resveratrol also inhibited the LPS-induced NLRP3, ASC, caspase-1 mRNA and protein expression, and NLRP3 inflammasome activation. Moreover, resveratrol administration not only suppressed the NF-κB p65 nuclear translocation, NF-κB activity and ROS production in the LPS-treated mice, but also inhibited the LPS-induced thioredoxin-interacting protein (TXNIP) protein expression and interaction of TXNIP-NLRP3 in lung tissue. Meanwhile, resveratrol obviously induced SIRT1 mRNA and protein expression in the LPS-challenged mice. Taken together, our study suggests that resveratrol protects against LPS-induced lung injury by NLRP3 inflammasome inhibition. These findings further suggest that resveratrol may be of great value in the treatment of ALI and a potential and an effective pharmacological agent for inflammasome-relevant diseases.

  4. Interleukin-19 mediates tissue damage in murine ischemic acute kidney injury.

    Yu-Hsiang Hsu

    Full Text Available Inflammation and renal tubular injury are major features of acute kidney injury (AKI. Many cytokines and chemokines are released from injured tubular cells and acts as proinflammatory mediators. However, the role of IL-19 in the pathogenesis of AKI is not defined yet. In bilateral renal ischemia/reperfusion injury (IRI-induced and HgCl2-induced AKI animal models, real-time quantitative (RTQ-PCR showed that the kidneys, livers, and lungs of AKI mice expressed significantly higher IL-19 and its receptors than did sham control mice. Immunohistochemical staining showed that IL-19 and its receptors were strongly stained in the kidney, liver, and lung tissue of AKI mice. In vitro, IL-19 upregulated MCP-1, TGF-β1, and IL-19, and induced mitochondria-dependent apoptosis in murine renal tubular epithelial M-1 cells. IL-19 upregulated TNF-α and IL-10 in cultured HepG2 cells, and it increased IL-1β and TNF-α expression in cultured A549 cells. In vivo, after renal IRI or a nephrotoxic dose of HgCl2 treatment, IL-20R1-deficient mice (the deficiency blocks IL-19 signaling showed lower levels of blood urea nitrogen (BUN in serum and less tubular damage than did wild-type mice. Therefore, we conclude that IL-19 mediates kidney, liver, and lung tissue damage in murine AKI and that blocking IL-19 signaling may provide a potent therapeutic strategy for treating AKI.

  5. The clinical significance of lung hypoexpansion in acute childhood asthma

    Spottswood, Stephanie E. [Department of Radiology, Medical College of Virginia, Virginia Commonwealth University Health System, Box 980615, 23298-0615, Richmond, VA (United States); Department of Radiology, The Children' s Hospital of the King' s Daughters, 601 Children' s Lane, Norfolk, VA 23507 (United States); Allison, Kelley Z.; Narla, Lakshmana D.; Lowry, Patricia A. [Department of Radiology, Medical College of Virginia, Virginia Commonwealth University Health System, Box 980615, 23298-0615, Richmond, VA (United States); Lopatina, Olga A.; Sethi, Narinder N. [School of Medicine, Medical College of Virginia, Virginia Commonwealth University Health System, Richmond, VA (United States); Nettleman, Mary D. [Department of Internal Medicine, B-427 Clinical Center, Michigan State University, East Lansing, MI 48824 (United States)

    2004-04-01

    Many children experiencing acute asthmatic episodes have chest radiographs, which may show lung hyperinflation, hypoinflation, or normal inflation. Lung hypoinflation may be a sign of respiratory fatigue and poor prognosis. To compare the clinical course in children with asthma according to the degree of lung inflation on chest radiographs. We conducted a retrospective study during a 24-month period (from July 1999 to July 2001) of children aged 0-17 years, who presented to a pediatric emergency department or outpatient clinic with an asthma exacerbation. Chest radiographs obtained at presentation were reviewed independently by three pediatric radiologists who were blinded to the admission status of the patient. The correlation between hypoinflation and hospital admission was assessed in three age groups: 0-2 years, 3-5 years, and 6-17 years. Hypoinflation on chest radiographs was significantly correlated with hospital admission for children aged 6-17 years (odds ratio 16.00, 95% confidence interval 1.89-135.43). The inter-reader agreement for interpretation of these radiographs was strong, with a kappa score of 0.76. Hypoinflation was not correlated with admission in younger children. Lung hypoinflation is associated with a greater likelihood of hospital admission in children aged 6 years or older. Therefore, hypoinflation was a poor prognostic sign and may warrant more aggressive therapy. (orig.)

  6. Intravenous transplantation of mesenchymal stem cells attenuates oleic acid induced acute lung injury in rats

    XU Yu-lin; LIU Ying-long; WANG Qiang; LI Gang; L(U) Xiao-dong; KONG Bo

    2012-01-01

    Background Acute lung injury (ALI) and end-stage acute respiratory distress syndrome (ARDS) were among the most common causes of death in intensive care units.The activation of an inflammatory response and the damage of pulmonary epithelium and endotheliumwerethe hallmark of ALI/ARDS.Recent studies had demonstrated the importance of mesenchymal stem cells (MSCs) in maintaining the normal pulmonary endothelial and epithelial function as well as participating in modulating the inflammatory response and they are involved in epithelial and endothelial repair after injury.Here,our study demonstrates MSCs therapeutic potential in a rat model of ALI/ARDS.Methods Bone marrow derived MSCs were obtained from Sprague-Dawley (SD) rats and their differential potential was verified.ALl was induced in rats byoleic acid (OA),and MSCs were transplanted intravenously.The lung injury and the concentration of cytokines in plasma and lung tissue extracts were assessed at 8 hours,24 hours and 48 hours after OA-injection.Results The histological appearance and water content in rat lung tissue were significantly improved at different time points in rats treated with MSCs.The concentration of tumor necrosis factor-α and intercellular adhesion molecular-1 in rats plasma and lung tissue extracts were significantly inhibited after intravenous transplantation of MSCs,whereas interleukin-10 was significantly higher after MSCs transplantation at 8 hours,24 hours and 48 hours after OA-challenge.Conclusions Intravenous transplantation of MSCs could maintain the integrity of the pulmonary alveolar-capillary barrier and modulate the inflammatory response to attenuate the experimental ALI/ARDS.Transplantation of MSCs could be a novel cell-based therapeutic strategy for prevention and treatment of ALI/ARDS.

  7. Oxidative Damage to Lung Tissue and Peripheral Blood in Endotracheal PM2.5-treated Rats

    ZHI-QING LIN; ZHU-GE XI; DAN-FENG YANG; FU-HUAN CHAO; HUA-SHAN ZHANG; WEI ZHANG; HUANG-LIANG LIU; ZAI-MING YANG; RU-BAO SUN

    2009-01-01

    Objective To investigate the oxidative damage to lung tissue and peripherial blood in PM2.5-treated rats.Methods PM2.5 samples were collected using an auto-sampling instrument in summer and winter.Treated samples were endotracheally instilled into rats.Activity of reduced glutathione peroxidase (GSH-Px) and concentration of malondialdehyde (MDA) were used as oxidative damage biomarkers of lung tissue and peripheral blood detected with the biochemical method.DNA migration length (μm) and rate of tail were used as DNA damage biomarkers of lung tissue and peripheral blood detected with the biochemical method. Results The activity of GSH-Px and the concentration of MDA in lung tissue significantly decreased after exposure to PM2.5 for 7-14 days.In peripheral blood,the concentration of MDA decreased,but the activity of GSH-Px increased 7 and 14 days after experiments.The two indicators had a dose-effect relation and similar changing tendency in lung tissue and peripheral blood.The DNA migration length (μm) and rate of tail in lung tissue and peripheral blood significantly increased 7 and 14 days after exposure to PM2.5.The two indicators had a dose-effect relation and similar changing tendency in lung tissue and peripheral blood. Conclusion PM2.5 has a definite oxidative effect on lung tissue and peripheral blood.The activity of GSH-Px and the concentration of MDA are valuable biomarkers of oxidative lung tissue damage induced by PM2.5.The DNA migration length (μm) and rate of tail are simple and valuable biomarkers of PM2.5-induced DNA damage in lung tissues and peripheral blood.The degree of DNA damage in peripheral blood can predict the degree of DNA damage in lung tissue.

  8. Pulmonary Surfactants for Acute and Chronic Lung Diseases (Part II

    O. A. Rozenberg

    2014-01-01

    Full Text Available Part 2 of the review considers the problem of surfactant therapy for acute respiratory distress syndrome (ARDS in adults and young and old children. It gives information on the results of surfactant therapy and prevention of ARDS in patients with severe concurrent trauma, inhalation injuries, complications due to complex expanded chest surgery, or severe pneumonias, including bilateral pneumonia in the presence of A/H1N1 influenza. There are data on the use of a surfactant in obstetric care and prevention of primary graft dysfunction during lung transplantation. The results of longterm use of surfactant therapy in Russia, suggesting that death rates from ARDS may be substantially reduced (to 20% are discussed. Examples of surfactant therapy for other noncritical lung diseases, such as permanent athelectasis, chronic obstructive pulmonary diseases, and asthma, as well tuberculosis, are also considered.

  9. [Ventilation in acute respiratory distress. Lung-protective strategies].

    Bruells, C S; Rossaint, R; Dembinski, R

    2012-11-01

    Ventilation of patients suffering from acute respiratory distress syndrome (ARDS) with protective ventilator settings is the standard in patient care. Besides the reduction of tidal volumes, the adjustment of a case-related positive end-expiratory pressure and preservation of spontaneous breathing activity at least 48 h after onset is part of this strategy. Bedside techniques have been developed to adapt ventilatory settings to the individual patient and the different stages of ARDS. This article reviews the pathophysiology of ARDS and ventilator-induced lung injury and presents current evidence-based strategies for ventilator settings in ARDS.

  10. Protective Effect of Isorhamnetin on Lipopolysaccharide-Induced Acute Lung Injury in Mice.

    Yang, Bo; Li, Xiao-Ping; Ni, Yun-Feng; Du, Hong-Yin; Wang, Rong; Li, Ming-Jiang; Wang, Wen-Chen; Li, Ming-Ming; Wang, Xu-Hui; Li, Lei; Zhang, Wei-Dong; Jiang, Tao

    2016-02-01

    Isorhamnetin has been reported to have anti-inflammatory, anti-oxidative, and anti-proliferative effects. The aim of this study was to investigate the protective effect of isorhamnetin on lipopolysaccharide (LPS)-induced acute lung injury (ALI) in mice by inhibiting the expression of cyclooxygenase-2 (COX-2). The effects of isorhamnetin on LPS-induced lung pathological damage, wet/dry ratios and the total protein level in bronchoalveolar lavage fluid (BALF), inflammatory cytokine release, myeloperoxidase (MPO) and superoxide dismutase (SOD) activities, and malondialdehyde (MDA) level were examined. In addition, the COX-2 activation in lung tissues was detected by Western blot. Isorhamnetin pretreatment improved the mice survival rates. Moreover, isorhamnetin pretreatment significantly attenuated edema and the pathological changes in the lung and inhibited protein extravasation in BALF. Isorhamnetin also significantly decreased the levels of inflammatory cytokines in BALF. In addition, isorhamnetin markedly prevented LPS-induced oxidative stress. Furthermore, isorhamnetin pretreatment significantly suppressed LPS-induced activation of COX-2. Isorhamnetin has been demonstrated to protect mice from LPS-induced ALI by inhibiting the expression of COX-2.

  11. TCM Therapeutic Strategy on Acute Lung Injury Caused by Infectious Atypical Pneumonia and Acute Respiratory Distress Syndrome

    唐光华

    2003-01-01

    @@ Infectious atypical pneumonia (IAP) is also called severe acute respiratory syndrome (SARS) by WHO. In its development, around 20% of SARS can develop into the stage of acute lung injury (ALI) or acute respiratory distress syndrome (ARDS), active and effective treatment of it constitutes the important basis for lowering mortality and reducing secondary pulmonary function impairment and pulmonary fibrosis.

  12. Inhaled nitric oxide for acute respiratory distress syndrome (ARDS) and acute lung injury in children and adults

    Afshari, Arash; Brok, Jesper; Møller, Ann

    2010-01-01

    Acute hypoxaemic respiratory failure (AHRF), defined as acute lung injury (ALI) and acute respiratory distress syndrome (ARDS), are critical conditions. AHRF results from a number of systemic conditions and is associated with high mortality and morbidity in all ages. Inhaled nitric oxide (INO) has...

  13. Smoking-promoted oxidative DNA damage response is highly correlated to lung carcinogenesis.

    Cao, Chao; Lai, Tianwen; Li, Miao; Zhou, Hongbin; Lv, Dan; Deng, Zaichun; Ying, Songmin; Chen, Zhihua; Li, Wen; Shen, Huahao

    2016-04-05

    Oxidative stress induced by tobacco smoking is one of the main causes of DNA damage and is known to be involved in various cancers. Smoking is the leading cause of lung cancer, while the role of cigarette smoke-induced oxidative DNA damage response during lung carcinogenesis is largely unknown. In this study, we investigated oxidative DNA damage response levels in smoking and nonsmoking patients with lung cancer, and evaluated the potential diagnostic value of 8-OHdG for lung cancer. We observed a higher level of 8-OHdG expression and secretion in airways of lung cancer patients than that of noncancer controls. 8-OHdG expression was associated with the TNM stages. Additionally, cigarette smoke-induced oxidative DNA damage response was observed in bronchial epithelial cells in vitro and in vivo. A statistical significance correlation was found between the levels of 8-OHdG and smoking index. With a cut-off value of 2.86 ng/ml, 8-OHdG showed a sensitivity and specificity of 70.0% and 73.7%, respectively, to identify a patient with lung cancer. These findings not only underscore the importance of smoking in oxidative DNA damage response of lung cancer patients, but also suggest 8-OHdG as a potential diagnostic biomarker for lung cancer.

  14. Acute lung injury and acute respiratory distress syndrome: experimental and clinical investigations

    Hsing I Chen

    2011-01-01

    Acute lung injury (ALI) or acute respiratory distress syndrome (ARDS) can be associated with various disorders.Recent investigation has involved clinical studies in collaboration with clinical investigators and pathologists on the pathogenetic mechanisms of ALl or ARDS caused by various disorders.This literature review includes a brief historical retrospective of ALI/ARDS, the neurogenic pulmonary edema due to head injury, the long-term experimental studies and clinical investigations from our laboratory, the detrimental role of NO, the risk factors, and the possible pathogenetic mechanisms as well as therapeutic regimen for ALI/ARDS.

  15. Attenuation of acute nitrogen mustard-induced lung injury, inflammation and fibrogenesis by a nitric oxide synthase inhibitor

    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

  16. Arctigenin attenuates lipopolysaccharide-induced acute lung injury in rats.

    Shi, Xianbao; Sun, Hongzhi; Zhou, Dun; Xi, Huanjiu; Shan, Lina

    2015-04-01

    Arctigenin (ATG) has been reported to possess anti-inflammatory properties. However, the effects of ATG on lipopolysaccharide (LPS)-induced acute lung injury (ALI) remains not well understood. In the present study, our investigation was designed to reveal the effect of ATG on LPS-induced ALI in rats. We found that ATG pretreatment attenuated the LPS-induced ALI, as evidenced by the reduced histological scores, myeloperoxidase activity, and wet-to-dry weight ratio in the lung tissues. This was accompanied by the decreased levels of tumor necrosis factor alpha (TNF-α), interleukin-1β (IL-1β), and interleukin-1 (IL-6) in the bronchoalveolar lavage fluid. Furthermore, ATG downregulated the expression of nuclear factor kappa B (NF-κB) p65, promoted the phosphorylation of inhibitor of nuclear factor-κB-α (IκBα) and activated the adenosine 5'-monophosphate (AMP)-activated protein kinase (AMPKα) in the lung tissues. Our results suggested that ATG attenuates the LPS-induced ALI via activation of AMPK and suppression of NF-κB signaling pathway.

  17. Acute lung injury | EU Clinical Trials Register [EU Clinical Trials Register

    Full Text Available reductase inhibition with simvastatin in Acute lung injury to Reduce Pulmonary dysfunction(HARP 2) A.3.1Tit...ical condition(s) being investigated Acute lung injury E.1.1.1Medical condition in easily understood languag...eclined to onset is defined as follows: th

  18. The role of the acute phase protein PTX3 in the ventilator-induced lung injury

    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.

  19. DNA damage in lung after oral exposure to diesel exhaust particles in Big Blue (R) rats

    Müller, Anne Kirstine; Farombi, E.O.; Møller, P.

    2004-01-01

    . Lung tissue is a target organ for DEP induced cancer following inhalation. Recent studies have provided evidence that the lung is also a target organ for DNA damage and cancer after oral exposure to other complex mixtures of PAHs. The genotoxic effect of oral administration of DEP was investigated...

  20. A new CT-based method to quantify radiation-induced lung damage in patients.

    Ghobadi, Ghazaleh; Wiegman, Erwin M; Langendijk, Johannes A; Widder, Joachim; Coppes, Robert P; van Luijk, Peter

    2015-10-01

    A new method to assess radiation-induced lung toxicity (RILT) using CT-scans was developed. It is more sensitive in detecting damage and corresponds better to physician-rated radiation pneumonitis than routinely-used methods. Use of this method may improve lung toxicity assessment and thereby facilitate development of more accurate predictive models for RILT.

  1. Black tea prevents cigarette smoke-induced apoptosis and lung damage

    Chattopadhyay Dhrubajyoti

    2007-02-01

    Full Text Available Abstract Background Cigarette smoking is a major cause of lung damage. One prominent deleterious effect of cigarette smoke is oxidative stress. Oxidative stress may lead to apoptosis and lung injury. Since black tea has antioxidant property, we examined the preventive effect of black tea on cigarette smoke-induced oxidative damage, apoptosis and lung injury in a guinea pig model. Methods Guinea pigs were subjected to cigarette smoke exposure from five cigarettes (two puffs/cigarette per guinea pig/day for seven days and given water or black tea to drink. Sham control guinea pigs were exposed to air instead of cigarette smoke. Lung damage, as evidenced by inflammation and increased air space, was assessed by histology and morphometric analysis. Protein oxidation was measured through oxyblot analysis of dinitrophenylhydrazone derivatives of the protein carbonyls of the oxidized proteins. Apoptosis was evidenced by the fragmentation of DNA using TUNEL assay, activation of caspase 3, phosphorylation of p53 as well as over-expression of Bax by immunoblot analyses. Results Cigarette smoke exposure to a guinea pig model caused lung damage. It appeared that oxidative stress was the initial event, which was followed by inflammation, apoptosis and lung injury. All these pathophysiological events were prevented when the cigarette smoke-exposed guinea pigs were given black tea infusion as the drink instead of water. Conclusion Cigarette smoke exposure to a guinea pig model causes oxidative damage, inflammation, apoptosis and lung injury that are prevented by supplementation of black tea.

  2. Reverse-migrated neutrophils regulated by JAM-C are involved in acute pancreatitis-associated lung injury.

    Wu, Deqing; Zeng, Yue; Fan, Yuting; Wu, Jianghong; Mulatibieke, Tunike; Ni, Jianbo; Yu, Ge; Wan, Rong; Wang, Xingpeng; Hu, Guoyong

    2016-02-04

    Junctional adhesion molecule-C (JAM-C) plays a key role in the promotion of the reverse transendothelial migration (rTEM) of neutrophils, which contributes to the dissemination of systemic inflammation and to secondary organ damage. During acute pancreatitis (AP), systemic inflammatory responses lead to distant organ damage and typically result in acute lung injury (ALI). Here, we investigated the role of rTEM neutrophils in AP-associated ALI and the molecular mechanisms by which JAM-C regulates neutrophil rTEM in this disorder. In this study, rTEM neutrophils were identified in the peripheral blood both in murine model of AP and human patients with AP, which elevated with increased severity of lung injury. Pancreatic JAM-C was downregulated during murine experimental pancreatitis, whose expression levels were inversely correlated with both increased neutrophil rTEM and severity of lung injury. Knockout of JAM-C resulted in more severe lung injury and systemic inflammation. Significantly greater numbers of rTEM neutrophils were present both in the circulation and pulmonary vascular washout in JAM-C knockout mice with AP. This study demonstrates that during AP, neutrophils that are recruited to the pancreas may migrate back into the circulation and then contribute to ALI. JAM-C downregulation may contribute to AP-associated ALI via promoting neutrophil rTEM.

  3. Proteasome inhibitor ameliorates severe acute pancreatitis and associated lung injury of rats

    Xi Chen; Shun-Le Li; Tao Wu; Ji-Dong Liu

    2008-01-01

    AIM:To observe the effect of proteasome inhibitor MG-132 on severe acute pancreatitis (SAP) and associated lung injury of rats.METHODS:Male adult SD rats were randomly divided into SAP group,sham-operation group,and MG-132 treatment group.A model of SAP was established by injection of 5% sodium taurocholate into the biliarypancreatic duct of rats.The MG-132 group was pretreated with 10 mg/kg MG-132 intraperitoneally (ip) 30 rnin before the induction of pancreatitis.The changes in serum amylase,myeloperoxidase (MPO) activity of pancreatic and pulmonary tissue were measured.The TNF-α level in pancreatic cytosolic fractions was assayed with an enzyme-linked immunosorbent assay (ELISA) kit.Meanwhile,the pathological changes in both pancreatic and pulmonary tissues were also observed.RESULTS:MG-132 significantly decreased serum amylase,pancreatic weight/body ratio,pancreatic TNF-α level,pancreatic and pulmonary MPO activity (P < 0.05).Histopathological examinations revealed that pancreatic and pulmonary samples from rats pretreated with MG-132 demonstrated milder edema,cellular damage,and inflammatory activity (P < 0.05).CONCLUSION:The proteasome inhibitor MG-132shows a protective effect on severe acute pancreatitis and associated lung injury of rats.

  4. Hepatic damage during acute pancreatitis in the rat

    A.M.M. Coelho

    1997-08-01

    Full Text Available We studied the alterations in the metabolism of liver mitochondria in rats with acute pancreatitis. Male Wistar rats were allocated to a control group (group I and to five other groups corresponding to 2, 4, 12, 24 and 48 h after the induction of acute pancreatitis by the injection of 5% sodium taurocholate into the pancreatic duct. Sham-operated animals were submitted to the same surgical steps except for the induction of acute pancreatitis. Mitochondrial oxidation and phosphorylation were measured polarographically by determining oxygen consumption without ADP (basal respiration, state 4 and in the presence of ADP (activated respiration, state 3. Serum amylase, transaminases (ALT and AST and protein were also determined. Ascitic fluid, contents of amylase, trypsin and total protein were also determined and arterial blood pressure was measured in all groups. In ascitic fluid, trypsin and amylase increased reaching a maximum at 2 and 4 h, respectively. Serum amylase increased at 2 h reaching a maximum at 4 h. Serum transaminase levels increased at 12 and 24 h. After 2 h (and also 4 h there was an increase in state 4 respiration (45.65 ± 1.79 vs 28.96 ± 1.50 and a decrease in respiration control rate (3.53 ± 0.09 vs 4.45 ± 0.08 and in the ADP/O ratio (1.77 ± 0.02 vs 1.91 ± 0.01 compared to controls (P<0.05. These results indicate a disruption of mitochondrial function, which recovered after 12 h. In the 48-h groups there was mitochondrial damage similar to that occurring in ischemic lesion. Beat-to-beat analysis (30 min showed that arterial blood pressure remained normal up to 24 h (111 ± 3 mmHg while a significant decrease occurred in the 48-h group (91 ± 4 mmHg. These data suggest biphasic damage in mitochondrial function in acute pancreatitis: an initial uncoupled phase, possibly secondary to enzyme activity, followed by a temporary recovery and then a late and final dysfunction, associated with arterial hypotension, possibly related

  5. Biomarkers of acute lung injury: worth their salt?

    Proudfoot Alastair G

    2011-12-01

    Full Text Available Abstract The validation of biomarkers has become a key goal of translational biomedical research. The purpose of this article is to discuss the role of biomarkers in the management of acute lung injury (ALI and related research. Biomarkers should be sensitive and specific indicators of clinically important processes and should change in a relevant timeframe to affect recruitment to trials or clinical management. We do not believe that they necessarily need to reflect pathogenic processes. We critically examined current strategies used to identify biomarkers and which, owing to expedience, have been dominated by reanalysis of blood derived markers from large multicenter Phase 3 studies. Combining new and existing validated biomarkers with physiological and other data may add predictive power and facilitate the development of important aids to research and therapy.

  6. Comparison of the effects of erdosteine and N-acetylcysteine on apoptosis regulation in endotoxin-induced acute lung injury.

    Demiralay, Rezan; Gürsan, Nesrin; Ozbilim, Gülay; Erdogan, Gülgün; Demirci, Elif

    2006-01-01

    This study was carried out to investigate comparatively the frequency of apoptosis in lung epithelial cells after intratracheal instillation of endotoxin [lipopolysaccharide (LPS)] in rats and the role of tumor necrosis factor alpha (TNF-alpha) on apoptosis, and the effects of erdosteine and N-acetylcysteine on the regulation of apoptosis. Female Wistar rats were given oral erdosteine (10-500 mg kg(-1)) or N-acetylcysteine (10-500 mg kg(-1)) once a day for 3 consecutive days. Then the rats were intratracheally instilled with LPS (5 mg kg(-1)) to induce acute lung injury. The rats were killed at 24 h after LPS administration. Lung tissue samples were stained with hematoxylin-eosin for histopathological assessments. The apoptosis level in the lung bronchial and bronchiolar epithelium was determined using the TUNEL (terminal deoxynucleotidyl transferase-mediated dUTP nick endlabelling) method. Cytoplasmic TNF-alpha was evaluated by immunohistochemistry. Pretreatment with erdosteine and pretreatment with N-acetylcysteine at a dose of 10 mg kg(-1) had no protective effect on LPS-induced lung injury. When the doses of drugs increased, the severity of the lung damage caused by LPS decreased. It was found that as the pretreatment dose of erdosteine was increased, the rate of apoptosis induced by LPS in lung epithelial cells decreased and this decrease was statistically significant in doses of 300 mg kg(-1) and 500 mg kg(-1). Pretreatment with N-acetylcysteine up to a dose of 500 mg kg(-1) did not show any significant effect on apoptosis regulation. It was noticed that both antioxidants had no significant effect on the local production level of TNF-alpha. These findings suggest that erdosteine could be a possible therapeutic agent for acute lethal lung injury and its mortality.

  7. Effects of peroxisome proliferator-activated receptor-β/δ on sepsis induced acute lung injury

    Wang Cairui; Zhou Guopeng; Zeng Zeng

    2014-01-01

    Background Acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) are the first steps in the development of multiple organ failure induced by sepsis.A systemic excessive inflammatory reaction is currently the accepted mechanism of the pathogenesis of sepsis.Several studies have suggested a protective role of the peroxisome proliferator activated receptor-β/δ (PPAR-β/δ) in related inflammatory diseases.But the role of PPARβ/δ in ALI remains uncertain.The aim of this study was to investigate the role and possible mechanism of PPARβ/δ in ALI induced by sepsis.Methods Cecal ligation and puncture (CLP) was used as a sepsis model.Rats were randomly divided into four groups,the control group (CON,n=6),sham-operation group (SHAM,n=12),cecal ligation and puncture group (CLP,n=30),GW501516 group (CLP+GW,n=25),which underwent CLP and were subcutaneously injected with the PPAR-β/δ agonist GW501516 (0.05 mg/100 g body weight).Survival was monitored to 24 hours after operation.Blood pressure,serum creatinine,blood urea nitrogen,aspartate aminotrasferase and alanine aminotrasferase were measured after CLP.Concentrations of tumor necrosis factor α (TNF-α) and interleukin (IL)-1β in serum were detected by enzyme linked immunosorbent assay (ELISA) kits.Lung tissue samples were stained with H&E and scored according to the degree of inflammation.Bacterial colonies were counted in the peritoneal fluid.Alveolar macrophages were cultured and incubated with GW501516 (0.15 μmol/L) and PPARβ/δ adenovirus and then treated with Lipopolysaccharide (2 μg/ml) for 2 hours.The TNF-α,IL-1β and IL-6 RNA in lung and alveolar macrophages were determined by real-time PCR.Phosphorylation of signal transducer and activator of transcription 3 (STAT3) in lung and alveolar macrophages was detected by Western blotting.Results GW501516 significantly increased the survival of septic rats,decreased histological damage of the lungs,reduced inflammatory cytokines in serum and

  8. Protective effects of erythropoietin against acute lung injury in a rat model of acute necrotizing pancreatitis

    2007-01-01

    AIM: To investigate the effect of exogenous erythropoietin (EPO) administration on acute lung injury (ALI) in an experimental model of sodium taurodeoxycholateinduced acute necrotizing pancreatitis (ANP).METHODS: Forty-seven male Wistar albino rats were randomly divided into 7 groups: sham group (n = 5),3 ANP groups (n = 7 each) and 3 EPO groups (n = 7each). ANP was induced by retrograde infusion of 5% sodium taurodeoxycholate into the common bile duct.Rats in EPO groups received 1000 U/kg intramuscular EPO immediately after induction of ANP. Rats in ANP groups were given 1 mL normal saline instead. All animals were sacrificed at postoperative 24 h, 48 h and 72 h. Serum amilase, IL-2, IL-6 and lung tissue malondialdehyde (MDA) were measured. Pleural effusion volume and lung/body weight (LW/BW) ratios were calculated. Tissue levels of TNF-α, IL-2 and IL-6 were screened immunohistochemically. Additionally, ox-LDL accumulation was assessed with immune-fluorescent staining. Histopathological alterations in the lungs were also scored.RESULTS: The mean pleural effusion volume, calculated LW/BW ratio, serum IL-6 and lung tissue MDA levels were significantly lower in EPO groups than in ANP groups. No statistically significant difference was observed in either serum or tissue values of IL-2 among the groups. The level of tumor necrosis factor-α (TNF-α)and IL-6 and accumulation of ox-LDL were evident in the lung tissues of ANP groups when compared to EPO groups, particularly at 72 h. Histopathological evaluation confirmed the improvement in lung injury parameters after exogenous EPO administration, particularly at 48 h and 72 h.CONCLUSION: EPO administration leads to a significant decrease in ALI parameters by inhibiting polymorphonuclear leukocyte (PMNL) accumulation,decreasing the levels of proinflammatory cytokines in circulation, preserving microvascular endothelial cell integrity and reducing oxidative stress-associated lipid peroxidation and therefore, can be

  9. Acute Lung Injury | EU Clinical Trials Register [EU Clinical Trials Register

    Full Text Available rnedUK - MHRA A.2EudraCT number2010-021186-70 A.3Full title of the trial Keratinocyte growth factor in Acute...reviated title of the trial where available Keratinocyte Growth Factor in Acute L...nder investigation E.1.1Medical condition(s) being investigated Acute Lung Injury

  10. Endothelial glycocalyx damage is associated with leptospirosis acute kidney injury.

    Libório, Alexandre Braga; Braz, Marcelo Boecker Munoz; Seguro, Antonio Carlos; Meneses, Gdayllon C; Neves, Fernanda Macedo de Oliveira; Pedrosa, Danielle Carvalho; Cavalcanti, Luciano Pamplona de Góes; Martins, Alice Maria Costa; Daher, Elizabeth de Francesco

    2015-03-01

    Leptospirosis is a common disease in tropical countries, and the kidney is one of the main target organs. Membrane proteins of Leptospira are capable of causing endothelial damage in vitro, but there have been no studies in humans evaluating endothelial glycocalyx damage and its correlation with acute kidney injury (AKI). We performed a cohort study in an outbreak of leptospirosis among military personnel. AKI was diagnosed in 14 of 46 (30.4%) patients. Leptospirosis was associated with higher levels of intercellular adhesion molecule-1 (ICAM-1; 483.1 ± 31.7 versus 234.9 ± 24.4 mg/L, P leptospirosis-associated AKI had increased level of syndecan-1 (112.1 ± 45.4 versus 41.5 ± 11.7 ng/mL, P = 0.021) and ICAM-1 (576.9 ± 70.4 versus 434.9 ± 35.3, P = 0.034) compared with leptospirosis patients with no AKI. Association was verified between syndecan-1 and ICAM-1 with serum creatinine elevation and neutrophil gelatinase-associated lipocalin (NGAL) levels. This association remained even after multivariate analysis including other AKI-associated characteristics. Endothelial injury biomarkers are associated with leptospirosis-associated renal damage.

  11. Protective effects of imipramine in murine endotoxin-induced acute lung injury.

    Yang, Jin; Qu, Jie-ming; Summah, Hanssa; Zhang, Jin; Zhu, Ying-gang; Jiang, Hong-ni

    2010-07-25

    The tricyclic antidepressant imipramine has recently emerged as a cytoprotective agent, exerting beneficial effects in inflammatory tissue injury. The present study aimed to investigate therapeutic effects of imipramine in murine model of endotoxin-induced acute lung injury. Mice were administrated intraperitoneally with LPS (lipopolysaccharide) from Escherichia coli or vehicle. Imipramine was administrated intraperitoneally 30 min before LPS challenge. Pretreatment of mice with imipramine reduced lethality. Impramine also significantly attenuated lung inflammation, lung edema, MPO (myeloperoxidase) activity, lung tissue pathological changes and nuclear factor-kappaB DNA binding activity. The results of this study suggest that imipramine can exert protective effects in endotoxin-induced acute lung injury by suppressing nuclear factor-kappaB-mediated expression of inflammatory genes. Thus, imipramine could be a potential novel therapeutic agent for the treatment for acute lung injury.

  12. Effects of resolvin D1 on inflammatory responses and oxidative stress of lipopolysaccharide-induced acute lung injury in mice

    Wang Lei; Yuan Ruixia; Yao Chengyue; Wu Qingping; Marie Christelle; Xie Wanli; Zhang Xingcai

    2014-01-01

    Background A variety of inflammatory mediators and effector cells participate together in acute lung injury,and lead to secondary injury that is due to an inflammatory cascade and secondary diffuse lung parenchyma injury.Inflammation is associated with an oxidative stress reaction,which is produced in the development of airway inflammation,and which has positive feedback on inflammation itself.Resolvin D1 can reduce the infiltration of neutrophils,regulate cytokine levels and reduce the inflammation reaction,and thereby promote the resolution of inflammation.The purpose of this study is to investigate the effects of resolvin D1 on an inflammatory response and oxidative stress during lipopolysaccharide (LPS)-induced acute lung injury.Methods LPS (3 mg/kg) was used to induce the acute lung injury model.Pretreatment resolvin D1 (100 ng/mouse) was given to mice 30 minutes before inducing acute lung injury.Mice were observed at 6 hours,12 hours,1 day,2 days,3 days,4 days and 7 days after LPS was administrated,then they were humanely sacrificed.We collected bronchoalveolar lavage fluid (BALF) and the lung tissues for further analysis.Paraffin section and HE staining of the lung tissues were made for histopathology observations.Parts of the lung tissues were evaluated for wet-to-dry (W/D) weight ratio.tumor necrosis factor (TNF)-α,inter leukin (IL)-1β,IL-10 and myeloperoxidase (MPO) were detected by enzyme-linked immunosorbent assay (ELISA).A lipid peroxidation malondialdehyde (MDA) assay kit was used to detect MDA.A total superoxide dismutase assay kit with WST-1 was used to analyze superoxide dismutase (SOD).We determined the apoptosis of neutrophils by Flow Cytometry.A real-time quantitative PCR Detecting System detected the expression of mRNA for heme oxygenase (HO)-1.Results Pretreatment with resolvin D1 reduced the pathological damage in the lung,decreased the recruitment of neutrophils and stimulated their apoptosis.It markedly decreased the expressions of TNF

  13. Surfactant protein D is a candidate biomarker for subclinical tobacco smoke-induced lung damage

    Johansson, Sofie L.; Tan, Qihua; Holst, René;

    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...

  14. Treadmill Exercise Preconditioning Attenuates Lung Damage Caused by Systemic Endotoxemia in Type 1 Diabetic Rats

    Ching-Hsia Hung

    2013-01-01

    Full Text Available Endotoxemia induces a series of inflammatory responses that may result in lung injury. However, heat shock protein72 (HSP72 has the potential to protect the lungs from damage. The objective of this study was to determine whether prior exercise conditioning could increase the expression of HSP72 in the lungs and attenuate lung damage in diabetic rats receiving lipopolysaccharide (LPS. Streptozotocin was used to induce diabetes in adult male Wistar rats. Rats were randomly assigned to sedentary or exercise groups. Rats in the exercise condition ran on a treadmill 5 days/week, 30–60 min/day, with an intensity of 1.0 mile/hour over a 3-week period. Rats received an intravenous infusion of LPS after 24 hrs from the last training session. Elevated lavage tumor necrosis factor-alpha (TNF-α level in response to LPS was more marked in diabetic rats. HSP72 expression in lungs was significantly increased after exercise conditioning, but less pronounced in diabetic rats. After administration of LPS, exercised rats displayed higher survival rate as well as decreased lavage TNF-α level and lung edema in comparison to sedentary rats. Our findings suggest that exercise conditioning could attenuate the occurrence of inflammatory responses and lung damage, thereby reducing mortality rate in diabetic rats during endotoxemia.

  15. Critical care in the ED: potentially fatal asthma and acute lung injury syndrome

    Hodder R

    2012-08-01

    Full Text Available Rick Hodder*Divisions of Pulmonary and Critical Care, University of Ottawa and The Ottawa Hospital, Ottawa, Canada, *Dr Rick Hodder passed away on Tuesday April 17,2012. Please see the Dedication for more information on Dr Hodder.Abstract: Emergency department clinicians are frequently called upon to assess, diagnose, and stabilize patients who present with acute respiratory failure. This review describes a rapid initial approach to acute respiratory failure in adults, illustrated by two common examples: (1 an airway disease – acute potentially fatal asthma, and (2 a pulmonary parenchymal disease – acute lung injury/acute respiratory distress syndrome. As such patients are usually admitted to hospital, discussion will be focused on those initial management aspects most relevant to the emergency department clinician.Keywords: acute asthma, acute lung injury, ARDS, acute respiratory failure

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

    Duan Yingli

    2012-01-01

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

  17. Inhaled aerosolized insulin ameliorates hyperglycemia-induced inflammatory responses in the lungs in an experimental model of acute lung injury

    Fan, Wei; Nakazawa, Koichi; Abe, Shinya; Inoue, Miori; Kitagawa, Masanobu; Nagahara, Noriyuki; Makita, Koshi

    2013-01-01

    Introduction Previous studies have shown that patients with diabetes mellitus appear to have a lower prevalence of acute lung injury. We assumed that insulin prescribed to patients with diabetes has an anti-inflammatory property and pulmonary administration of insulin might exert beneficial effects much more than intravenous administration. Methods Twenty-eight mechanically ventilated rabbits underwent lung injury by saline lavage, and then the animals were allocated into a normoglycemia grou...

  18. Monoacylglycerol lipase (MAGL inhibition attenuates acute lung injury in mice.

    Carolina Costola-de-Souza

    Full Text Available Endocannabinoid signaling is terminated by enzymatic hydrolysis, a process that, for 2-Arachidonoylglycerol (2-AG, is mediated by monoacylglycerol lipase (MAGL. The piperidine carbamate, 4-nitrophenyl- 4-(dibenzo[d] [1,3]dioxol-5-yl (hydroxy methyl piperidine- 1-carboxylate (JZL184, is a drug that inhibits MAGL and presents high potency and selectivity. Thus, JZL184 increases the levels of 2-AG, an endocannabinoid that acts on the CB1 and CB2 cannabinoid receptors. Here, we investigated the effects of MAGL inhibition, with a single dose (16 mg/kg, intraperitoneally (i.p. of JZL184, in a murine model of lipopolysaccharide (LPS -induced acute lung injury (ALI 6, 24 and 48 hours after the inflammatory insult. Treatment with JZL184 decreased the leukocyte migration into the lungs as well as the vascular permeability measured through the bronchoalveolar lavage fluid (BAL and histological analysis. JZL184 also reduced the cytokine and chemokine levels in the BAL and adhesion molecule expression in the blood and BAL. The CB1 and CB2 receptors were considered involved in the anti-inflammatory effects of JZL184 because the AM281 selective CB1 receptor antagonist (1-(2,4-dichlorophenyl-5-(4-iodophenyl-4-methyl-N-4-morpholinyl-1H-pyrazole-3-carboxamide and the AM630 selective CB2 receptor antagonist ([6-iodo-2-methyl-1-[2-(4-morpholinylethyl]-1H-indol-3-yl](4-methoxyphenyl-methanone blocked the anti-inflammatory effects previously described for JZL184. It was concluded that MAGL inhibition, and consequently the increase in 2-AG levels, produced anti-inflammatory effects in a murine model of LPS-induced ALI, a finding that was considered a consequence of the activation of the CB1 and CB2 receptors.

  19. Acute onset paraneoplastic cerebellar degeneration in a patient with small cell lung cancer

    Bhatia R

    2003-04-01

    Full Text Available A patient with small cell lung cancer presented with a rare presentation of an acute onset pancerebellar dysfunction. His clinical condition markedly improved following the surgical removal of the tumor and chemo- and radiotherapy.

  20. Role of TNF-α in lung tight junction alteration in mouse model of acute lung inflammation

    Cuzzocrea Salvatore

    2007-10-01

    Full Text Available Abstract In the present study, we used tumor necrosis factor-R1 knock out mice (TNF-αR1KO to understand the roles of TNF-α on epithelial function in models of carrageenan-induced acute lung inflammation. In order to elucidate whether the observed anti-inflammatory status is related to the inhibition of TNF-α, we also investigated the effect of etanercept, a TNF-α soluble receptor construct, on lung TJ function. Pharmacological and genetic TNF-α inhibition significantly reduced the degree of (1 TNF-α production in pleural exudates and in the lung tissues, (2 the inflammatory cell infiltration in the pleural cavity as well as in the lung tissues (evaluated by MPO activity, (3 the alteration of ZO-1, Claudin-2, Claudin-4, Claudin-5 and β-catenin (immunohistochemistry and (4 apoptosis (TUNEL staining, Bax, Bcl-2 expression. Taken together, our results demonstrate that inhibition of TNF-α reduces the tight junction permeability in the lung tissues associated with acute lung inflammation, suggesting a possible role of TNF-α on lung barrier dysfunction.

  1. β2 adrenergic agonists in acute lung injury? The heart of the matter

    Lee, Jae W

    2009-01-01

    Despite extensive research into its pathophysiology, acute lung injury/acute respiratory distress syndrome (ALI/ARDS) remains a devastating syndrome with mortality approaching 40%. Pharmacologic therapies that reduce the severity of lung injury in vivo and in vitro have not yet been translated to effective clinical treatment options, and innovative therapies are needed. Recently, the use of β2 adrenergic agonists as potential therapy has gained considerable interest due to their ability to in...

  2. Increased T cell glucose uptake reflects acute rejection in lung grafts

    Chen, Delphine L.; Wang, Xingan; Yamamoto, Sumiharu; Carpenter, Danielle; Engle, Jacquelyn T.; Li, Wenjun; Lin, Xue; Kreisel, Daniel; Krupnick, Alexander S.; Huang, Howard J.; Gelman, Andrew E.

    2013-01-01

    Although T cells are required for acute lung rejection, other graft-infiltrating cells such as neutrophils accumulate in allografts and are also high glucose utilizers. Positron emission tomography (PET) with the glucose probe [18F]fluorodeoxyglucose ([18F]FDG) has been employed to image solid organ acute rejection, but the sources of glucose utilization remain undefined. Using a mouse model of orthotopic lung transplantation, we analyzed glucose probe uptake in the graft...

  3. Blood transfusion : Transfusion-related acute lung injury: back to basics

    Peters, A.L.

    2017-01-01

    Transfusion-related acute lung injury (TRALI) is a life-threatening disease affecting the lungs. TRALI can develop within 6 hours after transfusion and almost all patients with TRALI require mechanical ventilation at the intensive care department. Nevertheless up to 40% of patients do not recover fr

  4. A case of lung cancer associated with acute respiratory distress syndrome after thoracic radiotherapy

    Enoki, Masafumi; Tojima, Hirokazu [Tokyo Rosai Hospital (Japan)

    1996-12-01

    A 73-year-old man presented with dyspnea, cough, fever, appetite loss and stridor due to bronchial stenosis. Fiber-optic bronchoscopy revealed an endobronchial lesion in the right main bronchus and biopsy specimens showed poorly differentiated squamous cell carcinoma. The clinical stage of lung cancer was IIIB (T4N2M0). The patient received 60 Gy in 30 fractions over 43 days to a field including the right hilum and mediastinum. The tumor decreased in size and stenosis of the bronchus disappeared. A week after completion of radiation the patient began to have high grade fever and dyspnea, and progressive hypoxia developed. A chest radiograph showed diffuse bilateral interstitial infiltrates. Despite mechanical ventilation with PEEP and the administration of steroids, he died of respiratory failure three weeks after completion of radiation. Necropsy specimens obtained from the left lung revealed massive deposition of fibrin in the alveolar airspaces associated with hyaline membranes and hyperplasia of type II cells indicating diffuse alveolar damage. The patient had mild pulmonary fibrosis on a CT scan taken before the start of radiotherapy. We conclude that care should be taken if the case has pulmonary fibrosis because radiation therapy can precipitate severe radiation pneumonitis and acute respiratory distress syndrome in such cases. (author)

  5. Acute lung injury induced by H9N2 virus in mice

    Li Yan; Shan Yunfeng; Chi Ying; Wen Tian; Han Xiaodong

    2014-01-01

    Background H9N2 avian influenza viruses (AIVs) have repeatedly caused infections in mammals even humans in many countries.The purpose of our study was to evaluate the acute lung injury (ALI) caused by H9N2 viral infection in mice.Methods Six-to eight-week-old female SPF C57BL/6 mice were infected intranasally with 1x104 MID50 of A/HONG KONG/2108/2003 [H9N2 (HK)] virus.Clinical signs,pathological changes,virus titration in tissues of mice,arterial blood gas,and cytokines in bronchoalveolar lavage fluid (BALF) and serum were observed at different time points after AIV infection.Results H9N2-AIV-infected mice exhibited severe respiratory syndrome,with a mortality rate of 50%.Lung histopathological changes in infected mice included diffuse pneumonia,alveolar damage,inflammatory cellular infiltration,interstitial and alveolar edema,and hemorrhage.In addition,H9N2 viral infection resulted in severe progressive hypoxemia,lymphopenia,and a significant increase in interleukin 1,interleukin 6,tumor necrosis factor,and interferon in BALF and serum.Conclusions The results suggest that H9N2 viral infection induces a typical ALl in mice that resembles the common features of ALl.Our data may facilitate the future studies of potential avian H9N2 disease in humans.

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

    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.

  7. Amniotic fluid stem cells from EGFP transgenic mice attenuate hyperoxia-induced acute lung injury.

    Shih-Tao Wen

    Full Text Available High concentrations of oxygen aggravate the severity of lung injury in patients requiring mechanical ventilation. Although mesenchymal stem cells have been shown to effectively attenuate various injured tissues, there is limited information regarding a role for amniotic fluid stem cells (AFSCs in treating acute lung injury. We hypothesized that intravenous delivery of AFSCs would attenuate lung injury in an experimental model of hyperoxia-induced lung injury. AFSCs were isolated from EGFP transgenic mice. The in vitro differentiation, surface markers, and migration of the AFSCs were assessed by specific staining, flow cytometry, and a co-culture system, respectively. The in vivo therapeutic potential of AFSCs was evaluated in a model of acute hyperoxia-induced lung injury in mice. The administration of AFSCs significantly reduced the hyperoxia-induced pulmonary inflammation, as reflected by significant reductions in lung wet/dry ratio, neutrophil counts, and the level of apoptosis, as well as reducing the levels of inflammatory cytokine (IL-1β, IL-6, and TNF-α and early-stage fibrosis in lung tissues. Moreover, EGFP-expressing AFSCs were detected and engrafted into a peripheral lung epithelial cell lineage by fluorescence microscopy and DAPI stain. Intravenous administration of AFSCs may offer a new therapeutic strategy for acute lung injury (ALI, for which efficient treatments are currently unavailable.

  8. Acute and repeated inhalation lung injury by 3-methoxybutyl chloroformate in rats: CT-pathologic correlation

    Lim, Yeon Soo [Department of Radiology, Holy Family Hospital, College of Medicine, Catholic University of Korea, 2, Sosa-dong, Wonmi-gu, Pucheon, Kyung gi-do 420-717 (Korea, Republic of); Chung, Myung Hee [Department of Radiology, Holy Family Hospital, College of Medicine, Catholic University of Korea, 2, Sosa-dong, Wonmi-gu, Pucheon, Kyung gi-do 420-717 (Korea, Republic of)]. E-mail: mhchung@catholic.ac.kr; Park, Seog Hee [Department of Radiology, Kangnam St. Mary Hospital, Catholic University of Korea, 505 Banpo-dong, Seocho-gu, Seoul 137-040 (Korea, Republic of); Kim, Hyeon-Yeong [Industrial Chemicals Research Center, Industrial Safety and Health Research Institute KISCO, 104-8, Moonji-dong, Yusong-gu, Taejon-si 305-380 (Korea, Republic of); Choi, Byung Gil [Department of Radiology, Kangnam St. Mary Hospital, Catholic University of Korea, 505 Banpo-dong, Seocho-gu, Seoul 137-040 (Korea, Republic of); Lim, Hyun Wook [Department of Radiology, Holy Family Hospital, College of Medicine, Catholic University of Korea, 2, Sosa-dong, Wonmi-gu, Pucheon, Kyung gi-do 420-717 (Korea, Republic of); Kim, Jin Ah [Department of Pathology, Holy Family Hospital, Catholic University of Korea, 2, Sosa-dong, Wonmi-gu, Pucheon-si, Kyung gi-do 420-717 (Korea, Republic of); Yoo, Won Jong [Department of Radiology, Holy Family Hospital, College of Medicine, Catholic University of Korea, 2, Sosa-dong, Wonmi-gu, Pucheon, Kyung gi-do 420-717 (Korea, Republic of)

    2007-05-15

    Objectives: To investigate the acute and repeated pulmonary damage in Sprague-Dawley rats caused by the inhalation of 3-methoxybutyl chloroformate (3-MBCF) using computed tomography (CT), and to correlate these results with those obtained from a pathological study. Methods: Sixty, 7-week-old rats were exposed to 3-MBCF vapor via inhalation (6 h/day) for 1 day (N = 20), 3 days (N = 20), and 28 days (5 days/week) (N = 20) using whole body exposure chambers at a concentration of 0 (control), 3, 6 and 12 ppm. CT examinations including densitometry and histopathologic studies were carried out. For the follow-up study, the rats exposed for 3 days were scanned using CT and their pathology was examined at 7, 14, and 28 days. Results: There was a significant decrease in the parenchymal density in the groups exposed to the 3-MBCF vapors for 1 day at 3 ppm (p = 0.022) or 6 ppm (p = 0.010), compared with the control. The parenchymal density of the rats exposed to12 ppm was significantly higher. The pathological findings in this period, the grades of vascular congestion, tracheobronchial exfoliation, and alveolar rupture were significant. In the groups exposed for 3 days, there was a large decrease in the parenchymal density with increasing dose (control: -675.48 {+-} 32.82 HU, 3 ppm: -720.65 {+-} 34.21 HU, 6 ppm: -756.41 {+-} 41.68 HU, 12 ppm: -812.56 {+-} 53.48 HU) (p = 0.000). There were significant density differences between each dose in the groups exposed for 28 days (p = 0.000). The CT findings include an irregular lung surface, areas of multifocal, wedge-shaped increased density, a heterogeneous lung density, bronchial dilatation, and axial peribronchovascular bundle thickening. The histopathology examination revealed the development of alveolar interstitial thickening and vasculitis, and an aggravation of the mainstem bronchial exudates and bronchial inflammation. The alveolar wall ruptures and bronchial dilatation became severe during this period. On the follow

  9. Effect of Contraction Velocity on Selected Muscle Damage Indices Following Acute Eccentric Exercise-Induced Muscle Damage: A Review

    Farzaneh Movaseghi

    2016-12-01

    Full Text Available Background & Objective: Eccentric muscle action is mechanically more efficient but employs a unique activation strategy which predisposes the muscle to damage. Type II muscle fibers are more susceptible than type I fibers to muscle damage; hence, velocity probably interferes with mechanical stress and thus may modulate muscle damage. The purpose of this review study was to investigate the effect of contraction velocity on selected muscle damage indices following acute eccentric exercise-induced muscle damage. Material & Method: Looking up related articles published in valid scientific databases such as PubMed, Springer, Elsevier, Science Direct, and SID with standard keywords and according to the research criteria, 16 studies (1980 to 2015 were selected. Results: Ten studies showed that high velocity eccentric exercise induced greater muscle damage. Five studies showed no differences between velocities, and a single study indicated a greater magnitude of muscle damage following slow eccentric exercise. Conclusion: Thus, greater magnitude of damage is induced by contractions performed at a higher velocity. However, considering differences during tension in the majority of studies, focusing on elbow flexor muscles and muscle damage profile variety in various muscle groups, and more animal and human studies in other muscular groups are necessary to confirm how the velocity of acute eccentric exercise would affect the muscle damage.

  10. DNA Damage of Lung Cells from Immature Cadmium-Ingested Mice

    Xue-feng Yang

    2014-01-01

    Full Text Available The objective of this study was to investigate the effects of cadmium on DNA damage of lung cells in immature animals. Seventy-two immature mice were randomly divided into twelve cadmium-ingested groups including low dose (1/100 LD50, 1.87 mg/kg BW, middle dose (1/50 LD50, 3.74 mg/kg BW, high dose (1/25 LD50, 7.48 mg/kg BW and control group, and exposed to cadmium chloride for 10, 20 and 30 days, respectively. Mice were sacrificed after cadmium exposure for different time, and lung cells were collected to investigate DNA damage by comet assay. The results showed that comet tailing ratio, tail length, comet length, tail moment, Olive tail moment and damaged grade of lung cells from immature mice increased along with increasing of cadmium exposure dose and time. In low dose group treated for 30 days, there was significance (P<0.05 in comet length or high significance (P<0.01 in other parameters compared with control group or low dose group treated for 10 days. When mice were exposed to cadmium at high dose for 30 days, DNA of lung cells was damaged most seriously. Our results indicate that cadmium can induce DNA damage of lung cells from immature mice in dose- dependent and time-dependent manners, and DNA will be damaged when immature mice exposed to cadmium for long time even at low dose. Meanwhile, comet assay can be considered as a powerful and sensitive biomarker assay in risk assessment of immature animals exposed to cadmium.

  11. Effects of budesonide and N-acetylcysteine on acute lung hyperinflation, inflammation and injury in rats.

    Jansson, Anne-Helene; Eriksson, Christina; Wang, Xiangdong

    2005-08-01

    Leukocyte activation and production of inflammatory mediators and reactive oxygen species are important in the pathogenesis of lipopolysaccharide (LPS)-induced acute lung injury. The present study investigated acute lung hyperinflation, edema, and lung inflammation 4 h after an intratracheal instillation of LPS (0.5, 2.5, 5, 10, 50, 100, 500, 1000, and 5000 microg/ml/kg). Effects of budesonide, an inhaled anti-inflammatory corticosteroids, and N-acetylcysteine (NAC), an antioxidant, were evaluated in Wistar rats receiving either low (2.5 microg/ml/kg) or high (50 microg/ml/kg) concentrations of LPS. This study demonstrates that LPS in a concentration-dependent pattern induces acute lung hyperinflation measured by excised lung gas volume (25-45% above control), lung injury indicated by increased lung weight (10-60%), and lung inflammation characterized by the infiltration of leukocytes (40-14000%) and neutrophils (80-17000%) and the production of cytokines (up to 2700%) and chemokines (up to 350%) in bronchoalveolar lavage fluid (BALF). Pretreatment with NAC partially prevented tumor necrosis factor alpha (TNFalpha) production induced by the low concentration of LPS, while pretreatment with budesonide totally prevented the increased production of TNFalpha, interleukin (IL)-1beta, IL-6, and monocyte chemoattractive protein (MCP)-1 after LPS challenge at both low and high concentrations. Budesonide failed to prevent BALF levels of macrophage inflammatory protein (MIP)-2 and cytokine-induced neutrophil chemoattractant 1 (GRO/CINC-1) as well as lung hyperinflation induced by both low and high concentrations of LPS. Pretreatment with budesonide totally prevented the formation of lung edema at the low concentration of LPS and had partial effects on acute lung injury and leukocyte influx at the high concentrations. Thus, our data indicate that therapeutic effects of budesonide and NAC are dependent upon the severity of the disease.

  12. Acute lung injury in children : from viral infection and mechanical ventilation to inflammation and apoptosis

    Bern, R.A.

    2010-01-01

    Acute lung injury (ALI), ook bekend als acute respiratory distress syndrome (ARDS), is een uitgebreide ontstekingsreactie in beide longen door een longziekte of een aandoening elders in het lichaam. Kinderen lijken minder gevoelig voor de ziekte dan volwassenen, wellicht door de manier waarop de lon

  13. Early preventive treatment for severe acute pancreatitis combined with lung injury

    刘学民; 刘青光; 潘承恩

    2002-01-01

    @@ Severe acute pancreatitis (SAP) can cause systematic inflammatory response syndrome (SIRS),which leads to injury or failure of the internal organs and systems.1 Among them,acute respiratory distress syndrome(ARDS)is a severe or fatal complication.In this article,the early preventive treatment for SAP combined with lung injure is studied.

  14. Changes in the bacterial microbiota in gut, blood, and lungs following acute LPS instillation into mice lungs.

    Marc A Sze

    Full Text Available Previous reports have shown that the gastrointestinal (GI bacterial microbiota can have profound effects on the lungs, which has been described as the "gut-lung axis". However, whether a "lung-gut" axis exists wherein acute lung inflammation perturbs the gut and blood microbiota is unknown.Adult C57/Bl6 mice were exposed to one dose of LPS or PBS instillation (n=3 for each group directly into lungs. Bacterial microbiota of the bronchoalveolar lavage fluid, blood, and cecum were determined using 454 pyrotag sequencing and quantitative polymerase chain reaction (qPCR at 4 through 168 hours post-instillation. We then investigated the effects of oral neomycin and streptomycin (n=8 on the microbiota at 4 and 24 hours post LPS instillation versus control treatment (n=5 at baseline and 4 hours, n=7 at 24 hours.At 24 hours post LPS instillation, the total bacterial count was significantly increased in the cecum (P<0.05; whereas the total bacterial count in blood was increased at 4, 48, and 72 hours (P<0.05. Antibiotic treatment reduced the total bacteria in blood but not in the cecum. The increase in total bacteria in the blood correlated with Phyllobacteriaceae OTU 40 and was significantly reduced in the blood for both antibiotic groups (P<0.05.LPS instillation in lungs leads to acute changes in the bacterial microbiota in the blood and cecum, which can be modulated with antibiotics.

  15. Genotoxic Evaluation of Mikania laevigata Extract on DNA Damage Caused by Acute Coal Dust Exposure

    Freitas, T.P.; Heuser, V.D.; Tavares, P.; Leffa, D.D.; da Silva, G.A.; Citadini-Zanette, V.; Romao, P.R.T.; Pinho, R.A.; Streck, E.L.; Andrade,V.M. [University of Extremo Catarinense, Criciuma, SC (Brazil)

    2009-06-15

    We report data on the possible antigenotoxic activity of Mikania laevigata extract (MLE) after acute intratracheal instillation of coal dust using the comet assay in peripheral blood, bone marrow, and liver cells and the micronucleus test in peripheral blood of Wistar rats. The animals were pretreated for 2 weeks with saline solution (groups 1 and 2) or MLE (100 mg/kg) (groups 3 and 4). On day 15, the animals were anesthetized with ketamine (80 mg/kg) and xylazine (20 mg/kg), and gross mineral coal dust (3 mg/0.3 mL saline) (groups 2 and 4) or saline solution (0.3 mL) (groups 1 and 3) was administered directly in the lung by intratracheal administration. Fifteen days after coal dust or saline instillation, the animals were sacrificed, and the femur, liver, and peripheral blood were removed. The results showed a general increase in the DNA damage values at 8 hours for all treatment groups, probably related to surgical procedures that had stressed the animals. Also, liver cells from rats treated with coal dust, pretreated or not with MLE, showed statistically higher comet assay values compared to the control group at 14 days after exposure. These results could be expected because the liver metabolizes a variety of organic compounds to more polar by-products. On the other hand, the micronucleus assay results did not show significant differences among groups. Therefore, our data do not support the antimutagenic activity of M. laevigata as a modulator of DNA damage after acute coal dust instillation.

  16. Damage of the auditory system associated with acute blast trauma.

    Roberto, M; Hamernik, R P; Turrentine, G A

    1989-05-01

    This paper reviews the results of several studies on the effects of blast wave exposure on the auditory system of the chinchilla, the pig, and the sheep. The chinchillas were exposed at peak sound pressure levels of approximately 160 dB under well-controlled laboratory conditions. A modified shock tube was used to generate the blast waves. The pigs and sheep were exposed under field conditions in an instrumented hard-walled enclosure. Blast trauma was induced by the impact of a single explosive projectile. The peak sound pressure levels varied between 178 and 209 dB. All animals were killed immediately following exposure, and their temporal bones were removed for fixation and histologic analysis using light microscopy and scanning electron microscopy. Middle ears were examined visually for damage to the conductive system. There were well-defined differences in susceptibility to acoustic trauma among species. However, common findings in each species were the acute mechanical fracture and separation of the organ of Corti from the basilar membrane, and tympanic membrane and ossicular failure.

  17. Oxidative stress, inflammation, and DNA damage in multiple organs of mice acutely exposed to amorphous silica nanoparticles

    Nemmar A

    2016-03-01

    Full Text Available Abderrahim Nemmar,1 Priya Yuvaraju,1 Sumaya Beegam,1 Javed Yasin,2 Elsadig E Kazzam,2 Badreldin H Ali3 1Department of Physiology, 2Department of Internal Medicine, College of Medicine and Health Sciences, United Arab Emirates University, Al Ain, UAE; 3Department of Pharmacology, College of Medicine and Health Sciences, Sultan Qaboos University, Muscat, Al-Khoudh, Sultanate of Oman Abstract: The use of amorphous silica (SiO2 in biopharmaceutical and industrial fields can lead to human exposure by injection, skin penetration, ingestion, or inhalation. However, the in vivo acute toxicity of amorphous SiO2 nanoparticles (SiNPs on multiple organs and the mechanisms underlying these effects are not well understood. Presently, we investigated the acute (24 hours effects of intraperitoneally administered 50 nm SiNPs (0.25 mg/kg on systemic toxicity, oxidative stress, inflammation, and DNA damage in the lung, heart, liver, kidney, and brain of mice. Lipid peroxidation was significantly increased by SiNPs in the lung, liver, kidney, and brain, but was not changed in the heart. Similarly, superoxide dismutase and catalase activities were significantly affected by SiNPs in all organs studied. While the concentration of tumor necrosis factor α was insignificantly increased in the liver and brain, its increase was statistically significant in the lung, heart, and kidney. SiNPs induced a significant elevation in pulmonary and renal interleukin 6 and interleukin-1 beta in the lung, liver, and brain. Moreover, SiNPs caused a significant increase in DNA damage, assessed by comet assay, in all the organs studied. SiNPs caused leukocytosis and increased the plasma activities of lactate dehydrogenase, creatine kinase, alanine aminotranferase, and aspartate aminotransferase. These results indicate that acute systemic exposure to SiNPs causes oxidative stress, inflammation, and DNA damage in several major organs, and highlight the need for thorough evaluation

  18. Atomization method for verifying size effects of inhalable particles on lung damage of mice.

    Tao, Chen; Tang, Yue; Zhang, Lan; Tian, Yonggang; Zhang, Yingmei

    2017-02-01

    To explore the size effects of inhalable particles on lung damage, aqueous aerosol containing cadmium was studied as a model to design a new type of two-stage atomization device that was composed of two adjustable parts with electronic ultrasonic atomization and pneumatic atomization. The working parameters and effectiveness of this device were tested with H2O atomization and CdCl2 inhalation, respectively. By gravimetrically detecting the mass concentrations of PM2.5 and PM10 and analysing the particle size with a laser sensor, we confirmed the particle size distribution of the aqueous aerosol produced by the new device under different working conditions. Then, we conducted experiments in male Kunming mice that inhaled CdCl2 to determine the size effects of inhalable particles on lung damage and to confirm the effectiveness of the device. The new device could effectively control the particle size in the aqueous aerosol. The inhaled CdCl2 entered and injured the lungs of the mice by causing tissue damage, oxidative stress, increasing endoplasmic reticulum stress and triggering an inflammatory response, which might be related to where the particles deposited. The smaller particles in the aqueous aerosol atomized by the new two-stage atomization device deposited deeper into lung causing more damage. This device could provide a new method for animal experiments involving inhalation with water-soluble toxins.

  19. Increased T cell glucose uptake reflects acute rejection in lung grafts

    Chen, Delphine L.; Wang, Xingan; Yamamoto, Sumiharu; Carpenter, Danielle; Engle, Jacquelyn T.; Li, Wenjun; Lin, Xue; Kreisel, Daniel; Krupnick, Alexander S.; Huang, Howard J.; Gelman, Andrew E.

    2013-01-01

    Although T cells are required for acute lung rejection, other graft-infiltrating cells such as neutrophils accumulate in allografts and are also high glucose utilizers. Positron emission tomography (PET) with the glucose probe [18F]fluorodeoxyglucose ([18F]FDG) has been employed to image solid organ acute rejection, but the sources of glucose utilization remain undefined. Using a mouse model of orthotopic lung transplantation, we analyzed glucose probe uptake in the grafts of syngeneic and allogeneic recipients with or without immunosuppression treatment. Pulmonary microPET scans demonstrated significantly higher [18F]FDG uptake in rejecting allografts when compared to transplanted lungs of either immunosuppressed or syngeneic recipients. [18F]FDG uptake was also markedly attenuated following T cell depletion therapy in lung recipients with ongoing acute rejection. Flow-cytometric analysis using the fluorescent deoxyglucose analog 2-NBDG revealed that T cells, and in particular CD8+ T cells, were the largest glucose utilizers in acutely rejecting lung grafts followed by neutrophils and antigen presenting cells. These data indicate that imaging modalities tailored toward assessing T cell metabolism may be useful in identifying acute rejection in lung recipients PMID:23927673

  20. The value of nitrogen washout/washin method in assessing alveolar recruitment volume in acute lung injury patients

    李洋

    2013-01-01

    Objective To evaluate the precision and feasibility of nitrogen washout/washin method in assessing lung recruitment of acute lung injury(ALI)patients.Methods Fifteen ALI patients underwent mechanical ventilation

  1. [Lung ultrasound in acute and critical care medicine].

    Zechner, P M; Seibel, A; Aichinger, G; Steigerwald, M; Dorr, K; Scheiermann, P; Schellhaas, S; Cuca, C; Breitkreutz, R

    2012-07-01

    The development of modern critical care lung ultrasound is based on the classical representation of anatomical structures and the need for the assessment of specific sonography artefacts and phenomena. The air and fluid content of the lungs is interpreted using few typical artefacts and phenomena, with which the most important differential diagnoses can be made. According to a recent international consensus conference these include lung sliding, lung pulse, B-lines, lung point, reverberation artefacts, subpleural consolidations and intrapleural fluid collections. An increased number of B-lines is an unspecific sign for an increased quantity of fluid in the lungs resembling interstitial syndromes, for example in the case of cardiogenic pulmonary edema or lung contusion. In the diagnosis of interstitial syndromes lung ultrasound provides higher diagnostic accuracy (95%) than auscultation (55%) and chest radiography (72%). Diagnosis of pneumonia and pulmonary embolism can be achieved at the bedside by evaluating subpleural lung consolidations. Detection of lung sliding can help to detect asymmetrical ventilation and allows the exclusion of a pneumothorax. Ultrasound-based diagnosis of pneumothorax is superior to supine anterior chest radiography: for ultrasound the sensitivity is 92-100% and the specificity 91-100%. For the diagnosis of pneumothorax a simple algorithm was therefore designed: in the presence of lung sliding, lung pulse or B-lines, pneumothorax can be ruled out, in contrast a positive lung point is a highly specific sign of the presence of pneumothorax. Furthermore, lung ultrasound allows not only diagnosis of pleural effusion with significantly higher sensitivity than chest x-ray but also visual control in ultrasound-guided thoracocentesis.

  2. Lung damage and pulmonary uptake of serotonin in intact dogs

    Dawson, C.A.; Christensen, C.W.; Rickaby, D.A.; Linehan, J.H.; Johnston, M.R.

    1985-06-01

    The authors examined the influence of glass bead embolization and oleic acid, dextran, and imipramine infusion on the pulmonary uptake of trace doses of (/sup 3/H)serotonin and the extravascular volume accessible to (/sup 14/C)antipyrine in anesthetized dogs. Embolization and imipramine decreased serotonin uptake by 53 and 61%, respectively, but no change was observed with oleic acid or dextran infusion. The extravascular volume accessible to the antipyrine was reduced by 77% after embolization and increased by 177 and approximately 44% after oleic acid and dextran infusion, respectively. The results suggest that when the perfused endothelial surface is sufficiently reduced, as with embolization, the uptake of trace doses of serotonin will be depressed. In addition, decreases in serotonin uptake in response to imipramine in this study and in response to certain endothelial toxins in other studies suggest that serotonin uptake can reveal certain kinds of changes in endothelial function. However, the lack of a response to oleic acid-induced damage in the present study suggests that serotonin uptake is not sensitive to all forms of endothelial damage.

  3. Protective effect of ulinastatin on acute lung injury after radiotherapy in patients with lung cancer and the related molecular mechanism

    Guang-Ping Fan

    2016-01-01

    Objective:To analyze the protective effect of ulinastatin on acute lung injury after radiotherapy in patients with lung cancer and the related molecular mechanism.Methods:A total of 78 patients who received radiotherapy and developed acute lung injury in our hospital between December 2013 and December 2015 were randomly divided into observation group and control group, control group received symptomatic treatment, observation group received symptomatic + ulinastatin treatment, and the content of growth factors, inflammatory factors, disease-related proteins in serum as well as the expression of P38MAPK signaling pathway molecules in alveolar lavage fluid were compared between two groups of patients after treatment.Results:Ten days after treatment, HGF, KGF, VEGF, IL-1β, IL-8, IL-10, IL-18, IL-13, PCT, S100A8, S100A9 and SP-D content in serum of observation group were significantly lower than those of control group while Clara cell protein content was significantly higher than that of control group; phosphorylated p38MAPK, MAPK, MKK3/6 and ATF-2 protein expression levels in alveolar lavage fluid were significantly lower than those of control group.Conclusions:Ulinastatin can alleviate the overall condition in patients with acute lung injury after radiotherapy, and the specific mechanism is associated with P38MAPK signaling pathway.

  4. The Effects of Quercetin on Acute Lung Injury and Biomarkers of Inflammation and Oxidative Stress in the Rat Model of Sepsis.

    Gerin, Fethullah; Sener, Umit; Erman, Hayriye; Yilmaz, Ahsen; Aydin, Bayram; Armutcu, Ferah; Gurel, Ahmet

    2016-04-01

    Experimental studies indicate that sepsis causes remote organ injury although the molecular mechanism has not been clearly defined. In this report, the role of oxidative damage, and inflammation on lung injury, following sepsis model by cecal ligation and puncture, and the effects of quercetin, antioxidant, and anti-inflammatory flavonoid, in the lung tissue were investigated. In the present study, we found that administration of single-dose quercetin before cecal ligation and puncture procedure, while markedly diminishing the levels of YKL-40 and oxidant molecules (xanthine oxidase (XO), nitric oxide (NO), and malondialdehyde (MDA)), increases the antioxidant enzymes levels. Quercetin is beneficial to acute lung injury by decreasing the levels of oxidative stress markers and increasing the antioxidant enzyme activities. Quercetin also causes a decrease in the serum levels of YKL-40 and periostin in the oxidative lung injury induced by the experimental sepsis model.

  5. Diagnostic and Therapeutic Aspects of Acute Lung Injury: empirical studies

    R.A. Lachmann

    2006-01-01

    textabstractThe thesis emphases research on prognostic markers as well as on different approaches for treating lung injury. Thereby, the prevention and treatment of pneumonia and possible ventilation induced bacterial translocation from the lung into the blood represents the main focus of th

  6. The role of pneumolysin in mediating lung damage in a lethal pneumococcal pneumonia murine model

    Pirofski Liise-Anne

    2007-01-01

    Full Text Available Abstract Background Intranasal inoculation of Streptococcus pneumoniae D39 serotype 2 causes fatal pneumonia in mice. The cytotoxic and inflammatory properties of pneumolysin (PLY have been implicated in the pathogenesis of pneumococcal pneumonia. Methods To examine the role of PLY in this experimental model we performed ELISA assays for PLY quantification. The distribution patterns of PLY and apoptosis were established by immunohistochemical detection of PLY, caspase-9 activity and TUNEL assay on tissue sections from mice lungs at various times, and the results were quantified with image analysis. Inflammatory and apoptotic cells were also quantified on lung tissue sections from antibody treated mice. Results In bronchoalveolar lavages (BAL, total PLY was found at sublytic concentrations which were located in alveolar macrophages and leukocytes. The bronchoalveolar epithelium was PLY-positive, while the vascular endothelium was not PLY reactive. The pattern and extension of cellular apoptosis was similar. Anti-PLY antibody treatment decreased the lung damage and the number of apoptotic and inflammatory cells in lung tissues. Conclusion The data strongly suggest that in vivo lung injury could be due to the pro-apoptotic and pro-inflammatory activity of PLY, rather than its cytotoxic activity. PLY at sublytic concentrations induces lethal inflammation in lung tissues and is involved in host cell apoptosis, whose effects are important to pathogen survival.

  7. Neutrophils as early immunologic effectors in hemorrhage- or endotoxemia-induced acute lung injury.

    Abraham, E; Carmody, A; Shenkar, R; Arcaroli, J

    2000-12-01

    Acute lung injury is characterized by accumulation of neutrophils in the lungs, accompanied by the development of interstitial edema and an intense inflammatory response. To assess the role of neutrophils as early immune effectors in hemorrhage- or endotoxemia-induced lung injury, mice were made neutropenic with cyclophosphamide or anti-neutrophil antibodies. Endotoxemia- or hemorrhage-induced lung edema was significantly reduced in neutropenic animals. Activation of the transcriptional regulatory factor nuclear factor-kappaB after hemorrhage or endotoxemia was diminished in the lungs of neutropenic mice compared with nonneutropenic controls. Hemorrhage or endotoxemia was followed by increases in pulmonary mRNA and protein levels for interleukin-1beta (IL-1beta), macrophage inflammatory protein-2 (MIP-2), and tumor necrosis factor-alpha (TNF-alpha). Endotoxin-induced increases in proinflammatory cytokine expression were greater than those found after hemorrhage. The amounts of mRNA or protein for IL-1beta, MIP-2, and TNF-alpha were significantly lower after hemorrhage in the lungs of neutropenic versus nonneutropenic mice. Neutropenia was associated with significant reductions in IL-1beta and MIP-2 but not in TNF-alpha expression in the lungs after endotoxemia. These experiments show that neutrophils play a central role in initiating acute inflammatory responses and causing injury in the lungs after hemorrhage or endotoxemia.

  8. First-pass studies of acute lung injury.

    Chu, R Y; Sidhu, N; Basmadjian, G; Burow, R; Allen, E W

    1993-10-01

    Mild hydrochloric acid was introduced to a caudal lung section in each of eight dogs to induce injury. Transits of 99mTc-labeled red blood cells (RBC) and [123I]iodoantipyrine (IAP) injected intravenously were recorded by a scintillation camera. Lungs and blood samples were analyzed post-mortem. Peak-to-equilibrium ratios (P/E) of RBC time-activity curves were computed to be 3.83 +/- 0.54 for the control lung, 2.58 +/- 0.55 for the injured lung and 2.23 +/- 0.58 for the injured caudal section. For IAP, the respective results were 3.78 +/- 0.29, 2.02 +/- 0.18 and 1.77 +/- 0.17. The decrease of P/E in injured areas was attributed to reduced blood flow. Using mean transit times of the tracers, we computed extravascular lung water per unit blood volume to be 0.35 +/- 0.18 for the control lungs and an increased value of 0.68 +/- 0.24 for the injured lungs. These results displayed sensitivity to injury, but were gross underestimates relative to the corresponding values of 2.04 +/- 0.54 and 4.56 +/- 1.85 in post-mortem analyses.

  9. First-pass studies of acute lung injury

    Chu, R.Y.L.; Sidhu, N.; Basmadjian, G.; Burow, R.; Allen, E.W. (Oklahoma Univ. and Dept. of Veterans Affairs Medical Centre, Oklahoma City, OK (United States))

    1993-10-01

    Mild hydrochloric acid was introduced to a caudal lung section in each of eight dogs to induce injury. Transits of [sup 99m]Tc-labeled red blood cells (RBC) and [[sup 123]I]iodoantipyrine (IAP) injected intravenously were recorded by a scintillation camera. Lungs and blood samples were analyzed post-mortem. Peak-to-equilibrium ratios (P/E) of RBC time-activity curves were computed to be 3.83 [+-] 0.54 for the control lung, 2.58 [+-] 0.55 for the injured lung and 2.23 [+-] 0.58 for the injured caudal section. For IAP, the respective results were 3.78 [+-] 0.29, 2.02 [+-] 0.18 and 1.77 [+-] 0.17. The decrease of P/E in injured areas was attributed to reduced blood flow. Using mean transit times of the tracers, we computed extravascular lung water per unit blood volume to be 0.35 [+-] 0.18 for the control lungs and an increased value of 0.68 [+-] 0.24 for the injured lungs. These results displayed sensitivity to injury, but were gross underestimates relative to the corresponding values of 2.04 [+-] 0.54 and 4.56 [+-] 1.85 in post-mortem analyses. (Author).

  10. Protective effect of ghrelin against paraquatinduced acute lung injury in mice

    刘瑶

    2014-01-01

    Objective To measure the levels of ghrelin-induced expression or activation of nuclear factor erythroid 2-re-lated factor 2(Nrf2),heme oxygenase-1(HO-1),and NAD(P)H:quinone oxidoreductase 1(NQO1)in the PQ-injured lungs of mice and to evaluate the protective effect of ghrelin against paraquat(PQ)-induced acute lung injury in mice.Methods According to the random number table method,50 ICR mice of clean grade were

  11. Dexmedetomidine protects from post-myocardial ischaemia reperfusion lung damage in diabetic rats

    Kip, Gülay; Çelik, Ali; Bilge, Mustafa; Alkan, Metin; Kiraz, Hasan Ali; Özer, Abdullah; Şıvgın, Volkan; Erdem, Özlem; Arslan, Mustafa; Kavutçu, Mustafa

    2015-01-01

    Objective Diabetic complications and lipid peroxidation are known to have a close association. Lipid peroxidation commonly occurs at sites exposed to ischaemia, but distant organs and tissues also get damaged during ischaemia/reperfusion (I/R). Some of these targets are vital organs, such as the lung, liver, and kidney; the lung is the most frequently affected. The aim of our study was to investigate the effects of dexmedetomidine on I/R damage in lung tissue and on the oxidant/anti-oxidant system in diabetic rats. Material and methods Diabetes was induced with streptozotocin (55 mg/kg) in 18 Wistar Albino rats, which were then randomly divided into three groups (diabetes control (DC), diabetes plus ischaemia-reperfusion (DIR), and diabetes plus dexmedetomidine-ischaemia/reperfusion (DIRD)) after the effects of diabetes were clearly evident. The rats underwent a left thoracotomy and then ischaemia was produced in the myocardium muscle by a left anterior descending artery ligation for 30 min in the DIR and DIRD groups. I/R was performed for 120 min. The DIRD group received a single intraperitoneal dose of dexmedetomidine (100 µg/kg); the DIR group received no dexmedetomidine. Group DC was evaluated as the diabetic control group and also included six rats (C group) in which diabetes was not induced. These mice underwent only left thoracotomy and were closed without undergoing myocardial ischaemia. Histopathological changes, activities of catalase (CAT) and glutathione-S-transferase anti-oxidant enzymes, and malondialdehyde (MDA) levels were evaluated in the lung tissues of all rats. Results Neutrophil infiltration/aggregation was higher in the DIR group than in the C, DC, and DIRD groups (p=0.001, p=0.013, and p=0.042, respectively). The lung injury score was significantly higher in the DIR group than in the C and DC groups (p<0.0001 and p=0.024, respectively). The levels of MDA were significantly higher in the DIR group than in the C and DIRD groups. CAT activity

  12. Dexmedetomidine protects from post-myocardial ischaemia reperfusion lung damage in diabetic rats

    Gülay Kip

    2015-09-01

    Full Text Available Objective: Diabetic complications and lipid peroxidation are known to have a close association. Lipid peroxidation commonly occurs at sites exposed to ischaemia, but distant organs and tissues also get damaged during ischaemia/reperfusion (I/R. Some of these targets are vital organs, such as the lung, liver, and kidney; the lung is the most frequently affected. The aim of our study was to investigate the effects of dexmedetomidine on I/R damage in lung tissue and on the oxidant/anti-oxidant system in diabetic rats. Material and methods: Diabetes was induced with streptozotocin (55 mg/kg in 18 Wistar Albino rats, which were then randomly divided into three groups (diabetes control (DC, diabetes plus ischaemia-reperfusion (DIR, and diabetes plus dexmedetomidine-ischaemia/reperfusion (DIRD after the effects of diabetes were clearly evident. The rats underwent a left thoracotomy and then ischaemia was produced in the myocardium muscle by a left anterior descending artery ligation for 30 min in the DIR and DIRD groups. I/R was performed for 120 min. The DIRD group received a single intraperitoneal dose of dexmedetomidine (100 µg/kg; the DIR group received no dexmedetomidine. Group DC was evaluated as the diabetic control group and also included six rats (C group in which diabetes was not induced. These mice underwent only left thoracotomy and were closed without undergoing myocardial ischaemia. Histopathological changes, activities of catalase (CAT and glutathione-S-transferase anti-oxidant enzymes, and malondialdehyde (MDA levels were evaluated in the lung tissues of all rats. Results: Neutrophil infiltration/aggregation was higher in the DIR group than in the C, DC, and DIRD groups (p=0.001, p=0.013, and p=0.042, respectively. The lung injury score was significantly higher in the DIR group than in the C and DC groups (p<0.0001 and p=0.024, respectively. The levels of MDA were significantly higher in the DIR group than in the C and DIRD groups. CAT

  13. Mesenchymal Stem Cell Derived Secretome and Extracellular Vesicles for Acute Lung Injury and Other Inflammatory Lung Diseases

    Monsel, Antoine; Zhu, Ying-gang; Gudapati, Varun; Lim, Hyungsun; Lee, Jae W.

    2017-01-01

    Introduction Acute respiratory distress syndrome is a major cause of respiratory failure in critically ill patients. Despite extensive research into its pathophysiology, mortality remains high. No effective pharmacotherapy exists. Based largely on numerous preclinical studies, administration of mesenchymal stem or stromal cell (MSC) as a therapeutic for acute lung injury holds great promise, and clinical trials are currently underway. However, concern for the use of stem cells, specifically the risk of iatrogenic tumor formation, remains unresolved. Accumulating evidence now suggest that novel cell-free therapies including MSC-derived conditioned medium and extracellular vesicles released from MSCs might constitute compelling alternatives. Areas covered The current review summarizes the preclinical studies testing MSC conditioned medium and/or MSC extracellular vesicles as treatment for acute lung injury and other inflammatory lung diseases. Expert opinion While certain logistical obstacles limit the clinical applications of MSC conditioned medium such as the volume required for treatment, the therapeutic application of MSC extracellular vesicles remains promising, primarily due to ability of extracellular vesicles to maintain the functional phenotype of the parent cell. However, utilization of MSC extracellular vesicles will require large-scale production and standardization concerning identification, characterization and quantification. PMID:27011289

  14. Nitrogen dioxide-induced acute lung injury in sheep.

    Januszkiewicz, A J; Mayorga, M A

    1994-05-20

    Lung mechanics, hemodynamics and blood chemistries were assessed in sheep (Ovis aries) before, and up to 24 h following, a 15-20 min exposure to either air (control) or approximately 500 ppm nitrogen dioxide (NO2). Histopathologic examinations of lung tissues were performed 24 h after exposure. Nose-only and lung-only routes of exposure were compared for effects on NO2 pathogenesis. Bronchoalveolar lavage fluids from air- and NO2-exposed sheep were analyzed for biochemical and cellular signs of NO2 insult. The influence of breathing pattern on NO2 dose was also assessed. Five hundred ppm NO2 exposure of intubated sheep (lung-only exposure) was marked by a statistically significant, albeit small, blood methemoglobin increase. The exposure induced an immediate tidal volume decrease, and an increase in both breathing rate and inspired minute ventilation. Pulmonary function, indexed by lung resistance and dynamic lung compliance, progressively deteriorated after exposure. Maximal lung resistance and dynamic lung compliance changes occurred at 24 h post exposure, concomitant with arterial hypoxemia. Bronchoalveolar lavage fluid epithelial cell number and total protein were significantly increased while macrophage number was significantly decreased within the 24 h post-exposure period. Histopathologic examination of lung tissue 24 h after NO2 revealed patchy edema, mild hemorrhage and polymorphonuclear and mononuclear leukocyte infiltration. The NO2 toxicologic profile was significantly attenuated when sheep were exposed to the gas through a face mask (nose-only exposure). Respiratory pattern was not significantly altered, lung mechanics changes were minimal, hypoxemia did not occur, and pathologic evidence of exudation was not apparent in nose-only, NO2-exposed sheep. The qualitative responses of this large animal species to high-level NO2 supports the concept of size dependent species sensitivity to NO2. In addition, when inspired minute ventilation was used as a dose

  15. Nitrogen Dioxide-Induced Acute Lung Injury in Sheep

    1994-01-01

    subsequent to inhalation expo- sure. Non- cardiogenic pulmonary edema is produced by brief exposure and unlike hyperoxia (Newman et al., 1983; Fukushima...macrophage number significantly decreased within the 24-h post-exposure period. Examination of lung tissue 24 after NO2 revealed patchy edema , mild hemorrhage...examination of lung tissue 24 h after NO, revealed patchy edema , mild hemorrhage and polymorphonuclear c, and mononuclear leukocyte infiltration. The NO

  16. Toll-like receptor and tumour necrosis factor dependent endotoxin-induced acute lung injury

    Togbe, Dieudonnée; Schnyder-Candrian, Silvia; Schnyder, Bruno; Doz, Emilie; Noulin, Nicolas; Janot, Laure; Secher, Thomas; Gasse, Pamela; Lima, Carla; Coelho, Fernando Rodrigues; Vasseur, Virginie; Erard, François; Ryffel, Bernhard; Couillin, Isabelle; Moser, Rene

    2007-01-01

    Recent studies on endotoxin/lipopolysaccharide (LPS)-induced acute inflammatory response in the lung are reviewed. The acute airway inflammatory response to inhaled endotoxin is mediated through Toll-like receptor 4 (TLR4) and CD14 signalling as mice deficient for TLR4 or CD14 are unresponsive to endotoxin. Acute bronchoconstriction, tumour necrosis factor (TNF), interleukin (IL)-12 and keratinocyte-derived chemokine (KC) production, protein leak and neutrophil recruitment in the lung are abrogated in mice deficient for the adaptor molecules myeloid differentiation factor 88 (MyD88) and Toll/Interleukin-1 receptor (TIR)-domain-containing adaptor protein (TIRAP), but independent of TIR-domain-containing adaptor-inducing interferon-beta (TRIF). In particular, LPS-induced TNF is required for bronchoconstriction, but dispensable for inflammatory cell recruitment. Lipopolysaccharide induces activation of the p38 mitogen-activated protein kinase (MAPK). Inhibition of pulmonary MAPK activity abrogates LPS-induced TNF production, bronchoconstriction, neutrophil recruitment into the lungs and broncho-alveolar space. In conclusion, TLR4-mediated, bronchoconstriction and acute inflammatory lung pathology to inhaled endotoxin are dependent on TLR4/CD14/MD2 expression using the adapter proteins TIRAP and MyD88, while TRIF, IL-1R1 or IL-18R signalling pathways are dispensable. Further downstream in this axis of signalling, TNF blockade reduces only acute bronchoconstriction, while MAPK inhibition abrogates completely endotoxin-induced inflammation. PMID:18039275

  17. Baclofen, a GABABR agonist, ameliorates immune-complex mediated acute lung injury by modulating pro-inflammatory mediators.

    Shunying Jin

    Full Text Available Immune-complexes play an important role in the inflammatory diseases of the lung. Neutrophil activation mediates immune-complex (IC deposition-induced acute lung injury (ALI. Components of gamma amino butyric acid (GABA signaling, including GABA B receptor 2 (GABABR2, GAD65/67 and the GABA transporter, are present in the lungs and in the neutrophils. However, the role of pulmonary GABABR activation in the context of neutrophil-mediated ALI has not been determined. Thus, the objective of the current study was to determine whether administration of a GABABR agonist, baclofen would ameliorate or exacerbate ALI. We hypothesized that baclofen would regulate IC-induced ALI by preserving pulmonary GABABR expression. Rats were subjected to sham injury or IC-induced ALI and two hours later rats were treated intratracheally with saline or 1 mg/kg baclofen for 2 additional hours and sacrificed. ALI was assessed by vascular leakage, histology, TUNEL, and lung caspase-3 cleavage. ALI increased total protein, tumor necrosis factor α (TNF-α and interleukin-1 receptor associated protein (IL-1R AcP, in the bronchoalveolar lavage fluid (BALF. Moreover, ALI decreased lung GABABR2 expression, increased phospho-p38 MAPK, promoted IκB degradation and increased neutrophil influx in the lung. Administration of baclofen, after initiation of ALI, restored GABABR expression, which was inhibited in the presence of a GABABR antagonist, CGP52432. Baclofen administration activated pulmonary phospho-ERK and inhibited p38 MAPK phosphorylation and IκB degradation. Additionally, baclofen significantly inhibited pro-inflammatory TNF-α and IL-1βAcP release and promoted BAL neutrophil apoptosis. Protective effects of baclofen treatment on ALI were possibly mediated by inhibition of TNF-α- and IL-1β-mediated inflammatory signaling. Interestingly, GABABR2 expression was regulated in the type II pneumocytes in lung tissue sections from lung injured patients, further suggesting

  18. Baclofen, a GABABR agonist, ameliorates immune-complex mediated acute lung injury by modulating pro-inflammatory mediators.

    Jin, Shunying; Merchant, Michael L; Ritzenthaler, Jeffrey D; McLeish, Kenneth R; Lederer, Eleanor D; Torres-Gonzalez, Edilson; Fraig, Mostafa; Barati, Michelle T; Lentsch, Alex B; Roman, Jesse; Klein, Jon B; Rane, Madhavi J

    2015-01-01

    Immune-complexes play an important role in the inflammatory diseases of the lung. Neutrophil activation mediates immune-complex (IC) deposition-induced acute lung injury (ALI). Components of gamma amino butyric acid (GABA) signaling, including GABA B receptor 2 (GABABR2), GAD65/67 and the GABA transporter, are present in the lungs and in the neutrophils. However, the role of pulmonary GABABR activation in the context of neutrophil-mediated ALI has not been determined. Thus, the objective of the current study was to determine whether administration of a GABABR agonist, baclofen would ameliorate or exacerbate ALI. We hypothesized that baclofen would regulate IC-induced ALI by preserving pulmonary GABABR expression. Rats were subjected to sham injury or IC-induced ALI and two hours later rats were treated intratracheally with saline or 1 mg/kg baclofen for 2 additional hours and sacrificed. ALI was assessed by vascular leakage, histology, TUNEL, and lung caspase-3 cleavage. ALI increased total protein, tumor necrosis factor α (TNF-α and interleukin-1 receptor associated protein (IL-1R AcP), in the bronchoalveolar lavage fluid (BALF). Moreover, ALI decreased lung GABABR2 expression, increased phospho-p38 MAPK, promoted IκB degradation and increased neutrophil influx in the lung. Administration of baclofen, after initiation of ALI, restored GABABR expression, which was inhibited in the presence of a GABABR antagonist, CGP52432. Baclofen administration activated pulmonary phospho-ERK and inhibited p38 MAPK phosphorylation and IκB degradation. Additionally, baclofen significantly inhibited pro-inflammatory TNF-α and IL-1βAcP release and promoted BAL neutrophil apoptosis. Protective effects of baclofen treatment on ALI were possibly mediated by inhibition of TNF-α- and IL-1β-mediated inflammatory signaling. Interestingly, GABABR2 expression was regulated in the type II pneumocytes in lung tissue sections from lung injured patients, further suggesting a

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

    Gupta, Arjun; Sen, Shiraj; Naina, Harris

    2016-04-06

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

  20. Obesity Is Associated with Neutrophil Dysfunction and Attenuation of Murine Acute Lung Injury

    Kordonowy, Lauren L.; Burg, Elianne; Lenox, Christopher C.; Gauthier, Lauren M.; Petty, Joseph M.; Antkowiak, Maryellen; Palvinskaya, Tatsiana; Ubags, Niki; Rincón, Mercedes; Dixon, Anne E.; Vernooy, Juanita H. J.; Fessler, Michael B.; Poynter, Matthew E.; Suratt, Benjamin T.

    2012-01-01

    Although obesity is implicated in numerous health complications leading to increased mortality, the relationship between obesity and outcomes for critically ill patients appears paradoxical. Recent studies have reported better outcomes and lower levels of inflammatory cytokines in obese patients with acute lung injury (ALI)/acute respiratory distress syndrome, suggesting that obesity may ameliorate the effects of this disease. We investigated the effects of obesity in leptin-resistant db/db o...

  1. Protection from Cigarette Smoke-Induced Lung Dysfunction and Damage by H2 Relaxin (Serelaxin).

    Pini, Alessandro; Boccalini, Giulia; Lucarini, Laura; Catarinicchia, Stefano; Guasti, Daniele; Masini, Emanuela; Bani, Daniele; Nistri, Silvia

    2016-06-01

    Cigarette smoke (CS) is the major etiologic factor of chronic obstructive pulmonary disease (COPD), which is characterized by airway remodeling, lung inflammation and fibrosis, emphysema, and respiratory failure. The current therapies can improve COPD management but cannot arrest its progression and reduce mortality. Hence, there is a major interest in identifying molecules susceptible of development into new drugs to prevent or reduce CS-induced lung injury. Serelaxin (RLX), or recombinant human relaxin-2, is a promising candidate because of its anti-inflammatory and antifibrotic properties highlighted in lung disease models. Here, we used a guinea pig model of CS-induced lung inflammation, and remodeling reproducing some of the hallmarks of COPD. Animals exposed chronically to CS (8 weeks) were treated with vehicle or RLX, delivered by osmotic pumps (1 or 10 μg/day) or aerosol (10 μg/ml/day) during CS treatment. Controls were nonsmoking animals. RLX maintained airway compliance to a control-like pattern, likely because of its capability to counteract lung inflammation and bronchial remodeling. In fact, treatment of CS-exposed animals with RLX reduced the inflammatory recruitment of leukocytes, accompanied by a significant reduction of the release of proinflammatory cytokines (tumor necrosis factor α and interleukin-1β). Moreover, RLX was able to counteract the adverse bronchial remodeling and emphysema induced by CS exposure by reducing goblet cell hyperplasia, smooth muscle thickening, and fibrosis. Of note, RLX delivered by aerosol has shown a comparable efficacy to systemic administration in reducing CS-induced lung dysfunction and damage. In conclusion, RLX emerges as a new molecule to counteract CS-induced inflammatory lung diseases.

  2. Acute effects of inhaled urban particles and ozone: lung morphology, macrophage activity, and plasma endothelin-1.

    Bouthillier, L; Vincent, R; Goegan, P; Adamson, I Y; Bjarnason, S; Stewart, M; Guénette, J; Potvin, M; Kumarathasan, P

    1998-12-01

    We studied acute responses of rat lungs to inhalation of urban particulate matter and ozone. Exposure to particles (40 mg/m3 for 4 hours; mass median aerodynamic diameter, 4 to 5 microm; Ottawa urban dust, EHC-93), followed by 20 hours in clean air, did not result in acute lung injury. Nevertheless, inhalation of particles resulted in decreased production of nitric oxide (nitrite) and elevated secretion of macrophage inflammatory protein-2 from lung lavage cells. Inhalation of ozone (0.8 parts per million for 4 hours) resulted in increased neutrophils and protein in lung lavage fluid. Ozone alone also decreased phagocytosis and nitric oxide production and stimulated endothelin-1 secretion by lung lavage cells but did not modify secretion of macrophage inflammatory protein-2. Co-exposure to particles potentiated the ozone-induced septal cellularity in the central acinus but without measurable exacerbation of the ozone-related alveolar neutrophilia and permeability to protein detected by lung lavage. The enhanced septal thickening was associated with elevated production of both macrophage inflammatory protein-2 and endothelin-1 by lung lavage cells. Interestingly, inhalation of urban particulate matter increased the plasma levels of endothelin-1, but this response was not influenced by the synergistic effects of ozone and particles on centriacinar septal tissue changes. This suggests an impact of the distally distributed particulate dose on capillary endothelial production or filtration of the vasoconstrictor. Overall, equivalent patterns of effects were observed after a single exposure or three consecutive daily exposures to the pollutants. The experimental data are consistent with epidemiological evidence for acute pulmonary effects of ozone and respirable particulate matter and suggest a possible mechanism whereby cardiovascular effects may be induced by particle exposure. In a broad sense, acute biological effects of respirable particulate matter from ambient air

  3. Isoforskolin pretreatment attenuates lipopolysaccharide-induced acute lung injury in animal models.

    Yang, Weimin; Qiang, Dongjin; Zhang, Min; Ma, Limei; Zhang, Yonghui; Qing, Chen; Xu, Yunlong; Zhen, Chunlan; Liu, Jikai; Chen, Yan-Hua

    2011-06-01

    Isoforskolin was isolated from Coleus forskohlii native to Yunnan in China. We hypothesize that isoforskolin pretreatment attenuates acute lung injury induced by lipopolysaccharide (endotoxin). Three acute lung injury models were used: situ perfused rat lung, rat and mouse models of endotoxic shock. Additionally, lipopolysaccharide stimulated proinflammatory cytokine production was evaluated in human mononuclear leukocyte. In situ perfused rat lungs, pre-perfusion with isoforskolin (100, and 200 μM) and dexamethasone (65 μM, positive control) inhibited lipopolysaccharide (10 mg/L) induced increases in lung neutrophil adhesion rate, myeloperoxidase activity, lung weight Wet/Dry ratio, permeability-surface area product value, and tumor necrosis factor (TNF)-α levels. In rats, pretreatments with isoforskolin (5, 10, and 20 mg/kg, i.p.) and dexamethasone (5mg/kg, i.p.) markedly reduced lipopolysaccharide (6 mg/kg i.v.) induced increases of karyocyte, neutrophil counts and protein content in bronchoalveolar lavage fluid, and plasma myeloperoxidase activity. Lung histopathology showed that morphologic changes induced by lipopolysaccharide were less pronounced in the isoforskolin and dexamethasone pretreated rats. In mice, 5 mg/kg isoforskolin and dexamethasone caused 100% and 80% survival, respectively, after administration of lipopolysaccharide (62.5mg/kg, i.v., 40% survival if untreated). In human mononuclear leukocyte, isoforskolin (50, 100, and 200 μM) and dexamethasone (10 μM) pre-incubation lowered lipopolysaccharide (2 μg/mL) induced secretion of the cytokine TNF-α, and interleukins (IL)-1β, IL-6, and IL-8. In conclusion, pretreatment with isoforskolin attenuates lipopolysaccharide-induced acute lung injury in several models, and it is involved in down-regulation of inflammatory responses and proinflammatory cytokines TNF-α, IL-1β, IL-6, and IL-8.

  4. Macrophage micro-RNA-155 promotes lipopolysaccharide-induced acute lung injury in mice and rats.

    Wang, Wen; Liu, Zhi; Su, Jie; Chen, Wen-Sheng; Wang, Xiao-Wu; Bai, San-Xing; Zhang, Jin-Zhou; Yu, Shi-Qiang

    2016-08-01

    Micro-RNA (miR)-155 is a novel gene regulator with important roles in inflammation. Herein, our study aimed to explore the role of miR-155 in LPS-induced acute lung injury(ALI). ALI in mice was induced by intratracheally delivered LPS. Loss-of-function experiments performed on miR-155 knockout mice showed that miR-155 gene inactivation protected mice from LPS-induced ALI, as manifested by preserved lung permeability and reduced lung inflammation compared with wild-type controls. Bone marrow transplantation experiments identified leukocytes, but not lung parenchymal-derived miR-155-promoted acute lung inflammation. Real-time PCR analysis showed that the expression of miR-155 in lung tissue was greatly elevated in wild-type mice after LPS stimulation. In situ hybridization showed that miR-155 was mainly expressed in alveolar macrophages. In vitro experiments performed in isolated alveolar macrophages and polarized bone marrow-derived macrophages confirmed that miR-155 expression in macrophages was increased in response to LPS stimulation. Conversely, miR-155 gain-of-function in alveolar macrophages remarkably exaggerated LPS-induced acute lung injury. Molecular studies identified the inflammation repressor suppressor of cytokine signaling (SOCS-1) as the downstream target of miR-155. By binding to the 3'-UTR of the SOCS-1 mRNA, miR-155 downregulated SOCS-1 expression, thus, permitting the inflammatory response during lung injury. Finally, we generated a novel miR-155 knockout rat strain and showed that the proinflammatory role of miR-155 was conserved in rats. Our study identified miR-155 as a proinflammatory factor after LPS stimulation, and alveolar macrophages-derived miR-155 has an important role in LPS-induced ALI.

  5. Neutrophil elastase causes tissue damage that decreases host tolerance to lung infection with burkholderia species.

    Manoranjan Sahoo

    2014-08-01

    Full Text Available Two distinct defense strategies can protect the host from infection: resistance is the ability to destroy the infectious agent, and tolerance is the ability to withstand infection by minimizing the negative impact it has on the host's health without directly affecting pathogen burden. Burkholderia pseudomallei is a Gram-negative bacterium that infects macrophages and causes melioidosis. We have recently shown that inflammasome-triggered pyroptosis and IL-18 are equally important for resistance to B. pseudomallei, whereas IL-1β is deleterious. Here we show that the detrimental role of IL-1β during infection with B. pseudomallei (and closely related B. thailandensis is due to excessive recruitment of neutrophils to the lung and consequent tissue damage. Mice deficient in the potentially damaging enzyme neutrophil elastase were less susceptible than the wild type C57BL/6J mice to infection, although the bacterial burdens in organs and the extent of inflammation were comparable between C57BL/6J and elastase-deficient mice. In contrast, lung tissue damage and vascular leakage were drastically reduced in elastase-deficient mice compared to controls. Bradykinin levels were higher in C57BL/6 than in elastase-deficient mice; administration of a bradykinin antagonist protected mice from infection, suggesting that increased vascular permeability mediated by bradykinin is one of the mechanisms through which elastase decreases host tolerance to melioidosis. Collectively, these results demonstrate that absence of neutrophil elastase increases host tolerance, rather than resistance, to infection by minimizing host tissue damage.

  6. Decay-Accelerating Factor Mitigates Controlled Hemorrhage-Instigated Intestinal and Lung Tissue Damage and Hyperkalemia in Swine

    2011-07-01

    Decay-Accelerating Factor Mitigates Controlled Hemorrhage- Instigated Intestinal and Lung Tissue Damage and Hyperkalemia in Swine Jurandir J. Dalle...DAF treatment improved hemorrhage- induced hyperkalemia . The protective effects of DAF appear to be related to its ability to reduce tissue complement...Decay-accelerating factor mitigates controlled hemorrhage-instigated intestinal and lung tissue damage and hyperkalemia in swine 5a. CONTRACT NUMBER

  7. Respiratory inductive plethysmography accuracy at varying PEEP levels and degrees of acute lung injury

    D.G. Markhorst (Dick); M.A. van Van Gestel (Miriam); H.R. van Genderingen (Huibert); J.J. Haitsma (Jack); B.F. Lachmann (Burkhard); A.J. van Vught (Adrianus)

    2006-01-01

    textabstractBackground and objective: This study was performed to assess the accuracy of respiratory inductive plethysmographic (RIP) estimated lung volume changes at varying positive end-expiratory pressures (PEEP) during different degrees of acute respiratory failure. Methods: Measurements of insp

  8. Alpha glucocorticoid receptor expression in different experimental rat models of acute lung injury

    Bertorelli,Giuseppina; Pesci, Alberto; Peveri, Silvia; Mergoni, Mario; Corradi, Attilio; Cantoni, Anna Maria; Tincani, Giovanni; Bobbio, Antonio; Rusca, Michele; Carbognani, Paolo

    2008-01-01

    Alpha glucocorticoid receptor expression in different experimental rat models of acute lung injury correspondence: Corresponding author. Tel.: +390521703883; fax: +390521703493. (Carbognani, Paolo) (Carbognani, Paolo) Dipartimento di Clinica Medica - Nefrologia e Scienze della Prevenzione--> , University of Parma--> - ITALY (Bertorelli, Giuseppina) Dipartimento di Clinica Medica - Nefrologia e Scienze della...

  9. Hemodynamic effects of partial liquid ventilation with perfluorocarbon in acute lung injury

    R.J.M. Houmes (Robert Jan); S.J.C. Verbrugge (Serge); E. Hendrik (Edwin); B.F. Lachmann (Burkhard)

    1995-01-01

    textabstractObjective: To assess the effect of partial liquid ventilation with perfluorocarbons on hemodynamics and gas exchange in large pigs with induced acute lung injury (ALI). Design: Randomized, prospective, double-control, experimental study. Setting: Experimental intensive care unit of a uni

  10. Acute lung injury in 2003%2003年度急性肺损伤

    Roger G SPRAGG

    2003-01-01

    During the past several decades, clinical investigators world-wide have continued to study the causes,pathophysiology, and treatment strategies for acute lung injury (ALl). This syndrome, which is characterized by nonhydrostatic pulmonary edema and hypoxemia associated with a variety of etiologies, is slowly becoming better understood as a result of these efforts.

  11. Non-invasive diagnosis of acute heart- or lung-transplant rejection using radiolabeled annexin V

    Blankenberg, F.G. [Stanford Univ., CA (United States). Dept. of Radiology; Strauss, H.W. [Stanford Univ., CA (United States). Nuclear Medicine Div.

    1999-05-01

    Background. Apoptosis is a ubiquitous set of cellular processes by which superfluous or unwanted cells are eliminated in the body without harming adjacent healthy tissues. When apoptosis is inappropriate (too little or too much), a variety of human diseases can occur, including acute heart or lung transplant rejection. Objective. Our group has developed a new radiopharmaceutical, radiolabeled annexin V, which can image apoptosis. Results and conclusion. Here we briefly review the biomolecular basis of apoptosis and its role in acute rejection. We also describe the possible use of radiolabeled annexin V to screen children noninvasively for acute rejection following organ transplantation. (orig.) With 6 figs., 53 refs.

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

    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.

  13. A numerical model of the respiratory modulation of pulmonary shunt and PaO2 oscillations for acute lung injury.

    Beda, Alessandro; Jandre, Frederico C; Giannella-Neto, Antonio

    2010-03-01

    It is an accepted hypothesis that the amplitude of the respiratory-related oscillations of arterial partial pressure of oxygen (DeltaPaO2) is primarily modulated by fluctuations of pulmonary shunt (Deltas), the latter generated mainly by cyclic alveolar collapse/reopening, when present. A better understanding of the relationship between DeltaPaO2, Deltas, and cyclic alveolar collapse/reopening can have clinical relevance for minimizing the severe lung damage that the latter can cause, for example during mechanical ventilation (MV) of patients with acute lung injury (ALI). To this aim, we numerically simulated the effect of such a relationship on an animal model of ALI under MV, using a combination of a model of lung gas exchange during tidal ventilation with a model of time dependence of shunt on alveolar collapse/opening. The results showed that: (a) the model could adequately replicate published experimental results regarding the complex dependence of DeltaPaO2 on respiratory frequency, driving pressure (DeltaP), and positive end-expiratory pressure (PEEP), while simpler models could not; (b) such a replication strongly depends on the value of the model parameters, especially of the speed of alveolar collapse/reopening; (c) the relationship between DeltaPaO2 and Deltas was overall markedly nonlinear, but approximately linear for PEEP>or=6 cmH2O, with very large DeltaPaO2 associated with relatively small Deltas.

  14. Upregulation of Shh and Ptc1 in hyperoxia‑induced acute lung injury in neonatal rats.

    Dang, Hongxing; Wang, Shaohua; Yang, Lin; Fang, Fang; Xu, Feng

    2012-08-01

    The aim of the present study was to observe the expression of sonic hedgehog (Shh) and Ptc signaling molecules in the lungs of newborn rats exposed to prolonged hyperoxia, and to explore the role of the SHH signaling pathway in hyperoxia‑induced lung injury. Newborn Sprague-Dawley rat pups were placed in chambers containing room air or oxygen above 95% for 14 days following birth. The rats were sacrificed after 3, 7 or 14 days and their lungs were removed. Sections were fixed and subjected to hematoxylin and eosin (H&E) staining. Shh and Ptc1 were quantitated by immunohistochemistry. The total RNA and protein were also extracted from lung tissue; real-time PCR (RT-PCR) and western blot analysis were utilized to assess the mRNA and protein expression of Shh and Ptc1. H&E staining demonstrated significant histomorphological changes in the hyperoxia‑exposed lungs at 3, 7 and 14 days of age. The results of the immunohistochemistry, RT-PCR and western blot analysis demonstrated that the expression of Shh was significantly higher in the hyperoxia-exposed lungs at 3, 7 and 14 days, while Ptc1 was significantly elevated at 7 and 14 days. Exposure of the neonatal rat lung to prolonged hyperoxia resulted in acute lung injury and histomorphological changes. Shh and Ptc1 were upregulated in a time-dependent manner in the course of hyperoxia-induced lung injury. The SHH signal pathway may be involved in the pathogenesis of hyperoxia-induced lung injury. This is the first evidence that in vivo hyperoxia induces activation of the SHH signal transduction pathway in newborn lung.

  15. Gallbladder Metastasis of Non-small Cell Lung Cancer Presenting as Acute Cholecystitis

    Yu-Sook Jeong; Seung-Taik Kim; Hye-Suk Han; Sung-Nam Lim; Mi-Jin Kim; Joung-Ho Han; Min-Ho Kang; Dong-Hee Ryu; Ok-Jun Lee; Ki-Hyeong Lee

    2012-01-01

    Although non-small cell lung cancer (NSCLC) can metastasize to almost any organ,metastasis to the gallbladder with significant clinical manifestation is relatively rare.Here,we report a case of gallbladder metastasis of NSCLC presenting as acute cholecystitis.A 79-year-old man presented with pain in the right upper quadrant and fever.A computed tomography (CT) scan of the chest and abdomen showed a cavitary mass in the right lower lobe of the lung and irregular wall thickening of the gallbladder.Open cholecystectomy and needle biopsy of the lung mass were performed.Histological examination of the gallbladder revealed a moderately-differentiated squamous cell carcinoma displaying the same morphology as the lung mass assessed by needle biopsy.Subsequent immunohistochemical examination of the gallbladder and lung tissue showed that the tumor cells were positive for P63 but negative for cytokeratin 7,cytokeratin 20 and thyroid transcription factor-1.A second primary tumor of the gallbladder was excluded by immunohistochemical methods,and the final pathological diagnosis was gallbladder metastasis of NSCLC.Although the incidence is extremely rare,acute cholecystitis can occur in association with lung cancer metastasis to the gallbladder.

  16. Bayesian inference of the lung alveolar spatial model for the identification of alveolar mechanics associated with acute respiratory distress syndrome

    Christley, Scott; Emr, Bryanna; Ghosh, Auyon; Satalin, Josh; Gatto, Louis; Vodovotz, Yoram; Nieman, Gary F.; An, Gary

    2013-06-01

    Acute respiratory distress syndrome (ARDS) is acute lung failure secondary to severe systemic inflammation, resulting in a derangement of alveolar mechanics (i.e. the dynamic change in alveolar size and shape during tidal ventilation), leading to alveolar instability that can cause further damage to the pulmonary parenchyma. Mechanical ventilation is a mainstay in the treatment of ARDS, but may induce mechano-physical stresses on unstable alveoli, which can paradoxically propagate the cellular and molecular processes exacerbating ARDS pathology. This phenomenon is called ventilator induced lung injury (VILI), and plays a significant role in morbidity and mortality associated with ARDS. In order to identify optimal ventilation strategies to limit VILI and treat ARDS, it is necessary to understand the complex interplay between biological and physical mechanisms of VILI, first at the alveolar level, and then in aggregate at the whole-lung level. Since there is no current consensus about the underlying dynamics of alveolar mechanics, as an initial step we investigate the ventilatory dynamics of an alveolar sac (AS) with the lung alveolar spatial model (LASM), a 3D spatial biomechanical representation of the AS and its interaction with airflow pressure and the surface tension effects of pulmonary surfactant. We use the LASM to identify the mechanical ramifications of alveolar dynamics associated with ARDS. Using graphical processing unit parallel algorithms, we perform Bayesian inference on the model parameters using experimental data from rat lung under control and Tween-induced ARDS conditions. Our results provide two plausible models that recapitulate two fundamental hypotheses about volume change at the alveolar level: (1) increase in alveolar size through isotropic volume change, or (2) minimal change in AS radius with primary expansion of the mouth of the AS, with the implication that the majority of change in lung volume during the respiratory cycle occurs in the

  17. Video-Assisted Thoracoscopic Lung Biopsy as a Possible Cause of Acute Interstitial Pneumonia in a Patient with Nonspecific Interstitial Pneumonia

    D Jeffrey Moore

    2004-01-01

    Full Text Available The present case report describes a 44-year-old woman who presented with dyspnea due to diffuse interstitial lung disease. High-resolution computed tomography showed features of usual interstitial pneumonia, but the lung biopsy obtained by video-assisted thoracoscopy was consistent with a histological pattern of nonspecific interstitial pneumonia. Following the procedure, the patient developed progressive respiratory distress and died on postoperative day 13 with a clinical picture of acute interstitial pneumonia. The autopsy showed evidence of diffuse alveolar damage superimposed on the background pattern of nonspecific interstitial pneumonia. The present case report supports the notion that patients with a variety of subtypes of idiopathic interstitial pneumonias may be at risk of exacerbation of their underlying disease following thoracic procedures, including video-assisted thoracoscopic lung biopsy.

  18. Inhaled Nitric Oxide for Acute Respiratory Distress Syndrome and Acute Lung Injury in Adults and Children: A Systematic Review with Meta-Analysis and Trial Sequential Analysis

    Afshari, Arash; Brok, Jesper; Møller, Ann

    2011-01-01

    BACKGROUND: Acute hypoxemic respiratory failure, defined as acute lung injury and acute respiratory distress syndrome, are critical conditions associated with frequent mortality and morbidity in all ages. Inhaled nitric oxide (iNO) has been used to improve oxygenation, but its role remains...... be recommended for patients with acute hypoxemic respiratory failure. iNO results in a transient improvement in oxygenation but does not reduce mortality and may be harmful....

  19. Inhibition of the mitochondrial respiratory chain function abrogates quartz induced DNA damage in lung epithelial cells

    Li Hui [Institut fuer umweltmedizinische Forschung (IUF) at the Heinrich-Heine-University, Auf' m Hennekamp 50, D-40225 Duesseldorf (Germany); Haberzettl, Petra [Institut fuer umweltmedizinische Forschung (IUF) at the Heinrich-Heine-University, Auf' m Hennekamp 50, D-40225 Duesseldorf (Germany); Albrecht, Catrin [Institut fuer umweltmedizinische Forschung (IUF) at the Heinrich-Heine-University, Auf' m Hennekamp 50, D-40225 Duesseldorf (Germany); Hoehr, Doris [Institut fuer umweltmedizinische Forschung (IUF) at the Heinrich-Heine-University, Auf' m Hennekamp 50, D-40225 Duesseldorf (Germany); Knaapen, Ad M. [Department of Health Risk Analysis and Toxicology, Nutrition and Toxicology Research Institute Maastricht (NUTRIM), University of Maastricht (Netherlands); Borm, Paul J.A. [Institut fuer umweltmedizinische Forschung (IUF) at the Heinrich-Heine-University, Auf' m Hennekamp 50, D-40225 Duesseldorf (Germany); Hogeschool Zuyd Heerlen (Netherlands); Schins, Roel P.F. [Institut fuer umweltmedizinische Forschung (IUF) at the Heinrich-Heine-University, Auf' m Hennekamp 50, D-40225 Duesseldorf (Germany)]. E-mail: roel.schins@uni-duesseldorf.de

    2007-04-01

    Respirable quartz dust has been classified as a human carcinogen by the International Agency for Research on Cancer. The aim of our study was to investigate the mechanisms of DNA damage by DQ12 quartz in RLE-6TN rat lung epithelial type II cells (RLE). Transmission electron microscopy and flow-cytometry analysis showed a rapid particle uptake (30 min to 4 h) of quartz by the RLE cells, but particles were not found within the cell nuclei. This suggests that DNA strand breakage and induction of 8-hydroxydeoxyguanosine - as also observed in these cells during these treatment intervals - did not result from direct physical interactions between particles and DNA, or from short-lived particle surface-derived reactive oxygen species. DNA damage by quartz was significantly reduced in the presence of the mitochondrial inhibitors rotenone and antimycin-A. In the absence of quartz, these inhibitors did not affect DNA damage, but they reduced cellular oxygen consumption. No signs of apoptosis were observed by quartz. Flow-cytometry analysis indicated that the reduced DNA damage by rotenone was not due to a possible mitochondria-mediated reduction of particle uptake by the RLE cells. Further proof of concept for the role of mitochondria was shown by the failure of quartz to elicit DNA damage in mitochondria-depleted 143B (rho-0) osteosarcoma cells, at concentrations where it elicited DNA damage in the parental 143B cell line. In conclusion, our data show that respirable quartz particles can elicit oxidative DNA damage in vitro without entering the nuclei of type II cells, which are considered to be important target cells in quartz carcinogenesis. Furthermore, our observations indicate that such indirect DNA damage involves the mitochondrial electron transport chain function, by an as-yet-to-be elucidated mechanism.

  20. Protective Effect of Rhubarb on Endotoxin-Induced Acute Lung Injury

    李春盛; 周景; 桂培春; 何新华

    2001-01-01

    To approach the mechanism of lipopolysaccharide (LPS) in causing acute lung injury (ALI) and the protective effect of rhubarb and dexamethasone, lung specimens were examined with macroscopy, microscopy, electron microscopy and the biological markers of ALI including lung wet/dry weight, the rate of neutrophils and protein content in the pulmonary alveolar lavage fluid, pulmonary capillary permeability and pulmonary alveolar permeability index were observed. The mechanism of the ALI is mainly due to direct injury of alveolar epithelium and pulmonary vascular endothelium. Rhubarb and dexamethasone could significantly reduce the edema of the lung tissue, decrease the red blood cell exudation, neutrophil infiltration and plasma protein exudation in the alveoli and all the biological markers in comparison with the ALI model rats, indicating they have protective action on vascular endothelium and alveolar epithelium.

  1. Piperine Ameliorates Lipopolysaccharide-Induced Acute Lung Injury via Modulating NF-κB Signaling Pathways.

    Lu, Ying; Liu, Jingyao; Li, Hongyan; Gu, Lina

    2016-02-01

    Piperine, one of the active components of black pepper, has been reported to have antioxidant and anti-inflammatory activities. However, the effects of piperine on lipolysaccharide (LPS)-induced acute lung injury (ALI) have not been reported. Thus, the protective effects of piperine against LPS-induced ALI were investigated in this study. LPS-induced lung injury was assessed by histological study, myeloperoxidase (MPO) activity, and inflammatory cytokine production. Our results demonstrated that piperine attenuated LPS-induced MPO activity, lung edema, and inflammatory cytokines TNF-α, IL-6, and IL-1β production. Histological studies showed that piperine obviously attenuated LPS-induced lung injury. In addition, piperine significantly inhibited LPS-induced NF-κB activation. In conclusion, our results demonstrated that piperine had a protective effect on LPS-induced ALI. The anti-inflammatory mechanism of piperine is through inhibition of NF-κB activation. Piperine may be a potential therapeutic agent for ALI.

  2. The effects of anesthetics and misonidazole on the development of radiation-induced lung damage in mice

    Down, J.D. (Inst. of Cancer Research, Surrey, England); Collis, C.H.; Jeffery, P.K.; Steel, G.G.

    1983-02-01

    The measurement of breathing frequency as a functional end-point of radiation-induced lung injury in mice allowed two phases of damage to be discerned; the first was manifest at 12-20 weeks after irradiation, the second beyond 28 weeks. Anesthesia by pentobarbitone sodium or steroids gave significant radioprotection of the lung during the early pneumonitic phase. Addition of the hypoxic cell sensitizer misonidazole removed the protective influence of the anesthetics but did not sensitize the lungs of unanesthetized mice. No anesthetic protection was detected for the late response, showing evidence for dissociation between early and late lung damage. The degree of epilation was measured on the dorsal thoracic region of the same mice. Protection by anesthetics and its reversal by misonidazole was also demonstrated. These results provide a warning of potential hazards in the laboratory evaluation of chemical radiosensitizers. The use of anesthetics at the time of irradiation could lead to an exaggerated enhancement of normal tissue damage.

  3. Intestinal epithelium is more susceptible to cytopathic injury and altered permeability than the lung epithelium in the context of acute sepsis.

    Julian, Mark W; Bao, Shengying; Knoell, Daren L; Fahy, Ruairi J; Shao, Guohong; Crouser, Elliott D

    2011-10-01

    Mitochondrial morphology and function are altered in intestinal epithelia during endotoxemia. However, it is unclear whether mitochondrial abnormalities occur in lung epithelial cells during acute sepsis or whether mitochondrial dysfunction corresponds with altered epithelial barrier function. Thus, we hypothesized that the intestinal epithelium is more susceptible to mitochondrial injury than the lung epithelium during acute sepsis and that mitochondrial dysfunction precedes impaired barrier function. Using a resuscitated feline model of Escherichia coli-induced sepsis, lung and ileal tissues were harvested after 6 h for histological and mitochondrial ultrastructural analyses in septic (n = 6) and time-matched controls (n = 6). Human lung epithelial cells (HLEC) and Caco-2 monolayers (n = 5) were exposed to 'cytomix' (TNFα: 40 ng/ml, IL-1β: 20 ng/ml, IFNγ: 10 ng/ml) for 24-72 h, and measurements of transepithelial electrical resistance (TER), epithelial permeability and mitochondrial membrane potential (ΔΨ) were taken. Lung epithelial morphology, mitochondrial ultrastructure and pulmonary gas exchange were unaltered in septic animals compared to matching controls. While histologically intact, ileal epithelia demonstrated marked mitochondrial ultrastructural damage during sepsis. Caco-2 monolayers treated with cytomix showed a significant decrease in mitochondrial ΔΨ within 24 h, which was associated with a progressive reduction in TER and increased epithelial permeability over the subsequent 48 h. In contrast, mitochondrial ΔΨ and epithelial barrier functions were preserved in HLEC following cytomix. These findings indicate that intestinal epithelium is more susceptible to mitochondrial damage and dysfunction than the lung epithelium in the context of sepsis. Early alterations in mitochondrial function portend subsequent epithelial barrier dysfunction.

  4. Leukotriene biosynthesis inhibition ameliorates acute lung injury following hemorrhagic shock in rats

    Hadi Najah R

    2011-06-01

    Full Text Available Abstract Background Hemorrhagic shock followed by resuscitation is conceived as an insult frequently induces a systemic inflammatory response syndrome and oxidative stress that results in multiple-organ dysfunction syndrome including acute lung injury. MK-886 is a leukotriene biosynthesis inhibitor exerts an anti inflammatory and antioxidant activity. Objectives The objective of present study was to assess the possible protective effect of MK-886 against hemorrhagic shock-induced acute lung injury via interfering with inflammatory and oxidative pathways. Materials and methods Eighteen adult Albino rats were assigned to three groups each containing six rats: group I, sham group, rats underwent all surgical instrumentation but neither hemorrhagic shock nor resuscitation was done; group II, Rats underwent hemorrhagic shock (HS for 1 hr then resuscitated with Ringer's lactate (1 hr (induced untreated group, HS; group III, HS + MK-886 (0.6 mg/kg i.p. injection 30 min before the induction of HS, and the same dose was repeated just before reperfusion period. At the end of experiment (2 hr after completion of resuscitation, blood samples were collected for measurement of serum tumor necrosis factor-α (TNF-α and interleukin-6 (IL-6. The trachea was then isolated and bronchoalveolar lavage fluid (BALF was carried out for measurement of leukotriene B4 (LTB4, leukotriene C4 (LTC4 and total protein. The lungs were harvested, excised and the left lung was homogenized for measurement of malondialdehyde (MDA and reduced glutathione (GSH and the right lung was fixed in 10% formalin for histological examination. Results MK-886 treatment significantly reduced the total lung injury score compared with the HS group (P 4, LTC4 & total protein compared with the HS group (P P Conclusions The results of the present study reveal that MK-886 may ameliorate lung injury in shocked rats via interfering with inflammatory and oxidative pathways implicating the role of

  5. Amiodarone-induced acute lung toxicity in an ICU setting.

    Skroubis, G; Skroubis, T; Galiatsou, E; Metafratzi, Z; Karahaliou, A; Kitsakos, A; Nakos, G

    2005-04-01

    Amiodarone is a highly effective antiarrhythmic drug, albeit notorious for its serious pulmonary toxicity. The incidence of amiodarone-induced pulmonary toxicity (APT) appears to be 1% per year (1). We report a case of very acute APT in a man suffering from postoperative atrial fibrillation.

  6. Genetic Deletion and Pharmacological Inhibition of PI3Kγ Reduces Neutrophilic Airway Inflammation and Lung Damage in Mice with Cystic Fibrosis-Like Lung Disease

    Maria Galluzzo

    2015-01-01

    Full Text Available Purpose. Neutrophil-dominated airway inflammation is a key feature of progressive lung damage in cystic fibrosis (CF. Thus, reducing airway inflammation is a major goal to prevent lung damage in CF. However, current anti-inflammatory drugs have shown several limits. PI3Kγ plays a pivotal role in leukocyte recruitment and activation; in the present study we determined the effects of genetic deletion and pharmacologic inhibition of PI3Kγ on airway inflammation and structural lung damage in a mouse model of CF lung disease. Methods. βENaC overexpressing mice (βENaC-Tg were backcrossed with PI3Kγ-deficient (PI3KγKO mice. Tissue damage was assessed by histology and morphometry and inflammatory cell number was evaluated in bronchoalveolar lavage fluid (BALF. Furthermore, we assessed the effect of a specific PI3Kγ inhibitor (AS-605240 on inflammatory cell number in BALF. Results. Genetic deletion of PI3Kγ decreased neutrophil numbers in BALF of PI3KγKO/βENaC-Tg mice, and this was associated with reduced emphysematous changes. Treatment with the PI3Kγ inhibitor AS-605240 decreased the number of neutrophils in BALF of βENaC-Tg mice, reproducing the effect observed with genetic deletion of the enzyme. Conclusions. These results demonstrate the biological efficacy of both genetic deletion and pharmacological inhibition of PI3Kγ in reducing chronic neutrophilic inflammation in CF-like lung disease in vivo.

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

    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.

  8. A model of hemorrhagic shock and acute lung injury in Landrace-Large White Swine.

    Xanthos, Theodoros T; Balkamou, Xanthippi A; Stroumpoulis, Kostantinos I; Pantazopoulos, Ioannis N; Rokas, Georgios I; Agrogiannis, Georgios D; Troupis, Georgios T; Demestiha, Theano D; Skandalakis, Panagiotis N

    2011-04-01

    Traumatic injury is a leading cause of death worldwide for people between 5 and 44 y of age, and it accounts for 10% of all deaths. The incidence of acute lung injury, a life-threatening complication in severely injured trauma patients remains between 30% and 50%. This study describes an experimental protocol of volume-controlled hemorrhage in Landrace-Large White swine. The experimental approach simulated the clinical situation associated with hemorrhagic shock in the trauma patient while providing controlled conditions to maximize reproducibility. The duration of the protocol was 8 h and was divided into 5 distinct phases-stabilization, hemorrhage, maintenance, resuscitation, and observation-after which the swine were euthanized. Lung tissue samples were analyzed histologically. All swine survived the protocol. The hemodynamic responses accurately reflected those seen in humans, and the development of acute lung injury was consistent among all swine. This experimental protocol of hemorrhagic shock and fluid resuscitation in Landrace-Large White swine may be useful for future study of hemorrhagic shock and acute lung injury.

  9. A Model of Hemorrhagic Shock and Acute Lung Injury in Landrace–Large White Swine

    Xanthos, Theodoros T; Balkamou, Xanthippi A; Stroumpoulis, Kostantinos I; Pantazopoulos, Ioannis N; Rokas, Georgios I; Agrogiannis, Georgios D; Troupis, Georgios T; Demestiha, Theano D; Skandalakis, Panagiotis N

    2011-01-01

    Traumatic injury is a leading cause of death worldwide for people between 5 and 44 y of age, and it accounts for 10% of all deaths. The incidence of acute lung injury, a life-threatening complication in severely injured trauma patients remains between 30% and 50%. This study describes an experimental protocol of volume-controlled hemorrhage in Landrace–Large White swine. The experimental approach simulated the clinical situation associated with hemorrhagic shock in the trauma patient while providing controlled conditions to maximize reproducibility. The duration of the protocol was 8 h and was divided into 5 distinct phases—stabilization, hemorrhage, maintenance, resuscitation, and observation—after which the swine were euthanized. Lung tissue samples were analyzed histologically. All swine survived the protocol. The hemodynamic responses accurately reflected those seen in humans, and the development of acute lung injury was consistent among all swine. This experimental protocol of hemorrhagic shock and fluid resuscitation in Landrace–Large White swine may be useful for future study of hemorrhagic shock and acute lung injury. PMID:21535927

  10. Apios americana Medik Extract Alleviates Lung Inflammation in Influenza Virus H1N1- and Endotoxin-Induced Acute Lung Injury.

    Sohn, Sung-Hwa; Lee, Sang-Yeon; Cui, Jun; Jang, Ho Hee; Kang, Tae-Hoon; Kim, Jong-Keun; Kim, In-Kyoung; Lee, Deuk-Ki; Choi, Seulgi; Yoon, Il-Sub; Chung, Ji-Woo; Nam, Jae-Hwan

    2015-12-28

    Apios americana Medik (hereinafter Apios) has been reported to treat diseases, including cancer, hypertension, obesity, and diabetes. The therapeutic effect of Apios is likely to be associated with its anti-inflammatory activity. This study was conducted to evaluate the protective effects of Apios in animal models of acute lung injury induced by lipopolysaccharide (LPS) or pandemic H1N1 2009 influenza A virus (H1N1). Mice were exposed to LPS or H1N1 for 2-4 days to induce acute lung injury. The treatment groups were administered Apios extracts via oral injection for 8 weeks before LPS treatment or H1N1 infection. To investigate the effects of Apios, we assessed the mice for in vivo effects of Apios on immune cell infiltration and the level of pro-inflammatory cytokines in the bronchoalveolar lavage (BAL) fluid, and histopathological changes in the lung. After induction of acute lung injury, the numbers of neutrophils and total cells were lower in the Apios-treated groups than in the non-Apios-treated LPS and H1N1 groups. The Apios groups tended to have lower levels of tumor necrosis factor-a and interleukin-6 in BAL fluid. In addition, the histopathological changes in the lungs were markedly reduced in the Apios-treated groups. These data suggest that Apios treatment reduces LPS- and H1N1-induced lung inflammation. These protective effects of Apios suggest that it may have therapeutic potential in acute lung injury.

  11. Mechanical ventilation strategies for intensive care unit patients without acute lung injury or acute respiratory distress syndrome: a systematic review and network meta-analysis

    Guo, Lei; Wang, Weiwei; Zhao, Nana; Guo, Libo; Chi, Chunjie; Hou, Wei; Wu, Anqi; Tong, Hongshuang; Wang, Yue; Wang, Changsong; Li, Enyou

    2016-01-01

    Background It has been shown that the application of a lung-protective mechanical ventilation strategy can improve the prognosis of patients with acute lung injury (ALI) or acute respiratory distress syndrome (ARDS). However, the optimal mechanical ventilation strategy for intensive care unit (ICU) patients without ALI or ARDS is uncertain. Therefore, we performed a network meta-analysis to identify the optimal mechanical ventilation strategy for these patients. Methods We searched the Cochra...

  12. Role of macrophage chemoattractant protein-1 in acute inflammation after lung contusion.

    Suresh, Madathilparambil V; Yu, Bi; Machado-Aranda, David; Bender, Matthew D; Ochoa-Frongia, Laura; Helinski, Jadwiga D; Davidson, Bruce A; Knight, Paul R; Hogaboam, Cory M; Moore, Bethany B; Raghavendran, Krishnan

    2012-06-01

    Lung contusion (LC), commonly observed in patients with thoracic trauma is a leading risk factor for development of acute lung injury/acute respiratory distress syndrome. Previously, we have shown that CC chemokine ligand (CCL)-2, a monotactic chemokine abundant in the lungs, is significantly elevated in LC. This study investigated the nature of protection afforded by CCL-2 in acute lung injury/acute respiratory distress syndrome during LC, using rats and CC chemokine receptor (CCR) 2 knockout (CCR2(-/-)) mice. Rats injected with a polyclonal antibody to CCL-2 showed higher levels of albumin and IL-6 in the bronchoalveolar lavage and myeloperoxidase in the lung tissue after LC. Closed-chest bilateral LC demonstrated CCL-2 localization in alveolar macrophages (AMs) and epithelial cells. Subsequent experiments performed using a murine model of LC showed that the extent of injury, assessed by pulmonary compliance and albumin levels in the bronchoalveolar lavage, was higher in the CCR2(-/-) mice when compared with the wild-type (WT) mice. We also found increased release of IL-1β, IL-6, macrophage inflammatory protein-1, and keratinocyte chemoattractant, lower recruitment of AMs, and higher neutrophil infiltration and phagocytic activity in CCR2(-/-) mice at 24 hours. However, impaired phagocytic activity was observed at 48 hours compared with the WT. Production of CCL-2 and macrophage chemoattractant protein-5 was increased in the absence of CCR2, thus suggesting a negative feedback mechanism of regulation. Isolated AMs in the CCR2(-/-) mice showed a predominant M1 phenotype compared with the predominant M2 phenotype in WT mice. Taken together, the above results show that CCL-2 is functionally important in the down-modulation of injury and inflammation in LC.

  13. Bronchoalveolar lavage alterations during prolonged ventilation of patients without acute lung injury.

    Tsangaris, I; Lekka, M E; Kitsiouli, E; Constantopoulos, S; Nakos, G

    2003-03-01

    Mechanical ventilation deteriorates previously injured lung, but little is known about its effect on healthy human lung. This work was designed to assess the effect of prolonged mechanical ventilation on bronchoalveolar lavage (BAL) fluid composition of patients without acute lung injury. Twenty-two ventilated patients (tidal volume 8-10 mL x kg(-1), positive end-expiratory pressure 3-5 cmH2O) without lung injury, who did not develop any complication from the respiratory system during the 2-week study period, were studied. They were subjected to three consecutive BALs, the first during 36 h from intubation, the second at the end of the first week of mechanical ventilation and the third at the end of the second week of mechanical ventilation. Total BAL protein increased during mechanical ventilation (148 +/- 62, 381 +/- 288, 353 +/- 215 microg x mL(-1) BAL for the first, second and third BAL, respectively). In contrast, BAL phospholipids decreased (2.7 +/- 1.1, 1.4 +/- 0.6, 1.2 +/- 0.7 microg x mL(-1) BAL, respectively). Large surfactant aggregates were reduced and inflammatory markers, such as platelet activating factor (PAF), PAF-acetylhydrolase and neutrophils, significantly increased after 1 week, but partially remitted after 2 weeks of mechanical ventilation. In summary, this study demonstrates that prolonged mechanical ventilation even of patients without acute lung injury is associated with the presence of inflammatory markers and surfactant alterations.

  14. NLRP3 inflammasome activation is essential for paraquat-induced acute lung injury.

    Liu, Zhenning; Zhao, Hongyu; Liu, Wei; Li, Tiegang; Wang, Yu; Zhao, Min

    2015-02-01

    The innate immune response is important in paraquat-induced acute lung injury, but the exact pathways involved are not elucidated. The objectives of this study were to determine the specific role of the NLRP3 inflammasome in the process. Acute lung injury was induced by administering paraquat (PQ) intraperitoneally. NLRP3 inflammasome including NLRP3, ASC, and caspase-1 mRNA and protein expression in lung tissue and IL-1β and IL-18 levels in BALF were detected at 4, 8, 24, and 72 h after PQ administration in rats. Moreover, rats were pretreated with 10, 30, and 50 mg/kg NLRP3 inflammasome blocker glybenclamide, respectively, 1 h before PQ exposure. At 72 h after PQ administration, lung histopathology changes, NLRP3, ASC, and caspase-1 protein expression, as well as secretion of cytokines including IL-1β and IL-18 in BALF were investigated. The NLRP3 inflammasome including NLRP3, ASC, caspase-1 expression, and cytokines IL-1β and IL-18 levels in PQ poisoning rats were significantly higher than that in the control group. NLRP3 inflammasome blocker glybenclamide pretreatment attenuated lung edema, inhibited the NLRP3, ASC, and caspase-1 activation, and reduced IL-1β and IL-18 levels in BALF. In the in vitro experiments, IL-1β and IL-18 secreted from RAW264.7 mouse macrophages treated with paraquat were attenuated by glybenclamide. In conclusion, paraquat can induce IL-1β/IL-18 secretion via NLRP3-ASC-caspase-1 pathway, and the NLRP3 inflammasome is essential for paraquat-induced acute lung injury.

  15. A genetic mouse model to investigate hyperoxic acute lung injury survival.

    Prows, Daniel R; Hafertepen, Amanda P; Gibbons, William J; Winterberg, Abby V; Nick, Todd G

    2007-08-20

    Acute lung injury (ALI) is a devastating disease that maintains a high mortality rate, despite decades of research. Hyperoxia, a universal treatment for ALI and other critically ill patients, can itself cause pulmonary damage, which drastically restricts its therapeutic potential. We stipulate that having the ability to use higher levels of supplemental O2 for longer periods would improve recovery rates. Toward this goal, a mouse model was sought to identify genes contributing to hyperoxic ALI (HALI) mortality. Eighteen inbred mouse strains were screened in continuous >95% O2. A significant survival difference was identified between sensitive C57BL/6J and resistant 129X1/SvJ strains. Although resistant, only one-fourth of 129X1/SvJ mice survived longer than any C57BL/6J mouse, demonstrating decreased penetrance of resistance. A survival time difference between reciprocal F1 mice implicated a parent-of-origin (imprinting) effect. To further evaluate imprinting and begin to delineate the genetic components of HALI survival, we generated and phenotyped offspring from all four possible intercrosses. Segregation analysis supported maternal inheritance of one or more genes but paternal inheritance of one or more contributor genes. A significant sex effect was demonstrated, with males more resistant than females for all F2 crosses. Survival time ranges and sensitive-to-resistant ratios of the different F2 crosses also supported imprinting and predicted that increased survival is due to dominant resistance alleles contributed by both the resistant and sensitive parental strains. HALI survival is multigenic with a complex mode of inheritance, which should be amenable to genetic dissection with this mouse model.

  16. Protection of Total Flavonoid Fraction from Nervilia fordii on Lipopolysaccharide-induced Acute Lung Injury in Rats

    HUANG Ming-qing; XIE You-liang; LAI Xiao-ping; LIN Ling; XU Yin-ji; LU Jin-jian; CHEN Xiu-ping

    2012-01-01

    Objective To investigate the effects of total flavonoid fraction(TFF)from Nervilia fordii on lipopolysaccharide(LPS)-induced acute lung injury(ALI)in rats,and to explore their protective mechanism.Methods LPS-induced ALI model was established by LPS(5 mg/kg)injection via left cervical vein.Blood samples were collected from the cervical artery of all rats at 5 and 6 h after LPS challenge for arterial blood gas test and cytokines measurements,and pulmonary microvascular permeability(PMP),lung wet/dry weight ratio(W/D),and pathological features were observed.Results Phytochemical study showed that the TFF contained 67.3% of flavonoids expressed in rutin and three flavone glycosides.The TFF pretreatment(6.24 and 12.48 mg/kg)attenuated the partial arterial pressure of oxygen decline in blood significantly,and decreased the PMP and lung W/D in ALI rats.In addition,the TFF(6.24 and 12.48 mg/kg)also ameliorated the LPS-induced lung damages including alveolar edema,neutrophils infiltration,alveolar hemorrhage,and thickening of the alveolar wall.Furthermore,the treatment with the TFF(6.24 and 12.48 mg/kg)also down-regulated the levels of pro-inflammatory cytokines,such as tumor necrosis factor-α(TNF-α),interleukin-6(IL-6),and intercellular adhesion molecule-1(ICAM-1),and up-regulated the level of anti-inflammatory cytokine IL-10 in serum of ALI rats simultaneously.Conclusion These results suggest that the TFF could protect LPS-induced ALI in rats,which may be mediated,at least in part,by adjusting the production of inflammatory cytokines including TNF-α,IL-6,ICAM-1,and IL-10.

  17. Cytokine levels in pleural fluid as markers of acute rejection after lung transplantation

    Priscila Cilene León Bueno de Camargo

    2014-08-01

    Full Text Available Our objective was to determine the levels of lactate dehydrogenase, IL-6, IL-8, and VEGF, as well as the total and differential cell counts, in the pleural fluid of lung transplant recipients, correlating those levels with the occurrence and severity of rejection. We analyzed pleural fluid samples collected from 18 patients at various time points (up to postoperative day 4. The levels of IL-6, IL-8, and VEGF tended to elevate in parallel with increases in the severity of rejection. Our results suggest that these levels are markers of acute graft rejection in lung transplant recipients.

  18. [Determination of capillary plasma C-reactive protein during therapy for acute infectious lung diseases].

    Makarenko, V V; Vavilikhina, N F; Kastrikina, T N; El'chaninova, S A

    2011-06-01

    Changes in the concentration of C-reactive protein (CRP), leukocytes, erythrocyte sedimentation rate, and differential blood count were comparatively estimated in the treatment of 66 infants (aged 1.12 +/- 0.95 years) with acute infectious lung diseases. There was a high correlation between capillary plasma and venous serum CRP concentrations. On the first day of effective antibiotic therapy, there was a significant decrease in CRP levels; the sensitivity and specificity were 96 and 94%, respectively. Thus, measurement of capillary blood CRP is an accessible and informative tool to monitor therapy for infectious lung diseases in infants.

  19. Cytokine levels in pleural fluid as markers of acute rejection after lung transplantation*

    de Camargo, Priscila Cilene León Bueno; Afonso, José Eduardo; Samano, Marcos Naoyuki; Acencio, Milena Marques Pagliarelli; Antonangelo, Leila; Teixeira, Ricardo Henrique de Oliveira Braga

    2014-01-01

    Our objective was to determine the levels of lactate dehydrogenase, IL-6, IL-8, and VEGF, as well as the total and differential cell counts, in the pleural fluid of lung transplant recipients, correlating those levels with the occurrence and severity of rejection. We analyzed pleural fluid samples collected from 18 patients at various time points (up to postoperative day 4). The levels of IL-6, IL-8, and VEGF tended to elevate in parallel with increases in the severity of rejection. Our results suggest that these levels are markers of acute graft rejection in lung transplant recipients. PMID:25210966

  20. Targeting Neutrophils to Prevent Malaria-Associated Acute Lung Injury/Acute Respiratory Distress Syndrome in Mice

    Soeiro-Pereira, Paulo V.; Gomes, Eliane; Neto, Antonio Condino; D' Império Lima, Maria R.; Alvarez, José M.; Portugal, Silvia; Epiphanio, Sabrina

    2016-01-01

    Malaria remains one of the greatest burdens to global health, causing nearly 500,000 deaths in 2014. When manifesting in the lungs, severe malaria causes acute lung injury/acute respiratory distress syndrome (ALI/ARDS). We have previously shown that a proportion of DBA/2 mice infected with Plasmodium berghei ANKA (PbA) develop ALI/ARDS and that these mice recapitulate various aspects of the human syndrome, such as pulmonary edema, hemorrhaging, pleural effusion and hypoxemia. Herein, we investigated the role of neutrophils in the pathogenesis of malaria-associated ALI/ARDS. Mice developing ALI/ARDS showed greater neutrophil accumulation in the lungs compared with mice that did not develop pulmonary complications. In addition, mice with ALI/ARDS produced more neutrophil-attracting chemokines, myeloperoxidase and reactive oxygen species. We also observed that the parasites Plasmodium falciparum and PbA induced the formation of neutrophil extracellular traps (NETs) ex vivo, which were associated with inflammation and tissue injury. The depletion of neutrophils, treatment with AMD3100 (a CXCR4 antagonist), Pulmozyme (human recombinant DNase) or Sivelestat (inhibitor of neutrophil elastase) decreased the development of malaria-associated ALI/ARDS and significantly increased mouse survival. This study implicates neutrophils and NETs in the genesis of experimentally induced malaria-associated ALI/ARDS and proposes a new therapeutic approach to improve the prognosis of severe malaria. PMID:27926944

  1. Nicotine overrides DNA damage-induced G1/S restriction in lung cells.

    Takashi Nishioka

    Full Text Available As an addictive substance, nicotine has been suggested to facilitate pro-survival activities (such as anchorage-independent growth or angiogenesis and the establishment of drug resistance to anticancer therapy. Tobacco smoking consists of a variety of carcinogens [such as benzopyrene (BP and nitrosamine derivatives] that are able to cause DNA double strand breaks. However, the effect of nicotine on DNA damage-induced checkpoint response induced by genotoxins remains unknown. In this study, we investigated the events occurred during G(1 arrest induced by γ-radiation or BP in nicotine-treated murine or human lung epithelial cells. DNA synthesis was rapidly inhibited after exposure to γ-radiation or BP treatment, accompanied with the activation of DNA damage checkpoint. When these cells were co-treated with nicotine, the growth restriction was compromised, manifested by upregulation of cyclin D and A, and attenuation of Chk2 phosphorylation. Knockdown of cyclin D or Chk2 by the siRNAs blocked nicotine-mediated effect on DNA damage checkpoint activation. However, nicotine treatment appeared to play no role in nocodazole-induced mitotic checkpoint activation. Overall, our study presented a novel observation, in which nicotine is able to override DNA damage checkpoint activated by tobacco-related carcinogen BP or γ-irradiation. The results not only indicates the potentially important role of nicotine in facilitating the establishment of genetic instability to promote lung tumorigenesis, but also warrants a dismal prognosis for cancer patients who are smokers, heavily exposed second-hand smokers or nicotine users.

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

    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

  3. Inflammatory potential of the spores of Penicillium spinulosum isolated from indoor air of a moisture-damaged building in mouse lungs.

    Jussila, Juha; Komulainen, Hannu; Kosma, Veli-Matti; Pelkonen, Jukka; Hirvonen, Maija-Riitta

    2002-10-01

    Excess moisture and microbial growth have been associated with adverse health effects, especially in the airways, of the inhabitants of moisture-damaged buildings. The spores of Penicillium spp. are commonly present in the indoor air, both in moisture-damaged and in reference buildings, though their numbers seem to be significantly higher in the damaged buildings. To assess the potential of Penicillium spinulosum to evoke harmful respiratory effects, mice were exposed via intratracheal instillation to a single dose of the spores of P. spinulosum, isolated from the indoor air of a moisture-damaged building (1×10(5), 1×10(6), 5×10(6), 1×10(7) or 5×10(7) spores). Inflammation and toxicity in lungs were evaluated 24 h later. The time-course of the effects was investigated with the dose of 5×10(6) spores for 28 days. The fungal spores caused mild transient inflammation. The spore exposure transiently increased proinflammatory cytokine (TNFα and IL-6) levels in bronchoalveolar lavage fluid (BALF) in a dose- and time-dependent manner. The highest concentrations of both cytokines were measured at 6 h after a single dosage. The spore exposure did not cause expression of inducible nitric oxide synthase in lavaged cells. Neutrophils were acutely recruited into airways, but the response leveled off in 3 days. Neither cytotoxicity nor major changes in vascular permeability (i.e. increases in albumin, total protein, lactate dehydrogenase or hemoglobin levels in BALF) were observed in the lungs. Considering the profile and magnitude of the changes and the dose of the spores, we conclude that P. spinulosum has a low potential to cause acute respiratory inflammation, nor does it cause direct cytotoxicity.

  4. Experimental Study on the Mechanism of Protective Effect of Free Fu on Gut-derived Endotoxin-Mediated Lung Damage

    李道本; 杨胜兰; 陈瑞

    2004-01-01

    The effect of tumor necrosis factor-α (TNF-α) on endotoxin (ET)-mediated lung damage caused by incomplete ligation of large intestine and the influence of free Fu on the expression of TNF-α mRNA were explored. Forty SD rats were randomly divided into 4 groups: normal control group, model group, ligation group and treatment group (n=10 in each group). The models were made by the method of partly ligating the rectum outside the body. The plasma level of lipopolysaccaride was measured by dynamic nephelo metric method and the serum level of TNF-α was detected by the method of radioactive immunity. The expression of TNF-α mRNA in lung tissue was detected by RT-PCR method. The results were compared among the 4 groups. The results showed the plasma levels of ET and serum TNF-α in the model group and the expression of TNF-α mRNA in the lung tissues were remarkably higher than those in the normal control group (P<0.01). After the treatment of free Fu, all of the above indexes in the treatment group were all decreased as compared with model group (all P<0.01), and the damage to lung was alleviated. It was concluded that TNF-α might play a very important role in the ET-mediated lung damage caused by incomplete ligation of large intestine, free Fu could protect the lung from damage.

  5. P21-PARP-1 Pathway Is Involved in Cigarette Smoke-Induced Lung DNA Damage and Cellular Senescence

    Yao, Hongwei; Sundar, Isaac K.; Gorbunova, Vera; Rahman, Irfan

    2013-01-01

    Persistent DNA damage triggers cellular senescence, which may play an important role in the pathogenesis of cigarette smoke (CS)-induced lung diseases. Both p21CDKN1A (p21) and poly(ADP-ribose) polymerase-1 (PARP-1) are involved in DNA damage and repair. However, the role of p21-PARP-1 axis in regulating CS-induced lung DNA damage and cellular senescence remains unknown. We hypothesized that CS causes DNA damage and cellular senescence through a p21-PARP-1 axis. To test this hypothesis, we determined the levels of γH2AX (a marker for DNA double-strand breaks) as well as non-homologous end joining proteins (Ku70 and Ku80) in lungs of mice exposed to CS. We found that the level of γH2AX was increased, whereas the level of Ku70 was reduced in lungs of CS-exposed mice. Furthermore, p21 deletion reduced the level of γH2AX, but augmented the levels of Ku70, Ku80, and PAR in lungs by CS. Administration of PARP-1 inhibitor 3-aminobenzamide increased CS-induced DNA damage, but lowered the levels of Ku70 and Ku80, in lungs of p21 knockout mice. Moreover, 3-aminobenzamide increased senescence-associated β-galactosidase activity, but decreased the expression of proliferating cell nuclear antigen in mouse lungs in response to CS. Interestingly, 3-aminobenzamide treatment had no effect on neutrophil influx into bronchoalveolar lavage fluid by CS. These results demonstrate that the p21-PARP-1 pathway is involved in CS-induced DNA damage and cellular senescence. PMID:24244594

  6. P21-PARP-1 pathway is involved in cigarette smoke-induced lung DNA damage and cellular senescence.

    Hongwei Yao

    Full Text Available Persistent DNA damage triggers cellular senescence, which may play an important role in the pathogenesis of cigarette smoke (CS-induced lung diseases. Both p21(CDKN1A (p21 and poly(ADP-ribose polymerase-1 (PARP-1 are involved in DNA damage and repair. However, the role of p21-PARP-1 axis in regulating CS-induced lung DNA damage and cellular senescence remains unknown. We hypothesized that CS causes DNA damage and cellular senescence through a p21-PARP-1 axis. To test this hypothesis, we determined the levels of γH2AX (a marker for DNA double-strand breaks as well as non-homologous end joining proteins (Ku70 and Ku80 in lungs of mice exposed to CS. We found that the level of γH2AX was increased, whereas the level of Ku70 was reduced in lungs of CS-exposed mice. Furthermore, p21 deletion reduced the level of γH2AX, but augmented the levels of Ku70, Ku80, and PAR in lungs by CS. Administration of PARP-1 inhibitor 3-aminobenzamide increased CS-induced DNA damage, but lowered the levels of Ku70 and Ku80, in lungs of p21 knockout mice. Moreover, 3-aminobenzamide increased senescence-associated β-galactosidase activity, but decreased the expression of proliferating cell nuclear antigen in mouse lungs in response to CS. Interestingly, 3-aminobenzamide treatment had no effect on neutrophil influx into bronchoalveolar lavage fluid by CS. These results demonstrate that the p21-PARP-1 pathway is involved in CS-induced DNA damage and cellular senescence.

  7. Cyclophosphamide-induced lung damage in mice: protection by a small preliminary dose.

    Collis, C. H.; Wilson, C. M.; Jones, J. M.

    1980-01-01

    Cycylphosphamide (Cy) produces an interstitial pneumonitis in CBA mice. The extent of the lung damage has been quantified by measuring the increase in ventilation rate over 6 weeks after an i.p. injection of Cy 200, 250 and 300 mg/kg. A dose-dependent response was found. When a preliminary ("priming") dose of Cy at 50 mg/kg was given 7, 9 or 14 days before a single large dose of 250 mg/kg, lung damage was reduced, as shown by a smaller increase in ventilation rate than in those receiving 250 mg/kg alone, and this difference was significant (P less than 0.01) in the Day-14-and highly significant (P<0.001) in the Day-7-"primed" groups. When primed less than 7 days before, there was a relative increase in ventilation rate, which was statistically significant (P less than 0.01) in the Day-1-primed group. Similar effects were also seen in the survival of the mice. PMID:7426315

  8. Intercellular Adhension Molecule-1 in the Pathogenesis of Heroin-induced Acute Lung Injury in Rats

    周琼; 白明; 邹世清

    2004-01-01

    The expression of intercellular adhesion molecule-1 (ICAM-1) in the pathogenesis of heroin-induced acute lung injury (ALI) in rats was investigated. The model of ALI was established by intravenous injection of heroin into tail vein in rats. Thirty-six rats were randomly divided into heroin-treated groups (1 h, 2 h, 4 h, 6 h and 24 h) and normal control group. Changes in histopathologic morphology and biological markers of ALI were measured. The expression of ICAM-1in lung tissue was detected by using immunohistochemistry and RT-PCR. The results showed that the W/D ratio and protein contents in BALF of the heroin-treated groups were significantly higher than that of the control group (P<0.01). The histopathological changes in the lung tissue were more obvious in heroin-treated groups. The ICAM-1 protein and mRNA expression in the lung tissue of heroin-treated groups were significantly increased as compared with that of the control group (P<0.01), and correlated with the ALI parameters in a time-dependent manner. Increasing of ICAM-1 expression was involved in the formation of heroin-induced lung injury. Furthermore, the level of expression was positively correlated with the severity of lung injury.

  9. Leptin attenuates lipopolysaccharide or oleic acid-induced acute lung injury in mice.

    Dong, Hai-Ying; Xu, Min; Ji, Zhen-Yu; Wang, Yan-Xia; Dong, Ming-Qing; Liu, Man-Ling; Xu, Dun-Quan; Zhao, Peng-Tao; Liu, Yi; Luo, Ying; Niu, Wen; Zhang, Bo; Ye, Jing; Li, Zhi-Chao

    2013-12-01

    Leptin is reported to be involved in acute lung injury (ALI). However, the role and underlying mechanisms of leptin in ALI remain unclear. The aim of this study was to determine whether leptin deficiency promoted the development of ALI. LPS or oleic acid (OA) were administered to wild-type and leptin deficient (ob/ob) mice to induce ALI. Leptin level, survival rate, and lung injury were examined. Results showed that leptin levels were predominantly increased in the lung, but also in the heart, liver, kidney, and adipose tissue after LPS adminiatration. Compared with wild-type mice, LPS- or OA-induced lung injury was worse and the survival rate was lower in ob/ob mice. Moreover, leptin deficiency promoted the release of proinflammatory cytokines. Exogenous administration of leptin reduced lethality in ob/ob mice and ameliorated lung injury partly through inhibiting the activation of NF-κB, p38, and ERK pathways. These results indicated that leptin deficiency contributed to the development of lung injury by enhancing inflammatory response, and a high level of leptin improved survival and protected against ALI.

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

    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.

  11. XB130 deficiency enhances lipopolysaccharide-induced septic response and acute lung injury

    Toba, Hiroaki; Tomankova, Tereza; Wang, Yingchun; Bai, Xiaohui; Cho, Hae-Ra; Guan, Zhehong; Adeyi, Oyedele A.; Tian, Feng; Keshavjee, Shaf; Liu, Mingyao

    2016-01-01

    XB130 is a novel oncoprotein that promotes cancer cell survival, proliferation and migration. Its physiological function in vivo is largely unknown. The objective of this study was to determine the role of XB130 in lipopolysaccharide (LPS)-induced septic responses and acute lung injury. LPS was intraperitoneally administrated to Xb130 knockout (KO) and wild type (WT) mice. There was a significant weight loss in KO mice at Day 2 and significantly higher disease scores during the 7 days of observation. The levels of tumor necrosis factor-alpha, monocyte chemoattractant protein-1, interleukin-6 and interleukin-10 in the serum were significantly higher in KO mice at Day 2. In KO mice there were a significantly higher lung injury score, higher wet/dry lung weight ratio, more apoptotic cells and less proliferative cells in the lung. Macrophage infiltration was significantly elevated in the lung of KO mice. There was significantly increased number of p-GSK-3β positive cells in KO mice, which were mainly neutrophils and macrophages. XB130 is expressed in alveolar type I and type II cells in the lung. The expression in these cells was significantly reduced after LPS challenge. XB130 deficiency delayed the recovery from systemic septic responses, and the presence of XB130 in the alveolar epithelial cells may provide protective mechanisms by reducing cell death and promoting cell proliferation, and reducing pulmonary permeability. PMID:27029000

  12. Lung ultrasound and chest x-ray for detecting pneumonia in an acute geriatric ward

    2016-01-01

    Abstract Background: Our aim was to compare the accuracy of lung ultrasound (LUS) and standard chest x-ray (CXR) for diagnosing pneumonia in older patients with acute respiratory symptoms (dyspnea, cough, hemoptysis, and atypical chest pain) admitted to an acute-care geriatric ward. Methods: We enrolled 169 (80 M, 89 F) multimorbid patients aged 83.0 ± 9.2 years from January 1 to October 31, 2015. Each participant underwent CXR and bedside LUS within 6 hours from ward admission. LUS was perfo...

  13. Sympathoadrenal activation and endothelial damage in patients with varying degrees of acute infectious disease

    Ostrowski, Sisse Rye; Gaïni, Shahin; Pedersen, Court;

    2015-01-01

    PURPOSE: To investigate levels, associations between, and predictive value of plasma catecholamines and biomarkers of endothelial damage in patients with acute infectious illness stratified according to infection type and sepsis severity. MATERIAL AND METHODS: This is a post hoc study of plasma s...

  14. 17β-Estradiol administration attenuates seawater aspiration-induced acute lung injury in rats.

    Fan, Qixin; Zhao, Pengtao; Li, Jiahuan; Xie, Xiaoyan; Xu, Min; Zhang, Yong; Mu, Deguang; Li, Wangping; Sun, Ruilin; Liu, Wei; Nan, Yandong; Zhang, Bo; Jin, Faguang; Li, Zhichao

    2011-12-01

    There is very little evidence on the value of administering estrogen in cases of seawater drowning which can induce acute lung injury/acute respiratory distress syndrome (ALI/ARDS). Therefore, this study aimed to investigate whether 17β-estradiol (E2) treatment can attenuate seawater aspiration-induced ALI in rats. In the experiment, ALI was induced by endotracheal instillation of seawater (4mL/kg) and the rats were then given intraperitoneal injection of E2 (5mg/kg) 20min after seawater instillation. Finally, the changes of arterial blood gases which contained hydrogen ion concentration (pH), arterial oxygen tension (PaO(2)) and arterial carbon dioxide tension (PaCO(2)) were measured and the measurement of extravascular lung water (EVLW) was observed. The pulmonary histological changes were evaluated by hematoxylin-eosin stain. The expression of aquaporins (AQPs) 1, AQP5, and estrogen receptor-β (ERβ) was measured by western blotting and immunohistochemical methods. The results showed that compared with normal saline water, seawater aspiration induced more serious ALI in rats which was markedly alleviated by E2 treatment. Meanwhile, the ERβ in lung tissues was activated after E2 administration. The seawater aspiration group also presented with severe pulmonary edema which was paralleled with over expressed AQP1 and AQP5. However, the up-regulation of AQP1 and AQP5 was suppressed by the administration of E2, resulting in an attenuation of lung edema. In conclusion, E2 treatment could effectively attenuate seawater aspiration-induced acute lung injury in rats by the down-regulation of AQP1 and AQP5.

  15. Protective effects of penehyclidine hydrochloride on acute lung injury caused by severe dichlorvos poisoning in swine

    CUI Juan; LI Chun-sheng; HE Xin-hua; SONG Yu-guo

    2013-01-01

    Background Organophosphate poisoning is an important health problem in developing countries which causes death mainly by inducing acute lung injury.In this study,we examined the effects of penehyclidine hydrochloride (PHC),a selective M-receptor inhibitor,on dichlorvos-induced acute lung injury in swine.Methods Twenty-two female swines were randomly divided into control (n=5),dichlorvos (n=6),atropine (n=6),and PHC (n=5) groups.Hemodynamic data,extravascular lung water index (EVLWI),and pulmonary vascular permeability index (PVPI) were monitored; blood gas analysis and acetylcholinesterase (AchE) levels were measured.PaO2/FiO2,cardiac index (Cl),and pulmonary vascular resistance indices (PVRI) were calculated.At termination of the study,pulmonary tissue was collected for ATPase activity determination and wet to dry weight ratio (W/D) testing 6 hours post-poisoning.TUNEL assay,and Bax,Bcl-2,and caspase-3 expression were applied to pulmonary tissue,and histopathology was observed.Results After poisoning,PHC markedly decreased PVRI,increased CI more effectively than atropine.Anticholinergic treatment reduced W/D,apoptosis index (AI),and mitigated injury to the structure of lung; however,PHC reduced AI and caspase-3 expression and improved Bcl-2/Bax more effectively than atropine.Atropine and PHC improved ATPase activities; a significant difference between groups was observed in Ca2+-ATPase activity,but not Na+-K+-ATPase activity.Conclusions The PHC group showed mild impairment in pathology,less apoptotic cells,and little impact on cardiac function compared with the atropine group in dichlorvos-induced acute lung injury.

  16. VEGF‐D promotes pulmonary oedema in hyperoxic acute lung injury

    Sato, Teruhiko; Paquet‐Fifield, Sophie; Harris, Nicole C; Roufail, Sally; Turner, Debra J.; Yuan, Yinan; Zhang, You‐Fang; Fox, Stephen B; Hibbs, Margaret L.; Wilkinson‐Berka, Jennifer L; Williams, Richard A.; Stacker, Steven A.; Peter D Sly; Achen, Marc G.

    2016-01-01

    Abstract Leakage of fluid from blood vessels, leading to oedema, is a key feature of many diseases including hyperoxic acute lung injury (HALI), which can occur when patients are ventilated with high concentrations of oxygen (hyperoxia). The molecular mechanisms driving vascular leak and oedema in HALI are poorly understood. VEGF‐D is a protein that promotes blood vessel leak and oedema when overexpressed in tissues, but the role of endogenous VEGF‐D in pathological oedema was unknown. To add...

  17. Pathogenesis of Septic Acute Lung Injury and Strategies for Immuno-Pharmacological Therapy.

    1996-10-01

    obtained from septic-NO animals revealed a qualitative reduction in alveolar and septal edema . Although qualitative in nature, parenchyma of septic-NO...pulmonary edema in a model of acute lung injury. Am. Rev. Respir. Dis. 142:1083- 1087. 18. McDonald, R. J. 1991. Pentoxifylline reduces injury to isolated...patients with uncomplicated sepsis and septic shock--comparison with cardiogenic shock. Thromb. Haemost. 58:709-713. 60. Carvalho, A. C., S. DeMarinis

  18. Analysis of regional compliance in a porcine model of acute lung injury.

    Czaplik, Michael; Biener, Ingeborg; Dembinski, Rolf; Pelosi, Paolo; Soodt, Thomas; Schroeder, Wolfgang; Leonhardt, Steffen; Marx, Gernot; Rossaint, Rolf; Bickenbach, Johannes

    2012-10-15

    Lung protective ventilation in acute lung injury (ALI) focuses on using low tidal volumes and adequate levels of positive end-expiratory pressure (PEEP). Identifying optimal pressure is difficult because pressure-volume (PV) relations differ regionally. Precise analysis demands local measurements of pressures and related alveolar morphologies. In a porcine model of surfactant depletion (n=24), we combined measuring static pressures with endoscopic microscopy and electrical impedance tomography (EIT) to examine regional PV loops and morphologic heterogeneities between healthy (control group; CON) and ALI lungs ventilated with low (LVT) or high tidal volumes (HVT). Quantification included indices for microscopy (Volume Air Index (VAI), Heterogeneity and Circularity Index), EIT analysis and calculation of regional compliances due to generated PV loops. We found that: (1) VAI decreased in lower lobe after ALI, (2) electrical impedance decreased in dorsal regions and (3) PV loops differed regionally. Further studies should prove the potentials of these techniques on individual respiratory settings and clinical outcome.

  19. Inhibition of extracellular HMGB1 attenuates hyperoxia-induced inflammatory acute lung injury

    Maria Entezari

    2014-01-01

    Full Text Available Prolonged exposure to hyperoxia results in acute lung injury (ALI, accompanied by a significant elevation in the levels of proinflammatory cytokines and leukocyte infiltration in the lungs. However, the mechanisms underlying hyperoxia-induced proinflammatory ALI remain to be elucidated. In this study, we investigated the role of the proinflammatory cytokine high mobility group box protein 1 (HMGB1 in hyperoxic inflammatory lung injury, using an adult mouse model. The exposure of C57BL/6 mice to ≥99% O2 (hyperoxia significantly increased the accumulation of HMGB1 in the bronchoalveolar lavage fluids (BALF prior to the onset of severe inflammatory lung injury. In the airways of hyperoxic mice, HMGB1 was hyperacetylated and existed in various redox forms. Intratracheal administration of recombinant HMGB1 (rHMGB1 caused a significant increase in leukocyte infiltration into the lungs compared to animal treated with a non-specific peptide. Neutralizing anti-HMGB1 antibodies, administrated before hyperoxia significantly attenuated pulmonary edema and inflammatory responses, as indicated by decreased total protein content, wet/dry weight ratio, and numbers of leukocytes in the airways. This protection was also observed when HMGB1 inhibitors were administered after the onset of the hyperoxic exposure. The aliphatic antioxidant, ethyl pyruvate (EP, inhibited HMGB1 secretion from hyperoxic macrophages and attenuated hyperoxic lung injury. Overall, our data suggest that HMGB1 plays a critical role in mediating hyperoxic ALI through the recruitment of leukocytes into the lungs. If these results can be translated to humans, they suggest that HMGB1 inhibitors provide treatment regimens for oxidative inflammatory lung injury in patients receiving hyperoxia through mechanical ventilation.

  20. Hemorrhage and resuscitation induce alterations in cytokine expression and the development of acute lung injury.

    Shenkar, R; Coulson, W F; Abraham, E

    1994-03-01

    Acute pulmonary injury occurs frequently following hemorrhage and injury. In order to better examine the sequence of events leading to lung injury in this setting, we investigated lung histology as well as in vivo mRNA levels for cytokines with proinflammatory and immunoregulatory properties (IL-1 beta, IL-6, IL-10, TNF-alpha, TGF-beta, IFN-gamma) over the 3 days following hemorrhage and resuscitation. Significant increases in mRNA levels for IL-1 beta, IL-6, IL-10, and IFN-gamma, but not TNF-alpha, were present among intraparenchymal pulmonary mononuclear cells obtained 1 and 3 days after hemorrhage. Among alveolar macrophages, TNF-alpha and IL-1 beta mRNA levels were increased 3 days after hemorrhage. Few changes in cytokine mRNA levels, with the exception of TNF-alpha at 3 days after hemorrhage, were present among peripheral blood mononuclear cells. Histologic examination of lungs from hemorrhaged animals showed no alterations 1 day after hemorrhage, but neutrophil and mononuclear cell infiltrates, edema, intra-alveolar hemorrhage, and fibrin generation were present 3 days after hemorrhage. These results suggest that hemorrhage-induced enhancement of proinflammatory cytokine gene transcription may be an important mechanism contributing to the frequent development of acute lung injury following blood loss and injury.

  1. A novel, stable and reproducible acute lung injury model induced by oleic acid in immature piglet

    ZHU Yao-bin; LING Feng; ZHANG Yan-bo; LIU Ai-jun; LIU Dong-hai; QIAO Chen-hui; WANG Qiang; LIU Ying-long

    2011-01-01

    Background Young children are susceptible to pulmonary injury,and acute lung injury (ALl) often results in a high mortality and financial costs in pediatric patients.A good ALl model will help us to gain a better understanding of the real pathophysiological picture and to evaluate novel treatment approaches to acute respiratory distress syndrome (ARDS) more accurately and liberally.This study aimed to establish a hemodynamically stable and reproducible model with ALl in piglet induced by oleic acid.Methods Six Chinese mini-piglets were used to establish ALl models by oleic acid.Hemodynamic and pulmonary function data were measured.Histopathological assessment was performed.Results Mean blood pressure,heart rate (HR),cardiac output (CO),central venous pressure (CVP) and left atrial pressure (LAP) were sharply decreased after oleic acid given,while the mean pulmonary arterial pressure (MPAP) was increased in comparison with baseline (P <0.05).pH,arterial partial pressure of O2 (PaO2),PaO2/inspired O2 fraction (FiO2) and lung compliance decreased,while PaCO2 and airway pressure increased in comparison with baseline (P <0.05).The lung histology showed severe inflammation,hyaline membranes,intra-alveolar and interstitial hemorrhage.Conclusion This experiment established a stable model which allows for a diversity of studies on early lung injury.

  2. Role of Kupffer cells in acute hemorrhagic necrotizing pancreatitis-associated lung injury of rats

    Hong-Bin Liu; Nai-Qiang Cui; Dong-Hua Li; Chang Chen

    2006-01-01

    AIM: To investigate the role of Kupffer cells (KCs) in acute hemorrhagic necrotizing pancreatitis-associated lung injury (AHNP-LI).METHODS: Forty-two rats were allocated to four groups [sham operation, AHNP model, gadolinium chloride (GdCl3) pretreatment, GdCl3 control]. In GdCl3pretreatment group, GdCl3 was administered by caudal vein injection 24 h before the AHNP model induction.Blood from the iliac artery, alveolar macrophages and tissues from the pancreas and lung, were collected in six animals per group 3 and 6 h after acute pancreatitis induction. TNF-α, IL-1 of serum, myeloperoxidase (MPO)of lung tissue, NF-κB activation of alveolar macrophages were detected. Serum AST and ALT in sham operation group and GdCl3 control group were tested. In addition,histopathological changes of the pancreas and lung were observed under light microscope.RESULTS: MPO of lung tissue and TNF-α, IL-1 levels of serum were all reduced significantly in GdCl3pretreatment group compared to those in AHNP group(P<0.01). NF-κB activation of alveolar macrophages was also attenuated significantly in GdCl3 pretreatment group compared to that in AHNP group (P<0.01). The pathological injury of the lung was ameliorated obviously in GdCl3 pretreatment group compared to that in AHNP group. Nevertheless, the serum amylase level did not reduce and injury of the pancreas was not prevented in GdCl3 pretreatment group.CONCLUSION: Pulmonary injury induced by AHNP is mediated by KC activation and AHNP-LI can be significantly ameliorated by pretreatment with GdCl3 and KCs play a vital role in AHNP-LI.

  3. Clinical evaluation of sivelestat for acute lung injury/acute respiratory distress syndrome following surgery for abdominal sepsis

    Tsuboko Y

    2012-10-01

    Full Text Available Yoshiaki Tsuboko,1 Shinhiro Takeda,1,2 Seiji Mii,1 Keiko Nakazato,1 Keiji Tanaka,2 Eiji Uchida,3 Atsuhiro Sakamoto11Department of Anesthesiology, Nippon Medical School, 2Intensive Care Unit and Cardiac Care Unit, Nippon Medical School Hospital, 3Department of Surgery, Nippon Medical School, Tokyo, JapanBackground: The efficacy of sivelestat in the treatment of acute lung injury/acute respiratory distress syndrome (ALI/ARDS has not been established. In part, this is due to the wide variety of factors involved in the etiology of ALI/ARDS. In this study, we examined the efficacy of sivelestat in patients with ALI/ARDS associated with abdominal sepsis.Methods: The subjects were 49 patients with ALI/ARDS after surgery for abdominal sepsis. The efficacy of sivelestat was retrospectively assessed in two treatment groups, ie, a sivelestat group (n = 34 and a non-sivelestat group (n = 15.Results: The sivelestat group showed significant improvements in oxygenation, thrombocytopenia, and multiple organ dysfunction score. The number of ventilator days (6.6 ± 6.1 versus 11.1 ± 8.4 days; P = 0.034 and length of stay in the intensive care unit (8.5 ± 6.2 versus 13.3 ± 9.5 days; P = 0.036 were significantly lower in the sivelestat group. The hospital mortality rate decreased by half in the sivelestat group, but was not significantly different between the two groups.Conclusion: Administration of sivelestat to patients with ALI/ARDS following surgery for abdominal sepsis resulted in early improvements of oxygenation and multiple organ dysfunction score, early ventilator weaning, and early discharge from the intensive care unit.Keywords: sivelestat, acute lung injury, acute respiratory distress syndrome, abdominal sepsis

  4. Effect of inhalation of nebulized NO donor substance on acute hypoxic lung injury in newborn piglets

    XIA Hong-ping; HUANG Guo-ying; ZHU Jian-xing; SUN Bo

    2008-01-01

    Background Birth asphyxia may result in multiple organ dysfunction such as lung injury.Inhalation of nebulized nitric oxide precursor can selectively reduce pulmonary hypertension.However,it is unknown whether such precursors can alleviate lung injury induced by hypoxia.We evaluated the effect of inhalation of nebulized nitroglycerine and sodium nitroprusside on acute hypoxic lung injury in newborn piglets.Methods Acute hypoxic lung injury was induced by inspiring 10% O2 for 1 hour.Twenty-four anaesthetized and mechanically ventilated piglets (5-7 days old) were randomly divided into four groups:(1) group S,not hypoxic;(2) group C,nebulized saline after hypoxia;(3) group NTG,nebulized nitroglycerine after hypoxia;(4) group SNP,nebulized sodium nitroprusside after hypoxia.Respiratory dynamic compliance and resistance of respiratory system were recorded at baseline,0.5 hour and 1 hour of hypoxia;then 0.5 hour,1 hour,3 hours and 5 hours following hypoxia.After nebulization,arterial blood was collected for measuring methaemoglobin and nitrate/nitrite levels.Right lung tissue,wet-dry ratio and myeloperoxidase level were determined.White blood cell count (WBC),total surfactant phospholipids (TPL) and disaturated phosphatidyl choline (DSPC) of the bronchoalveolar lavage fluid (BALF) were calculated,Left lungs were used for examining pathological changes.Results No significant difference was observed in respiratory dynamic compliance,resistance of respiratory system,wet-dry ratio,levels of methaemoglobin and nitrate/nitrite after nebulization,TPL or DSPC/TPL among four groups.WBC in BALF in groups NTG and SNP significantly decreased as compared with group C:similarly for myeloperoxidase level in lung tissue.Lung histological findings showed infiltration of neutrophils in groups NTG and SNP decreased significantly as compared with group C.Conclusion Inhalation of nebulized nitroglycerine or sodium nitroprusside can alleviate the infiltration of neutrophils,while it affects

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

    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.

  6. Application of the adductome approach to assess intertissue DNA damage variations in human lung and esophagus

    Kanaly, Robert A. [Department of Technology and Ecology, Graduate School of Global Environmental Studies, Kyoto University, Kyoto 606-8501 (Japan); Department of Environmental Biosciences, International Graduate School of Arts and Sciences, Yokohama City University, Yokohama 236-0027 (Japan); Matsui, Saburo [Department of Technology and Ecology, Graduate School of Global Environmental Studies, Kyoto University, Kyoto 606-8501 (Japan); Hanaoka, Tomoyuki [Epidemiology and Prevention Division, National Cancer Center Research Institute, Tokyo 104-0045 (Japan); Matsuda, Tomonari [Department of Technology and Ecology, Graduate School of Global Environmental Studies, Kyoto University, Kyoto 606-8501 (Japan)], E-mail: matsuda@z05.mbox.media.kyoto-u.ac.jp

    2007-12-01

    Methods for determining the differential susceptibility of human organs to DNA damage have not yet been explored to any large extent due to technical constraints. The development of comprehensive analytical approaches by which to detect intertissue variations in DNA damage susceptibility may advance our understanding of the roles of DNA adducts in cancer etiology and as exposure biomarkers at least. A strategy designed for the detection and comparison of multiple DNA adducts from different tissue samples was applied to assess esophageal and peripherally- and centrally-located lung tissue DNA obtained from the same person. This adductome approach utilized LC/ESI-MS/MS analysis methods designed to detect the neutral loss of 2'-deoxyribose from positively ionized 2'-deoxynucleoside adducts transmitting the [M+H]{sup +} > [M+H-116]{sup +} transition over 374 transitions. In the final analyses, adductome maps were produced which facilitated the visualization of putative DNA adducts and their relative levels of occurrence and allowed for comprehensive comparisons between samples, including a calf thymus DNA negative control. The largest putative adducts were distributed similarly across the samples, however, differences in the relative amounts of putative adducts in lung and esophagus tissue were also revealed. The largest-occurring lung tissue DNA putative adducts were 90% similar (n = 50), while putative adducts in esophagus tissue DNA were shown to be 80 and 84% similar to central and peripheral lung tissue DNA respectively. Seven DNA adducts, N{sup 2}-ethyl-2'-deoxyguanosine (N{sup 2}-ethyl-dG), 1,N{sup 6}-etheno-2'-deoxyadenosine ({epsilon}dA), {alpha}-S- and {alpha}-R-methyl-{gamma}-hydroxy-1,N{sup 2}-propano-2'-deoxyguanosine (1,N{sup 2}-PdG{sub 1}, 1,N{sup 2}-PdG{sub 2}), 3-(2'-deoxyribosyl)-5,6,7,8-tetrahydro-8-hydroxy-pyrimido[1,2-a] purine-(3H)-one (8-OH-PdG) and the two stereoisomers of 3-(2'-deoxyribosyl)-5,6,7,8-tetrahydro

  7. Tumor necrosis factor α antibody prevents brain damage of rats with acute necrotizing pancreatitis

    Yan-Ling Yang; Ji-Peng Li; Kai-Zong Li; Ke-Feng Dou

    2004-01-01

    AIM: To study the protective effects of tumor necrosis factor á (TNFα) antibody on pancreatic encephalopathy in rats.METHODS:One hundred and twenty SD rats were randomly divided into normal control group,acute necrotizing pancreatitis group and TNFα antibody treated group.Acute hemorrhage necrotizing pancreatitis model in rats was induced by retrograde injection of 50 g/L sodium taurocholate into the pancreatobiliary duct.Serum TNFα was detected and animals were killed 12 h after drug administration.Changes in content of brain water,MDA and SOD as well as leucocyte adhesion of brain microvessels were measured.RESULTS:In TNFα antibody treated group,serum TNFálevel was decreased.Content of brain water,MDA and SOD as well as leucocyte adhesion were decreased significantly in comparison with those of acute necrotizing pancreatitis group (P<0.05).CONCLUSION:TNFα antibody can alleviate the brain damage of rats with acute hemorrhage necrotizing pancreatitis.

  8. Allergic airway inflammation decreases lung bacterial burden following acute Klebsiella pneumoniae infection in a neutrophil- and CCL8-dependent manner.

    Dulek, Daniel E; Newcomb, Dawn C; Goleniewska, Kasia; Cephus, Jaqueline; Zhou, Weisong; Reiss, Sara; Toki, Shinji; Ye, Fei; Zaynagetdinov, Rinat; Sherrill, Taylor P; Blackwell, Timothy S; Moore, Martin L; Boyd, Kelli L; Kolls, Jay K; Peebles, R Stokes

    2014-09-01

    The Th17 cytokines interleukin-17A (IL-17A), IL-17F, and IL-22 are critical for the lung immune response to a variety of bacterial pathogens, including Klebsiella pneumoniae. Th2 cytokine expression in the airways is a characteristic feature of asthma and allergic airway inflammation. The Th2 cytokines IL-4 and IL-13 diminish ex vivo and in vivo IL-17A protein expression by Th17 cells. To determine the effect of IL-4 and IL-13 on IL-17-dependent lung immune responses to acute bacterial infection, we developed a combined model in which allergic airway inflammation and lung IL-4 and IL-13 expression were induced by ovalbumin sensitization and challenge prior to acute lung infection with K. pneumoniae. We hypothesized that preexisting allergic airway inflammation decreases lung IL-17A expression and airway neutrophil recruitment in response to acute K. pneumoniae infection and thereby increases the lung K. pneumoniae burden. As hypothesized, we found that allergic airway inflammation decreased the number of K. pneumoniae-induced airway neutrophils and lung IL-17A, IL-17F, and IL-22 expression. Despite the marked reduction in postinfection airway neutrophilia and lung expression of Th17 cytokines, allergic airway inflammation significantly decreased the lung K. pneumoniae burden and postinfection mortality. We showed that the decreased lung K. pneumoniae burden was independent of IL-4, IL-5, and IL-17A and partially dependent on IL-13 and STAT6. Additionally, we demonstrated that the decreased lung K. pneumoniae burden associated with allergic airway inflammation was both neutrophil and CCL8 dependent. These findings suggest a novel role for CCL8 in lung antibacterial immunity against K. pneumoniae and suggest new mechanisms of orchestrating lung antibacterial immunity.

  9. Xanthohumol, a prenylated flavonoid from hops (Humulus lupulus L., protects rat tissues against oxidative damage after acute ethanol administration

    Carmen Pinto

    2014-01-01

    Full Text Available Ethanol-mediated free radical generation is directly involved in alcoholic liver disease. In addition, chronic alcohol bingeing also induces pathological changes and dysfunction in multi-organs. In the present study, the protective effect of xanthohumol (XN on ethanol-induced damage was evaluated by determining antioxidative parameters and stress oxidative markers in liver, kidney, lung, heart and brain of rats. An acute treatment (4 g/kg b.w. of ethanol resulted in the depletion of superoxide dismutase, catalase and glutathione S-transferase activities and reduced glutathione content. This effect was accompanied by the increased activity of tissue damage marker enzymes (glutamate oxaloacetate transaminase, glutamate pyruvate transaminase and lactate dehydrogenase and a significant increase in lipid peroxidation and hydrogen peroxide concentrations. Pre-treatment with XN protected rat tissues from ethanol-induced oxidative imbalance and partially mitigated the levels to nearly normal levels in all tissues checked. This effect was dose dependent, suggesting that XN reduces stress oxidative and protects rat tissues from alcohol-induced injury.

  10. Involvement of phosphoinositide 3-kinases in neutrophil activation and the development of acute lung injury.

    Yum, H K; Arcaroli, J; Kupfner, J; Shenkar, R; Penninger, J M; Sasaki, T; Yang, K Y; Park, J S; Abraham, E

    2001-12-01

    Activated neutrophils contribute to the development and severity of acute lung injury (ALI). Phosphoinositide 3-kinases (PI3-K) and the downstream serine/threonine kinase Akt/protein kinase B have a central role in modulating neutrophil function, including respiratory burst, chemotaxis, and apoptosis. In the present study, we found that exposure of neutrophils to endotoxin resulted in phosphorylation of Akt, activation of NF-kappaB, and expression of the proinflammatory cytokines IL-1beta and TNF-alpha through PI3-K-dependent pathways. In vivo, endotoxin administration to mice resulted in activation of PI3-K and Akt in neutrophils that accumulated in the lungs. The severity of endotoxemia-induced ALI was significantly diminished in mice lacking the p110gamma catalytic subunit of PI3-K. In PI3-Kgamma(-/-) mice, lung edema, neutrophil recruitment, nuclear translocation of NF-kappaB, and pulmonary levels of IL-1beta and TNF-alpha were significantly lower after endotoxemia as compared with PI3-Kgamma(+/+) controls. Among neutrophils that did accumulate in the lungs of the PI3-Kgamma(-/-) mice after endotoxin administration, activation of NF-kappaB and expression of proinflammatory cytokines was diminished compared with levels present in lung neutrophils from PI3-Kgamma(+/+) mice. These results show that PI3-K, and particularly PI3-Kgamma, occupies a central position in regulating endotoxin-induced neutrophil activation, including that involved in ALI.

  11. Effects of low potassium dextran glucose solution on oleic acid-induced acute lung injury in juvenile piglets

    LING Feng; LIU Ying-long; LIU Ai-jun; WANG Dong; WANG Qiang

    2011-01-01

    Background Epithelial dysfunction in lungs plays a key role in the pathogenesis of acute lung injury. The beneficial effects of low potassium dextran glucose solution (LPD) have been reported in lung preservation, and LPD enables injured alveolar pneumocytes to recover. So we hypothesized that systemic administration of LPD may have benefits in treating acute lung injury. We investigated the effects of LPD on arterial blood gas and levels of some cytokines in oleic acid-induced acute lung injury in juvenile piglets.Methods Oleic acid (0.1 ml/kg) was intrapulmonarily administered to healthy anesthetized juvenile piglets. Ten animals were randomly assigned to two groups (n=5 each): oleic acid-induced group (control group) with intravenous infusion of 12.5 ml/kg of lactated Ringer's solution 30 minutes before administration of oleic acid and LPD group with systemic administration of LPD (12.5 ml/kg) 30 minutes before injecting oleic acid. Blood gas variables and concentrations of tumor necrosis factor alpha, endothelin 1 and interleukin 10 were measured before and every 1 hour for 6 hours after initial lung injury.Results Compared with control group, blood pH, partial pressure of arterial oxygen to fraction of inspired oxygen ratio,partial pressure of arterial carbon dioxide, and mean pulmonary arterial pressure in LPD group were improved (P<0.05or 0.01). Six hours after lung injury, concentration of tumor necrosis factor alpha in lung tissue was lower in LPD group than control group (P<0.05). Plasmic concentration of endothelin 1 showed lower in LPD group while plasmic concentration of interleukin 10 showed higher in LPD group (P<0.05).Conclusions Before lung injury, systemic administration of LPD can improve gas exchange, attenuate pulmonary hypertension, decrease plasmic levels of endothelin 1, increase interleukin 10 and decrease concentration of tumor necrosis factor alpha in lung tissue in oleic acid-induced acute lung injury in juvenile piglets.

  12. Acute fibrinous and organising pneumonia following lung transplantation is associated with severe allograft dysfunction and poor outcome: a case series

    Keith Meyer

    2015-01-01

    Full Text Available   Acute fibrinous and organising pneumonia (AFOP is a histopathologic variant of acute lung injury that has been associated with infection and inflammatory disorders and has been reported as a complication of lung transplantation. A retrospective chart review was performed for all patients transplanted at the University of Wisconsin Hospital and Clinics from January 1995 to December 2013 (n = 561. We identified 6 recipients whose clinical course was complicated by AFOP. All recipients were found to have AFOP on lung biopsy or at post-mortem examination, and 5 of the 6 patients suffered progressive allograft dysfunction that led to fatal outcome. Only 1 of the 6 patients stabilised with augmented immunosuppression and had subsequent improvement and stabilisation of allograft function. We could not clearly identify any specific cause of AFOP, such as drug toxicity or infection. Lung transplantation can be complicated by lung injury with an AFOP pattern on histopathologic examination of lung biopsy specimens. The presence of an AFOP pattern was associated with irreversible decline in lung function that was refractory to therapeutic interventions in 5 of our 6 cases and was associated with severe allograft dysfunction and death in these 5 individuals. AFOP should be considered as a potential diagnosis when lung transplant recipients develop progressive decline in lung function that is consistent with a clinical diagnosis of chronic lung allograft dysfunction.  

  13. Systemic complement activation, lung injury, and products of lipid peroxidation.

    Ward, P. A.; Till, G O; Hatherill, J. R.; Annesley, T M; Kunkel, R G

    1985-01-01

    Previously we have demonstrated that systemic activation of the complement system after intravenous injection of cobra venom factor (CVF) results in acute lung injury as reflected by increases in the vascular permeability of the lung as well as by morphologic evidence of damage to lung vascular endothelial cells. In using the vascular permeability of the lung as the reference, the current studies show a quantitative correlation between lung injury and the appearance in plasma of lipid peroxid...

  14. Quantification of radiation-induced lung damage with CT scans - The possible benefit for radiogenomics

    De Ruysscher, Dirk [Radiation Oncology, Univ. Hospitals Leuven/KU Leuven, Leuven (Belgium); Dept. of Radiation Oncology (Maastro clinic), Maastricht Univ. Medical Center, Maastricht (Netherlands)], e-mail: dirk.deruysscher@uzleuven.be; Sharifi, Hoda [Dept. of Radiation Oncology (Maastro clinic), Maastricht Univ. Medical Center, Maastricht (Netherlands); Defraene, Gilles [Radiation Oncology, Univ. Hospitals Leuven/KU Leuven, Leuven (Belgium)] [and others

    2013-10-15

    Background: Radiation-induced lung damage (RILD) is an important problem. Although physical parameters such as the mean lung dose are used in clinical practice, they are not suited for individualised radiotherapy. Objective, quantitative measurements of RILD on a continuous instead of on an ordinal, semi-quantitative, semi-subjective scale, are needed. Methods: Hounsfield unit (HU) changes before versus three months post-radiotherapy were correlated per voxel with the radiotherapy dose in 95 lung cancer patients. Deformable registration was used to register pre- and post-CT scans and the density increase was quantified for various dose bins. The dose-response curve for increased HU was quantified using the slope of a linear regression (HU/Gy). The end-point for the toxicity analysis was dyspnoea = grade 2. Results: Radiation dose was linearly correlated with the change in HU (mean R2 = 0.74 {+-} 0.28). No differences in HU/Gy between groups treated with stereotactic radiotherapy, conventional radiotherapy alone, sequential or concurrent chemo-radiotherapy were observed. In the whole patient group, 33/95 (34.7%) had dyspnoea {>=} G2. Of the 48 patients with a HU/Gy below the median, 16 (33.3%) developed dyspnoea = G2, while in the 47 patients with a HU/Gy above the median, 17 (36.1%) had dyspnoea {>=}G2 (not significant). Individual patients showed a nearly 21-fold difference in radiosensitivity, with HU/Gy ranging from 0 to 10 HU/Gy. Conclusions: HU changes identify objectively the whole range of individual radiosensitivity on a continuous, quantitative scale. CT density changes may allow more robust and accurate radiogenomics studies.

  15. Exaggerated Acute Lung Injury and Impaired Antibacterial Defenses During Staphylococcus aureus Infection in Rats with the Metabolic Syndrome.

    Xiaomei Feng

    Full Text Available Rats with Metabolic Syndrome (MetaS have a dysregulated immune response to the aseptic trauma of surgery. We hypothesized that rats with MetaS would have dysregulated inflammation, increased lung injury, and less effective antibacterial defenses during Staphylococcus (S. aureus sepsis as compared to rats without MetaS. Low capacity runner (LCR; a model of MetaS and high capacity runner (HCR rats were challenged intravenously with S. aureus bacteria. After 48 h, inflammatory mediators and bacteria were quantified in the blood, bronchoalveolar lavage fluid (BALF, and lung homogenates. Lungs were analyzed histologically. BALF protein and lung wet-dry ratios were quantified to assess for vascular leak. Endpoints were compared in infected LCR vs HCR rats. LCR rats had higher blood and lung S. aureus counts, as well as higher levels of IL-6 in plasma, lungs and BALF, MIP-2 in plasma and lung, and IL-17A in lungs. Conversely, LCR rats had lower levels of IL-10 in plasma and lungs. Although lactate levels, and liver and renal function tests were similar between groups, LCR rats had higher BALF protein and lung wet-dry ratios, and more pronounced acute lung injury histologically. During S. aureus bacteremia, as compared with HCR rats, LCR (MetaS rats have heightened pro-inflammatory responses, accompanied by increased acute lung injury and vascular leak. Notably, despite an augmented pro-inflammatory phenotype, LCR rats have higher bacterial levels in their blood and lungs. The MetaS state may exacerbate lung injury and vascular leak by attenuating the inflammation-resolving response, and by weakening antimicrobial defenses.

  16. Exaggerated Acute Lung Injury and Impaired Antibacterial Defenses During Staphylococcus aureus Infection in Rats with the Metabolic Syndrome.

    Feng, Xiaomei; Maze, Mervyn; Koch, Lauren G; Britton, Steven L; Hellman, Judith

    2015-01-01

    Rats with Metabolic Syndrome (MetaS) have a dysregulated immune response to the aseptic trauma of surgery. We hypothesized that rats with MetaS would have dysregulated inflammation, increased lung injury, and less effective antibacterial defenses during Staphylococcus (S.) aureus sepsis as compared to rats without MetaS. Low capacity runner (LCR; a model of MetaS) and high capacity runner (HCR) rats were challenged intravenously with S. aureus bacteria. After 48 h, inflammatory mediators and bacteria were quantified in the blood, bronchoalveolar lavage fluid (BALF), and lung homogenates. Lungs were analyzed histologically. BALF protein and lung wet-dry ratios were quantified to assess for vascular leak. Endpoints were compared in infected LCR vs HCR rats. LCR rats had higher blood and lung S. aureus counts, as well as higher levels of IL-6 in plasma, lungs and BALF, MIP-2 in plasma and lung, and IL-17A in lungs. Conversely, LCR rats had lower levels of IL-10 in plasma and lungs. Although lactate levels, and liver and renal function tests were similar between groups, LCR rats had higher BALF protein and lung wet-dry ratios, and more pronounced acute lung injury histologically. During S. aureus bacteremia, as compared with HCR rats, LCR (MetaS) rats have heightened pro-inflammatory responses, accompanied by increased acute lung injury and vascular leak. Notably, despite an augmented pro-inflammatory phenotype, LCR rats have higher bacterial levels in their blood and lungs. The MetaS state may exacerbate lung injury and vascular leak by attenuating the inflammation-resolving response, and by weakening antimicrobial defenses.

  17. Establishment of the critical period of severe acute pancreatitis-associated lung injury

    Yi-Peng Chen; Jian-Wen Ning; Feng Ji

    2009-01-01

    BACKGROUND: Since respiratory dysfunction is the main cause of death in patients with severe acute pancreatitis (SAP), elucidating the critical period of acute pancreatitis-associated lung injury (APALI) is of important clinical value. This study aimed to define the risk period of APALI by a series of studies including a dynamic analysis of total water content, ultrastructure and number of type Ⅱ alveolar epithelial cells, and reactive oxygen metabolites (ROMs) of lung tissue in a mouse model of SAP, and a clinical analysis of APALI patients. METHODS: ICR mice were selected to establish a SAP model. They were given 7 intraperitoneal injections of cerulein (50 μg/kg body weight) at hourly intervals, followed by an intraperitoneal injection of lipopolysaccharide (15 mg/kg body weight). The total water content, ultrastructure, and number of type Ⅱ alveolar epithelial cells, and ROMs of lung tissue were assessed before (0 hour) and after the establishment of SAP model (6 hours, 12 hours, 1 day, 4 days, and 7 days). In addition, we analyzed the data from 215 patients with APALI (PaO2 RESULTS: The total water content and ultrastructure of type Ⅱ alveolar epithelial cells (mitochondria and lamellar bodies) of the lung in the SAP mice were significantly altered at 12 hours after the establishment of SAP model, and reached a maximum at 1 to 4 days. The number of type Ⅱ alveolar epithelial cells and ROMs increased maximally at 1 day after the establishment of the model. Furthermore, clinical results showed that lung injury occurred at a mean of 3.1435±1.0199 days in patients with SAP. These clinical data were almost consistent with the results of the SAP model. CONCLUSION: The risk period for APALI is between the first and fourth day during the course of SAP.

  18. Hydrogen sulfide donor regulates alveolar epithelial cell apoptosis in rats with acute lung injury

    LIU Wen-li; LIU Zhi-wei; LI Tian-shui; WANG Cong; ZHAO Bin

    2013-01-01

    Background Acute lung injury (ALl) is a common syndrome associated with high morbidity and mortality in emergency medicine.Cell apoptosis plays a key role in the pathogenesis of ALl.Hydrogen sulfide (H2S) plays a protective role during acute lung injury.We designed this study to examine the role of H2S in the lung alveolar epithelial cell apoptosis in rats with ALl.Methods Sixty-nine male Sprague Dawley rats were used.ALl was induced by intra-tail vein injection of oleic acid (OA).NaHS solution was injected intraperitonally 30 minutes before OA injection as the NaHS pretreatment group.Single sodium hydrosulfide pretreatment group and control group were designed.Index of quantitative assessment (IQA),wet/dry weight (W/D) ratio and the percentage of polymorphonuclear leukocyte (PMN) cells in the bronchoalveolar lavage fluid (BALF) were determined.H2S level in lung tissue was measured by a sensitive sulphur electrode.Apoptosis was evaluated by terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) staining and Fas protein was measured by immunohistochemical staining.Results The level of endogenous H2S in lung tissue decreased with the development of ALl induced by OA injection.Apoptosis and Fas protein in alveolar epithelial cells increased in the ALl of rats but NaHS lessened apoptosis and Fas protein expression in alveolar epithelial cells of rats with ALl.Conclusion Endogenous H2S protects rats from oleic acid-induced ALl,probably by inhibiting cell apoptosis.

  19. Quantification of Lung Damage in an Elastase-Induced Mouse Model of Emphysema

    Arrate Muñoz-Barrutia

    2012-01-01

    Full Text Available Objective. To define the sensitivity of microcomputed tomography- (micro-CT- derived descriptors for the quantification of lung damage caused by elastase instillation. Materials and Methods. The lungs of 30 elastase treated and 30 control A/J mice were analyzed 1, 6, 12, and 24 hours and 7 and 17 days after elastase instillation using (i breath-hold-gated micro-CT, (ii pulmonary function tests (PFTs, (iii RT-PCR for RNA cytokine expression, and (iv histomorphometry. For the latter, an automatic, parallel software toolset was implemented that computes the airspace enlargement descriptors: mean linear intercept (Lm and weighted means of airspace diameters (D0, D1, and D2. A Support Vector Classifier was trained and tested based on three nonhistological descriptors using D2 as ground truth. Results. D2 detected statistically significant differences (P<0.01 between the groups at all time points. Furthermore, D2 at 1 hour (24 hours was significantly lower (P<0.01 than D2 at 24 hours (7 days. The classifier trained on the micro-CT-derived descriptors achieves an area under the curve (AUC of 0.95 well above the others (PFTS AUC = 0.71; cytokine AUC = 0.88. Conclusion. Micro-CT-derived descriptors are more sensitive than the other methods compared, to detect in vivo early signs of the disease.

  20. Effect of captopril on serum TNF-α level in acute lung injury rats induced by HCL

    Hong-Mei Liu; Yu-Na Guo

    2014-01-01

    Objective:To observe the effect of captopril on the tumor necrosis factor-α (TNF-α) level and arterial blood gases in acute lung injury (ALI) induced by HCL in rats, and to analyze its protective mechanism. Methods:Fifty Wistar rats were selected and randomly divided into three groups, with 20 rats in GroupⅠandⅡ, respectively and 10 animals in GroupⅢ. ALI model was constructed by intratracheal injection of diluted hydrochloric acid (pH=1.25, 1.2 mL/kg). Group I rats received not any treatment after construction of ALI model. GroupⅡrats were treated with captopril (5 mg/kg, i.p.) 5 min after induction of ALI. GroupⅢserved as normal control without any treatment. Ninety minutes after construction of ALI model, all the rats were sacrificed. Blood was withdrawn for detection of TNF-αlevel and arterial blood gases index. And lung tissue slices of the three groups were prepared for observation of pathologic histology changes. Results:TNF-αlevel in serum of GroupⅠand Ⅱrats was significantly higher than that in GroupⅢ(P<0.05), while TNF-αlevel in serum of GroupⅡwas significantly lower in Group I (P<0.05). PaCO2 level was significantly higher (P<0.05), while PaO2 was significantly lower (P<0.05) in Group I andⅡrats than those in GroupⅢ. PaCO2 was significantly lower (P<0.05) and PaO2 was significantly higher (P<0.05) in GroupⅡthan those in Group I. Histological observation showed diffuse congestion and severe edema of lung tissue, obvious thickening and structure damage of alveolar walls and a large amount of neutrophil infiltration in Group I rats. GroupⅡrats showed mild edema of lung tissue;only a small portion of alveolar walls showed thickening and only a few of neutrophil infiltration could be observed. The degree of injury was remarkably slighter than that of Group I rats. GroupⅢrats showed clear lung tissue structure and normal morphology;alveolar walls were uniform and the margin was smooth and few neutrophil could be observed

  1. Cytoprotective roles of GSH, SOD and solcoseryl against ischemic damage and reperfusion injury to warm ischemic lung. Study of Canine warm ischemic lung.

    Taniguchi, Hideki; Kawahara, Katsunobu; Nakasone, Tomonori; Ikari, Hideki; Honjoh, Seiji; Hisano, Hiroshi; Takahashi, Takao; Kusano, Hiroyuki; Ayabe, Hiroyoshi; Tomita, Masao

    1990-01-01

    This study was performed to clarify the roles of reduced glutathion (GSH), superoxide dismutase (SOD), and solcosaryl in ischemic damage and reperfusion injury to the warm ischemic lungs of experimental animals. Fifty-one warm ischemic canine lungs were made by hilar stripping and clamping of the left PA, PV and bronchus for 2-3 hours. In the Non-perfusion group, GSH (50mg/ kg, I. V.: Group II) and solcoseryl (50mg/kg, I. V.: Group III) were administered. In the perfusion group, Euro-Collins ...

  2. Lung clearance of /sup 99m/Tc-DTPA in patients with acute lung injury and pulmonary edema

    Coates, G.; O' Brodovich, H.; Dolovich, M.

    1988-07-01

    Several acute and chronic conditions that alter the integrity of the pulmonary epithelium increased the rate of absorption or clearance into the circulation of small solutes deposited in the alveoli. Technetium 99m diethylenetriamine pentaacetic acid can be deposited in the lungs as a submicronic aerosol and its rate of clearance measured with a gamma camera or simple probe. This clearance technique is currently being used to evaluate patients who have developed pulmonary edema and also to detect those patients from a high risk group who are likely to develop adult respiratory distress syndrome (ARDS). Its role in the evaluation of patients with pulmonary edema is still under active investigation. It is clear that a single measurement in patients who smoke is not useful, but repeated measurements may provide important information. The lung clearance measurement is very sensitive to changes in epithelial integrity but is not specific for ARDS. It may be most useful in combination with other predictive tests or when the clearance rate is normal. 54 references.

  3. Protective effects of pretreatment with Radix Paeoniae Rubra on acute lung injury induced by intestinal ischemia/ reperfusion in rats

    CHEN Chang; ZHANG Fan; XIA Zhong-yuan; LIN Hui; MO An-sheng

    2008-01-01

    Objective: To investigate the effect of pretreatment with Radix Paeoniae Rubra (RPR) on acute lung injury induced by intestinal ischemia/reperfusion in rats and its protective mechanism.Methods:n lung tissues was detected by immunohistochemistry and morphometry computer image analysis. Arterial blood gas analysis, lung permeability index, malondialdehyde (MDA) and superoxide dismutase (SOD) contents in lungs were measured. The histological changes of lung tissue were observed under light microscope.Results:The expression of HO-1 in RPR-pretreatment group and hemin group was obviously higher than that in sham-operation group and I/R group (P < 0.01). The level of MDA and lung permeability index in RPR-pretreatment and hemin group were significantly lower than those in I/R group (P<0.01 or P<0.05), while the activity of SOD in RPR-pretreatment and hemin group was obviously higher than that in I/R group (P<0.01 ). Under light microscope, the pathologic changes induced by I/R were significantly attenuated by RPR.Conclusion : Intestinal ischemia/reperfusion may result in acute lung injury and pretreatment with RPR injection can attenuate the injury. The protective effect of RPR on the acute lung injury is related to its property of inducing HO-1 expression and inhibiting lipid peroxidation.

  4. Therapeutic inhibition of TRF1 impairs the growth of p53-deficient K-RasG12V-induced lung cancer by induction of telomeric DNA damage.

    García-Beccaria, María; Martínez, Paula; Méndez-Pertuz, Marinela; Martínez, Sonia; Blanco-Aparicio, Carmen; Cañamero, Marta; Mulero, Francisca; Ambrogio, Chiara; Flores, Juana M; Megias, Diego; Barbacid, Mariano; Pastor, Joaquín; Blasco, Maria A

    2015-07-01

    Telomeres are considered anti-cancer targets, as telomere maintenance above a minimum length is necessary for cancer growth. Telomerase abrogation in cancer-prone mouse models, however, only decreased tumor growth after several mouse generations when telomeres reach a critically short length, and this effect was lost upon p53 mutation. Here, we address whether induction of telomere uncapping by inhibition of the TRF1 shelterin protein can effectively block cancer growth independently of telomere length. We show that genetic Trf1 ablation impairs the growth of p53-null K-Ras(G12V)-induced lung carcinomas and increases mouse survival independently of telomere length. This is accompanied by induction of telomeric DNA damage, apoptosis, decreased proliferation, and G2 arrest. Long-term whole-body Trf1 deletion in adult mice did not impact on mouse survival and viability, although some mice showed a moderately decreased cellularity in bone marrow and blood. Importantly, inhibition of TRF1 binding to telomeres by small molecules blocks the growth of already established lung carcinomas without affecting mouse survival or tissue function. Thus, induction of acute telomere uncapping emerges as a potential new therapeutic target for lung cancer.

  5. Potential role of Saudi red propolis in alleviating lung damage induced by methicillin resistant Staphylococcus aureus virulence in rats.

    Saddiq, Amna Ali; Mohamed, Azza Mostafa

    2016-07-01

    The aim of this study was to explore the protective impact of aqueous extract of Saudi red propolis against rat lung damage induced by the pathogenic bacteria namely methicillin resistant Staphylococcus aureus (MRSA) ATCC 6538 strain. Infected rats were received a single intraperitoneal (i.p.) injection of bacterial suspension at a dose of 1 X 10(6) CFU / 100g body weight. Results showed that oral administration of an aqueous extract of propolis (50mg/100g body weight) daily for two weeks to infected rats simultaneously with bacterial infection, effectively ameliorated the alteration of oxidative stress biomarker, malondialdehyde (MDA), as well as the antioxidant markers, glutathione peroxidase (GPx) and superoxide dismutase (SOD), in lungs of infected rats compared with infected untreated ones. Also, the used propolis extract successfully modulated the alterations in proinflammatory mediators, tumor necrosis factor-α (TNF- α) and vascular endothelial growth factor (VEGF) in serum. In addition, the propolis extract successfully modulated the oxidative DNA damage and the apoptosis biomarker, caspase 3, in lungs of S aureus infected rats compared with infected untreated animals. The biochemical results were supported by histo-pathological observation of lung tissues. In conclusion, the beneficial prophylactic role of the aqueous extract of Saudi red propolis against lung damage induced by methicillin resistant S aureus may be related to the antioxidant, anti-inflammatory, immunomodulatory and antiapoptosis of its active constituents.

  6. Melatonin alleviates acute lung injury through inhibiting the NLRP3 inflammasome.

    Zhang, Yong; Li, Xiru; Grailer, Jamison J; Wang, Na; Wang, Mingming; Yao, Jianfei; Zhong, Rui; Gao, George F; Ward, Peter A; Tan, Dun-Xian; Li, Xiangdong

    2016-05-01

    Acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) are clinically severe respiratory disorders, and there are currently no Food and Drug Administration-approved drug therapies. Melatonin is a well-known anti-inflammatory molecule, which has proven to be effective in ALI induced by many conditions. Emerging studies suggest that the NLRP3 inflammasome plays a critical role during ALI. How melatonin directly blocks activation of the NLRP3 inflammasome in ALI remains unclear. In this study, using an LPS-induced ALI mouse model, we found intratracheal (i.t.) administration of melatonin markedly reduced the pulmonary injury and decreased the infiltration of macrophages and neutrophils into lung. During ALI, the NLRP3 inflammasome is significantly activated with a large amount of IL-1β and the activated caspase-1 occurring in the lung. Melatonin inhibits the activation of the NLRP3 inflammasome by both suppressing the release of extracellular histones and directly blocking histone-induced NLRP3 inflammasome activation. Notably, i.t. route of melatonin administration opens a more efficient therapeutic approach for treating ALI.

  7. Effects of Liver × receptor agonist treatment on signal transduction pathways in acute lung inflammation

    Bramanti Placido

    2010-02-01

    Full Text Available Abstract Background Liver × receptor α (LXRα and β (LXRβ are members of the nuclear receptor super family of ligand-activated transcription factors, a super family which includes the perhaps better known glucocorticoid receptor, estrogen receptor, thyroid receptor, and peroxisome proliferator-activated receptors. There is limited evidence that LXL activation may reduces acute lung inflammation. The aim of this study was to investigate the effects of T0901317, a potent LXR receptor ligand, in a mouse model of carrageenan-induced pleurisy. Methods Injection of carrageenan into the pleural cavity of mice elicited an acute inflammatory response characterized by: accumulation of fluid containing a large number of neutrophils (PMNs in the pleural cavity, infiltration of PMNs in lung tissues and subsequent lipid peroxidation, and increased production of nitrite/nitrate (NOx, tumor necrosis factor-α, (TNF-α and interleukin-1β (IL-1β. Furthermore, carrageenan induced the expression of iNOS, nitrotyrosine and PARP, as well as induced apoptosis (TUNEL staining and Bax and Bcl-2 expression in the lung tissues. Results Administration of T0901317, 30 min after the challenge with carrageenan, caused a significant reduction in a dose dependent manner of all the parameters of inflammation measured. Conclusions Thus, based on these findings we propose that LXR ligand such as T0901317, may be useful in the treatment of various inflammatory diseases.

  8. Antiplatelet antibody may cause delayed transfusion-related acute lung injury

    Torii Y

    2011-09-01

    Full Text Available Yoshitaro Torii1, Toshiki Shimizu1, Takashi Yokoi1, Hiroyuki Sugimoto1, Yuichi Katashiba1, Ryotaro Ozasa1, Shinya Fujita1, Yasushi Adachi2, Masahiko Maki3, Shosaku Nomura11The First Department of Internal Medicine, Kansai Medical University, Osaka, 2Department of Clinical Pathology, Toyooka Hospital, Hyogo, 3First Department of Pathology, Kansai Medical University, Osaka, JapanAbstract: A 61-year-old woman with lung cancer developed delayed transfusion-related acute lung injury (TRALI syndrome after transfusion of plasma- and leukoreduced red blood cells (RBCs for gastrointestinal bleeding due to intestinal metastasis. Acute lung injury (ALI recurred 31 days after the first ALI episode. Both ALI episodes occurred 48 hours after transfusion. Laboratory examinations revealed the presence of various antileukocyte antibodies including antiplatelet antibody in the recipient's serum but not in the donors' serum. The authors speculate that antiplatelet antibodies can have an inhibitory effect in the recipient, which can modulate the bona fide procedure of ALI and lead to a delay in the onset of ALI. This case illustrates the crucial role of a recipient's platelets in the development of TRALI.Keywords: delayed TRALI syndrome, recurrence, anti-platelet antibody

  9. Imbalance of Th17/Tregs in rats with smoke inhalation-induced acute lung injury

    Zhang, Fan; Li, Mian-yang; Lan, Ya-ting; Wang, Cheng-bin

    2016-01-01

    T helper (Th) 17 cells and CD4+ CD25+ regulatory T (Treg) cells are supposed to be critically involved in regulating autoimmune and inflammatory diseases. The aim of this study was to investigate the Th17/Treg pattern in rats with gunpowder smog-induced acute lung injury. Wistar rats were equally randomized to three groups: normal control group, ALI 6 h group (smoke inhalation for 6 h) and ALI 24 h group (smoke inhalation for 24 h). We observed changes in cell counting in bronchoalveolar lavage fluid (BALF), alveolar-capillary membrane permeability and lung tissue pathology. Moreover, rats in ALI 6 h and ALI 24 h group showed increased expression of Th17 cell and related cytokines (IL-17 A, IL-6, TGF-β and IL-23). Meanwhile, Treg prevalence and related cytokines (IL-10, IL-2 and IL-35) were decreased. Consequently, the ratio of Th17/Treg was higher after smoke inhalation. Additionally, Th1 cell decreased while Th2 cell increased at 6 h and 24 h after smoke inhalation. In conclusion, Th17/Treg imbalance exists in rats with smoke inhalation-induced acute lung injury, suggesting its potential role in the pathogenesis of this disease. PMID:26884314

  10. Proinflammatory role of inducible nitric oxide synthase in acute hyperoxic lung injury

    Kupatt Christian

    2004-09-01

    Full Text Available Abstract Background Hyperoxic exposures are often found in clinical settings of respiratory insufficient patients, although oxygen therapy (>50% O2 can result in the development of acute hyperoxic lung injury within a few days. Upon hyperoxic exposure, the inducible nitric oxide synthase (iNOS is activated by a variety of proinflammatory cytokines both in vitro and in vivo. In the present study, we used a murine hyperoxic model to evaluate the effects of iNOS deficiency on the inflammatory response. Methods Wild-type and iNOS-deficient mice were exposed to normoxia, 60% O2 or >95% O2 for 72 h. Results Exposure to >95% O2 resulted in an increased iNOS mRNA and protein expression in the lungs from wild-type mice. No significant effects of iNOS deficiency on cell differential in bronchoalveolar lavage fluid were observed. However, hyperoxia induced a significant increase in total cell count, protein concentration, LDH activity, lipid peroxidation, and TNF-α concentration in the bronchoalveolar lavage fluid compared to iNOS knockout mice. Moreover, binding activity of NF-κB and AP-1 appeared to be higher in wild-type than in iNOS-deficient mice. Conclusion Taken together, our results provide evidence to suggest that iNOS plays a proinflammatory role in acute hyperoxic lung injury.

  11. Lung damage in mice after inhalation of nanofilm spray products: the role of perfluorination and free hydroxyl groups

    Nørgaard, Asger W; Larsen, Søren T.; Hammer, Maria;

    2010-01-01

    Exposures to two commercial nanofilm spray products (NFPs), a floor sealant (NFP 1) and a coating product for tiles (NFP 2), were investigated for airway irritation, airway inflammation, and lung damage in a mouse inhalation model. The particle exposure was characterized by particle number, parti...... groups in the silanes/alkylsiloxanes was also critical for the toxicity....

  12. DIVALENT METAL TRANSPORTER-1 REGULATION BY IRON AND VANADIUM MODULATES HYDROGEN PEROXIDE-INDUCED DNA DAMAGE IN LUNG CELLS

    The divalent metal transporter-1 (DMT1) participates in the detoxification of metals that can damage lung epithelium. Elevated iron levels increase the expression of DMT1 in bronchial epithelial cells stimulating its uptake and storage in ferritin, thus making iron unavailable t...

  13. Lung T lymphocyte trafficking and activation during ischemic acute kidney injury.

    Lie, Mihaela L; White, Laura E; Santora, Rachel J; Park, Jong M; Rabb, Hamid; Hassoun, Heitham T

    2012-09-15

    Despite advances in renal replacement therapy, the mortality rate for acute kidney injury (AKI) remains unacceptably high, likely owing to extrarenal organ dysfunction. Kidney ischemia-reperfusion injury (IRI) activates cellular and soluble mediators that facilitate organ crosstalk and induce caspase-dependent lung apoptosis and injury through a TNFR1-dependent pathway. Given that T lymphocytes mediate local IRI in the kidney and are known to drive TNFR1-mediated apoptosis, we hypothesized that T lymphocytes activated during kidney IRI would traffic to the lung and mediate pulmonary apoptosis during AKI. In an established murine model of kidney IRI, we identified trafficking of CD3+ T lymphocytes to the lung during kidney IRI by flow cytometry and immunohistochemistry. T lymphocytes were primarily of the CD3+CD8+ phenotype; however, both CD3+CD4+ and CD3+CD8+ T lymphocytes expressed CD69 and CD25 activation markers during ischemic AKI. The activated lung T lymphocytes did not demonstrate an increased expression of intracellular TNF-α or surface TNFR1. Kidney IRI induced pulmonary apoptosis measured by caspase-3 activation in wild-type controls, but not in T cell-deficient (T(nu/nu)) mice. Adoptive transfer of murine wild-type T lymphocytes into T(nu/nu) mice restored the injury phenotype with increased cellular apoptosis and lung microvascular barrier dysfunction, suggesting that ischemic AKI-induced pulmonary apoptosis is T cell dependent. Kidney-lung crosstalk during AKI represents a complex biological process, and although T lymphocytes appear to serve a prominent role in the interorgan effects of AKI, further experiments are necessary to elucidate the specific role of activated T cells in modulating pulmonary apoptosis.

  14. Protective Role of Liriodendrin in Sepsis-Induced Acute Lung Injury.

    Yang, Lei; Li, Dihua; Zhuo, Yuzhen; Zhang, Shukun; Wang, Ximo; Gao, Hongwei

    2016-10-01

    In current study, we investigated the role of liriodendrin, a constituent isolated from Sargentodoxa cuneata (Oliv.) Rehd. Et Wils (Sargentodoxaceae), in cecal ligation and puncture (CLP)-induced acute lung inflammatory response and injury (ALI). The inflammatory mediator levels in bronchoalveolar lavage fluid (BALF) were determined by enzyme-linked immunosorbent assay (ELISA). Pathologic changes in lung tissues were evaluated via pathological section with hematoxylin and eosin (H&E) staining. To investigate the mechanism whereby liriodendrin regulates lung inflammation, the phosphorylation of the NF-kB (p65) and expression of vascular endothelial growth factor (VEGF) were determined by western blot assay. We show that liriodendrin treatment significantly improved the survival rate of mice with CLP-induced sepsis. Pulmonary histopathologic changes, alveolar hemorrhage, and neutrophil infiltration were markedly decreased by liriodendrin. In addition, liriodendrin decreased the production of the proinflammatory mediators including (TNF-α, IL-1β, MCP-1, and IL-6) in lung tissues. Vascular permeability and lung myeloperoxidase (MPO) accumulation in the liriodendrin-treated mice were substantially reduced. Moreover, liriodendrin treatment significantly suppressed the expression of VEGF and activation of NF-kB in the lung. We further show that liriodendrin significantly reduced the production of proinflammatory mediators and downregulated NF-kB signaling in LPS-stimulated RAW 264.7 macrophage cells. Moreover, liriodendrin prevented the generation of reactive oxygen species (ROS) by upregulating the expression of SIRT1 in RAW 264.7 cells. These findings provide a novel theoretical basis for the possible application of liriodendrin in clinic.

  15. Regulatory T cells reduce acute lung injury fibroproliferation by decreasing fibrocyte recruitment.

    Garibaldi, Brian T; D'Alessio, Franco R; Mock, Jason R; Files, D Clark; Chau, Eric; Eto, Yoshiki; Drummond, M Bradley; Aggarwal, Neil R; Sidhaye, Venkataramana; King, Landon S

    2013-01-01

    Acute lung injury (ALI) causes significant morbidity and mortality. Fibroproliferation in ALI results in worse outcomes, but the mechanisms governing fibroproliferation remain poorly understood. Regulatory T cells (Tregs) are important in lung injury resolution. Their role in fibroproliferation is unknown. We sought to identify the role of Tregs in ALI fibroproliferation, using a murine model of lung injury. Wild-type (WT) and lymphocyte-deficient Rag-1(-/-) mice received intratracheal LPS. Fibroproliferation was characterized by histology and the measurement of lung collagen. Lung fibrocytes were measured by flow cytometry. To dissect the role of Tregs in fibroproliferation, Rag-1(-/-) mice received CD4(+)CD25(+) (Tregs) or CD4(+)CD25(-) Tcells (non-Tregs) at the time of LPS injury. To define the role of the chemokine (C-X-C motif) ligand 12 (CXCL12)-CXCR4 pathway in ALI fibroproliferation, Rag-1(-/-) mice were treated with the CXCR4 antagonist AMD3100 to block fibrocyte recruitment. WT and Rag-1(-/-) mice demonstrated significant collagen deposition on Day 3 after LPS. WT mice exhibited the clearance of collagen, but Rag-1(-/-) mice developed persistent fibrosis. This fibrosis was mediated by the sustained epithelial expression of CXCL12 (or stromal cell-derived factor 1 [SDF-1]) that led to increased fibrocyte recruitment. The adoptive transfer of Tregs resolved fibroproliferation by decreasing CXCL12 expression and subsequent fibrocyte recruitment. Blockade of the CXCL12-CXCR4 axis with AMD3100 also decreased lung fibrocytes and fibroproliferation. These results indicate a central role for Tregs in the resolution of ALI fibroproliferation by reducing fibrocyte recruitment along the CXCL12-CXCR4 axis. A dissection of the role of Tregs in ALI fibroproliferation may inform the design of new therapeutic tools for patients with ALI.

  16. CT Manifestations of Lung Changes and Complications in Patients with Severe Acute Respiratory Syndrome

    张雪哲; 王武; 卢延; 黄振国; 洪闻; 尚燕宁; 任安

    2003-01-01

    Objective:To investigate the role of CT scanning in diagnosing severe acute respiratory syndrome(SARS). Methods: One hundred and twelve times of spiral CT scanning, 106 times on the chest with standard pulmonary and mediastinal window, 5 on the brain and once on the abdomen, were performed in 82 patients (37 males and 45 females) of SARS. Results: Bilateral shadows showed in 66 patients (80.48%) and unilateral shadow in 16 (19.52%). The lung CT findings were sub-pleural focal consolidation in 26 patients (31.70%), flaky cloudy opacity in 53 (64.63%), large area consolidation in 9 (10.97%), ground-glass blurry shadow in 31 (37.80%), alveolar substantive shadow in 14 (17.07%) and interstitial changes in 16 (19.51%). The pulmonary CT signs of SARS were relatively characterized by: (1) The lesions tending to multiply occur, mostly to be bilaterally distributed and commonly involved in the lower lung field. (2) The lung shadows mostly showed as sub-pleural focal consolidation, flaky cloudy shadow, large area consolidation, ground-glass blurry shadow, and often accompanied with signs of broncho-inflation. (3) Having opacified nodular shadows in the alveolar cavities. (4) Rapid progressions or changes on the size, amount, and distribution of the lesions likely to be found in dynamic observation of chest X-ray and CT scanning, i.e., markedly dynamic changes found within 24 to 48 hrs. Lesions with these characteristics may be recognized as pulmonary changes possibly induced by SARS. Complications were found in 6 patients (7.31%), including tuberculosis of lung and brain accompanied with pneumomediastinum in one patient, secondary infection of lung in 2, pneumothorax in 1, pulmonary fungus in 1, and pyothorax in 1.Conclusion: CT scanning is a sensitive method for diagnosis of SARS, by which more accurate assessment of the abnormal changes of lung and occurrence of complications in SARS patients can be made.

  17. Protective Effects of Apigenin Against Paraquat-Induced Acute Lung Injury in Mice.

    Luan, Rui-Ling; Meng, Xiang-Xi; Jiang, Wei

    2016-04-01

    This study aimed to investigate the protective effects of apigenin against paraquat (PQ)-induced acute lung injury (ALI) in mice. Male Kunming mice were randomly divided into five groups: group 1 (control), group 2 (PQ), group 3 (PQ + apigenin 25 mg/kg), group 4 (PQ + apigenin 50 mg/kg), and group 5 (PQ + apigenin 100 mg/kg). The PQ + apigenin group received apigenin by gavage daily for consecutive 7 days, respectively, while the mice in control and PQ groups were given an equivalent volume of saline. We detected the lung wet/dry weight ratios and the histopathology of the lung. The levels of interleukin-6 (IL-6), tumor necrosis factor-alpha (TNF-α), malondialdehyde (MDA), myeloperoxidase (MPO), superoxide dismutase (SOD), and glutathione peroxidase (GSH-Px) were determined using enzyme-linked immunosorbent assay (ELISA) kits. The activity of nuclear factor (NF)-κB was also determined. The results indicated that apigenin administration decreased biochemical parameters of inflammation and oxidative stress, and improved oxygenation and lung edema in a dose-dependent manner. These protective effects of apigenin were associated with inhibition of NF-κB. In conclusion, apigenin reduces PQ-induced ALI by inhibition of inflammation and oxidative stress.

  18. Simvastatin reduces endotoxin-induced acute lung injury by decreasing neutrophil recruitment and radical formation.

    Jochen Grommes

    Full Text Available INTRODUCTION: Treatment of acute lung injury (ALI remains an unsolved problem in intensive care medicine. As simvastatin exerts protective effects in inflammatory diseases we explored its effects on development of ALI and due to the importance of neutrophils in ALI also on neutrophil effector functions. METHODS: C57Bl/6 mice were exposed to aerosolized LPS (500 µg/ml for 30 min. The count of alveolar, interstitial, and intravasal neutrophils were assessed 4 h later by flow cytometry. Lung permeability changes were assessed by FITC-dextran clearance and albumin content in the BAL fluid. In vitro, we analyzed the effect of simvastatin on neutrophil adhesion, degranulation, apoptosis, and formation of reactive oxygen species. To monitor effects of simvastatin on bacterial clearance we performed phagocytosis and bacterial killing studies in vitro as well as sepsis experiments in mice. RESULTS: Simvastatin treatment before and after onset of ALI reduces neutrophil influx into the lung as well as lung permeability indicating the protective role of simvastatin in ALI. Moreover, simvastatin reduces the formation of ROS species and adhesion of neutrophils without affecting apoptosis, bacterial phagocytosis and bacterial clearance. CONCLUSION: Simvastatin reduces recruitment and activation of neutrophils hereby protecting from LPS-induced ALI. Our results imply a potential role for statins in the management of ALI.

  19. Regional pulmonary inflammation in an endotoxemic ovine acute lung injury model.

    Fernandez-Bustamante, A; Easley, R B; Fuld, M; Mulreany, D; Chon, D; Lewis, J F; Simon, B A

    2012-08-15

    The regional distribution of inflammation during acute lung injury (ALI) is not well known. In an ovine ALI model we studied regional alveolar inflammation, surfactant composition, and CT-derived regional specific volume change (sVol) and specific compliance (sC). 18 ventilated adult sheep received IV lipopolysaccharide (LPS) until severe ALI was achieved. Blood and bronchoalveolar lavage (BAL) samples from apical and basal lung regions were obtained at baseline and injury time points, for analysis of cytokines (IL-6, IL-1β), BAL protein and surfactant composition. Whole lung CT images were obtained in 4 additional sheep. BAL protein and IL-1β were significantly higher in injured apical vs. basal regions. No significant regional surfactant composition changes were observed. Baseline sVol and sC were lower in apex vs. base; ALI enhanced this cranio-caudal difference, reaching statistical significance only for sC. This study suggests that apical lung regions show greater inflammation than basal ones during IV LPS-induced ALI which may relate to differences in regional mechanical events.

  20. Effects of Ischemic Acute Kidney Injury on Lung Water Balance: Nephrogenic Pulmonary Edema?

    Rajit K. Basu

    2011-01-01

    Full Text Available Pulmonary edema worsens the morbidity and increases the mortality of critically ill patients. Mechanistically, edema formation in the lung is a result of net flow across the alveolar capillary membrane, dependent on the relationship of hydrostatic and oncotic pressures. Traditionally, the contribution of acute kidney injury (AKI to the formation of pulmonary edema has been attributed to bulk fluid accumulation, increasing capillary hydrostatic pressure and the gradient favoring net flow into the alveolar spaces. Recent research has revealed more subtle, and distant, effects of AKI. In this review we discuss the concept of nephrogenic pulmonary edema. Pro-inflammatory gene upregulation, chemokine over-expression, altered biochemical channel function, and apoptotic dysregulation manifest in the lung are now understood as “extra-renal” and pulmonary effects of AKI. AKI should be counted as a disease process that alters the endothelial integrity of the alveolar capillary barrier and has the potential to overpower the ability of the lung to regulate fluid balance. Nephrogenic pulmonary edema, therefore, is the net effect of fluid accumulation in the lung as a result of both the macroscopic and microscopic effects of AKI.

  1. Reactive oxygen species produced by NADPH oxidase and mitochondrial dysfunction in lung after an acute exposure to Residual Oil Fly Ashes

    Magnani, Natalia D.; Marchini, Timoteo; Vanasco, Virginia [Instituto de Bioquímica Medicina Molecular (IBIMOL-UBA-CONICET), Facultad de Farmacia y Bioquímica, Universidad de Buenos Aires, Buenos Aires (Argentina); Tasat, Deborah R. [CESyMA, Escuela de Ciencia y Tecnología, Universidad Nacional de San Martín, San Martín, Buenos Aires (Argentina); Alvarez, Silvia [Instituto de Bioquímica Medicina Molecular (IBIMOL-UBA-CONICET), Facultad de Farmacia y Bioquímica, Universidad de Buenos Aires, Buenos Aires (Argentina); Evelson, Pablo, E-mail: pevelson@ffyb.uba.ar [Instituto de Bioquímica Medicina Molecular (IBIMOL-UBA-CONICET), Facultad de Farmacia y Bioquímica, Universidad de Buenos Aires, Buenos Aires (Argentina)

    2013-07-01

    Reactive O{sub 2} species production triggered by particulate matter (PM) exposure is able to initiate oxidative damage mechanisms, which are postulated as responsible for increased morbidity along with the aggravation of respiratory diseases. The aim of this work was to quantitatively analyse the major sources of reactive O{sub 2} species involved in lung O{sub 2} metabolism after an acute exposure to Residual Oil Fly Ashes (ROFAs). Mice were intranasally instilled with a ROFA suspension (1.0 mg/kg body weight), and lung samples were analysed 1 h after instillation. Tissue O{sub 2} consumption and NADPH oxidase (Nox) activity were evaluated in tissue homogenates. Mitochondrial respiration, respiratory chain complexes activity, H{sub 2}O{sub 2} and ATP production rates, mitochondrial membrane potential and oxidative damage markers were assessed in isolated mitochondria. ROFA exposure was found to be associated with 61% increased tissue O{sub 2} consumption, a 30% increase in Nox activity, a 33% increased state 3 mitochondrial O{sub 2} consumption and a mitochondrial complex II activity increased by 25%. During mitochondrial active respiration, mitochondrial depolarization and a 53% decreased ATP production rate were observed. Neither changes in H{sub 2}O{sub 2} production rate, nor oxidative damage in isolated mitochondria were observed after the instillation. After an acute ROFA exposure, increased tissue O{sub 2} consumption may account for an augmented Nox activity, causing an increased O{sub 2}{sup ·−} production. The mitochondrial function modifications found may prevent oxidative damage within the organelle. These findings provide new insights to the understanding of the mechanisms involving reactive O{sub 2} species production in the lung triggered by ROFA exposure. - Highlights: • Exposure to ROFA alters the oxidative metabolism in mice lung. • The augmented Nox activity contributes to the high tissue O{sub 2} consumption. • Exposure to ROFA

  2. Role of macrophage inflammatory protein-1 alpha (MIP-1 alpha) in acute lung injury in rats

    Shanley, T P; Schmal, H; Friedl, H P

    1995-01-01

    The role of macrophage inflammatory protein-1 alpha (MIP-1 alpha) in the pathogenesis of acute lung injury in rats after intrapulmonary deposition of IgG immune complexes or intratracheal administration of LPS has been assessed. Critical to these studies was the cloning and functional expression...... of rat MIP-1 alpha. The resulting product shared 92% and 90% homology with the known murine sequence at the cDNA level and protein level, respectively. Recombinant rat MIP-1 alpha exhibited dose-dependent chemotactic activity for both rat and human monocytes and neutrophils, which could be blocked...... by anti-murine MIP-1 alpha Ab. Rat MIP-1 alpha mRNA and protein expression were determined as a function of time in both injury models. A time-dependent increase in MIP-1 alpha mRNA in lung extracts was observed in both models. In the LPS model, MIP-1 alpha protein could also be detected...

  3. Rosiglitazone dampens pulmonary inflammation in a porcine model of acute lung injury.

    Mirakaj, Valbona; Mutz, Christian; Vagts, Dierk; Henes, Janek; Haeberle, Helene A; Husung, Susanne; König, Tony; Nöldge-Schomburg, Gabriele; Rosenberger, Peter

    2014-08-01

    The hallmarks of acute lung injury (ALI) are the compromised alveolar-capillary barrier and the extravasation of leukocytes into the alveolar space. Given the fact that the peroxisome proliferator-activated receptor-γ agonist rosiglitazone holds significant anti-inflammatory properties, we aimed to evaluate whether rosiglitazone could dampen these hallmarks of local pulmonary inflammation in a porcine model of lung injury. For this purpose, we used a model of lipopolysaccharide (LPS, 50 μg/kg)-induced ALI. One hundred twenty minutes following the infusion of LPS, we started the exposure to rosiglitazone through inhalation or infusion. We found that intravenous rosiglitazone significantly controlled local pulmonary inflammation as determined through the expression of cytokines within the alveolar compartment. Furthermore, we found a significant reduction of the protein concentration and neutrophil activity within the alveolar space. In summary, we therefore conclude that the treatment with rosiglitazone might dampen local pulmonary inflammation during the initial stages of ALI.

  4. Sesamin Attenuates Lipopolysaccharide-Induced Acute Lung Injury by Inhibition of TLR4 Signaling Pathways.

    Qiang, Li; Yuan, Jiang; Shouyin, Jiang; Yulin, Li; Libing, Jiang; Jian-An, Wang

    2016-02-01

    Recent studies suggested that TLR4 signaling pathways played an important role in the development of LPS-induced acute lung injury (ALI). Sesamin, a sesame lignan exacted from sesame seeds, has been shown to exhibit significant anti-inflammatory activity. The purpose of this study was to investigate the anti-inflammatory effects of sesamin on LPS-induced ALI in mice. Mice ALI model was induced by intratracheal instillation of LPS. Sesamin was given 1 h after LPS challenge. Our results showed that sesamin inhibited LPS-induced lung pathological change, edema, and myeloperoxidase (MPO) activity. Sesamin suppressed LPS-induced inflammatory cytokines TNF-α, IL-6, and IL-1β production. Furthermore, sesamin inhibited LPS-induced TLR4 expression and NF-κB activation. In conclusion, the results of this study indicated that sesamin protected against LPS-induced ALI by inhibition of TLR4 signaling pathways.

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

    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.

  6. Identification and examination of a novel 9-bp insert/deletion polymorphism on porcine SFTPA1 exon 2 associated with acute lung injury using an oleic acid-acute lung injury model.

    Zhang, Yuebo; Zhang, Longchao; Wang, Ligang; Qiao, Lijuan; Liang, Jing; Yan, Hua; Zhao, Kebin; Liu, Xin; Wang, Lixian

    2015-06-01

    The pulmonary surfactant-associated protein (SFTPA1, SP-A) gene has been studied as a candidate gene for lung disease resistance in humans and livestock. The objective of the present study was to identify polymorphisms of the porcine SFTPA1 gene coding region and its association with acute lung injury (ALI). Through DNA sequencing and the PCR-single-strand conformation polymorphism method, a novel 9-bp nucleotide insertion (+) or deletion (-) was detected on exon 2 of SFTPA1, which causes a change in three amino acids, namely, alanine (Ala), glycine (Gly) and proline (Pro). Individuals of three genotypes (-/-, +/- and +/+) were divided into equal groups from 60 Rongchang pigs that were genotyped. These pigs were selected for participation in the oleic acid (OA)-ALI model by 1-h and 3-h injections of OA, and there were equal numbers of pigs in the control and injection groups. The lung water content, a marker for acute lung injury, was measured in this study; there is a significant correlation between high lung water content and the presence of the 9-bp indel polymorphism (P polymorphism causing altered expression of the gene. The individuals with the -/- genotype showed lower lung water content than the +/+ genotype pigs, which suggests that polymorphism could be a potential marker for lung disease-resistant pig breeding and that pig can be a potential animal model for human lung disease resistance in future studies.

  7. Activation of adherent vascular neutrophils in the lung during acute endotoxemia

    Laskin Jeffrey D

    2002-08-01

    Full Text Available Abstract Background Neutrophils constitute the first line of defense against invading microorganisms. Whereas these cells readily undergo apoptosis under homeostatic conditions, their survival is prolonged during inflammatory reactions and they become biochemically and functionally activated. In the present study, we analyzed the effects of acute endotoxemia on the response of a unique subpopulation of neutrophils tightly adhered to the lung vasculature. Methods Rats were treated with 5 mg/kg lipopolysaccharide (i.v. to induce acute endotoxemia. Adherent neutrophils were isolated from the lung vasculature by collagenase digestion and sequential filtering. Agarose gel electrophoresis, RT-PCR, western blotting and electrophoretic mobility shift assays were used to evaluate neutrophil activity. Results Adherent vascular neutrophils isolated from endotoxemic animals exhibited decreased apoptosis when compared to cells from control animals. This was associated with a marked increase in expression of the anti-apoptotic protein, Mcl-1. Cells isolated 0.5–2 hours after endotoxin administration were more chemotactic than cells from control animals and expressed increased tumor necrosis factor-alpha and cyclooxygenase-2 mRNA and protein, demonstrating that they are functionally activated. Endotoxin treatment of the animals also induced p38 and p44/42 mitogen activated protein kinases in the adherent lung neutrophils, as well as nuclear binding activity of the transcription factors, NF-κB and cAMP response element binding protein. Conclusion These data demonstrate that adherent vascular lung neutrophils are highly responsive to endotoxin and that pathways regulating apoptosis and cellular activation are upregulated in these cells.

  8. Review: Acute lung injury/acute respiratory distress syndrome (ALI/ARDS): the mechanism, present strategies and future perspectives of therapies

    LUH Shi-ping; CHIANG Chi-huei

    2007-01-01

    Acute lung injury/acute respiratory distress syndrome (ALI/ARDS), which manifests as non-cardiogenic pulmonary edema, respiratory distress and hypoxemia, could be resulted from various processes that directly or indirectly injure the lung.Extensive investigations in experimental models and humans with ALI/ARDS have revealed many molecular mechanisms that offer therapeutic opportunities for cell or gene therapy. Herein the present strategies and future perspectives of the treatment for ALI/ARDS, include the ventilatory, pharmacological, as well as cell therapies.

  9. Postmortem changes in lungs in severe closed traumatic brain injury complicated by acute respiratory failure

    V. A. Tumanskiy

    2013-08-01

    Full Text Available V.А. Tumanskіy, S.І. Ternishniy, L.M. Tumanskaya Pathological changes in the lungs were studied in the work of 42 patiens who died from severe closed intracranial injury (SCII. It was complicated with acute respiratory insufficient (ARI. The most modified subpleural areas were selected from every lobe of the lungs for pathological studies. Prepared histological sections were stained by means of hemotoxylin and eosin and by Van Giеson for light microscopy. The results of the investigation have shown absence of the significant difference of pathological changes in the lungs of patients who died from ARI because of severe brain injury and traumatic intracranial hemorrhage. Pathognomic pathological changes in the lungs as a result of acute lung injury syndrome (ALIS were found in deceased patients on the third day since the SCII (n=8. There was a significant bilateral interstitial edema and mild alveolar edema with the presence of red and blood cells in the alveoli, vascular plethora of the septum interalveolar and stasis of blood in the capillaries, the slight pericapillary leukocyte infiltration, subpleural hemorrhage and laminar pulmonary atelectasis. In deceased patients on 4-6 days after SCII that was complicated with ARI (n=14, morphological changes had been detected in the lungs. It was pathognomic for acute respiratory distress syndrome (ARDS with local pneumonic to be layered. A significant interstitial pulmonary edema was observed in the respiratory part of the lungs. The edema has spread from the walls of the alveoli into the interstitial spaces of the bronchioles and blood vessels, and also less marked serous-hemorrhagic alveolar edema with presence of the fibrin in the alveoli and macrophages. The ways of intrapleural lymphatic drainage were dilatated. Histopathological changes in the lungs of those who died on the 7-15th days after severe closed craniocerebral injury with ARI to be complicated (n=12 have been indicative of two

  10. Abdominal Muscle Activity during Mechanical Ventilation Increases Lung Injury in Severe Acute Respiratory Distress Syndrome.

    Xianming Zhang

    Full Text Available It has proved that muscle paralysis was more protective for injured lung in severe acute respiratory distress syndrome (ARDS, but the precise mechanism is not clear. The purpose of this study was to test the hypothesis that abdominal muscle activity during mechanically ventilation increases lung injury in severe ARDS.Eighteen male Beagles were studied under mechanical ventilation with anesthesia. Severe ARDS was induced by repetitive oleic acid infusion. After lung injury, Beagles were randomly assigned into spontaneous breathing group (BIPAPSB and abdominal muscle paralysis group (BIPAPAP. All groups were ventilated with BIPAP model for 8h, and the high pressure titrated to reached a tidal volume of 6ml/kg, the low pressure was set at 10 cmH2O, with I:E ratio 1:1, and respiratory rate adjusted to a PaCO2 of 35-60 mmHg. Six Beagles without ventilator support comprised the control group. Respiratory variables, end-expiratory volume (EELV and gas exchange were assessed during mechanical ventilation. The levels of Interleukin (IL-6, IL-8 in lung tissue and plasma were measured by qRT-PCR and ELISA respectively. Lung injury scores were determined at end of the experiment.For the comparable ventilator setting, as compared with BIPAPSB group, the BIPAPAP group presented higher EELV (427±47 vs. 366±38 ml and oxygenation index (293±36 vs. 226±31 mmHg, lower levels of IL-6(216.6±48.0 vs. 297.5±71.2 pg/ml and IL-8(246.8±78.2 vs. 357.5±69.3 pg/ml in plasma, and lower express levels of IL-6 mRNA (15.0±3.8 vs. 21.2±3.7 and IL-8 mRNA (18.9±6.8 vs. 29.5±7.9 in lung tissues. In addition, less lung histopathology injury were revealed in the BIPAPAP group (22.5±2.0 vs. 25.2±2.1.Abdominal muscle activity during mechanically ventilation is one of the injurious factors in severe ARDS, so abdominal muscle paralysis might be an effective strategy to minimize ventilator-induce lung injury.

  11. Circulating miRNAs as Biomarkers of Acute Muscle Damage in Rats.

    Siracusa, Julien; Koulmann, Nathalie; Bourdon, Stéphanie; Goriot, Marie-Emmanuelle; Banzet, Sébastien

    2016-05-01

    Skeletal muscle damage is an often-occurring event. Diagnosis using the classic blood marker creatine kinase sometimes yields unsatisfactory results due to great interindividual variability. Therefore, the identification of reliable biomarkers is important. Our aim was to detect and characterize circulating miRNAs in plasma in response to acute notexin-induced muscle damage in rats. Real-time quantitative RT-PCR profiling led to the identification of miRNAs that were highly increased in plasma in response to notexin injection into several muscles, namely miR-1-3p, -133a-3p, -133b-3p, -206-3p, -208b-3p, and -499-5p, as well as miR-378a-3p and miR-434-3p. Peak values of miRNAs appeared 12 hours after injury, and were contained both in the vesicular and nonvesicular fractions of plasma. Receiver operating characteristic curve analysis showed that circulating miRNAs could accurately discriminate between damaged and nondamaged tissues. Furthermore, we tested the robustness of expression profiles in slow- and fast-type fibers. Upon inducing damage in slow- or fast-type muscle, we found that the damaged-muscle phenotype had a very limited impact on the miRNA response. Similarly, the circulating miRNAs selected were not affected by hemolysis or platelets, two pre-analytical factors known to affect plasma miRNA profiles. Taken together, our results show that circulating muscle-specific miRNAs, miR-378a-3p and miR-434-3p, are robust and promising biomarkers of acute muscle damage in rats.

  12. Temporal relationship of serum markers and tissue damage during acute intestinal ischemia/reperfusion

    la Garza, Francisco Javier Guzmán-de; Ibarra-Hernández, Juan Manuel; Cordero-Pérez, Paula; Villegas-Quintero, Pablo; Villarreal-Ovalle, Claudia Ivette; Torres-González, Liliana; Oliva-Sosa, Norma Edith; Alarcón-Galván, Gabriela; Fernández-Garza, Nancy Esthela; Muñoz-Espinosa, Linda Elsa; Cámara-Lemarroy, Carlos Rodrigo; Carrillo-Arriaga, José Gerardo

    2013-01-01

    OBJECTIVE: It is essential to identify a serological marker of injury in order to study the pathophysiology of intestinal ischemia reperfusion. In this work, we studied the evolution of several serological markers after intestinal ischemia reperfusion injury in rats. The markers of non-specific cell damage were aspartate aminotransferase, alanine aminotransaminase, and lactic dehydrogenase, the markers of inflammation were tumor necrosis factor alpha, interleukin-6, and interleukin-1 beta, and the markers of intestinal mucosal damage were intestinal fatty acid binding protein and D-lactate. We used Chiús classification to grade the histopathological damage. METHODS: We studied 35 Wistar rats divided into groups according to reperfusion time. The superior mesenteric artery was clamped for 30 minutes, and blood and biopsies were collected at 1, 3, 6, 12, 24, and 48 hours after reperfusion. We plotted the mean ± standard deviation and compared the baseline and maximum values for each marker using Student's t-test. RESULTS: The maximum values of interleukin-1 beta and lactic dehydrogenase were present before the maximal histopathological damage. The maximum tumor necrosis factor alpha and D-lactate expressions coincided with histopathological damage. Alanine aminotransaminase and aspartate aminotransferase had a maximum expression level that increased following the histopathological damage. The maximum expressions of interluken-6 and intestinal fatty acid binding protein were not significantly different from the Sham treated group. CONCLUSION: For the evaluation of injury secondary to acute intestinal ischemia reperfusion with a 30 minute ischemia period, we recommend performing histopathological grading, quantification of D-lactate, which is synthesized by intestinal bacteria and is considered an indicator of mucosal injury, and quantification of tumor necrosis factor alpha as indicators of acute inflammation three hours after reperfusion. PMID:23917671

  13. Temporal relationship of serum markers and tissue damage during acute intestinal ischemia/reperfusion

    Francisco Javier Guzmán-de la Garza

    2013-07-01

    Full Text Available OBJECTIVE: It is essential to identify a serological marker of injury in order to study the pathophysiology of intestinal ischemia reperfusion. In this work, we studied the evolution of several serological markers after intestinal ischemia reperfusion injury in rats. The markers of non-specific cell damage were aspartate aminotransferase, alanine aminotransaminase, and lactic dehydrogenase, the markers of inflammation were tumor necrosis factor alpha, interleukin-6, and interleukin-1 beta, and the markers of intestinal mucosal damage were intestinal fatty acid binding protein and D-lactate. We used Chiús classification to grade the histopathological damage. METHODS: We studied 35 Wistar rats divided into groups according to reperfusion time. The superior mesenteric artery was clamped for 30 minutes, and blood and biopsies were collected at 1, 3, 6, 12, 24, and 48 hours after reperfusion. We plotted the mean ± standard deviation and compared the baseline and maximum values for each marker using Student’s t-test. RESULTS: The maximum values of interleukin-1 beta and lactic dehydrogenase were present before the maximal histopathological damage. The maximum tumor necrosis factor alpha and D-lactate expressions coincided with histopathological damage. Alanine aminotransaminase and aspartate aminotransferase had a maximum expression level that increased following the histopathological damage. The maximum expressions of interluken-6 and intestinal fatty acid binding protein were not significantly different from the Sham treated group. CONCLUSION: For the evaluation of injury secondary to acute intestinal ischemia reperfusion with a 30 minute ischemia period, we recommend performing histopathological grading, quantification of D-lactate, which is synthesized by intestinal bacteria and is considered an indicator of mucosal injury, and quantification of tumor necrosis factor alpha as indicators of acute inflammation three hours after reperfusion.

  14. EFFECT OF HELICOBACTER PYLORI INFECTION ON ACUTE STRESS-RELATED GASTRIC MUCOSAL DAMAGE OF SERIOUSLY ILL PATIENTS

    赵超; 肖文; 叶光福; 周建平; 周其璋

    2002-01-01

    Emergency endoscopy studies have shown that the most of seriously ill patients develop acute stress-related mucosal damage and ulceration within 24 hours of admission, which manifest the upper gastrointestinal tract

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

    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.

  16. Bone marrow-derived mesenchymal stem cells protect rats from endotoxin-induced acute lung injury

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

    2011-01-01

    Background Acute lung injury (ALI) is a serious and common condition for which there are currently no specific strategies for treatment.Recent studies have suggested that bone marrow-derived multipotent mesenchymal stem cells (MSCs) may have therapeutic applications in multiple clinical disorders.We explored the biological effects of MSCs during endotoxin-induced ALl and the mechanisms involved.Methods MSCs were isolated from male rat bone marrow and the ALl model was induced by intravenous endotoxin injection.Female rats were sacrificed at 6 hours,24 hours,4 days,1 week and 3 weeks post-injection of MSCs or saline and the lung tissue,bronchoalveolar lavage fluid,and serum were harvested for analysis.We further evaluated the survival of the rats and examined the effects of endotoxin-induced injury on the interaction between alveolar macrophages (AMs) and MSCs in ex vivo.Results There was a significant decrease in numbers of neutrophils in bronchoalveolar lavage fluid (P <0.05),and myeloperoxidase activity in the lung (P<0.01),and of TNF-α and IL-1β in serum (P <0.05) in the MSC treated rats at 4 days.Furthermore,MSC treated rats exhibited improved survival,lower lung injury score,higher concentration of IL-10 in the serum and a reduced hydroxyproline content,but these differences were not statistically significant.Moreover,co-cultures of MSCs and AMs had significantly reduced levels of TNF-α,IL-1β and macrophage inflammatory protein (MIP)-1α and significantly increased levels of IL-10 (P<0.05) in the culture supernatants.Conclusions Treatment with intravenous injection of bone marrow-derived MSCs have beneficial effects on endotoxin-induced ALl in rats.The beneficial effect might be achieved through the engraftment of differentiated MSCs in the lungs and appears derive more from their capacity to secrete soluble factors that modulate immune responses.

  17. Protective Effects of Cucurbitacin B on Acute Lung Injury Induced by Sepsis in Rats

    Hua, Shu; Liu, Xing; Lv, Shuguang; Wang, Zhifang

    2017-01-01

    Background The aim of this study was to investigate the protective effects of cucurbitacin B (CuB) on sepsis-induced acute lung injury (ALI) in rats. Material/Methods An ALI model was made by cecal ligation and puncture (CLP) in SD rats. Rats were randomly divided into 5 groups (n=15 per group): animals undergoing a sham CLP (sham group); animals undergoing CLP (CLP control group); animals undergoing CLP and treated with CuB at 1 mg/kg of body weight (bw) (low-dose CuB [L-CuB] group), animals undergoing CuB at 2 mg/kg of bw (mid-dose CuB [M-CuB] group); and animals undergoing CuB at 5 mg/kg of bw (high-dose CuB [H-CuB] group). Samples of blood and lung tissue were harvested at different time points (6, 12, and 24 hour post-CLP surgery) for the detection of indicators which represented ALI. Five rats were respectively sacrificed at each time point. Pathological changes of lung tissue were observed by H&E staining. Another 50 rats were distributed into the same five groups to record the 72 hour survival rates. Results Treatment with CuB significantly increased the blood gas PaO2 levels and decreased lung wet/dry (W/D) ratio (ptumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6), (pprotection effects in a dose-depended manner. Conclusions CuB can effectively improve the pulmonary gas exchange function, reduce pulmonary edema, and inhibit the inflammatory response in the lung, revealing that CuB may serve as a potential therapeutic strategy for sepsis-induced ALI. PMID:28315572

  18. Lysine acetylsalicylate ameliorates lung injury in rats acutely exposed to paraquat

    HUANG Wei-dong; WANG Jie-zan; LU Yuan-qiang; DI Ya-min; JIANG Jiu-kun; ZHANG Qin

    2011-01-01

    Background Paraquat (PQ), an effective and widely used herbicide, has been proven to be safe when appropriately applied to eliminate weeds. However, PQ poisoning is an extremely frustrating clinical condition with a high mortality and with a lack of effective treatments in humans. PQ mainly accumulates in the lung, and the main molecular mechanism of PQ toxicity is based on redox cycling and intracellular oxidative stress generation. The aim of this study was to evaluate whether lysine acetylsalicylate (LAS) could protect the lung from the damage of PQ poisoning and to study the mechanisms of protection.Methods A model of PQ poisoning was established in 75 Sprague-Dawley rats by intragastric administration of 50 mg/kg PQ, followed by treatment with 200 mg/kg of LAS. The rats were randomly divided into sham, PQ, and PQ+LAS groups, with 25 in each group. We assessed and compared the malonaldehyde (MDA) content, superoxide dismutase activity (SOD), glutathion peroxidase (GSH-Px), and catalase (CAT) in serum and lung and the hydroxyproline (HYP)content, pathological changes, apoptosis and expression of Bcl-2/Bax protein in lung of rats on days 1, 3, 7, 14 and 21after PQ poisoning and LAS treatment.Results Compared to the PQ group rats, early treatment with LAS reduced the MDA and HYP contents, and increased the SOD, GSH-Px, and CAT activities in the serum and lung on days 1, 3, 7, 14, and 21 after PQ poisoning (all P<0.05).After early LAS treatment, the apoptotic rate and Bax expression of lung decreased, the Bcl-2 expression increased, and the Bcl-2/Bax ratio increased, compared to the PQ group rats. Furthermore, the pathological results of lungs revealed that after LAS treatment, early manifestations of PQ poisoning, such as hemorrhage, edema and inflammatory-cell infiltration, were improved to some degree, and collagen fibers in the pulmonary interstitium were also obviously reduced.Conclusion In this rat model of PQ poisoning, LAS effectively ameliorated the lung

  19. Toxin-induced necroptosis is a major mechanism of Staphylococcus aureus lung damage.

    Kitur, Kipyegon; Parker, Dane; Nieto, Pamela; Ahn, Danielle S; Cohen, Taylor S; Chung, Samuel; Wachtel, Sarah; Bueno, Susan; Prince, Alice

    2015-04-01

    Staphylococcus aureus USA300 strains cause a highly inflammatory necrotizing pneumonia. The virulence of this strain has been attributed to its expression of multiple toxins that have diverse targets including ADAM10, NLRP3 and CD11b. We demonstrate that induction of necroptosis through RIP1/RIP3/MLKL signaling is a major consequence of S. aureus toxin production. Cytotoxicity could be prevented by inhibiting either RIP1 or MLKL signaling and S. aureus mutants lacking agr, hla or Hla pore formation, lukAB or psms were deficient in inducing cell death in human and murine immune cells. Toxin-associated pore formation was essential, as cell death was blocked by exogenous K+ or dextran. MLKL inhibition also blocked caspase-1 and IL-1β production, suggesting a link to the inflammasome. Rip3(-/-) mice exhibited significantly improved staphylococcal clearance and retained an alveolar macrophage population with CD200R and CD206 markers in the setting of acute infection, suggesting increased susceptibility of these leukocytes to necroptosis. The importance of this anti-inflammatory signaling was indicated by the correlation between improved outcome and significantly decreased expression of KC, IL-6, TNF, IL-1α and IL-1β in infected mice. These findings indicate that toxin-induced necroptosis is a major cause of lung pathology in S. aureus pneumonia and suggest the possibility of targeting components of this signaling pathway as a therapeutic strategy.

  20. Toxin-induced necroptosis is a major mechanism of Staphylococcus aureus lung damage.

    Kipyegon Kitur

    2015-04-01

    Full Text Available Staphylococcus aureus USA300 strains cause a highly inflammatory necrotizing pneumonia. The virulence of this strain has been attributed to its expression of multiple toxins that have diverse targets including ADAM10, NLRP3 and CD11b. We demonstrate that induction of necroptosis through RIP1/RIP3/MLKL signaling is a major consequence of S. aureus toxin production. Cytotoxicity could be prevented by inhibiting either RIP1 or MLKL signaling and S. aureus mutants lacking agr, hla or Hla pore formation, lukAB or psms were deficient in inducing cell death in human and murine immune cells. Toxin-associated pore formation was essential, as cell death was blocked by exogenous K+ or dextran. MLKL inhibition also blocked caspase-1 and IL-1β production, suggesting a link to the inflammasome. Rip3(-/- mice exhibited significantly improved staphylococcal clearance and retained an alveolar macrophage population with CD200R and CD206 markers in the setting of acute infection, suggesting increased susceptibility of these leukocytes to necroptosis. The importance of this anti-inflammatory signaling was indicated by the correlation between improved outcome and significantly decreased expression of KC, IL-6, TNF, IL-1α and IL-1β in infected mice. These findings indicate that toxin-induced necroptosis is a major cause of lung pathology in S. aureus pneumonia and suggest the possibility of targeting components of this signaling pathway as a therapeutic strategy.

  1. Post-irradiation dietary vitamin E does not affect the development of radiation-induced lung damage in rats.

    Wiegman, Erwin M; van Gameren, Mieke M; Kampinga, Harm H; Szabó, Ben G; Coppes, Rob P

    2004-07-01

    The purpose of this study was to investigate whether application of post-irradiation vitamin E, an anti-oxidant, could prevent the development of radiation induced lung damage. Wistar rats were given vitamin E enriched or vitamin E deprived food starting from 4 weeks after 18Gy single dose irradiation of the right thorax. Neither breathing frequencies nor CT density measurements revealed differences between the groups. It is concluded that post-irradiation vitamin E does not influence radiation-induced fibrosis to the lung.

  2. Ventilator „Chirana Aura V“ In Two Models Of Neonatal Acute Lung Injury - A Pilot Study

    Tomclkova L.

    2014-05-01

    Full Text Available In severe respiratory insufficiency, neonatal and pediatric patients should be ventilated artificially by a ventilator. Aim of this experimental study was to evaluate whether the newly developed ventilator Chirana Aura V may effectively ventilate the lungs of animals with two different models of acute lung injury: acute respiratory distress syndrome (ARDS induced by repetitive saline lavage and meconium aspiration syndrome (MAS induced by intratracheal instillation of neonatal meconium. The experiments were performed on 10 adult rabbits (New Zealand white. In ARDS group (n=5, the lungs were repetitively lavaged with saline (30 ml/kg until partial pressure of oxygen (PaO2 in arterial blood was under 26.7 kPa at inspiratory fraction of oxygen FiO2=1.0. In MAS group (n=5, animals were instilled 4 ml/kg of suspension of human meconium (25 mg/ml. When the model of acute lung injury was developed, animals were ventilated for additional 2 hours with pressure control ventilation (PCV regime by ventilator Chirana Aura V. Ventilatory parameters, blood gases, acid-base balance, end-tidal CO2, O2 saturation of hemoglobin, oxygenation indexes, ventilation efficiency index, dynamic lung compliance, and right-to-left pulmonary shunts were measured and calculated in regular time intervals. In both experimental groups, used ventilatory settings provided acceptable gas exchange within the period of observation. Thus, the results indicate that ventilator Chirana Aura V might be suitable for ventilation of animal models of acute lung injury. However, further pre-clinical investigation is needed before its use may be recommended in neonatal and/or pediatric patients with acute lung injury.

  3. Double isotope albuminflux measurement: diagnosis and monitoring of acute lung injury; Doppelisotopen-Albuminfluxmessung: Diagnose und Therapiemonitoring des Acute Lung Injury

    Hoegerle, S. [Freiburg Univ. (Germany). Abt. Nuklearmedizin; Braeutigam, P. [Freiburg Univ. (Germany). Abt. Nuklearmedizin; Benzing, A. [Freiburg Univ. (Germany). Anaesthesiologische Klinik; Nitzsche, E. [Freiburg Univ. (Germany). Abt. Nuklearmedizin; Mols, G. [Freiburg Univ. (Germany). Anaesthesiologische Klinik; Geiger, K. [Freiburg Univ. (Germany). Anaesthesiologische Klinik; Moser, E. [Freiburg Univ. (Germany). Abt. Nuklearmedizin

    1997-06-01

    Purpose: Acute Lung Injury (ALI) is a clincial condition which is associated with a high lethality. It is characterized by an increased pulmonary capillary permeability and non-cardiogenic pulmonary edema. This study was designed to answer the question whether double isotope albuminflux measurement is a useful tool both for diagnosis of increased pulmonary capillary permeability and for monitoring therapeutic interventions (nitric oxide (NO) inhalation). Method: In 12 patients with clinical signs of ALI, transvascular albuminflux was measured by a double radioisotope technique before, during and after NO inhalation {sup 99m}Tc labeled albumin and {sup 51}Cr labeled autologous erythrocytes were used as tracer. The radioactivity of both radiopharmaceuticals was measured externally over the right lung by a radiation probe and simultaneously in arterial blood. For quantification of transvascular albuminflux Normalized Index (NI) and Normalized Slope Index (NSI) were calculated. Furthermore, pulmonal vascular pressures and other physiological parameters were recorded. Results: All 12 patients showed markedly increased NSI before inhalation of NO. NSI decreased from 0.0074{+-}0.0046 min{sup -1} without nitric oxide to -0.0051{+-}0.0041 min{sup -1} during nitric oxide and increased to 0.0046{+-}0.0111 min{sup -1} after nitric oxide. The decrease of the NSI correlated well with decrease of venous pulmonary resistance during inhalation of NO. Conclusion: Inhalation of NO reduces transvascular albuminflux in patients with ALI. Double isotope albuminflux measurement enables diagnosis of increased capillary permeability as well as monitoring therapeutic interventions. (orig.) [Deutsch] Ziel: Acute Lung Injury (ALI) ist ein Krankheitsbild mit hoher Letalitaet, das durch eine erhoehte pulmonale Kapillarpermeabilitaet mit einem nichtkardialen Lungenoedem gekennzeichnet ist. In der vorliegenden Studie sollte ueberprueft werden, ob die Doppelisotopen-Albuminfluxmessung sich neben

  4. Effects ofSalmonella infection on hepatic damage following acute liver injury in rats

    Yong-Tao Li; Cheng-Bo Yu; Dong Yan; Jian-Rong Huang; Lan-Juan Li

    2016-01-01

    BACKGROUND: Acute liver injury is a common clinical disor-der associated with intestinal barrier injury and disturbance of intestinal microbiota. Probiotic supplementation has been reported to reduce liver injury; however, it is unclear whether enteropathogen infection exacerbates liver injury. The pur-pose of this study was to address this unanswered question using a rat model. METHODS: Oral supplementation withSalmonella enterica serovar enteritidis (S. enteritidis) was given to rats for 7 days. Different degrees of acute liver injury were then induced by intraperitoneal injection of D-galactosamine. The presence and extent of liver injury was assayed by measuring the con-centrations of serum alanine aminotransferase, aspartate aminotransferase, and total bilirubin. Histology was used to observe liver tissue damage. Additionally, we measured the changes in plasma endotoxin, serum cytokines and bacterial translocation to clarify the mechanisms underlying intestinal microbiota associated liver injury. RESULTS: The levels of liver damage and endotoxin were sig-niifcantly increased in theSalmonella infected rats with severe liver injury compared with the no infection rats with severe liver injury (P CONCLUSIONS: OralS. enteritidis administration exacer-bates acute liver injury, especially when injury was severe. Major factors of the exacerbation include inlfammatory and oxidative stress injuries induced by the translocated bacteria and associated endotoxins, as well as over-activation of the immune system in the intestine and liver.

  5. Association between Peripheral Oxidative Stress and White Matter Damage in Acute Traumatic Brain Injury

    Wei-Ming Lin

    2014-01-01

    Full Text Available The oxidative stress is believed to be one of the mechanisms involved in the neuronal damage after acute traumatic brain injury (TBI. However, the disease severity correlation between oxidative stress biomarker level and deep brain microstructural changes in acute TBI remains unknown. In present study, twenty-four patients with acute TBI and 24 healthy volunteers underwent DTI. The peripheral blood oxidative biomarkers, like serum thiol and thiobarbituric acid-reactive substances (TBARS concentrations, were also obtained. The DTI metrics of the deep brain regions, as well as the fractional anisotropy (FA and apparent diffusion coefficient, were measured and correlated with disease severity, serum thiol, and TBARS levels. We found that patients with TBI displayed lower FAs in deep brain regions with abundant WMs and further correlated with increased serum TBARS level. Our study has shown a level of anatomic detail to the relationship between white matter (WM damage and increased systemic oxidative stress in TBI which suggests common inflammatory processes that covary in both the peripheral and central reactions after TBI.

  6. In vivo microscopy in a porcine model of acute lung injury.

    Bickenbach, Johannes; Czaplik, Michael; Dembinski, Rolf; Pelosi, Paolo; Schroeder, Wolfgang; Marx, Gernot; Rossaint, Rolf

    2010-07-31

    Regional inhomogeneity and alveolar mechanics in a porcine model of acute lung injury (ALI) was evaluated using confocal laser scanning microscopy (CLSM). CLSM was performed through thoracic windows of the upper and lower lobes. Image quantification was conducted by use of a volume air index (VAI). Twelve anesthetized, mechanically ventilated pigs were randomized to non-injury (control group, n = 6) or ALI induced by surfactant depletion (ALI group, n = 6). CLSM was performed at baseline, after 1 h at 5 mbar and after 2 h at 15 mbar positive end-expiratory pressure (PEEP). Haemodynamics, respiratory mechanics and calculation of pulmonary ventilation-perfusion distribution by MIGET were determined. At baseline, VAI was not different. In the upper lobes, VAI significantly decreased in ALI compared to control group, with no changes after PEEP application. In the lower lobes, VAI significantly decreased in ALI compared to control group. Incremental PEEP significantly increased VAI in ALI, but not in control group. Haemodynamics were significantly compromised in the ALI group. A significant deterioration in oxygenation and ventilation-perfusion distribution could be seen being restored after PEEP adjustment. The VAI may help to assess regional inhomogeneity of the acutely injured lung.

  7. Focused Sonographic Examination of the Heart, Lungs and Deep Veins in Acute Admitted Patients with Respiratory Symptoms

    Laursen, Christian Borbjerg; Sloth, Erik; Lassen, Annmarie Touborg;

    2012-01-01

    of the clinical examination. In addition, most of the diseases, which are commonly seen in patients with acute respiratory symptoms, can be diagnosed using sonography. Sonography could be integrated as a part of the primary evaluation, potentially improving the diagnostic performance. We therefore evaluated...... the use of sonographic examination of the heart, lungs and deep veins, performed within one hour of the primary evaluation, in acute admitted patients with respiratory symptoms. Methods: We performed a prospective cross sectional blinded observational study, conducted in a medical emergency department....... Patients were included if one or more of the following symptoms or clinical findings were present: respiratory rate > 20, saturation heart, lungs and deep veins...

  8. DNA damage response signaling in lung adenocarcinoma A549 cells following gamma and carbon beam irradiation

    Ghosh, Somnath [Radiation Biology and Health Sciences Division, Bhabha Atomic Research Centre, Trombay, Mumbai 400 085 (India); Narang, Himanshi, E-mail: himinarang@gmail.com [Radiation Biology and Health Sciences Division, Bhabha Atomic Research Centre, Trombay, Mumbai 400 085 (India); Sarma, Asitikantha [Radiation Biology Laboratory, Inter University Accelerator Centre, Aruna Asaf Ali Marg, New Delhi 110 067 (India); Krishna, Malini [Radiation Biology and Health Sciences Division, Bhabha Atomic Research Centre, Trombay, Mumbai 400 085 (India)

    2011-11-01

    Carbon beams (5.16 MeV/u, LET = 290 keV/{mu}m) are high linear energy transfer (LET) radiation characterized by higher relative biological effectiveness than low LET radiation. The aim of the current study was to determine the signaling differences between {gamma}-rays and carbon ion-irradiation. A549 cells were irradiated with 1 Gy carbon or {gamma}-rays. Carbon beam was found to be three times more cytotoxic than {gamma}-rays despite the fact that the numbers of {gamma}-H2AX foci were same. Percentage of cells showing ATM/ATR foci were more with {gamma}-rays however number of foci per cell were more in case of carbon irradiation. Large BRCA1 foci were found in all carbon irradiated cells unlike {gamma}-rays irradiated cells and prosurvival ERK pathway was activated after {gamma}-rays irradiation but not carbon. The noteworthy finding of this study is the early phase apoptosis induction by carbon ions. In the present study in A549 lung adenocarcinoma, authors conclude that despite activation of same repair molecules such as ATM and BRCA1, differences in low and high LET damage responses might be due to their distinct macromolecular complexes rather than their individual activation and the activation of cytoplasmic pathways such as ERK, whether it applies to all the cell lines need to be further explored.

  9. DNA damage response (DDR) pathway engagement in cisplatin radiosensitization of non-small cell lung cancer.

    Sears, Catherine R; Cooney, Sean A; Chin-Sinex, Helen; Mendonca, Marc S; Turchi, John J

    2016-04-01

    Non-small cell lung cancers (NSCLC) are commonly treated with a platinum-based chemotherapy such as cisplatin (CDDP) in combination with ionizing radiation (IR). Although clinical trials have demonstrated that the combination of CDDP and IR appear to be synergistic in terms of therapeutic efficacy, the mechanism of synergism remains largely uncharacterized. We investigated the role of the DNA damage response (DDR) in CDDP radiosensitization using two NSCLC cell lines. Using clonogenic survival assays, we determined that the cooperative cytotoxicity of CDDP and IR treatment is sequence dependent, requiring administration of CDDP prior to IR (CDDP-IR). We identified and interrogated the unique time and agent-dependent activation of the DDR in NSCLC cells treated with cisplatin-IR combination therapy. Compared to treatment with CDDP or IR alone, CDDP-IR combination treatment led to persistence of γH2Ax foci, a marker of DNA double-strand breaks (DSB), for up to 24h after treatment. Interestingly, pharmacologic inhibition of DDR sensor kinases revealed the persistence of γ-H2Ax foci in CDDP-IR treated cells is independent of kinase activation. Taken together, our data suggest that delayed repair of DSBs in NSCLC cells treated with CDDP-IR contributes to CDDP radiosensitization and that alterations of the DDR pathways by inhibition of specific DDR kinases can augment CDDP-IR cytotoxicity by a complementary mechanism.

  10. Effects of SDF-1/CXCR4 on Acute Lung Injury Induced by Cardiopulmonary Bypass.

    Shi, Hai; Lu, Rujian; Wang, Shuo; Chen, Honglin; Wang, Fei; Liu, Kun

    2017-03-11

    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.

  11. Acute Lung Injury and Fibrosis in a Baboon Model of Escherichia coli Sepsis

    Keshari, Ravi S.; Silasi-Mansat, Robert; Zhu, Hua; Popescu, Narcis I.; Peer, Glenn; Chaaban, Hala; Lambris, John D.; Polf, Holly; Lupu, Cristina; Kinasewitz, Gary

    2014-01-01

    Sepsis-induced inflammation of the lung leads to acute respiratory distress syndrome (ARDS), which may trigger persistent fibrosis. The pathology of ARDS is complex and poorly understood, and the therapeutic approaches are limited. We used a baboon model of Escherichia coli sepsis that mimics the complexity of human disease to study the pathophysiology of ARDS. We performed extensive biochemical, histological, and functional analyses to characterize the disease progression and the long-term effects of sepsis on the lung structure and function. Similar to humans, sepsis-induced ARDS in baboons displays an early inflammatory exudative phase, with extensive necrosis. This is followed by a regenerative phase dominated by proliferation of type 2 epithelial cells, expression of epithelial-to-mesenchymal transition markers, myofibroblast migration and proliferation, and collagen synthesis. Baboons that survived sepsis showed persistent inflammation and collagen deposition 6–27 months after the acute episodes. Long-term survivors had almost double the amount of collagen in the lung as compared with age-matched control animals. Immunostaining for procollagens showed persistent active collagen synthesis within the fibroblastic foci and interalveolar septa. Fibroblasts expressed markers of transforming growth factor-β and platelet-derived growth factor signaling, suggesting their potential role as mediators of myofibroblast migration and proliferation, and collagen deposition. In parallel, up-regulation of the inhibitors of extracellular proteases supports a deregulated matrix remodeling that may contribute to fibrosis. The primate model of sepsis-induced ARDS mimics the disease progression in humans, including chronic inflammation and long-lasting fibrosis. This model helps our understanding of the pathophysiology of fibrosis and the testing of new therapies. PMID:24066737

  12. MARESIN 1 PREVENTS LIPOPOLYSACCHARIDE-INDUCED NEUTROPHIL SURVIVAL AND ACCELERATES RESOLUTION OF ACUTE LUNG INJURY.

    Gong, Jie; Liu, Hong; Wu, Jing; Qi, Hong; Wu, Zhou-Yang; Shu, Hua-Qing; Li, Hong-Bin; Chen, Lin; Wang, Ya-Xin; Li, Bo; Tang, Min; Ji, Yu-Dong; Yuan, Shi-Ying; Yao, Shang-Long; Shang, You

    2015-10-01

    Acute lung injury (ALI) is characterized by lung inflammation and diffuse infiltration of neutrophils. Neutrophil apoptosis is recognized as an important control point in the resolution of inflammation. Maresin 1 (MaR1) is a new docosahexaenoic acid-derived proresolving agent that promotes the resolution of inflammation. However, its function in neutrophil apoptosis is unknown. In this study, isolated human neutrophils were incubated with MaR1, the pan-caspase inhibitor z-VAD-fmk, and lipopolysaccharide (LPS) to determine the mechanism of neutrophil apoptosis. Acute lung injury was induced by intratracheal instillation of LPS. In addition, mice were treated with MaR1 intravenously at the peak of inflammation and administered z-VAD-fmk intraperitoneally. We found that culture of isolated human neutrophils with LPS dramatically delayed neutrophil apoptosis through the phosphorylation of AKT, ERK, and p38 to upregulate the expression of the antiapoptotic proteins Mcl-1 and Bcl-2, which was blocked by pretreatment with MaR1 in vitro. In mice, MaR1 accelerated the resolution of inflammation in LPS-induced ALI through attenuation of neutrophil accumulation, pathohistological changes, and pulmonary edema. Maresin 1 promoted resolution of inflammation by accelerating caspase-dependent neutrophil apoptosis. Moreover, MaR1 also reduced the LPS-induced production of proinflammatory cytokines and upregulated the production of the anti-inflammatory cytokine interleukin-10. In contrast, treatment with z-VAD-fmk inhibited the proapoptotic action of MaR1 and attenuated the protective effects of MaR1 in LPS-induced ALI. Taken together, MaR1 promotes the resolution of LPS-induced ALI by overcoming LPS-mediated suppression of neutrophil apoptosis.

  13. 腹腔镜-胆道手术后-急性肺损伤%Laparoscopic-After billiard surgery-Acute lung injury

    谢健; 招伟贤; 王海燕

    2011-01-01

    A case of acute lung injury after laparoscopic biliary surgery was reported. The 56-year-old male patient underwent laparoscopic cholecystectomy and choledocholithotomy under general anesthesia. He showed severe hypoxemia after the operation, and was resuscitated after 3 days of non-invasive BiPAP respiratory support and anti-inflammatory treatment. According to the features of significant hypoxemia without notable respiratory distress manifestation, severe infiltration in the lung, and attenuated breath sounds without obvious wet or dry rales, the diagnosis of a low pressure interstitial pulmonary edema was suggested. The pathogenesis may be due to the pulmonary capillary endothelial damage and increased permeability, thus both of water and plasma protein leaked into the lung interstitial. It should be noticed that the amino acid oxidase in hemocoagnlase could also induce acute lung injury.%报道1例56岁男性患者,在全身麻醉下行腹腔镜胆囊切除及胆总管切开取石术,术毕发生急性肺损伤,出现严重低氧血症.后经面罩双水平正压通气(bilevel positive airway pressure,BiPAP)呼吸支持及抗炎治疗3 d康复.患者低氧血症明显但无明显呼吸窘迫、双肺弥漫性浸润明显而听诊除呼吸音较弱外无明显干湿啰音的特点,提示为低压性肺间质水肿,其原因可能由于肺毛细血管内皮受损、通透性增加,水和血浆蛋白漏出进入肺间质所致.应当关注蛇毒中氨基酸氧化酶诱发的急性肺损伤.

  14. Bone marrow-derived cells participate in stromal remodeling of the lung following acute bacterial pneumonia in mice.

    Serikov, Vladimir B; Mikhaylov, Viatcheslav M; Krasnodembskay, Anna D; Matthay, Michael A

    2008-01-01

    Bone marrow-derived cells (BMDC) have been shown to graft injured tissues, differentiate in specialized cells, and participate in repair. The importance of these processes in acute lung bacterial inflammation and development of fibrosis is unknown. The goal of this study was to investigate the temporal sequence and lineage commitment of BMDC in mouse lungs injured by bacterial pneumonia. We transplanted GFP-tagged BMDC into 5-Gy-irradiated C57BL/6 mice. After 3 months of recovery, mice were subjected to LD(50) intratracheal instillation of live E. coli (controls received saline) which produced pneumonia and subsequent areas of fibrosis. Lungs were investigated by immunohistology for up to 6 months. At the peak of lung inflammation, the predominant influx of BMDC were GFP(+) leukocytes. Postinflammatory foci of lung fibrosis were evident after 1-2 months. The fibrotic foci in lung stroma contained clusters of GFP(+) CD45(+) cells, GFP(+) vimentin-positive cells, and GFP(+) collagen I-positive fibroblasts. GFP(+) endothelial or epithelial cells were not identified. These data suggest that following 5-Gy irradiation and acute bacterial pneumonia, BMDC may temporarily participate in lung postinflammatory repair and stromal remodeling without long-term engraftment as specialized endothelial or epithelial cells.

  15. Protective effect of Eleteria cardamomum (L.) Maton against Pan masala induced damage in lung of male Swiss mice

    Sweety Kumari; Abhijit Dutta

    2013-01-01

    Objective: To study the potential ameliorating properties of cardamom Elettaria cardamomum (E. cardamomum) L. Maton against pan masala induced damage in lung of male Swiss mice. Methods: The experimental animals were divided into 3 groups (control, pan masala treated group and pan masala with cardamom treated group) to evaluate pan masala toxicity. The observations were substantiated with profound changes in the lung tissue as revealed in the histologic and transmission electron microscopic examinations. Results: Lung of pan masala treated group showed adenocarcinoma, edema, and inflammation with increased activity of acid phosphatase, alkaline phosphatase, and lactate dehydrogenase. The deleterious effects were seen to be less in cardamom treated group and the enzymatic activity also decreased significantly (P<0.05) in the ameliorating group. Conclusions: Thus, the present experiment exciting results are observed when cardamom is supplemented with pan masala, or when given alone.

  16. Comparison of exogenous surfactant therapy, mechanical ventilation with high end-expiratory pressure and partial liquid ventilation in a model of acute lung injury

    A. Hartog (Anneke); G.F. Vazquez de Anda; D.A.M.P.J. Gommers (Diederik); U. Kaisers; S.J.C. Verbrugge (Serge); R. Schnabel; B.F. Lachmann (Burkhard)

    1999-01-01

    textabstractWe have compared three treatment strategies, that aim to prevent repetitive alveolar collapse, for their effect on gas exchange, lung mechanics, lung injury, protein transfer into the alveoli and surfactant system, in a model of acute lung injury. In adult r

  17. Oxidative damage and histopathological changes in lung of rat chronically exposed to nicotine alone or associated to ethanol.

    Dhouib, H; Jallouli, M; Draief, M; Bouraoui, S; El-Fazâa, S

    2015-12-01

    Smoking is the most important preventable risk factor of chronic obstructive pulmonary disease and lung cancer. This study was designed to investigate oxidative damage and histopathological changes in lung tissue of rats chronically exposed to nicotine alone or supplemented with ethanol. Twenty-four male Wistar rats divided into three groups were used for the study. The nicotine group received nicotine (2.5mg/kg/day); the nicotine-ethanol group was given simultaneously same dose of nicotine plus ethanol (0.2g/kg/day), while the control group was administered only normal saline (1 ml/kg/day). The treatment was administered by subcutaneous injection once daily for a period of 18 weeks. Chronic nicotine administration alone or combined to ethanol caused a significant increase in malondialdehyde (MDA) level, superoxide dismutase (SOD) activity and catalase (CAT) activity in lung tissue compared to control rats suggesting an oxidative damage. However, these increases were mostly prominent in nicotine group. The histopathological examination of lung tissue of rats in both treated groups revealed many alterations in the pulmonary structures such as emphysema change (disappearance of the alveolar septa, increased irregularity and size of air sacs) and marked lymphocytic infiltration in perivascular and interstitial areas. However, the changes characterized in the nicotine group (pulmonary congestion, hemorrhage into alveoli and interstitial areas, edema) were more drastic than those observed in the nicotine-ethanol group, and they can be attributed to a significant degree of capillary endothelial permeability and microvascular leak. Conversely, the ethanol supplementation caused an appearance of fatty change and fibrosis in pulmonary tissue essentially due to a metabolism of ethanol. Finally, the lung damage illustrated in nicotine group was more severe than that observed in the nicotine-ethanol group. We conclude that the combined administration of nicotine and ethanol

  18. Targeting the Renin–Angiotensin System Combined With an Antioxidant Is Highly Effective in Mitigating Radiation-Induced Lung Damage

    Mahmood, Javed [Ontario Cancer Institute and the Campbell Family Institute for Cancer Research, Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario (Canada); Radiation Medicine Program, STTARR Innovation Centre, Princess Margaret Cancer Centre, Toronto, Ontario (Canada); Jelveh, Salomeh [Radiation Medicine Program, STTARR Innovation Centre, Princess Margaret Cancer Centre, Toronto, Ontario (Canada); Zaidi, Asif [Ontario Cancer Institute and the Campbell Family Institute for Cancer Research, Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario (Canada); Doctrow, Susan R. [Pulmonary Center, Department of Medicine, Boston University, Boston, Massachusetts (United States); Medhora, Meetha [Department of Radiation Oncology, Medical College of Wisconsin, Milwaukee, Wisconsin (United States); Hill, Richard P., E-mail: hill@uhnres.utoronto.ca [Ontario Cancer Institute and the Campbell Family Institute for Cancer Research, Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario (Canada); Departments of Medical Biophysics and Radiation Oncology, University of Toronto, Toronto, Ontario (Canada)

    2014-07-15

    Purpose: To investigate the outcome of suppression of the renin angiotensin system using captopril combined with an antioxidant (Eukarion [EUK]-207) for mitigation of radiation-induced lung damage in rats. Methods and Materials: The thoracic cavity of female Sprague-Dawley rats was irradiated with a single dose of 11 Gy. Treatment with captopril at a dose of 40 mg/kg/d in drinking water and EUK-207 given by subcutaneous injection (8 mg/kg daily) was started 1 week after irradiation (PI) and continuing until 14 weeks PI. Breathing rate was monitored until the rats were killed at 32 weeks PI, when lung fibrosis was assessed by lung hydroxyproline content. Lung levels of the cytokine transforming growth factor-β1 and macrophage activation were analyzed by immunohistochemistry. Oxidative DNA damage was assessed by 8-hydroxy-2-deoxyguanosine levels, and lipid peroxidation was measured by a T-BARS assay. Results: The increase in breathing rate in the irradiated rats was significantly reduced by the drug treatments. The drug treatment also significantly decreased the hydroxyproline content, 8-hydroxy-2-deoxyguanosine and malondialdehyde levels, and levels of activated macrophages and the cytokine transforming growth factor-β1 at 32 weeks. Almost complete mitigation of these radiation effects was observed by combining captopril and EUK-207. Conclusion: Captopril and EUK-207 can provide mitigation of radiation-induced lung damage out to at least 32 weeks PI after treatment given 1-14 weeks PI. Overall the combination of captopril and EUK-207 was more effective than the individual drugs used alone.

  19. Metabolic fingerprinting to understand therapeutic effects and mechanisms of silybin on acute liver damage in rat

    Qun Liang

    2015-01-01

    Full Text Available Background: Metabolic fingerprinting is a rapid and noninvasive analysis, representing a powerful approach for the characterization of phenotypes and the distinction of specific metabolic states due to environmental alterations. It has become a valuable analytical approach for the characterization of phenotypes and is the rapidly evolving field of the comprehensive measurement of ideally all endogenous metabolites in bio-samples. Silybin has displayed bright prospects in the prevention and therapy of liver injury, and we had conducted a preliminary exploration on the molecular mechanism of the hepatoprotective effects of silybin. Because the knowledge on the metabolic responses of an acute liver damage rat to the silybin is still scarce, metabolic fi ngerprinting can provide relevant information on the intrinsic metabolic adjustments. Materials and Methods: Here, the physiological and metabolic changes in the acute liver damage rat were investigated by performing a metabolic analysis. The phenotypic response was assessed by liquid chromatography/mass spectrometry (LC/MS combined with pattern recognition approaches such as principal components analysis and partial least squares projection to supervised latent structures and discriminant analysis. Multivariate analysis of the data showed trends in scores plots that were related to the concentration of the silybin. Results: Results indicate 10 ions (7 upregulated and 3 downregulated as differentiating metabolites. Key observations include perturbations of metabolic pathways linked to glutathione metabolism, tryptophan metabolism, cysteine and methionine metabolism, etc., Overall, this investigation illustrates the power of the LC/MS combined with the pattern recognition methods that can engender new insights into silybin affecting on metabolism pathways of an acute liver damage rat. Conclusion: The present study demonstrates that the combination of metabolic fi ngerprinting with appropriate

  20. Protective effect of low potassium dextran solution on acute kidney injury following acute lung injury induced by oleic acid in piglets

    WU Rui-ping; LIANG Xiu-bin; GUO Hui; ZHOU Xiao-shuang; ZHAO Li; WANG Chen; LI Rong-shan

    2012-01-01

    Background Low potassium dextran (LPD) solution can attenuate acute lung injury (ALI).However,LPD solution for treating acute kidney injury secondary to ALI has not been reported.The present study was performed to examine the renoprotective effect of LPD solution in ALI induced by oleic acid (OA) in piglets.Methods Twelve animals that suffered an ALI induced by administration of OA into the right atrium were divided into two groups:the placebo group (n=6) pretreated with normal saline and the LPD group (n=6),pretreated with LPD solution.LPD solution was injected intravenously at a dose of 12.5 ml/kg via the auricular vein 1 hour before OA injection.Results All animals survived the experiments with mild histopathological injury to the kidney.There were no significant differences in mean arterial pressure (MAP),creatinin and renal damage scores between the two groups.Compared with the placebo group,the LPD group had better gas exchange parameters at most of the observation points ((347.0±12.6)mmHg vs.(284.3±11.3) mmHg at 6 hours after ALI,P<0.01).After 6 hours of treatment with OA,the plasma concentrations of NGAL and interleukin (IL)-6 in both groups increased dramatically compared to baseline ((6.0±0.6) and (2.50±0.08) folds in placebo group; and (2.5±0.5) and (1.40±0.05) folds in LPD group),but the change of both parameters in the LPD group was significantly lower (P <0.01) than in the placebo group.And 6 hours after ALl the kidney tissue concentration of IL-6 in the LPD group ((165.7 ± 22.5) pg.ml-1.g-1 protein) was significantly lower (P <0.01) than that in placebo group ((67.2± 25.3) pg.ml-1.g-1 protein).Conclusion These findings suggest that pretreatment with LPD solution via systemic administration might attenuate acute kidney injury and the cytokine response of IL-6 in the ALl piglet model induced by OA injection.

  1. Mechanisms of attenuation of abdominal sepsis induced acute lung injury by ascorbic acid.

    Fisher, Bernard J; Kraskauskas, Donatas; Martin, Erika J; Farkas, Daniela; Wegelin, Jacob A; Brophy, Donald; Ward, Kevin R; Voelkel, Norbert F; Fowler, Alpha A; Natarajan, Ramesh

    2012-07-01

    Bacterial infections of the lungs and abdomen are among the most common causes of sepsis. Abdominal peritonitis often results in acute lung injury (ALI). Recent reports demonstrate a potential benefit of parenteral vitamin C [ascorbic acid (AscA)] in the pathogenesis of sepsis. Therefore we examined the mechanisms of vitamin C supplementation in the setting of abdominal peritonitis-mediated ALI. We hypothesized that vitamin C supplementation would protect lungs by restoring alveolar epithelial barrier integrity and preventing sepsis-associated coagulopathy. Male C57BL/6 mice were intraperitoneally injected with a fecal stem solution to induce abdominal peritonitis (FIP) 30 min prior to receiving either AscA (200 mg/kg) or dehydroascorbic acid (200 mg/kg). Variables examined included survival, extent of ALI, pulmonary inflammatory markers (myeloperoxidase, chemokines), bronchoalveolar epithelial permeability, alveolar fluid clearance, epithelial ion channel, and pump expression (aquaporin 5, cystic fibrosis transmembrane conductance regulator, epithelial sodium channel, and Na(+)-K(+)-ATPase), tight junction protein expression (claudins, occludins, zona occludens), cytoskeletal rearrangements (F-actin polymerization), and coagulation parameters (thromboelastography, pro- and anticoagulants, fibrinolysis mediators) of septic blood. FIP-mediated ALI was characterized by compromised lung epithelial permeability, reduced alveolar fluid clearance, pulmonary inflammation and neutrophil sequestration, coagulation abnormalities, and increased mortality. Parenteral vitamin C infusion protected mice from the deleterious consequences of sepsis by multiple mechanisms, including attenuation of the proinflammatory response, enhancement of epithelial barrier function, increasing alveolar fluid clearance, and prevention of sepsis-associated coagulation abnormalities. Parenteral vitamin C may potentially have a role in the management of sepsis and ALI associated with sepsis.

  2. Activation of MTOR in pulmonary epithelium promotes LPS-induced acute lung injury.

    Hu, Yue; Lou, Jian; Mao, Yuan-Yuan; Lai, Tian-Wen; Liu, Li-Yao; Zhu, Chen; Zhang, Chao; Liu, Juan; Li, Yu-Yan; Zhang, Fan; Li, Wen; Ying, Song-Min; Chen, Zhi-Hua; Shen, Hua-Hao

    2016-12-01

    MTOR (mechanistic target of rapamycin [serine/threonine kinase]) plays a crucial role in many major cellular processes including metabolism, proliferation and macroautophagy/autophagy induction, and is also implicated in a growing number of proliferative and metabolic diseases. Both MTOR and autophagy have been suggested to be involved in lung disorders, however, little is known about the role of MTOR and autophagy in pulmonary epithelium in the context of acute lung injury (ALI). In the present study, we observed that lipopolysaccharide (LPS) stimulation induced MTOR phosphorylation and decreased the expression of MAP1LC3B/LC3B (microtubule-associated protein 1 light chain 3 β)-II, a hallmark of autophagy, in mouse lung epithelium and in human bronchial epithelial (HBE) cells. The activation of MTOR in HBE cells was mediated by TLR4 (toll-like receptor 4) signaling. Genetic knockdown of MTOR or overexpression of autophagy-related proteins significantly attenuated, whereas inhibition of autophagy further augmented, LPS-induced expression of IL6 (interleukin 6) and IL8, through NFKB signaling in HBE cells. Mice with specific knockdown of Mtor in bronchial or alveolar epithelial cells exhibited significantly attenuated airway inflammation, barrier disruption, and lung edema, and displayed prolonged survival in response to LPS exposure. Taken together, our results demonstrate that activation of MTOR in the epithelium promotes LPS-induced ALI, likely through downregulation of autophagy and the subsequent activation of NFKB. Thus, inhibition of MTOR in pulmonary epithelial cells may represent a novel therapeutic strategy for preventing ALI induced by certain bacteria.

  3. Acute lung injury following inhalation exposure to nerve agent VX in guinea pigs.

    Wright, Benjamin S; Rezk, Peter E; Graham, Jacob R; Steele, Keith E; Gordon, Richard K; Sciuto, Alfred M; Nambiar, Madhusoodana P

    2006-05-01

    A microinstillation technique of inhalation exposure was utilized to assess lung injury following chemical warfare nerve agent VX [methylphosphonothioic acid S-(2-[bis(1-methylethyl)amino]ethyl) O-ethyl ester] exposure in guinea pigs. Animals were anesthetized using Telazol-meditomidine, gently intubated, and VX was aerosolized using a microcatheter placed 2 cm above the bifurcation of the trachea. Different doses (50.4 microg/m3, 70.4 micro g/m(m3), 90.4 microg/m(m3)) of VX were administered at 40 pulses/min for 5 min. Dosing of VX was calculated by the volume of aerosol produced per 200 pulses and diluting the agent accordingly. Although the survival rate of animals exposed to different doses of VX was similar to the controls, nearly a 20% weight reduction was observed in exposed animals. After 24 h of recovery, the animals were euthanized and bronchoalveolar lavage (BAL) was performed with oxygen free saline. BAL was centrifuged and separated into BAL fluid (BALF) and BAL cells (BALC) and analyzed for indication of lung injury. The edema by dry/wet weight ratio of the accessory lobe increased 11% in VX-treated animals. BAL cell number was increased in VX-treated animals compared to controls, independent of dosage. Trypan blue viability assay indicated an increase in BAL cell death in 70.4 microg/m(m3) and 90.4 microg/m(m3) VX-exposed animals. Differential cell counting of BALC indicated a decrease in macrophage/monocytes in VX-exposed animals. The total amount of BAL protein increased gradually with the exposed dose of VX and was highest in animals exposed to 90.4 microg/m(m3), indicating that this dose of VX caused lung injury that persisted at 24 h. In addition, histopathology results also suggest that inhalation exposure to VX induces acute lung injury.

  4. Acute and chronic administration of gold nanoparticles cause DNA damage in the cerebral cortex of adult rats.

    Cardoso, Eria; Rezin, Gislaine Tezza; Zanoni, Elton Torres; de Souza Notoya, Frederico; Leffa, Daniela Dimer; Damiani, Adriani Paganini; Daumann, Francine; Rodriguez, Juan Carlos Ortiz; Benavides, Roberto; da Silva, Luciano; Andrade, Vanessa M; da Silva Paula, Marcos Marques

    2014-01-01

    The use of gold nanoparticles is increasing in medicine; however, their toxic effects remain to be elucidated. Studies show that gold nanoparticles can cross the blood-brain barrier, as well as accumulate in the brain. Therefore, this study was undertaken to better understand the effects of gold nanoparticles on rat brains. DNA damage parameters were evaluated in the cerebral cortex of adult rats submitted to acute and chronic administration of gold nanoparticles of two different diameters: 10 and 30nm. During acute administration, adult rats received a single intraperitoneal injection of either gold nanoparticles or saline solution. During chronic administration, adult rats received a daily single injection for 28 days of the same gold nanoparticles or saline solution. Twenty-four hours after either single (acute) or last injection (chronic), the rats were euthanized by decapitation, their brains removed, and the cerebral cortices isolated for evaluation of DNA damage parameters. Our study showed that acute administration of gold nanoparticles in adult rats presented higher levels of damage frequency and damage index in their DNA compared to the control group. It was also observed that gold nanoparticles of 30nm presented higher levels of damage frequency and damage index in the DNA compared to the 10nm ones. When comparing the effects of chronic administration of gold nanoparticles of 10 and 30nm, we observed that occurred significant different index and frequency damage, comparing with control group. However, there is no difference between the 10 and 30nm groups in the levels of DNA damage for both parameters of the Comet assay. Results suggest that gold nanoparticles for both sizes cause DNA damage for chronic as well as acute treatments, although a higher damage was observed for the chronic one.

  5. Torsade de pointes indicates early neurologic damage in acute ischemic stroke.

    Huang, Li-Yen; Lin, Wei-Shiang; Lin, Wen-Yu; Cheng, Cheng-Chung; Cheng, Shu-Meng; Tsai, Tsung-Neng

    2013-12-01

    Torsade de pointes (TdP) is a life-threatening polymorphic ventricular tachycardia that is related to QT prolongation. Although QT prolongation is commonly seen in acute stroke, TdP is rare. We report the case of a 78-year-old woman with ischemic stroke who presented with TdP as the initial manifestation of early neurologic deterioration. We hypothesized that an increase in intracranial pressure may result in neurohormonal activation, QT prolongation, and then myocardial damage, leading to TdP. We highlight that new onset of TdP in a patient with stroke may reflect neurologic deterioration, requiring further evaluation and specific intervention.

  6. Extracorporeal gas exchange in acute lung injury: step by step towards expanded indications?

    Dembinski, Rolf; Kuhlen, Ralf

    2010-01-01

    Extracorporeal membrane oxygenation (ECMO) is widely accepted as a rescue therapy in patients with acute life-threatening hypoxemia in the course of severe acute respiratory distress syndrome (ARDS). However, possible side effects and complications are considered to limit beneficial outcome effects. Therefore, widening indications with the aim of reducing ventilator induced lung injury (VILI) is still controversial. Consequently, technological progress is an important strategy. Miniaturized ECMO systems are believed to simplify handling and reduce side effects and complications. Mueller and co-workers evaluated such a small-sized device in 60 patients with severe ARDS. They accomplished both the treatment of severe hypoxemia and reduction of VILI, demonstrating feasibility, a moderate rate of severe complications, and a 45% intensive care survival rate. Although neither randomized nor controlled, this study should encourage others to implement such systems in clinical practice. From a strategic perspective, this is another small but useful step towards implementing extracorporeal gas exchange for the prevention of VILI. It is already common sense that the prevention of acute life-threatening hypoxemia usually outweighs the risks of this technique. The next step should be to prove that prevention of life-threatening VILI balances the risks too.

  7. [Acute respiratory insufficiency due to severe lung injury - ARDS and ALI].

    Pfeifer, M

    2010-09-01

    As a consequence of the novel therapeutic option of mechanical ventilation in early intensive care medicine, the acute respiratory distress syndrome (ARDS) was defined as a disease entity of its own representing the most severe form of acute lung injury (ALI). Since its first description four decades ago, our knowledge about the aetiology, physiology, histology and epidemiology of this lethal pulmonary complication of severe acute diseases such as pneumonia or sepsis has been increasing steadily. The initial major therapeutic advances were due to improvements in intensive care medical procedures and monitoring. The large ARDS Network clinical trial on the magnitude of tidal volume impressively demonstrated the feasibility of targeted clinical trials in patients with ARDS that provide robust evidence in this field. This clinical trial, as well as following large-scale trials in ARDS patients, led to significant changes of ventilation therapy and therapeutic strategies that improve the outcome of this disease entity. Advances in the standardisation of care for ARDS patients involving innovative therapeutic procedures such as extracorporeal gas exchange systems will lead to a further improvement in ARDS management and outcome. Modern pulmonary medicine can play a pivotal role in this process and can contribute its rich experiences in all areas of the respiratory system.

  8. Expression of TLR4 and CD40 in activated macrophage surface after transfusion-related acute lung injury in rats

    Guang-Xiu Cai

    2016-01-01

    Objective:To study the expression of TLR4 and CD40 in activated macrophage surface after transfusion-related acute lung injury in rats. Methods:SD rats were selected as experimental animals, lipopolysaccharide and plasma were transfused in turn, animal models with transfusion-related acute lung injury (TRALI) were established, lung tissue was collected to detect wet to dry weight ratio as well as mRNA expression levels of TLR4, NF-κB, CD40, TNF-α, IL-1β, MIP-2 and GRP78, serum was collected to detect TNF-α, IL-1βand MIP-2 contents, and macrophages in peripheral blood were collected to detect mRNA expression levels of TLR4, NF-κB and CD40. Results:Lung tissue wet to dry weight ratio of TRALI group was significantly higher than that of Sham group;mRNA expression levels of TLR4, NF-κB and CD40 in macrophages of TRALI group were significantly higher than those of Sham group;mRNA expression levels of TLR4, NF-κB, CD40, TNF-α, IL-1β, MIP-2 and GRP78 in lung tissue of TRALI group were significantly higher than those of Sham group;serum TNF-α, IL-1βand MIP-2 contents of TRALI group were significantly higher than those of Sham group;SOD and GSH contents in lung tissue of TRALI group were lower than those of Sham group, and contents of MDA and 8-OhdG were higher than those of Sham group. Conclusion:Expression levels of TLR4 and CD40 in activated macrophage surface significantly increase after transfusion-related acute lung injury in rats, which will cause lung injury through inflammatory response, oxidative stress response, endoplasmic reticulum stress and others aspects.

  9. Direct acute tubular damage contributes to Shigatoxin-mediated kidney failure.

    Porubsky, Stefan; Federico, Giuseppina; Müthing, Johannes; Jennemann, Richard; Gretz, Norbert; Büttner, Stefan; Obermüller, Nicholas; Jung, Oliver; Hauser, Ingeborg A; Gröne, Elisabeth; Geiger, Helmut; Gröne, Hermann-Josef; Betz, Christoph

    2014-09-01

    The pathogenesis and therapy of Shigatoxin 2 (Stx2)-mediated kidney failure remain controversial. Our aim was to test whether, during an infection with Stx2-producing E. coli (STEC), Stx2 exerts direct effects on renal tubular epithelium and thereby possibly contributes to acute renal failure. Mice represent a suitable model because they, like humans, express the Stx2-receptor Gb3 in the tubular epithelium but, in contrast to humans, not in glomerular endothelia, and are thus free of glomerular thrombotic microangiopathy (TMA). In wild-type mice, Stx2 caused acute tubular dysfunction with consequent electrolyte disturbance, which was most likely the cause of death. Tubule-specific depletion of Gb3 protected the mice from acute renal failure. In vitro, Stx2 induced secretion of proinflammatory cytokines and apoptosis in human tubular epithelial cells, thus implicating a direct effect of Stx2 on the tubular epithelium. To correlate these results to human disease, kidney biopsies and outcome were analysed in patients with Stx2-associated kidney failure (n = 11, aged 22-44 years). The majority of kidney biopsies showed different stages of an ongoing TMA; however, no glomerular complement activation could be demonstrated. All biopsies, including those without TMA, showed severe acute tubular damage. Due to these findings, patients were treated with supportive therapy without complement-inhibiting antibodies (eculizumab) or immunoadsorption. Despite the severity of the initial disease [creatinine 6.34 (1.31-17.60) mg/dl, lactate dehydrogenase 1944 (753-2792) U/l, platelets 33 (19-124)/nl and haemoglobin 6.2 (5.2-7.8) g/dl; median (range)], all patients were discharged after 33 (range 19-43) days with no neurological symptoms and no dialysis requirement [creatinine 1.39 (range 0.84-2.86) mg/dl]. The creatinine decreased further to 0.90 (range 0.66-1.27) mg/dl after 24 months. Based on these data, one may surmise that acute tubular damage represents a separate

  10. Severe acute interstitial lung disease in a patient with anaplastic lymphoma kinase rearrangement-positive non-small cell lung cancer treated with alectinib.

    Yamamoto, Yuzo; Okamoto, Isamu; Otsubo, Kohei; Iwama, Eiji; Hamada, Naoki; Harada, Taishi; Takayama, Koichi; Nakanishi, Yoichi

    2015-10-01

    Alectinib, the second generation anaplastic lymphoma kinase (ALK) inhibitor, has significant potency in patients with ALK rearrangement positive non-small cell lung cancer (NSCLC), and its toxicity is generally well tolerable. We report a patient who developed severe acute interstitial lung disease after alectinib treatment. An 86-year-old woman with stage IV lung adenocarcinoma positive for rearrangement of ALK gene was treated with alectinib. On the 215th day after initiation of alectinib administration, she was admitted to our hospital with the symptom of progressive dyspnea. Computed tomography (CT) revealed diffuse ground glass opacities and consolidations in both lungs, and analysis of bronchoalveolar lavage fluid revealed pronounced lymphocytosis. There was no evidence of infection or other specific causes of her condition, and she was therefore diagnosed with interstitial lung disease induced by alectinib. Her CT findings and respiratory condition improved after steroid pulse therapy. As far as we are aware, this is the first reported case of alectinib-induced severe interstitial lung disease (ILD). We should be aware of the possibility of such a severe adverse event and should therefore carefully monitor patients treated with this drug.

  11. RGD-tagged helical rosette nanotubes aggravate acute lipopolysaccharide-induced lung inflammation

    Suri SS

    2011-12-01

    Full Text Available Sarabjeet Singh Suri1, Steven Mills1, Gurpreet Kaur Aulakh1, Felaniaina Rakotondradany2, Hicham Fenniri2, Baljit Singh11Department of Veterinary Biomedical Sciences, University of Saskatchewan, Saskatoon; 2National Institute for Nanotechnology and Department of Chemistry, Edmonton, CanadaAbstract: Rosette nanotubes (RNT are a novel class of self-assembled biocompatible nanotubes that offer a built-in strategy for engineering structure and function through covalent tagging of synthetic self-assembling modules (G∧C motif. In this report, the G∧C motif was tagged with peptide Arg-Gly-Asp-Ser-Lys (RGDSK-G∧C and amino acid Lys (K-G∧C which, upon co-assembly, generate RNTs featuring RGDSK and K on their surface in predefined molar ratios. These hybrid RNTs, referred to as Kx/RGDSKy-RNT, where x and y refer to the molar ratios of K-G∧C and RGDSK–G∧C, were designed to target neutrophil integrins. A mouse model was used to investigate the effects of intravenous Kx/RGDSKy-RNT on acute lipopolysaccharide (LPS-induced lung inflammation. Healthy male C57BL/6 mice were treated intranasally with Escherichia coli LPS 80 µg and/or intravenously with K90/RGDSK10-RNT. Here we provide the first evidence that intravenous administration of K90/RGDSK10-RNT aggravates the proinflammatory effect of LPS in the mouse. LPS and K90/RGDSK10-RNT treatment groups showed significantly increased infiltration of polymorphonuclear cells in bronchoalveolar lavage fluid at all time points compared with the saline control. The combined effect of LPS and K90/RGDSK10-RNT was more pronounced than LPS alone, as shown by a significant increase in the expression of interleukin-1ß, MCP-1, MIP-1, and KC-1 in the bronchoalveolar lavage fluid and myeloperoxidase activity in the lung tissues. We conclude that K90/RGDSK10-RNT promotes acute lung inflammation, and when used along with LPS, leads to exaggerated immune response in the lung.Keywords: RGD peptide, helical rosette

  12. Partial ventilatory support modalities in acute lung injury and acute respiratory distress syndrome-a systematic review.

    Sarah M McMullen

    Full Text Available PURPOSE: The efficacy of partial ventilatory support modes that allow spontaneous breathing in patients with acute lung injury (ALI and acute respiratory distress syndrome (ARDS is unclear. The objective of this scoping review was to assess the effects of partial ventilatory support on mortality, duration of mechanical ventilation, and both hospital and intensive care unit (ICU lengths of stay (LOS for patients with ALI and ARDS; the secondary objective was to describe physiologic effects on hemodynamics, respiratory system and other organ function. METHODS: MEDLINE (1966-2009, Cochrane, and EmBase (1980-2009 databases were searched using common ventilator modes as keywords and reference lists from retrieved manuscripts hand searched for additional studies. Two researchers independently reviewed and graded the studies using a modified Oxford Centre for Evidence-Based Medicine grading system. Studies in adult ALI/ARDS patients were included for primary objectives and pre-clinical studies for supporting evidence. RESULTS: Two randomized controlled trials (RCTs were identified, in addition to six prospective cohort studies, one retrospective cohort study, one case control study, 41 clinical physiologic studies and 28 pre-clinical studies. No study was powered to assess mortality, one RCT showed shorter ICU length of stay, and the other demonstrated more ventilator free days. Beneficial effects of preserved spontaneous breathing were mainly physiological effects demonstrated as improvement of gas exchange, hemodynamics and non-pulmonary organ perfusion and function. CONCLUSIONS: The use of partial ventilatory support modalities is often feasible in patients with ALI/ARDS, and may be associated with short-term physiological benefits without appreciable impact on clinically important outcomes.

  13. Intensive insulin treatment attenuates burn-initiated acute lung injury in rats: role of the protective endothelium.

    Zhang, Wan-Fu; Zhu, Xiong-Xiang; Hu, Da-Hai; Xu, Cheng-Feng; Wang, Yun-Chuan; Lv, Gen-Fa

    2011-01-01

    Nonmetabolic effects of intensive insulin therapy in critically ill patients have been reported, but the underlying mechanisms are unclear. This study was designed to test the hypothesis that intensive insulin treatment would attenuate burn-induced acute lung injury by protecting the pulmonary microvascular endothelium. The rat model of burn injury was achieved by exposure to 92°C water for 18 seconds. The rats were randomly allocated into the sham, burn/normal saline (NS), and burn/intensive insulin treatment groups. Blood glucose level was maintained between 5 and 7 mmol/L in rats in the burn/intensive insulin treatment group. Pulmonary injury was assessed by hematoxylin and eosin staining, scanning electron microscopy, bronchoalveolar lavage fluid protein concentrations, the lung wet:dry weight ratio, and lung myeloperoxidase activity. Pulmonary microvascular endothelial cells were examined by transmission electron microscopy. Western blotting was used to determine the protein expression of caspase-3. Intensive insulin treatment markedly attenuated the acute lung injury, revealed by improvements in histological features and significant decreases in bronchoalveolar lavage fluid protein concentrations, pulmonary wet:dry weight ratio, and myeloperoxidase activity at 12 hours after injury (P insulin treatment group when compared with the burn/NS group. Overall, intensive insulin treatment efficiently attenuated pulmonary microvascular endothelial cell dysfunction, decreased cell apoptosis, and inhibited acute lung injury after a burn. These findings may be useful in preventing organ failure after burn injury.

  14. IL-17 response mediates acute lung injury induced by the 2009 Pandemic Influenza A(H1N1)Virus

    Chenggang Li; Chen Wang; Zhongwei Chen; Li Xing; Chong Tang; Xiangwu Ju; Feng Guo; Jiejie Deng; Yan Zhao; Peng Yang; Jun Tang; Penghui Yang; Huanling Wang; Zhongpeng Zhao; Zhinan Yin; Bin Cao; Xiliang Wang; Chengyu Jiang; Yang Sun; Taisheng Li; Chen Wang; Zhong Wang; Zhen Zou; Yiwu Yan; Wei Wang

    2012-01-01

    The 2009 flu pandemic involved the emergence of a new strain of a swine-origin H1N1 influenza virus(S-OIV H1N1)that infected almost every country in the world.Most infections resulted in respiratory illness and some severe cases resulted in acute lung injury.In this report,we are the first to describe a mouse model of S-OIV virus infection with acute lung injury and immune responses that reflect human clinical disease.The clinical efficacy of the antiviral oseltamivir(Tamiflu)administered in the early stages of S-OIV H1N1 infection was confirmed in the mouse model.Moreover,elevated levels of IL-17,Th-17 mediators and IL-17-responsive cytokines were found in serum samples of S-OIV-infected patients in Beijing.IL-17 deficiency or treatment with monoclonal antibodies against IL-17-ameliorated acute lung injury induced by the S-OIV H1N1 virus in mice.These results suggest that IL-17 plays an important role in S-OIV-induced acute lung injury and that monoclonal antibodies against IL-17 could be useful as a potential therapeutic remedy for future S-OIV H1N1 pandemics.

  15. Anti-human tissue factor antibody ameliorated intestinal ischemia reperfusion-induced acute lung injury in human tissue factor knock-in mice.

    Xiaolin He

    Full Text Available BACKGROUND: Interaction between the coagulation and inflammation systems plays an important role in the development of acute respiratory distress syndrome (ARDS. Anti-coagulation is an attractive option for ARDS treatment, and this has promoted development of new antibodies. However, preclinical trials for these antibodies are often limited by the high cost and availability of non-human primates. In the present study, we developed a novel alternative method to test the role of a humanized anti-tissue factor mAb in acute lung injury with transgenic mice. METHODOLOGY/PRINCIPAL FINDINGS: Human tissue factor knock-in (hTF-KI transgenic mice and a novel humanized anti-human tissue factor mAb (anti-hTF mAb, CNTO859 were developed. The hTF-KI mice showed a normal and functional expression of hTF. The anti-hTF mAb specifically blocked the pro-coagulation activity of brain extracts from the hTF-KI mice and human, but not from wild type mice. An extrapulmonary ARDS model was used by intestinal ischemia-reperfusion. Significant lung tissue damage in hTF-KI mice was observed after 2 h reperfusion. Administration of CNTO859 (5 mg/kg, i.v. attenuated the severity of lung tissue injury, decreased the total cell counts and protein concentration in bronchoalveolar lavage fluid, and reduced Evans blue leakage. In addition, the treatment significantly reduced alveolar fibrin deposition, and decreased tissue factor and plasminogen activator inhibitor-1 activity in the serum. This treatment also down-regulated cytokine expression and reduced cell death in the lung. CONCLUSIONS: This novel anti-hTF antibody showed beneficial effects on intestinal ischemia-reperfusion induced acute lung injury, which merits further investigation for clinical usage. In addition, the use of knock-in transgenic mice to test the efficacy of antibodies against human-specific proteins is a novel strategy for preclinical studies.

  16. Changes in lung parenchyma after acute respiratory distress syndrome (ARDS): assessment with high-resolution computed tomography

    Noebauer-Huhmann, I.-M.; Eibenberger, K.; Schaefer-Prokop, C.; Herold, C.J. [Vienna Univ. (Austria). Inst. fuer Radiologie; Steltzer, H.; Strasser, K.; Fridrich, P. [Dept. of General Anesthesia and Intensive Care, Univ. of Vienna (Austria); Schlick, W. [Dept. of Cardio-Thoracic Surgery, Univ. of Vienna (Austria)

    2001-12-01

    The aim of this study was to evaluate the appearance, extent, and distribution of parenchymal changes in the lung after acute respiratory distress syndrome (ARDS) as a function of disease severity and therapeutic procedures. High-resolution computed tomography (HRCT), clinical examination, and lung function tests were performed in 15 patients, 6-10 months after ARDS. The appearance and extent of parenchymal changes were compared with the severity of ARDS, as well as with clinical and therapeutic data. Lung parenchymal changes resembling those found in the presence of pulmonary fibrosis were observed in 13 of 15 patients (87%). The changes were significantly more frequent and more pronounced in the ventral than in the dorsal portions of the lung (p<0.01). A significant correlation was observed between the extent of lung alterations and the severity of ARDS (p<0.01), and the duration in which patients had received mechanical ventilation either with a peak inspiratory pressure greater than 30 mmHg (p<0.05), or with more than 70% oxygen (p<0.01). Acute respiratory distress syndrome frequently is followed by fibrotic changes in lung parenchyma. The predominantly ventral distribution of these changes indicates that they may be caused by the ventilation regimen and the oxygen therapy rather than by the ARDS. (orig.)

  17. Identification of oxidative stress and Toll-like receptor 4 signaling as a key pathway of acute lung injury.

    Imai, Yumiko; Kuba, Keiji; Neely, G Greg; Yaghubian-Malhami, Rubina; Perkmann, Thomas; van Loo, Geert; Ermolaeva, Maria; Veldhuizen, Ruud; Leung, Y H Connie; Wang, Hongliang; Liu, Haolin; Sun, Yang; Pasparakis, Manolis; Kopf, Manfred; Mech, Christin; Bavari, Sina; Peiris, J S Malik; Slutsky, Arthur S; Akira, Shizuo; Hultqvist, Malin; Holmdahl, Rikard; Nicholls, John; Jiang, Chengyu; Binder, Christoph J; Penninger, Josef M

    2008-04-18

    Multiple lung pathogens such as chemical agents, H5N1 avian flu, or SARS cause high lethality due to acute respiratory distress syndrome. Here we report that Toll-like receptor 4 (TLR4) mutant mice display natural resistance to acid-induced acute lung injury (ALI). We show that TLR4-TRIF-TRAF6 signaling is a key disease pathway that controls the severity of ALI. The oxidized phospholipid (OxPL) OxPAPC was identified to induce lung injury and cytokine production by lung macrophages via TLR4-TRIF. We observed OxPL production in the lungs of humans and animals infected with SARS, Anthrax, or H5N1. Pulmonary challenge with an inactivated H5N1 avian influenza virus rapidly induces ALI and OxPL formation in mice. Loss of TLR4 or TRIF expression protects mice from H5N1-induced ALI. Moreover, deletion of ncf1, which controls ROS production, improves the severity of H5N1-mediated ALI. Our data identify oxidative stress and innate immunity as key lung injury pathways that control the severity of ALI.

  18. Indoxyl Sulfate as a Mediator Involved in Dysregulation of Pulmonary Aquaporin-5 in Acute Lung Injury Caused by Acute Kidney Injury

    Nozomi Yabuuchi

    2016-12-01

    Full Text Available High mortality of acute kidney injury (AKI is associated with acute lung injury (ALI, which is a typical complication of AKI. Although it is suggested that dysregulation of lung salt and water channels following AKI plays a pivotal role in ALI, the mechanism of its dysregulation has not been elucidated. Here, we examined the involvement of a typical oxidative stress-inducing uremic toxin, indoxyl sulfate (IS, in the dysregulation of the pulmonary predominant water channel, aquaporin 5 (AQP-5, in bilateral nephrectomy (BNx-induced AKI model rats. BNx evoked AKI with the increases in serum creatinine (SCr, blood urea nitrogen (BUN and serum IS levels and exhibited thickening of interstitial tissue in the lung. Administration of AST-120, clinically-used oral spherical adsorptive carbon beads, resulted in a significant decrease in serum IS level and thickening of interstitial tissue, which was accompanied with the decreases in IS accumulation in various tissues, especially lung. Interestingly, a significant decrease in AQP-5 expression of lung was observed in BNx rats. Moreover, the BNx-induced decrease in pulmonary AQP-5 protein expression was markedly restored by oral administration of AST-120. These results suggest that BNx-induced AKI causes dysregulation of pulmonary AQP-5 expression, in which IS could play a toxico-physiological role as a mediator involved in renopulmonary crosstalk.

  19. Attenuation of hypoxic pulmonary vasoconstriction in acute oleic acid lung injury--significance of vasodilator prostanoids.

    Yamaguchi, K; Mori, M; Kawai, A; Asano, K; Takasugi, T; Umeda, A; Yokoyama, T

    1992-01-01

    To assess a significant role of hypoxic pulmonary vasoconstriction, HPV, on maintaining the gas exchange efficiency in acute lung injury, 24 mongrel dogs were treated with intravenously injecting 0.07 ml/kg of oleic acid. Hemodynamic and gas-exchange parameters were investigated at varied inspired O2 concentration, FIO2. To know a possible contribution of vasoactive prostanoids in regulating vascular reactivity under these circumstances, observations were repeated after infusion of indomethacin. The impairment of gas exchange in injured lungs was examined by measuring the fractional retention, R, of the gas in arterial blood. For this evaluation, a normal saline containing five foreign inert gases such as sulfur hexafluoride, SF6, ethane, cyclopropane, halothane and diethyl ether was infused at a constant rate through a peripheral vein. After a steady state was established, the expired gas was collected and the samples of both arterial and mixed venous blood were simultaneously taken for the inert-gas analysis. The concentrations of the indicator gases in the samples were measured in terms of a gas chromatograph equipped with an electron capture detector for SF6 and a flame ionization detector for the other four gases. Although pulmonary vascular resistance, PVR, after injecting oleic acid at FIO2 0.60 was significantly smaller than that obtained at FIO2 0.21, cardiac output, QT as well as extravascular lung water were not different between the two conditions. R value for the indicator gas was consistently lower at FIO2 0.60 irrespective of the gas species. As increasing FIO2, R estimate concerning SF6, RSF6, rational index of the fractional blood flow perfusing shunt area, decreased significantly. Administration of indomethacin caused the rise in PVR without an appreciable change in either QT or extravascular lung water but a considerable diminution in R value for the inert gas. RSF6 after infusion of indomethacin decreased from 0.35 to 0.27, accompanied by a

  20. Sulfur dioxide attenuates LPS-induced acute lung injury via enhancing polymorphonuclear neutrophil apoptosis

    Hui-jie MA; Xin-li HUANG; Yan LIU; Ya-min FAN

    2012-01-01

    Aim:We speculated that the enhanced apoptosis of polymorphonuclear neutrophil (PMN) might be responsible for the inhibition of PMN infiltration in the lung.This study was designed to investigate the effects of sulfur dioxide (SO2) on PMN apoptosis in vivo and in vitro,which may mediate the protective action of SO2 on pulmonary diseases.Methods:Acute lung injury (ALI) was induced by intratracheally instillation of lipopolysaccharide (LPS,100 μg/100 g.in 200 μL saline) in adult male SD rats.SO2 solution (25 μmol/kg) was administered intraperitoneally 30 min before LPS treatment.The rats were killed 6 h after LPS treatment.Lung tissues were collected for histopathologic study and SO2 concentration assay.Bronchoalveolar lavage fluid (BALF) was collected for the measurement of PMN apoptosis.For in vitro experiments,rat peripheral blood PMNs were cultured and treated with LPS (30 mg/L) and S02 (10,20 and 30 μmol/L) for 6 h,and apoptosis-related protein expression was detected by Western blotting,and apoptosis rate was measured with flow cytometry.Results:LPS treatment significantly reduced the SO2 concentrations in the lung tissue and peripheral blood,as compared with the control group.Pretreatment with SO2 prevented LPS-induced reduction of the SO2 concentration in the lung tissue and peripheral blood.LPS treatment significantly reduced PMN apoptosis both in vivo and in vitro,which could be prevented by the pretreatment with SO2.The protein levels of caspase-3 and Bax was significantly increased,but Bcl-2 was decreased by the pretreatment with SO2,as compared with LPS administration alone.Conclusion:SO2 plays an important role as the modulator of PMN apoptosis during LPS-induced ALl,which might be one of the mechanisms underlying the protective action of SO2 on pulmonary diseases.

  1. Radioisotope albumin flux measurement of microvascular lung permeability: an independent parameter in acute respiratory failure?

    Hoegerle, S.; Nitzsche, E.U.; Reinhardt, M.J.; Moser, E. [Freiburg Univ. (Germany). Div. of Nuclear Medicine; Benzing, A.; Geiger, K. [Freiburg Univ. (Germany). Dept. of Anesthesiology; Schulte Moenting, J. [Freiburg Univ. (Germany). Dept. of Medical Biometry and Statistics

    2001-04-01

    Aim: To evaluate the extent to which single measurements of microvascular lung permeability may be relevant as an additional parameter in a heterogenous clinical patient collective with Acute Lung Injury (ALI) and Acute Respiratory Distress Syndrome (ARDS). Methods: In 36 patients with pneumonia (13), non pneumogenic sepsis (9) or trauma (14) meeting the consensus conference criteria of ALI or ARDS double-isotope protein flux measurements ({sup 51}Cr erythrocytes as intravascular tracer, Tc-99m human albumin as diffusible tracer) of microvascular lung permeability were performed using the Normalized Slope Index (NSI). The examination was to determine whether there is a relationship between the clinical diagnosis of ALI/ARDS, impaired permeability and clinical parameters, that is the underlying disease, oxygenation, duration of mechanical ventilation and mean pulmonary-artery pressure (PAP). Results: At the time of study, 25 patients presented with increased permeability (NSI > 1 x 10{sup -3} min{sup -1}) indicating an exudative stage of disease, and 11 patients with normal permeability. The permeability impairment correlated with the underlying disease (p > 0.05). With respect to survival, there was a negative correlation to PAP (p < 0.01). Apart from that no correlations between the individual parameters were found. Especially no correlation was found between permeability impairment and oxygenation, duration of disease of PAP. Conclusion: In ALI and ARDS, pulmonary capillary permeability is a diagnostic parameter which is independent from clinical variables. Permeability measurement makes a stage classification (exudative versus non exudative phase) of ALI/ARDS possible based on a measurable pathophysiological correlate. (orig.) [German] Ziel: Es sollte evaluiert werden, inwieweit Einzelmessungen der mikrovaskulaeren Lungenpermeabilitaet als zusaetzlicher Parameter bei einem heterogenen klinischen Patientenkollektiv mit Acute Lung Injury (ALI) und akuten

  2. DNA damage focus analysis in blood samples of minipigs reveals acute partial body irradiation.

    Andreas Lamkowski

    Full Text Available Radiation accidents frequently involve acute high dose partial body irradiation leading to victims with radiation sickness and cutaneous radiation syndrome that implements radiation-induced cell death. Cells that are not lethally hit seek to repair ionizing radiation (IR induced damage, albeit at the expense of an increased risk of mutation and tumor formation due to misrepair of IR-induced DNA double strand breaks (DSBs. The response to DNA damage includes phosphorylation of histone H2AX in the vicinity of DSBs, creating foci in the nucleus whose enumeration can serve as a radiation biodosimeter. Here, we investigated γH2AX and DNA repair foci in peripheral blood lymphocytes of Göttingen minipigs that experienced acute partial body irradiation (PBI with 49 Gy (± 6% Co-60 γ-rays of the upper lumbar region. Blood samples taken 4, 24 and 168 hours post PBI were subjected to γ-H2AX, 53BP1 and MRE11 focus enumeration. Peripheral blood lymphocytes (PBL of 49 Gy partial body irradiated minipigs were found to display 1-8 DNA damage foci/cell. These PBL values significantly deceed the high foci numbers observed in keratinocyte nuclei of the directly γ-irradiated minipig skin regions, indicating a limited resident time of PBL in the exposed tissue volume. Nonetheless, PBL samples obtained 4 h post IR in average contained 2.2% of cells displaying a pan-γH2AX signal, suggesting that these received a higher IR dose. Moreover, dispersion analysis indicated partial body irradiation for all 13 minipigs at 4 h post IR. While dose reconstruction using γH2AX DNA repair foci in lymphocytes after in vivo PBI represents a challenge, the DNA damage focus assay may serve as a rapid, first line indicator of radiation exposure. The occurrence of PBLs with pan-γH2AX staining and of cells with relatively high foci numbers that skew a Poisson distribution may be taken as indicator of acute high dose partial body irradiation, particularly when samples are available

  3. Proteomic Analysis of Lung Tissue in a Rat Acute Lung Injury Model: Identification of PRDX1 as a Promoter of Inflammation

    Dongdong Liu

    2014-01-01

    Full Text Available Acute respiratory distress syndrome (ARDS remains a high morbidity and mortality disease entity in critically ill patients, despite decades of numerous investigations into its pathogenesis. To obtain global protein expression changes in acute lung injury (ALI lung tissues, we employed a high-throughput proteomics method to identify key components which may be involved in the pathogenesis of ALI. In the present study, we analyzed lung tissue proteomes of Pseudomonas aeruginosa-induced ALI rats and identified eighteen proteins whose expression levels changed more than twofold as compared to normal controls. In particular, we found that PRDX1 expression in culture medium was elevated by a lipopolysaccharide (LPS challenge in airway epithelial cells in vitro. Furthermore, overexpression of PRDX1 increased the expression of proinflammatory cytokines interleukin-6 (IL-6, interleukin-8 (IL-8, and tumor necrosis factor-α (TNF-α, whereas knockdown of PRDX1 led to downregulated expression of cytokines induced by LPS. In conclusion, our findings provide a global alteration in the proteome of lung tissues in the ALI rat model and indicate that PRDX1 may play a critical role in the pathogenesis of ARDS by promoting inflammation and represent a novel strategy for the development of new therapies against ALI.

  4. Adalimumab-induced acute interstitial lung disease in a patient with rheumatoid arthritis

    Olivia Meira Dias

    2014-01-01

    Full Text Available The use of immunobiological agents for the treatment of autoimmune diseases is increasing in medical practice. Anti-TNF therapies have been increasingly used in refractory autoimmune diseases, especially rheumatoid arthritis, with promising results. However, the use of such therapies has been associated with an increased risk of developing other autoimmune diseases. In addition, the use of anti-TNF agents can cause pulmonary complications, such as reactivation of mycobacterial and fungal infections, as well as sarcoidosis and other interstitial lung diseases (ILDs. There is evidence of an association between ILD and the use of anti-TNF agents, etanercept and infliximab in particular. Adalimumab is the newest drug in this class, and some authors have suggested that its use might induce or exacerbate preexisting ILDs. In this study, we report the first case of acute ILD secondary to the use of adalimumab in Brazil, in a patient with rheumatoid arthritis and without a history of ILD.

  5. Effects of inhaled CO administration on acute lung injury in baboons with pneumococcal pneumonia

    Kraft, Bryan D.; Hess, Dean R.; Harris, R. Scott; Wolf, Monroe A.; Suliman, Hagir B.; Roggli, Victor L.; Davies, John D.; Winkler, Tilo; Stenzler, Alex; Baron, Rebecca M.; Thompson, B. Taylor; Choi, Augustine M.; Welty-Wolf, Karen E.; Piantadosi, Claude A.

    2015-01-01

    Inhaled carbon monoxide (CO) gas has therapeutic potential for patients with acute respiratory distress syndrome if a safe, evidence-based dosing strategy and a ventilator-compatible CO delivery system can be developed. In this study, we used a clinically relevant baboon model of Streptococcus pneumoniae pneumonia to 1) test a novel, ventilator-compatible CO delivery system; 2) establish a safe and effective CO dosing regimen; and 3) investigate the local and systemic effects of CO therapy on inflammation and acute lung injury (ALI). Animals were inoculated with S. pneumoniae (108-109 CFU) (n = 14) or saline vehicle (n = 5); in a subset with pneumonia (n = 5), we administered low-dose, inhaled CO gas (100–300 ppm × 60–90 min) at 0, 6, 24, and/or 48 h postinoculation and serially measured blood carboxyhemoglobin (COHb) levels. We found that CO inhalation at 200 ppm for 60 min is well tolerated and achieves a COHb of 6–8% with ambient CO levels ≤ 1 ppm. The COHb level measured at 20 min predicted the 60-min COHb level by the Coburn-Forster-Kane equation with high accuracy. Animals given inhaled CO + antibiotics displayed significantly less ALI at 8 days postinoculation compared with antibiotics alone. Inhaled CO was associated with activation of mitochondrial biogenesis in the lung and with augmentation of renal antioxidative programs. These data support the feasibility of safely delivering inhaled CO gas during mechanical ventilation and provide preliminary evidence that CO may accelerate the resolution of ALI in a clinically relevant nonhuman primate pneumonia model. PMID:26320156

  6. Acute ozone-induced differential gene expression profiles in rat lung.

    Nadadur, Srikanth S; Costa, Daniel L; Slade, Ralph; Silbjoris, Robert; Hatch, Gary E

    2005-12-01

    Ozone is an oxidant gas that can directly induce lung injury. Knowledge of the initial molecular events of the acute O3 response would be useful in developing biomarkers of exposure or response. Toward this goal, we exposed rats to toxic concentrations of O3 (2 and 5 ppm) for 2 hr and the molecular changes were assessed in lung tissue 2 hr postexposure using a rat cDNA expression array containing 588 characterized genes. Gene array analysis indicated differential expression in almost equal numbers of genes for the two exposure groups: 62 at 2 ppm and 57 at 5 ppm. Most of these genes were common to both exposure groups, suggesting common roles in the initial toxicity response. However, we also identified the induction of nine genes specific to 2-ppm (thyroid hormone-beta receptor c-erb-A-beta; and glutathione reductase) or 5-ppm exposure groups (c-jun, induced nitric oxide synthase, macrophage inflammatory protein-2, and heat shock protein 27). Injury markers in bronchoalveolar lavage fluid (BALF) were used to assess immediate toxicity and inflammation in rats similarly exposed. At 2 ppm, injury was marked by significant increases in BALF total protein, N-acetylglucosaminidase, and lavageable ciliated cells. Because infiltration of neutrophils was observed only at the higher 5 ppm concentration, the distinctive genes suggested a potential amplification role for inflammation in the gene profile. Although the specific gene interactions remain unclear, this is the first report indicating a dose-dependent direct and immediate induction of gene expression that may be separate from those genes involved in inflammation after acute O3 exposure.

  7. Changes in liquid clearance of alveolar epithelium after oleic acid-induced acute lung injury in rats

    陶军; 杨天德; 陈祥瑞; 黄河

    2004-01-01

    Objective:Impaired active fluid transport of alveolar epithelium may involve in the pathogenesis and resolution of alveolar edema. Thc objective of this study was to explore the changes in alveolar epithelial liquid clearance during lung edema following acute lung injury induced by oleic acid. Methods:Forty-eight Wistar rats were randomly divided into six groups, I.e. , injured, amiloride, ouabain, amiloride plus ouabain and terbutaline groups. Twenty- four hours after the induction of acute lung injury by intravenous oleic acid (0.25 ml/kg), 5% albumin solution with 1.5 μCi 125Ⅰ-labeled albumin (5 ml/kg) was delivered into both lungs via trachea. Alveolar liquid clearance (ALC), extravascular lung water ( EVLW ) content and arterial blood gases were measured one hour thereafter.Results: At 24 h after the infusion of oleic acid, the rats developed pulmonary edema and severe hypoxemia, with EVLW increased by 47.9% and ALC decreased by 49.2%. Addition of either 2 × 10-3 M amiloride or 5 × 10-4 M ouabain to the instillation further reduced ALC and increased EVLW. ALC increased by approximately 63.7% and EVLW decreased by 46.9% with improved hypoxemia in the Terbutaline (10-4 M) group, compared those in injured rats. A significant negative correlation was found between the increment of EVLW and the reduction of ALC. Onclusions:Active fluid transport of alveolar epithelium might play a role in the pathogenesis of lung edema in acute lung injury.

  8. Rabdosia japonica var. glaucocalyx Flavonoids Fraction Attenuates Lipopolysaccharide-Induced Acute Lung Injury in Mice

    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. Acute morphine treatment alters cellular immune function in the lungs of healthy rats.

    Coussons-Read, M E; Giese, S

    2001-08-01

    Previous work has shown that morphine suppresses the pulmonary immune response to infection and reduces pulmonary inflammation. No published studies have addressed the impact of morphine on lymphocyte function in the lungs without infection. This study addressed this question by assessing the impact of acute morphine treatment on proliferation, cytokine production, and natural killer (NK) cell activity in resident pulmonary lymphocytes from healthy rats. Male Lewis rats received either a single 15 mg/kg morphine sulfate or vehicle injection 1 h prior to sacrifice. Lungs were minced and passed through wire mesh following collagenase digestion. The resulting cell preparations were pooled (2 rats/pool) to yield sufficient cell numbers for the functional assays, and a portion of these suspensions were separated using a density gradient. Crude and purified cell suspensions were used in assays of NK cell activity and mitogen-induced proliferation and cytokine production. Morphine significantly suppressed lymphocyte proliferation and cytokine production in whole cell suspensions, but not in purified cultures. NK activity was enhanced by morphine treatment in purified treated cultures. Studies of nitrate/nitrite levels in crude and purified cultures suggest that macrophage-derived nitric oxide may be a mechanism of the suppression observed in whole cell suspensions following morphine treatment. These data are consistent with previous work showing that morphine suppresses mitogenic responsiveness and NK activity in the spleen and peripheral blood, and may do so through a macrophage-derived nitric oxide mechanism.

  10. Galantamine protects against lipopolysaccharide-induced acute lung injury in rats

    G. Li

    2016-01-01

    Full Text Available Lipopolysaccharide (LPS-induced endotoxemia triggers the secretion of proinflammatory cytokines and can cause acute lung injury (ALI. The high mobility group box 1 (HMGB1 protein plays an important role as a late mediator of sepsis and ALI. Galantamine (GAL is a central acetylcholinesterase inhibitor that inhibits the expression of HMGB1. This study evaluated the effects of GAL by measuring levels of inflammatory mediators and observing histopathological features associated with LPS-induced ALI. Sixty 8-10 week old male Sprague-Dawley rats (200-240 g were randomized into three groups as follows: control group, LPS group (7.5 mg/kg LPS, and LPS+GAL group (5 mg/kg GAL before LPS administration. Histopathological examination of lung specimens obtained 12 h after LPS administration was performed to analyze changes in wet-to-dry (W/D weight ratio, myeloperoxidase (MPO activity, and HMGB1 expression level. Additionally, plasma concentrations of tumor necrosis factor-α, interleukin-6, and HMGB1 were measured using an enzyme-linked immunosorbent assay at 0 (baseline, 3, 6, 9, and 12 h after LPS administration. Mortality in the three groups was recorded at 72 h. LPS-induced ALI was characterized by distortion of pulmonary architecture and elevation of MPO activity, W/D weight ratio, and levels of pro-inflammatory cytokines, including tumor necrosis factor-α, interleukin-6, and HMGB1. Pretreatment with GAL significantly reduced the LPS-induced lung pathological changes, W/D weight ratio, levels of pro-inflammatory cytokines and MPO activity (ANOVA. Moreover, GAL treatment significantly decreased the mortality rate (ANOVA. In conclusion, we demonstrated that GAL exerted a protective effect on LPS-induced ALI in rats.

  11. Sex-specific differences in hyperoxic lung injury in mice: Implications for acute and chronic lung disease in humans

    Lingappan, Krithika, E-mail: lingappa@bcm.edu [Department of Pediatrics, Section of Neonatology, Texas Children' s Hospital, Baylor College of Medicine, 1102 Bates Avenue, MC: FC530.01, Houston, TX 77030 (United States); Jiang, Weiwu; Wang, Lihua; Couroucli, Xanthi I. [Department of Pediatrics, Section of Neonatology, Texas Children' s Hospital, Baylor College of Medicine, 1102 Bates Avenue, MC: FC530.01, Houston, TX 77030 (United States); Barrios, Roberto [Department of Pathology and Genomic Medicine, The Methodist Hospital Physician Organization, 6565 Fannin Street, Suite M227, Houston, TX 77030 (United States); Moorthy, Bhagavatula [Department of Pediatrics, Section of Neonatology, Texas Children' s Hospital, Baylor College of Medicine, 1102 Bates Avenue, MC: FC530.01, Houston, TX 77030 (United States)

    2013-10-15

    Sex-specific differences in pulmonary morbidity in humans are well documented. Hyperoxia contributes to lung injury in experimental animals and humans. The mechanisms responsible for sex differences in the susceptibility towards hyperoxic lung injury remain largely unknown. In this investigation, we tested the hypothesis that mice will display sex-specific differences in hyperoxic lung injury. Eight week-old male and female mice (C57BL/6J) were exposed to 72 h of hyperoxia (FiO{sub 2} > 0.95). After exposure to hyperoxia, lung injury, levels of 8-iso-prostaglandin F{sub 2} alpha (8-iso-PGF 2α) (LC–MS/MS), apoptosis (TUNEL) and inflammatory markers (suspension bead array) were determined. Cytochrome P450 (CYP)1A expression in the lung was assessed using immunohistochemistry and western blotting. After exposure to hyperoxia, males showed greater lung injury, neutrophil infiltration and apoptosis, compared to air-breathing controls than females. Pulmonary 8-iso-PGF 2α levels were higher in males than females after hyperoxia exposure. Sexually dimorphic increases in levels of IL-6 (F > M) and VEGF (M > F) in the lungs were also observed. CYP1A1 expression in the lung was higher in female mice compared to males under hyperoxic conditions. Overall, our results support the hypothesis that male mice are more susceptible than females to hyperoxic lung injury and that differences in inflammatory and oxidative stress markers contribute to these sex-specific dimorphic effects. In conclusion, this paper describes the establishment of an animal model that shows sex differences in hyperoxic lung injury in a temporal manner and thus has important implications for lung diseases mediated by hyperoxia in humans. - Highlights: • Male mice were more susceptible to hyperoxic lung injury than females. • Sex differences in inflammatory markers were observed. • CYP1A expression was higher in females after hyperoxia exposure.

  12. Extracorporeal Membrane Oxygenation (ECMO) for Lung Injury in Severe Acute Respiratory Distress Syndrome (ARDS): Review of the Literature.

    Paolone, Summer

    2016-11-10

    Despite advances in mechanical ventilation, severe acute respiratory distress syndrome (ARDS) is associated with high morbidity and mortality rates ranging from 26% to 58%. Extracorporeal membrane oxygenation (ECMO) is a modified cardiopulmonary bypass circuit that serves as an artificial membrane lung and blood pump to provide gas exchange and systemic perfusion for patients when their own heart and lungs are unable to function adequately. ECMO is a complex network that provides oxygenation and ventilation and allows the lungs to rest and recover from respiratory failure while minimizing iatrogenic ventilator-induced lung injury. In critical care settings, ECMO is proven to improve survival rates and outcomes in patients with severe ARDS. This review defines severe ARDS; describes the ECMO circuit; and discusses recent research, optimal use of the ECMO circuit, limitations of therapy including potential complications, economic impact, and logistical factors; and discusses future research considerations.

  13. Mycobacterium terrae isolated from indoor air of a moisture-damaged building induces sustained biphasic inflammatory response in mouse lungs.

    Jussila, Juha; Komulainen, Hannu; Huttunen, Kati; Roponen, Marjut; Iivanainen, Eila; Torkko, Pirjo; Kosma, Veli-Matti; Pelkonen, Jukka; Hirvonen, Maija-Riitta

    2002-11-01

    Occupants in moisture-damaged buildings suffer frequently from respiratory symptoms. This may be partly due to the presence of abnormal microbial growth or the altered microbial flora in the damaged buildings. However, the specific effects of the microbes on respiratory health and the way they provoke clinical manifestations are poorly understood. In the present study, we exposed mice via intratracheal instillation to a single dose of Mycobacterium terrae isolated from the indoor air of a moisture-damaged building (1 X 10(7), 5 X 10(7), or 1 X 10(8) microbes). Inflammation and toxicity in lungs were evaluated 2 hr later. The time course of the effects was assessed with the dose of 1 X 10(8) bacterial cells for up to 28 days. M. terrae caused a sustained biphasic inflammation in mouse lungs. The characteristic features for the first phase, which lasted from 6 hr to 3 days, were elevated proinflammatory cytokine [i.e., tumor necrosis factor alpha (TNF-alpha) and interleukin-6 (IL-6)] levels in the bronchoalveolar lavage fluid (BALF). TNF-alpha was produced in the lungs more intensively than was IL-6. Neutrophils were the most abundant cells in the airways during the first phase, although their numbers in BALF remained elevated up to 21 days. The characteristics of the second phase, which lasted from 7 to 28 days, were elevated TNF-alpha levels in BALF, expression of inducible nitric oxide synthase in BAL cells, and recruitment of mononuclear cells such as lymphocytes and macrophages into the airways. Moreover, total protein, albumin, and lactate dehydrogenase concentrations were elevated in both phases in BALF. The bacteria were detected in lungs up to 28 days. In summary, these observations indicate that M. terrae is capable of provoking a sustained, biphasic inflammation in mouse lungs and can cause a moderate degree of cytotoxicity. Thus, M. terrae can be considered a species with potential to adversely affect the health of the occupants of moisture-damaged

  14. Nigella sativa improves the carbon tetrachloride-induced lung damage in rats through repression of erk/akt pathway

    Abdullah Aslan

    2015-08-01

    Full Text Available The objective of this study was to examine whether Nigella sativa plays a protective role against the damage in the lung by administering carbon tetra-chloride (CCl4 to rats. Male Wistar albino (n=28, 8 weeks old rats were divided into 4 groups: a negative control: Normal water consuming group to which no CCl4 and N. sativa was administered; b Positive control: Normal water consuming group to which no CCl4 was administered but N. sativa was administered; c CCl4 Group: Normal water consuming and group to which CCl4 was administered (1.5 mL/kg, ip; d N. sativa plus CCl4 group: CCl4 and N. sativa administered group (1.5 mL/kg, ip. Caspase-3, caspase -9, erk, akt protein syntheses were examined via Western blotting. Malondialdehyde determination in lung tissue was made using spectrophotometer. As a results, malondialdehyde amount was decreased in the CCl4 plus N. sativa group in comparison to CCl4 group whereas caspase-3, caspase-9 was increased and erk, akt had decreased. These results show that N. sativa protects the lung against oxidative damage.

  15. [Ultrastructural changes in the lung in acute adult respiratory distress syndrome].

    Szemenyei, K; Széll, K; Kádas, L

    1980-04-01

    Morphological alterations of the lung in respiratory distress syndrome of adults (ARDS) were analyzed in 10 cases with traumatic-and septic shock, laryngitis subglottica descendens and bronchopneumonia. For the better understanding of the pathomechanism of the disease in addition to the standard methods, first of all ultrastructural alterations were studied. Two phases of the morphologic alterations could be distinguished, the phase of the destruction and the phase of the repair. These two processes are not sharply distinguishable. Genesis of the characteristic histological alterations (damage to the epithelial and endothelial cells, formation of hyaline membranes, microcoagulation, proliferation of the type II pneumocytes and fibroblasts, fibrosis) is discussed, with regard to the data of the literature.

  16. Protective effect of raloxifene on lipopolysaccharide and acid- induced acute lung injury in rats

    Guang-ju ZHOU; Hong ZHANG; Sheng-de ZHI; Guo-ping JIANG; Jing WANG; Mao ZHANGI; Jian-xin GAN; Shao-wen XU; Guan-yu JIANG

    2007-01-01

    Aim: To evaluate the protective effect of oral raloxifene on acute lung injury.Methods: Thirty adult, male Sprague-Dawley rats each weighing 180-210 g were used and divided into 3 groups: the raloxifene-lipopolysacchadde (LPS)-HC1 group(n=10), the LPS-raloxifene-HCl group (n=10), and the placebo group (n=10). All the rats were injected intraperitoneally (ip) with 5 mg/kg LPS, and raloxifene (30mg/kg) was orally administered 1 h before and 14 h after LPS injection into the raloxifene-LPS-HCl and the LPS-raloxifene-HCl groups, respectively; the placebo group received nothing. Sixteen hours after LPS injection, all the animals were anesthetized and the femoral artery was cannulated. All the rats received a direct intratracheal (IT) injection ofHCl (pH 1.2; 0.5 mL/kg). The mean arterial pressure(MAP) and blood gas concentrations were measured. Fifteen rats (5 in each group, respectively) underwent a micro positron emission to mography (microPET)scan of the thorax 4 h after HC1 instillation. The wet/dry (W/D) weight ratio determination and histopathological examination were also performed. Results:The rats in the LPS-raloxifene-HC1 group had a lower [18F]fluorodeoxyglucose uptake compared with the rats in the placebo group (4.67±1.33 vs 9.01±1.58,respectively, P<0.01). The rats in the LPS-raloxifene-HC1 group also had a lower histological lung injury score (8.20±1.23 vs 12.6±0.97, respectively, P<0.01) and W/D weight ratio (5.335±0.198 vs 5.886±0.257, respectively, P<0.01) compared to the placebo group. The rats in this group also showed better pulmonary gas exchange and more stable mean arterial pressure (MAP) compared to the placebo group. Conclusion: Raloxifene provides a significant protective effect on acute lung injury in rats induced first by LPS ip injection and then by HC1 IT instillation.

  17. Soluble Endothelial Selectin in Acute Lung Injury Complicated by Severe Pneumonia

    Daisuke Osaka, Yoko Shibata, Kazunori Kanouchi, Michiko Nishiwaki, Tomomi Kimura, Hiroyuki Kishi, Shuichi Abe, Sumito Inoue, Yoshikane Tokairin, Akira Igarashi, Keiko Yamauchi, Yasuko Aida, Takako Nemoto, Keiko Nunomiya, Koji Fukuzaki, Isao Kubota

    2011-01-01

    Full Text Available Background: Pneumonia is still one of the most frequent causes of death in the elderly. Complication of acute lung injury (ALI/acute respiratory distress syndrome (ARDS by pneumonia makes patients very ill due to severe respiratory failure. Biomarkers that can discriminate the presence of complicating ALI/ARDS are required for early detection. The aim of this research was to investigate whether soluble endothelial selectin (sES could be a biomarker for ALI.Methods: Serum sES levels were measured in 27 pneumonia patients, who were enrolled between April 2006 and September 2007. Among these patients, six had ALI or a condition that was clinically comparable to ALI (cALI. All patients who were enrolled were successfully treated and survived.Results: Circulating sES levels were elevated in pneumonia patients with ALI/cALI, and sES levels decreased following treatment of their pneumonia. Univariate and multivariate logistic regression analyses showed that sES was the only significant factor for identifying complicating ALI/cALI, independently of C-reactive protein (CRP and lactate dehydrogenase (LDH. By receiver operating characteristic (ROC curve analysis, the cut-off value for sES was 40.1 ng/mL, with a sensitivity of 0.8 and a specificity of 0.8.Conclusion: sES may be a useful biomarker for discriminating complicating ALI/cALI in patients with severe pneumonia.

  18. Acute respiratory failure in critically ill patients with interstitial lung disease.

    Lara Zafrani

    Full Text Available Patients with chronic known or unknown interstitial lung disease (ILD may present with severe respiratory flares that require intensive management. Outcome data in these patients are scarce.Clinical and radiological features were collected in 83 patients with ILD-associated acute respiratory failure (ARF. Determinants of hospital mortality and response to corticosteroid therapy were identified by logistic regression.Hospital and 1-year mortality rates were 41% and 54% respectively. Pulmonary hypertension, computed tomography (CT fibrosis and acute kidney injury were independently associated with mortality (odds ratio (OR 4.55; 95% confidence interval (95%CI (1.20-17.33; OR, 7.68; (1.78-33.22 and OR 10.60; (2.25-49.97 respectively. Response to steroids was higher in patients with shorter time from hospital admission to corticosteroid therapy. Patients with fibrosis on CT had lower response to steroids (OR, 0.03; (0.005-0.21. In mechanically ventilated patients, overdistension induced by high PEEP settings was associated with CT fibrosis and hospital mortality.Mortality is high in ILD-associated ARF. CT and echocardiography are valuable prognostic tools. Prompt corticosteroid therapy may improve survival.

  19. Mesenchymal Stem Cell Attenuates Neutrophil-predominant Inflammation and Acute Lung Injury in an In Vivo Rat Model of Ventilator-induced Lung Injury

    Tian-Shun Lai

    2015-01-01

    Full Text Available Background: Subsequent neutrophil (polymorphonuclear neutrophil [PMN]-predominant inflammatory response is a predominant feature of ventilator-induced lung injury (VILI, and mesenchymal stem cell (MSC can improve mice survival model of endotoxin-induced acute lung injury, reduce lung impairs, and enhance the repair of VILI. However, whether MSC could attenuate PMN-predominant inflammatory in the VILI is still unknown. This study aimed to test whether MSC intervention could attenuate the PMN-predominate inflammatory in the mechanical VILI. Methods: Sprague-Dawley rats were ventilated for 2 hours with large tidal volume (20 mL/kg. MSCs were given before or after ventilation. The inflammatory chemokines and gas exchange were observed and compared dynamically until 4 hours after ventilation, and pulmonary pathological change and activation of PMN were observed and compared 4 hours after ventilation. Results: Mechanical ventilation (MV caused significant lung injury reflected by increasing in PMN pulmonary sequestration, inflammatory chemokines (tumor necrosis factor-alpha, interleukin-6 and macrophage inflammatory protein 2 in the bronchoalveolar lavage fluid, and injury score of the lung tissue. These changes were accompanied with excessive PMN activation which reflected by increases in PMN elastase activity, production of radical oxygen series. MSC intervention especially pretreatment attenuated subsequent lung injury, systemic inflammation response and PMN pulmonary sequestration and excessive PMN activation initiated by injurious ventilation. Conclusions: MV causes profound lung injury and PMN-predominate inflammatory responses. The protection effect of MSC in the VILI rat model is related to the suppression of the PMN activation.

  20. Mesenchymal Stem Cell Attenuates Neutrophil-predominant Inflammation and Acute Lung Injury in an In Vivo Rat Model of Ventilator-induced Lung Injury

    Tian-Shun Lai; Zhi-Hong Wang; Shao-Xi Cai

    2015-01-01

    Background:Subsequent neutrophil (polymorphonuclear neutrophil [PMN])-predominant inflammatory response is a predominant feature of ventilator-induced lung injury (VILI),and mesenchymal stem cell (MSC) can improve mice survival model of endotoxin-induced acute lung injury,reduce lung impairs,and enhance the repair of VILI.However,whether MSC could attenuate PMN-predominant inflammatory in the VILI is still unknown.This study aimed to test whether MSC intervention could attenuate the PMN-predominate inflammatory in the mechanical VILI.Methods:Sprague-Dawley rats were ventilated for 2 hours with large tidal volume (20 mL/kg).MSCs were given before or after ventilation.The inflammatory chemokines and gas exchange were observed and compared dynamically until 4 hours after ventilation,and pulmonary pathological change and activation of PMN were observed and compared 4 hours after ventilation.Results:Mechanical ventilation (MV) caused significant lung injury reflected by increasing in PMN pulmonary sequestration,inflammatory chemokines (tumor necrosis factor-alpha,interleukin-6 and macrophage inflammatory protein 2) in the bronchoalveolar lavage fluid,and injury score of the lung tissue.These changes were accompanied with excessive PMN activation which reflected by increases in PMN elastase activity,production of radical oxygen series.MSC intervention especially pretreatment attenuated subsequent lung injury,systemic inflammation response and PMN pulmonary sequestration and excessive PMN activation initiated by injurious ventilation.Conclusions:MV causes profound lung injury and PMN-predominate inflammatory responses.The protection effect of MSC in the VILI rat model is related to the suppression of the PMN activation.

  1. Therapeutic experience of the application of anisodamine on acute lung injury

    Nan-Bin Yu

    2016-01-01

    Objective: To investigate the effect of anisodamine combining with conventional ther-apy on the degree of lung injury and inflammatory reaction of patients with acute pul-monary contusion. Methods: A total of 48 patients with acute pulmonary contusion treated in our hospital emergency department from April 2011 to October 2015 were enrolled as the research object and were divided into experimental group and control group by using a method of random number table. Experimental group received anisodamine combining with con-ventional therapy and control group received conventional therapy. In the process of the treatment, the mechanical ventilation time, hospital stays in intensive care unit and the number of cases developed into acute respiratory distress syndrome and multiple organ dysfunction syndromes of patients in two groups were observed. Oxygenation indexes of patients were respectively calculated on Days 1, 2 and 3 after treatment. The contents of inflammatory mediators in serum were detected on Day 3 after treatment. Results: The mechanical ventilation time and hospital stays in intensive care unit [(9.52 ± 1.41) vs. (14.57 ± 2.51) days] of patients in experimental group were signifi-cantly shorter than those in control group, and the number of cases developed into acute respiratory distress syndrome [1 (4.17%) vs. 9 (37.50%)] and multiple organ dysfunction syndrome [1 (4.17%) vs. 7 (29.17%)] was significantly less than those in control group. Oxygenation indexes (294.52 ± 41.26 vs. 257.63 ± 38.52; 357.74 ± 47.74 vs. 279.87 ± 31.46; 396.71 ± 55.12 vs. 279.87 ± 31.46) of patients were respectively calculated on Days 1, 2 and 3 after treatment, which were significantly higher than those in the control group. On Day 3 after treatment, the contents of serum C-reactive protein [(7.94 ± 1.05) vs. (14.49 ± 2.97) mg/L], tumor necrosis factor a [(264.69 ± 41.58) vs. (417.87 ± 64.51) ng/L], interleukin-6 (IL-6) [(147.72 ± 21.36) vs. (257.68 ± 41.54) ng

  2. Therapeutic exper ience of the application of anisodamine on acute lung injur y

    Nan-Bin Yu

    2016-09-01

    Full Text Available Objective: To investigate the effect of anisodamine combining with conventional therapy on the degree of lung injury and inflammatory reaction of patients with acute pulmonary contusion. Methods: A total of 48 patients with acute pulmonary contusion treated in our hospital emergency department from April 2011 to October 2015 were enrolled as the research object and were divided into experimental group and control group by using a method of random number table. Experimental group received anisodamine combining with conventional therapy and control group received conventional therapy. In the process of the treatment, the mechanical ventilation time, hospital stays in intensive care unit and the number of cases developed into acute respiratory distress syndrome and multiple organ dysfunction syndromes of patients in two groups were observed. Oxygenation indexes of patients were respectively calculated on Days 1, 2 and 3 after treatment. The contents of inflammatory mediators in serum were detected on Day 3 after treatment. Results: The mechanical ventilation time and hospital stays in intensive care unit [(9.52 ± 1.41 vs. (14.57 ± 2.51 days] of patients in experimental group were signifi- cantly shorter than those in control group, and the number of cases developed into acute respiratory distress syndrome [1 (4.17% vs. 9 (37.50%] and multiple organ dysfunction syndrome [1 (4.17% vs. 7 (29.17%] was significantly less than those in control group. Oxygenation indexes (294.52 ± 41.26 vs. 257.63 ± 38.52; 357.74 ± 47.74 vs. 279.87 ± 31.46; 396.71 ± 55.12 vs. 279.87 ± 31.46 of patients were respectively calculated on Days 1, 2 and 3 after treatment, which were significantly higher than those in the control group. On Day 3 after treatment, the contents of serum C-reactive protein [(7.94 ± 1.05 vs. (14.49 ± 2.97 mg/L], tumor necrosis factor a [(264.69 ± 41.58 vs. (417.87 ± 64.51 ng/L], interleukin-6 (IL-6 [(147.72 ± 21.36 vs. (257.68 ± 41

  3. Low Doses of Oxygen Ion Irradiation Cause Acute Damage to Hematopoietic Cells in Mice.

    Jianhui Chang

    Full Text Available One of the major health risks to astronauts is radiation on long-duration space missions. Space radiation from sun and galactic cosmic rays consists primarily of 85% protons, 14% helium nuclei and 1% high-energy high-charge (HZE particles, such as oxygen (16O, carbon, silicon, and iron ions. HZE particles exhibit dense linear tracks of ionization associated with clustered DNA damage and often high relative biological effectiveness (RBE. Therefore, new knowledge of risks from HZE particle exposures must be obtained. In the present study, we investigated the acute effects of low doses of 16O irradiation on the hematopoietic system. Specifically, we exposed C57BL/6J mice to 0.1, 0.25 and 1.0 Gy whole body 16O (600 MeV/n irradiation and examined the effects on peripheral blood (PB cells, and bone marrow (BM hematopoietic stem cells (HSCs and hematopoietic progenitor cells (HPCs at two weeks after the exposure. The results showed that the numbers of white blood cells, lymphocytes, monocytes, neutrophils and platelets were significantly decreased in PB after exposure to 1.0 Gy, but not to 0.1 or 0.25 Gy. However, both the frequency and number of HPCs and HSCs were reduced in a radiation dose-dependent manner in comparison to un-irradiated controls. Furthermore, HPCs and HSCs from irradiated mice exhibited a significant reduction in clonogenic function determined by the colony-forming and cobblestone area-forming cell assays. These acute adverse effects of 16O irradiation on HSCs coincided with an increased production of reactive oxygen species (ROS, enhanced cell cycle entry of quiescent HSCs, and increased DNA damage. However, none of the 16O exposures induced apoptosis in HSCs. These data suggest that exposure to low doses of 16O irradiation induces acute BM injury in a dose-dependent manner primarily via increasing ROS production, cell cycling, and DNA damage in HSCs. This finding may aid in developing novel strategies in the protection of the

  4. Fibroblast Growth Factor-10 (FGF-10) Mobilizes Lung-resident Mesenchymal Stem Cells and Protects Against Acute Lung Injury.

    Tong, Lin; Zhou, Jian; Rong, Linyi; Seeley, Eric J; Pan, Jue; Zhu, Xiaodan; Liu, Jie; Wang, Qin; Tang, Xinjun; Qu, Jieming; Bai, Chunxue; Song, Yuanlin

    2016-02-12

    FGF-10 can prevent or reduce lung specific inflammation due to traumatic or infectious lung injury. However, the exact mechanisms are poorly characterized. Additionally, the effect of FGF-10 on lung-resident mesenchymal stem cells (LR-MSCs) has not been studied. To better characterize the effect of FGF-10 on LR-MSCs, FGF-10 was intratracheally delivered into the lungs of rats. Three days after instillation, bronchoalveolar lavage was performed and plastic-adherent cells were cultured, characterized and then delivered therapeutically to rats after LPS intratracheal instillation. Immunophenotyping analysis of FGF-10 mobilized and cultured cells revealed expression of the MSC markers CD29, CD73, CD90, and CD105, and the absence of the hematopoietic lineage markers CD34 and CD45. Multipotency of these cells was demonstrated by their capacity to differentiate into osteocytes, adipocytes, and chondrocytes. Delivery of LR-MSCs into the lungs after LPS injury reduced the inflammatory response as evidenced by decreased wet-to-dry ratio, reduced neutrophil and leukocyte recruitment and decreased inflammatory cytokines compared to control rats. Lastly, direct delivery of FGF-10 in the lungs of rats led to an increase of LR-MSCs in the treated lungs, suggesting that the protective effect of FGF-10 might be mediated, in part, by the mobilization of LR-MSCs in lungs.

  5. Lung function in patients with acute exacerbation and stable COPD and its correlation with serum proinflammatory cytokines and chemokines

    Xin-Jie Wang

    2016-01-01

    Objective:To analyze the lung function in patients with acute exacerbation and stable COPD and its correlation with serum proinflammatory factors and chemokines.Methods:A total of 87 patients with chronic obstructive pulmonary disease (COPD) were divided into observation group (n=32) at acute exacerbation phase and control group (n=55) at stable phase according to the illness. Differences in lung function indexes and serum levels of proinflammatory cytokines, chemokines were compared between two groups of patients, and the correlation between lung function indexes and serum levels of proinflammatory cytokines and chemokines was further analyzed.Results: FEV1, FVC, FEV1/FVC, FEF75, PEF and IC levels of observation group were significantly lower than those of control group; serum proinflammatory cytokines IL-1β, IL-4, IL-18, IL-23, TNF-α and IFN-γ content were significantly higher than those of control group; serum chemokines Eotaxin, MDC, FKN, MCP-1, CCL18 and RANTES content were significantly higher than those of control group. FEV1, FVC and FEV1/FVC levels in patients with COPD were negatively correlated with the content of proinflammatory cytokines and chemokines.Conclusions: Lung function declines in acute exacerbation COPD, and the changes in levels of both proinflammatory cytokines and chemokines are involved in it.

  6. Effect of resveratrol on microcirculation disorder and lung injury following severe acute pancreatitis in rats

    Yong Meng; Mei Zhang; Jun Xu; Xue-Min Liu; Qing-Yong Ma

    2005-01-01

    AIM: To investigate the mechanism of resveratrol underlying the microcirculation disorder and lung injury following severe acute pancreatitis (SAP).METHODS: Twenty-four rats were divided into 3 groups (SAP, sham and resveratrol groups) randomly. SAP model was established by injecting 4% sodium taurocholate 1 mL/kg through puncturing pancreatic ducts. Sham (control) group (8 rats) was established by turning over the duodenum.Resveratrol was given at 0.1 mg/kg b.m. intraperitoneally.Rats were sacrificed 9 h after SAP was induced. Blood samples were obtained for hemorrheological examination.Lung tissues were used for pathological observation, and examination of microvascular permeability, dry/wet ratio and myeloperoxidase (MPO) activity. Gene expression of intercellular adhesion molecule-1 (ICAM-1) was detected by RT-PCR.RESULTS: Compared with SAP group, resveratrol relieved the edema and infiltration of leukocytes in the lungs. Resveratrol improved markers of hemorrheology:high VTB (5.77±1.18 mPas vs9.49±1.34 mPas), low VTB (16.12±3.20 mPas vs30.91±7.28 mPas), PV (4.69±1.68 mPas vs8.00±1.34 mPas), BSR (1.25±0.42 mm/h vs 0.03±0.03mm/h), VPC (54.67±3.08% vs 62.17±3.39%), fibrinogen (203.2±87.8 g/L vs 51.3±19.1 g/L), original hemolysis (0.45±0.02 vs 0.49±0.02), and complete hemolysis (0.41±0.02 vs0.43±0.02) (P<0.05). Resveratrol decreased the OD ratio of ICAM-1 gene (0.800±0.03 vs 1.188±0.10),dry/wet ratio (0.74±0.02 vs 0.77±0.03), microvascular permeability (0.079±0.006 vs 0.112±0.004) and MPO activity (4.42±0.32 vs 5.03±0.51) significantly (P<0.05).CONCLUSION: Resveratrol can improve the microcirculation disorder of the lung by decreasing leukocyte-endothelial interaction, reducing blood viscosity, improving the decrease of blood flow, and stabilizing erythrocytes in SAP rats. It may be a potential candidate to treat SAP and its severe complications (ALI).

  7. TRAIL+ monocytes and monocyte-related cells cause lung damage and thereby increase susceptibility to influenza-Streptococcus pneumoniae coinfection.

    Ellis, Gregory T; Davidson, Sophia; Crotta, Stefania; Branzk, Nora; Papayannopoulos, Venizelos; Wack, Andreas

    2015-09-01

    Streptococcus pneumoniae coinfection is a major cause of influenza-associated mortality; however, the mechanisms underlying pathogenesis or protection remain unclear. Using a clinically relevant mouse model, we identify immune-mediated damage early during coinfection as a new mechanism causing susceptibility. Coinfected CCR2(-/-) mice lacking monocytes and monocyte-derived cells control bacterial invasion better, show reduced epithelial damage and are overall more resistant than wild-type controls. In influenza-infected wild-type lungs, monocytes and monocyte-derived cells are the major cell populations expressing the apoptosis-inducing ligand TRAIL. Accordingly, anti-TRAIL treatment reduces bacterial load and protects against coinfection if administered during viral infection, but not following bacterial exposure. Post-influenza bacterial outgrowth induces a strong proinflammatory cytokine response and massive inflammatory cell infiltrate. Depletion of neutrophils or blockade of TNF-α facilitate bacterial outgrowth, leading to increased mortality, demonstrating that these factors aid bacterial control. We conclude that inflammatory monocytes recruited early, during the viral phase of coinfection, induce TRAIL-mediated lung damage, which facilitates bacterial invasion, while TNF-α and neutrophil responses help control subsequent bacterial outgrowth. We thus identify novel determinants of protection versus pathology in influenza-Streptococcus pneumoniae coinfection.

  8. Acute O 3 damage on first year coppice sprouts of aspen and maple sprouts in an open-air experiment.

    Darbah, Joseph N T; Jones, Wendy S; Burton, Andrew J; Nagy, John; Kubiske, Mark E

    2011-09-01

    We studied the effect of high ozone (O(3)) concentration (110-490 nmol mol(-1)) on regenerating aspen (Populus tremuloides) and maple (Acer saccharum) trees at an open-air O(3) pollution experiment near Rhinelander WI USA. This study is the first of its kind to examine the effects of acute O(3) exposure on aspen and maple sprouts after the parent trees, which were grown under elevated O(3) and/or CO(2) for 12 years, were harvested. Acute O(3) damage was not uniform within the crowns of aspen suckers; it was most severe in the mature, fully expanded photosynthesizing leaves. Young expanding leaves showed no visible signs of acute O(3) damage contrary to expectations. Stomatal conductance played a primary role in the severity of acute O(3) damage as it directly controlled O(3) uptake. Maple sprouts, which had lower stomatal conductance, smaller stomatal aperture, higher stomatal density and larger leaf surface area, were tolerant of acute O(3) exposure. Moreover, elevated CO(2) did not ameliorate the adverse effects of acute O(3) dose on aspen and maple sprouts, in contrast to its ability to counteract the effects of long-term chronic exposure to lower O(3) levels.

  9. Acute O3 damage on first year coppice sprouts of aspen and maple sprouts in an open-air experiment

    Darbah, J.N.; Nagy, J.; Jones, W. S.; Burton, A. J.; Kubiske, M. E.

    2011-10-01

    We studied the effect of high ozone (O{sub 3}) concentration (110-490 nmol mol{sup -1}) on regenerating aspen (Populus tremuloides) and maple (Acer saccharum) trees at an open-air O{sub 3} pollution experiment near Rhinelander WI USA. This study is the first of its kind to examine the effects of acute O{sub 3} exposure on aspen and maple sprouts after the parent trees, which were grown under elevated O{sub 3} and/or CO{sub 2} for 12 years, were harvested. Acute O{sub 3} damage was not uniform within the crowns of aspen suckers; it was most severe in the mature, fully expanded photosynthesizing leaves. Young expanding leaves showed no visible signs of acute O{sub 3} damage contrary to expectations. Stomatal conductance played a primary role in the severity of acute O{sub 3} damage as it directly controlled O{sub 3} uptake. Maple sprouts, which had lower stomatal conductance, smaller stomatal aperture, higher stomatal density and larger leaf surface area, were tolerant of acute O{sub 3} exposure. Moreover, elevated CO{sub 2} did not ameliorate the adverse effects of acute O{sub 3} dose on aspen and maple sprouts, in contrast to its ability to counteract the effects of long-term chronic exposure to lower O{sub 3} levels.

  10. Diagnostic usefulness of the oedema-infarct ratio to differentiate acute from chronic myocardial damage using magnetic resonance imaging

    Yamada, Kiyoyasu; Suzuki, Susumu; Kinoshita, Kousuke; Yokouchi, Kazuhiko; Iwata, Hirokazu; Sawada, Ken [Gifu Social Insurance Hospital, Department of Cardiology, Gifu (Japan); Isobe, Satoshi; Ohshima, Satoru; Murohara, Toyoaki [Nagoya University Graduate School of Medicine, Department of Cardiology, Nagoya (Japan); Hirai, Makoto [Nagoya University School of Health Sciences, Department of Nursing, Nagoya (Japan)

    2012-04-15

    To differentiate acute from chronic damage to the myocardium in patients with myocardial infarction (MI) using DE and T2w MR. Short-axis T2w and DE MR images were acquired twice after the onset of MI in 36 patients who successfully underwent emergency coronary revascularisation. The areas of infarct and oedema were measured. The oedema-infarct ratio (O/I) of the left ventricular area was calculated by dividing the oedema by the infarct area. The oedema size on T2w MR was significantly larger than the infarct size on DE MR in the acute phase. Both the oedema size on T2w MR and the infarct size on DE MR in the acute phase were significantly larger than those in the chronic phase. The O/I was significantly greater in the acute phase compared with that in the chronic phase (P < 0.05). An analysis of relative cumulative frequency distributions revealed an O/I of 1.4 as a cut-off value for differentiating acute from chronic myocardial damage with the sensitivity, specificity, and accuracy of 85.1%, 82.7% and 83.9%, respectively. The oedema-infarct ratio may be a useful index in differentiating acute from chronic myocardial damage in patients with MI. (orig.)

  11. Effect of Coenzyme Q10 on Acute Pulmonary Damage Following the Experimental Thoracic Trauma

    Murat Koyuncu

    2016-04-01

    Full Text Available Aim: Pulmonary contusion negatively affects prognosis in the case of damages following a trauma. Objective of this experimental study performed in Turkey was to evaluate effects of coenzyme Q10 on primary and secondary damages of pulmonary contusion following experimental thoracic blunt trauma using biochemical and histopathological parameters. Material and Method: A total of 56 Wistar Albino female rats with a mean weight of 205±45 g were included in this study. Rats were randomly divided into seven groups with each group having eight rats. A trauma device which consisted of a fixed platform, and an aluminium tube was prepared. Rats were administered 2.45 J of chest impact energy in order to generate pulmonary contusion. Control and Study groups were named according to the sacrificed time. No process (trauma and/or medication was performed in the sham group, while only trauma was induced in the controls. On the other hand, after induced trauma, intraperitoneal Q10 (0. - 24. - 48. hours was administered to study group. Rats were sacrificed at the end of the after trauma 24, 48 and 72 hours, and their blood and lung tissue samples were analyzed. Results: No significant difference was found between sham and Study-72 groups in terms of high-sensitivity C-reactive protein. On the histopathological examination, no significant difference was found between study and control groups. While no significant difference was found between the sham and study groups, significant difference was observed between sham and control groups. Discussion: Coenzyme Q10, an antioxidant agent, can be used as an antioxidant agent in order to reduce the secondary damage in blunt thoracic trauma.

  12. Fisetin Alleviates Lipopolysaccharide-Induced Acute Lung Injury via TLR4-Mediated NF-κB Signaling Pathway in Rats.

    Feng, Guang; Jiang, Ze-yu; Sun, Bo; Fu, Jie; Li, Tian-zuo

    2016-02-01

    Acute lung injury (ALI), a common component of systemic inflammatory disease, is a life-threatening condition without many effective treatments. Fisetin, a natural flavonoid from fruits and vegetables, was reported to have wide pharmacological properties such as anti-inflammatory, antioxidant, and anticancer activities. The aim of this study was to detect the effects of fisetin on lipopolysaccharide (LPS)-induced acute lung injury and investigate the potential mechanism. Fisetin was injected (1, 2, and 4 mg/kg, i.v.) 30 min before LPS administration (5 mg/kg, i.v.). Our results showed that fisetin effectively reduced the inflammatory cytokine release and total protein in bronchoalveolar lavage fluids (BALF), decreased the lung wet/dry ratios, and obviously improved the pulmonary histology in LPS-induced ALI. Furthermore, fisetin inhibited LPS-induced increases of neutrophils and macrophage infiltration and attenuated MPO activity in lung tissues. Additionally, fisetin could significantly inhibit the Toll-like receptor 4 (TLR4) expression and the activation of NF-κB in lung tissues. Our data indicates that fisetin has a protective effect against LPS-induced ALI via suppression of TLR4-mediated NF-κB signaling pathways, and fisetin may be a promising candidate for LPS-induced ALI treatment.

  13. Prevention of LPS-induced acute lung injury in mice by mesenchymal stem cells overexpressing angiopoietin 1.

    Shirley H J Mei

    2007-09-01

    Full Text Available BACKGROUND: The acute respiratory distress syndrome (ARDS, a clinical complication of severe acute lung injury (ALI in humans, is a leading cause of morbidity and mortality in critically ill patients. ALI is characterized by disruption of the lung alveolar-capillary membrane barrier and resultant pulmonary edema associated with a proteinaceous alveolar exudate. Current specific treatment strategies for ALI/ARDS are lacking. We hypothesized that mesenchymal stem cells (MSCs, with or without transfection with the vasculoprotective gene angiopoietin 1 (ANGPT1 would have beneficial effects in experimental ALI in mice. METHODS AND FINDINGS: Syngeneic MSCs with or without transfection with plasmid containing the human ANGPT1 gene (pANGPT1 were delivered through the right jugular vein of mice 30 min after intratracheal instillation of lipopolysaccharide (LPS to induce lung injury. Administration of MSCs significantly reduced LPS-induced pulmonary inflammation, as reflected by reductions in total cell and neutrophil counts in bronchoalveolar lavage (BAL fluid (53%, 95% confidence interval [CI] 7%-101%; and 60%, CI 4%-116%, respectively as well as reducing levels of proinflammatory cytokines in both BAL fluid and lung parenchymal homogenates. Furthermore, administration of MSCs transfected with pANGPT1 resulted in nearly complete reversal of LPS-induced increases in lung permeability as assessed by reductions in IgM and albumin levels in BAL (96%, CI 6%-185%; and 74%, CI 23%-126%, respectively. Fluorescently tagged MSCs were detected in the lung tissues by confocal microscopy and flow cytometry in both naïve and LPS-injured animals up to 3 d. CONCLUSIONS: Treatment with MSCs alone significantly reduced LPS-induced acute pulmonary inflammation in mice, while administration of pANGPT1-transfected MSCs resulted in a further improvement in both alveolar inflammation and permeability. These results suggest a potential role for cell-based ANGPT1 gene therapy

  14. NOD-like receptors in lung diseases

    Catherine eChaput

    2013-11-01

    Full Text Available The lung is a particularly vulnerable organ at the interface of the body and the exterior environment. It is constantly exposed to microbes and particles by inhalation. The innate immune system needs to react promptly and adequately to potential dangers posed by these microbes and particles, while at the same time avoiding extensive tissue damage. NOD-like receptors (NLRs represent a group of key sensors for microbes and damage in the lung. As such they are important players in various infectious as well as acute and chronic sterile inflammatory diseases, such as pneumonia, chronic obstructive lung disease (COPD, acute lung injury/ARDS, pneumoconiosis and asthma. Activation of most known NLRs leads to the production and release of pro-inflammatory cytokines, and/or to the induction of cell death. We will review NLR functions in the lung during infection and sterile inflammation.

  15. Acute MUS81 depletion leads to replication fork slowing and a constitutive DNA damage response

    Xing, Meichun; Wang, Xiaohui; Palmai-Pallag, Timea;

    2015-01-01

    The MUS81 protein belongs to a conserved family of DNA structure-specific nucleases that play important roles in DNA replication and repair. Inactivation of the Mus81 gene in mice has no major deleterious consequences for embryonic development, although cancer susceptibility has been reported. We...... have investigated the role of MUS81 in human cells by acutely depleting the protein using shRNAs. We found that MUS81 depletion from human fibroblasts leads to accumulation of ssDNA and a constitutive DNA damage response that ultimately activates cellular senescence. Moreover, we show that MUS81...... is required for efficient replication fork progression during an unperturbed S-phase, and for recovery of productive replication following replication stalling. These results demonstrate essential roles for the MUS81 nuclease in maintenance of replication fork integrity....

  16. Arterial damages in acute elbow dislocations: which diagnostic tests are required?

    Lutter, Christoph; Pfefferkorn, Ronny; Schoeffl, Volker

    2016-07-19

    Blunt vessel injuries of peripheral arteries caused by a direct trauma are rare. Studies have described the frequency of arterial ruptures following closed elbow dislocations in 0.3-1.7% of all cases. However, arterial damage does not always necessarily appear as a complete rupture of the vessel with a loss of peripheral circulation and ischaemic symptoms; a relatively strong periarticular system of collaterals can maintain circulation. Furthermore, the traumatic dislocation can also cause intimal tears, arterial dissections and aneurysms or thrombosis. In all cases of vessel injury, including total disruption, a peripheral pulse might still be palpable. 3 weeks after an acute elbow dislocation, we have diagnosed a patient with a long-segment stenosis of the brachial artery and a thrombosis of the radial artery. Therefore, the close anatomic proximity to the neurovascular structures should always be considered in cases of elbow dislocations, even if peripheral pulses are traceable.

  17. Selective cyclooxygenase-2 inhibition protects against myocardial damage in experimental acute ischemia

    Alberto Carnieto Jr.

    2009-03-01

    Full Text Available BACKGROUND: Acute myocardial infarction is associated with tissue inflammation. Early coronary reperfusion clearly improves the outcome but may help propagate the inflammatory response and enhance tissue damage. Cyclooxygenase-2 is an enzyme that catalyzes the initial step in the formation of inflammatory prostaglandins from arachidonic acid. Cyclooxygenase-2 levels are increased when ischemic cardiac events occur. The overall function of COX-2 in the inflammatory process generated by myocardial ischemic damage has not yet been elucidated. GOAL: The objective of this study was to determine whether a selective cyclooxygenase-2 inhibitor (rofecoxib could alter the evolution of acute myocardial infarction after reperfusion. METHODS AND RESULTS: This study was performed with 48 mongrel dogs divided into two groups: controls and those treated with the drug. All animals were prepared for left anterior descending coronary artery occlusion. The dogs then underwent 180 minutes of coronary occlusion, followed by 30 minutes of reperfusion. Blood samples were collected from the venous sinus immediately before coronary occlusion and after 30 minutes of reperfusion for measurements of CPK-MB, CPK-MBm and troponin I. During the experiment we observed the mean blood pressure, heart rate and coronary flow. The coronary flow and heart rate did not change, but in the control group, there was blood pressure instability, in addition to maximal levels of CPK-MB post-infarction. The same results were observed for CPK-MBm and troponin I. CONCLUSION: In a canine model of myocardial ischemia-reperfusion, selective inhibition of Cyclooxygenase-2 with rofecoxib was not associated with early detrimental effects on the hemodynamic profile or the gross extent of infarction; in fact, it may be beneficial by limiting cell necrosis.

  18. First case of atypical takotsubo cardiomyopathy in a bilateral lung-transplanted patient due to acute respiratory failure.

    Ghadri, Jelena R; Bataisou, Roxana D; Diekmann, Johanna; Lüscher, Thomas F; Templin, Christian

    2015-10-01

    Takotsubo cardiomyopathy which is characterised by a transient left ventricular wall motion abnormality was first described in 1990. The disease is still not well known, and as such it is suggested that an emotional trigger is mandatory in this disease. We present the case of a 51-year old female patient seven years after bilateral lung transplantation, who developed acute respiratory distress syndrome and subsequently suffered from atypical takotsubo cardiomyopathy with transient severe reduction of ejection fraction and haemodynamic instability needing acute intensive care treatment. Acute respiratory failure has emerged as an important physical trigger factor in takotsubo cardiomyopathy. Little is known about the association of hypoxia and takotsubo cardiomyopathy which can elicit a life-threatening condition requiring acute intensive care. Therefore, experimental studies are needed to investigate the role of hypoxia in takotsubo cardiomyopathy.

  19. Effects of Xuanbai Chengqi decoction on lung compliance for patients with exogenous pulmonary acute respiratory distress syndrome

    Mao ZR

    2016-02-01

    Full Text Available Zhengrong Mao,1 Haifeng Wang2,3 1Department of Critical Care Medicine, The First Affiliated Hospital of Henan, University of Traditional Chinese Medicine, 2Department of Respiratory Medicine, The First Affiliated Hospital of Henan University of Traditional Chinese Medicine, 3Collaborative Innovation Center for Respiratory Disease Diagnosis and Treatment & Chinese Medicine Development of Henan Province, Zhengzhou City, Henan, People’s Republic of China Objective: To observe the effects of Xuanbai Chengqi decoction on lung compliance for patients with exogenous pulmonary acute respiratory distress syndrome. Subjects and methods: A total of 53 patients with exogenous pulmonary acute respiratory distress syndrome, who were admitted to the intensive care unit of the First Affiliated Hospital of Henan University of Traditional Chinese Medicine from March 2009 to February 2013, were selected. They were randomly divided into the treatment group (25 cases and the control group (28 cases. Both the groups were treated with conventional treatment and lung-protective ventilation strategy; apart from these, enema therapy with Xuanbai Chengqi decoction was given to the treatment group. Meanwhile, static lung compliance, dynamic lung compliance, peak airway pressure, plateau pressure, and positive end-expiratory pressure (PEEP for patients in both the groups were observed and recorded at 24, 48, and 72 hours after the drug was used. Moreover, variations in the duration of parenteral nutrition, incidence rate of complications, and case fatality rate in patients after treatment were recorded. Results: For patients in the treatment group, at 48 and 72 hours after treatment, the static lung compliance and dynamic lung compliance were significantly higher than those in the control group, while plateau pressure, peak airway pressure, and PEEP were significantly lower than those before treatment. At the same time, PEEP for patients in the treatment group at 72

  20. Effect of Black Grape Juice against Heart Damage from Acute Gamma TBI in Rats

    Edson Ramos de Andrade

    2013-09-01

    Full Text Available The aim of this study was to evaluate the potential positive effect of black grape juice (BGJ on lipid peroxidation considering Total Body Irradiation (TBI in Wistar rats. As a potential feasible means of evaluation in situ, blood serum lactate dehydrogenase (LDH levels were evaluated as a marker for heart damage from acute radiation syndrome (ARS. Twenty rats were divided into four groups, two of them being irradiated by gamma-rays from a Co-60 source. Animals were treated by gavage with 2 mL per day of BGJ or placebo for one week before and 4 days after 6 Gy whole body gamma-irradiation, when they were euthanasiated. LDH on serum and lipid peroxidation on heart tissue were evaluated. High concentration of metabolites from lipid peroxidation in heart, and high LDH level on serum were found only in gamma-irradiated group given placebo, mainly at the first 24 h after radiation. Phytochemical analysis of BGJ was performed by determining total phenolics, flavonoids, and tannins followed by a high-performance liquid chromatography (HPLC/DAD analysis, which showed resveratrol as the major constituent. Results suggest that BGJ is a good protective candidate compound against heart damage from ARS and its effects suggest its use as a radiomodifier.

  1. Ca2+ toxicity and mitochondrial damage in acute pancreatitis: translational overview

    Maléth, József; Hegyi, Péter

    2016-01-01

    Acute pancreatitis (AP) is a leading cause of hospitalization among non-malignant gastrointestinal disorders. The mortality of severe AP can reach 30–50%, which is most probably owing to the lack of specific treatment. Therefore, AP is a major healthcare problem, which urges researchers to identify novel drug targets. Studies from the last decades highlighted that the toxic cellular Ca2+ overload and mitochondrial damage are key pathogenic steps in the disease development affecting both acinar and ductal cell functions. Moreover, recent observations showed that modifying the cellular Ca2+ signalling might be beneficial in AP. The inhibition of Ca2+ release from the endoplasmic reticulum or the activity of plasma membrane Ca2+ influx channels decreased the severity of AP in experimental models. Similarly, inhibition of mitochondrial permeability transition pore (MPTP) opening also seems to improve the outcome of AP in in vivo animal models. At the moment MPTP blockers are under detailed clinical investigation to test whether interventions in MPTP openings and/or Ca2+ homeostasis of the cells can be specific targets in prevention or treatment of cell damage in AP. This article is part of the themed issue ‘Evolution brings Ca2+ and ATP together to control life and death’. PMID:27377719

  2. Maltol, a Food Flavoring Agent, Attenuates Acute Alcohol-Induced Oxidative Damage in Mice

    Ye Han

    2015-01-01

    Full Text Available The purpose of this study was to evaluate the hepatoprotective effect of maltol, a food-flavoring agent, on alcohol-induced acute oxidative damage in mice. Maltol used in this study was isolated from red ginseng (Panax ginseng C.A Meyer and analyzed by high performance liquid chromatography (HPLC and mass spectrometry. For hepatoprotective activity in vivo, pretreatment with maltol (12.5, 25 and 50 mg/kg; 15 days drastically prevented the elevated activities of aspartate transaminase (AST, alanine transaminase (ALT, alkaline phosphatase (ALP and triglyceride (TG in serum and the levels of malondialdehyde (MDA, tumor necrosis factor-α (TNF-α, interleukin-1β (IL-1β in liver tissue (p < 0.05. Meanwhile, the levels of hepatic antioxidant, such as catalase (CAT, superoxide dismutase (SOD, glutathione peroxidase (GSH-Px were elevated by maltol pretreatment, compared to the alcohol group (p < 0.05. Histopathological examination revealed that maltol pretreatment significantly inhibited alcohol-induced hepatocyte apoptosis and fatty degeneration. Interestingly, pretreatment of maltol effectively relieved alcohol-induced oxidative damage in a dose-dependent manner. Maltol appeared to possess promising anti-oxidative and anti-inflammatory capacities. It was suggested that the hepatoprotective effect exhibited by maltol on alcohol-induced liver oxidative injury may be due to its potent antioxidant properties.

  3. Association between insertion/deletion polymorphism in angiotensin-converting enzyme gene and acute lung injury/acute respiratory distress syndrome: a meta-analysis

    Matsuda Akihisa

    2012-08-01

    Full Text Available Abstract Background A previous meta-analysis reported a positive association between an insertion/deletion (I/D polymorphism in the angiotensin-converting enzyme gene (ACE and the risk of acute lung injury (ALI/acute respiratory distress syndrome (ARDS. Here, we updated this meta-analysis and additionally assessed the association of this polymorphism with ALI/ARDS mortality. Methods We searched electronic databases through October 2011 for the terms “angiotensin-converting enzyme gene”, “acute lung injury”, and “acute respiratory distress syndrome,” and reviewed all studies that reported the relationship of the I/D polymorphism in ACE with ALI/ARDS in humans. Seven studies met the inclusion criteria, comprising 532 ALI/ARDS patients, 3032 healthy controls, and 1432 patients without ALI/ARDS. We used three genetic models: the allele, dominant, and recessive models. Results The ACE I/D polymorphism was not associated with susceptibility to ALI/ARDS for any genetic model. However, the ACE I/D polymorphism was associated with the mortality risk of ALI/ARDS in Asian subjects ( Pallele Pdominant = 0.001, Precessive = 0.002. This finding remained significant after correction for multiple comparisons. Conclusions There is a possible association between the ACE I/D polymorphism genotype and the mortality risk of ALI/ARDS in Asians.

  4. The role of iron in Libby amphibole-induced acute lung injury and inflammation.

    Shannahan, Jonathan H; Ghio, Andrew J; Schladweiler, Mette C; McGee, John K; Richards, Judy H; Gavett, Stephen H; Kodavanti, Urmila P

    2011-05-01

    Complexation of host iron (Fe) on the surface of inhaled asbestos fibers has been postulated to cause oxidative stress contributing to in vivo pulmonary injury and inflammation. We examined the role of Fe in Libby amphibole (LA; mean length 4.99 µm ± 4.53 and width 0.28 µm ± 0.19) asbestos-induced inflammogenic effects in vitro and in vivo. LA contained acid-leachable Fe and silicon. In a cell-free media containing FeCl(3), LA bound #17 µg of Fe/mg of fiber and increased reactive oxygen species generation #3.5 fold, which was reduced by deferoxamine (DEF) treatment. In BEAS-2B cells exposure to LA, LA loaded with Fe (FeLA), or LA with DEF did not increase HO-1 or ferritin mRNA expression. LA increased IL-8 expression, which was reduced by Fe loading but increased by DEF. To determine the role of Fe in LA-induced lung injury in vivo, spontaneously hypertensive rats were exposed intratracheally to either saline (300 µL), DEF (1 mg), FeCl(3) (21 µg), LA (0.5 mg), FeLA (0.5 mg), or LA + DEF (0.5 mg). LA caused BALF neutrophils to increase 24 h post-exposure. Loading of Fe on LA but not chelation slightly decreased neutrophilic influx (LA + DEF > LA > FeLA). At 4 h post-exposure, LA-induced lung expression of MIP-2 was reduced in rats exposed to FeLA but increased by LA + DEF (LA + DEF > LA > FeLA). Ferritin mRNA was elevated in rats exposed to FeLA compared to LA. In conclusion, the acute inflammatory response to respirable fibers and particles may be inhibited in the presence of surface-complexed or cellular bioavailable Fe. Cell and tissue Fe-overload conditions may influence the pulmonary injury and inflammation caused by fibers.

  5. Prone position prevents regional alveolar hyperinflation and mechanical stress and strain in mild experimental acute lung injury.

    Santana, Maria Cristina E; Garcia, Cristiane S N B; Xisto, Débora G; Nagato, Lilian K S; Lassance, Roberta M; Prota, Luiz Felipe M; Ornellas, Felipe M; Capelozzi, Vera L; Morales, Marcelo M; Zin, Walter A; Pelosi, Paolo; Rocco, Patricia R M

    2009-06-30

    Prone position may delay the development of ventilator-induced lung injury (VILI), but the mechanisms require better elucidation. In experimental mild acute lung injury (ALI), arterial oxygen partial pressure (Pa O2), lung mechanics and histology, inflammatory markers [interleukin (IL)-6 and IL-1 beta], and type III procollagen (PCIII) mRNA expressions were analysed in supine and prone position. Wistar rats were randomly divided into two groups. In controls, saline was intraperitoneally injected while ALI was induced by paraquat. After 24-h, the animals were mechanically ventilated for 1-h in supine or prone positions. In ALI, prone position led to a better blood flow/tissue ratio both in ventral and dorsal regions and was associated with a more homogeneous distribution of alveolar aeration/tissue ratio reducing lung static elastance and viscoelastic pressure, and increasing end-expiratory lung volume and Pa O2. PCIII expression was higher in the ventral than dorsal region in supine position, with no regional changes in inflammatory markers. In conclusion, prone position may protect the lungs against VILI, thus reducing pulmonary stress and strain.

  6. Propofol pretreatment attenuates lipopolysaccharide-induced acute lung injury in rats by activating the phosphoinositide-3-kinase/Akt pathway

    Zhao, L.L. [Department of Anesthesiology, The Affiliated Hospital of Xuzhou Medical College, Xuzhou, Jiangsu Province (China); Hu, G.C. [Department of Pharmacology, College of Medicine, University of Illinois at Chicago, Chicago, IL (United States); Zhu, S.S. [Department of Anesthesiology, The Affiliated Hospital of Xuzhou Medical College, Xuzhou, Jiangsu Province (China); Li, J.F. [Department of Anesthesiology, Tengzhou Central People' s Hospital, Liaocheng, Shandong Province (China); Liu, G.J. [Department of Anesthesiology, The Affiliated Hospital of Xuzhou Medical College, Xuzhou, Jiangsu Province (China)

    2014-10-14

    The aim of this study was to investigate the effect of propofol pretreatment on lipopolysaccharide (LPS)-induced acute lung injury (ALI) and the role of the phosphoinositide-3-kinase/protein kinase B (PI3K/Akt) pathway in this procedure. Survival was determined 48 h after LPS injection. At 1 h after LPS challenge, the lung wet- to dry-weight ratio was examined, and concentrations of protein, tumor necrosis factor-α (TNF-α), and interleukin-6 (IL-6) in bronchoalveolar lavage fluid (BALF) were determined using the bicinchoninic acid method or ELISA. Lung injury was assayed via lung histological examination. PI3K and p-Akt expression levels in the lung tissue were determined by Western blotting. Propofol pretreatment prolonged survival, decreased the concentrations of protein, TNF-α, and IL-6 in BALF, attenuated ALI, and increased PI3K and p-Akt expression in the lung tissue of LPS-challenged rats, whereas treatment with wortmannin, a PI3K/Akt pathway specific inhibitor, blunted this effect. Our study indicates that propofol pretreatment attenuated LPS-induced ALI, partly by activation of the PI3K/Akt pathway.

  7. Roger S. Mitchell lecture. Uses of expression microarrays in studies of pulmonary fibrosis, asthma, acute lung injury, and emphysema.

    Sheppard, Dean

    2002-03-01

    Expression microarrays are a powerful tool that could provide new information about the molecular pathways regulating common lung diseases. To exemplify how this tool can be useful, selected examples of informative experiments are reviewed. In studies relevant to asthma, the cytokine interleukin-13 has been shown to produce many of the phenotypic features of this disease, but the cellular targets in the airways and the molecular pathways activated are largely unknown. We have used microarrays to begin to dissect the different transcriptional responses of primary lung cells to this cytokine. In experiments designed to identify global transcriptional programs responsible for regulating lung inflammation and pulmonary fibrosis, we performed microarray experiments on lung tissue from wild-type mice and mice lacking a member of the integrin family know to be involved in activation of latent transforming growth factor (TGF)-beta. In addition to identifying distinct cluster of genes involved in each of these processes, these studies led to the identification of novel pathways by which TGF-beta can regulate acute lung injury and emphysema. Together, these examples demonstrate how careful application and thorough analysis of expression microarrays can facilitate the discovery of novel molecular targets for intervening in common lung diseases.

  8. A novel telomerase activator suppresses lung damage in a murine model of idiopathic pulmonary fibrosis.

    Le Saux, Claude Jourdan; Davy, Philip; Brampton, Christopher; Ahuja, Seema S; Fauce, Steven; Shivshankar, Pooja; Nguyen, Hieu; Ramaseshan, Mahesh; Tressler, Robert; Pirot, Zhu; Harley, Calvin B; Allsopp, Richard

    2013-01-01

    The emergence of diseases associated with telomere dysfunction, including AIDS, aplastic anemia and pulmonary fibrosis, has bolstered interest in telomerase activators. We report identification of a new small molecule activator, GRN510, with activity ex vivo and in vivo. Using a novel mouse model, we tested the potential of GRN510 to limit fibrosis induced by bleomycin in mTERT heterozygous mice. Treatment with GRN510 at 10 mg/kg/day activated telomerase 2-4 fold both in hematopoietic progenitors ex vivo and in bone marrow and lung tissue in vivo, respectively. Telomerase activation was countered by co-treatment with Imetelstat (GRN163L), a potent telomerase inhibitor. In this model of bleomycin-induced fibrosis, treatment with GRN510 suppressed the development of fibrosis and accumulation of senescent cells in the lung via a mechanism dependent upon telomerase activation. Treatment of small airway epithelial cells (SAEC) or lung fibroblasts ex vivo with GRN510 revealed telomerase activating and replicative lifespan promoting effects only in the SAEC, suggesting that the mechanism accounting for the protective effects of GRN510 against induced lung fibrosis involves specific types of lung cells. Together, these results support the use of small molecule activators of telomerase in therapies to treat idiopathic pulmonary fibrosis.

  9. A novel telomerase activator suppresses lung damage in a murine model of idiopathic pulmonary fibrosis.

    Claude Jourdan Le Saux

    Full Text Available The emergence of diseases associated with telomere dysfunction, including AIDS, aplastic anemia and pulmonary fibrosis, has bolstered interest in telomerase activators. We report identification of a new small molecule activator, GRN510, with activity ex vivo and in vivo. Using a novel mouse model, we tested the potential of GRN510 to limit fibrosis induced by bleomycin in mTERT heterozygous mice. Treatment with GRN510 at 10 mg/kg/day activated telomerase 2-4 fold both in hematopoietic progenitors ex vivo and in bone marrow and lung tissue in vivo, respectively. Telomerase activation was countered by co-treatment with Imetelstat (GRN163L, a potent telomerase inhibitor. In this model of bleomycin-induced fibrosis, treatment with GRN510 suppressed the development of fibrosis and accumulation of senescent cells in the lung via a mechanism dependent upon telomerase activation. Treatment of small airway epithelial cells (SAEC or lung fibroblasts ex vivo with GRN510 revealed telomerase activating and replicative lifespan promoting effects only in the SAEC, suggesting that the mechanism accounting for the protective effects of GRN510 against induced lung fibrosis involves specific types of lung cells. Together, these results support the use of small molecule activators of telomerase in therapies to treat idiopathic pulmonary fibrosis.

  10. Soluble CD59 is a Novel Biomarker for the Prediction of Obstructive Chronic Lung Allograft Dysfunction after Lung Transplantation

    Budding, Kevin; Van De Graaf, Eduard A.; Kardol-Hoefnagel, Tineke; Kwakkel-van Erp, Johanna M.; Luijk, Bart D.; Oudijk, Erik Jan D; Van Kessel, Diana A.; Grutters, Jan C.; Hack, C. Erik; Otten, Henderikus G.

    2016-01-01

    CD59 is a complement regulatory protein that inhibits membrane attack complex formation. A soluble form of CD59 (sCD59) is present in various body fluids and is associated with cellular damage after acute myocardial infarction. Lung transplantation (LTx) is the final treatment for end-stage lung dis

  11. α1-ANTITRYPSIN ATTENUATES ENDOTOXIN-INDUCED ACUTE LUNG INJURY IN RABBITS

    揭志军; 蔡映云; 杨文兰; 金美玲; 朱威; 祝慈芳

    2003-01-01

    Objective To investigate whether pretreatment with α1-AT can attenuate acute lung injury (ALI) in rabbits induced with endotoxin. Methods Thirty-two New Zealand rabbits were randomly assigned to four groups(n=8):1.Infusion of endotoxin(Lipopolysaccharide,LPS 500μg/kg)without α1-AT (group LPS).2.Infusion α1-AT 120mg/kg at 15min before challenge with LPS(group LAV).3.Infusion of α1-AT 120mg/kg(group AAT).4 Infusion of saline 4ml/kg as control (group NS).Arterial blood gases,peripheral leukocyte counts and airway pressure were recorded every 1h.Physiologic intrapulmonary shunting (Qs/Qt) was measured every 4h.After 8h the bloods were collected for measurement of plasma concentration and activity of α1-AT.Then bronchoalveolar lavage fluid (BALF)was collected for measurement of concentrations of total protein (TP),interleukin-8(IL-8),tumor necrosis factor(TNF-α),the activities of elastase-like and α1-AT,total phospholipids(TPL) and disaturated phosphatidylcholine (DSPC).In addition,the wet-to-dry lung weight ratio(W/D) was measured. Results After infusion of endotoxin,it was observed that PaO2,peripheral luekocyte counts,total respiratory compliance progressively decreased and Ppeak and Qs/Qt increased comparing with the baseline values.In contrast to group NS,the increased plasma concentration but reduced activity of α1-AT was found in group LPS.In the BALF,the activity of α1-AT,TPL,DSPC/TPL were lower,but the concentrations of albumin,IL-8,TNF-α,and the activity of NE were higher.The ratio of W/D also increased.The pretreatment of α1-AT attenuated the deterioration of oxygenation,the reduction of compliance and the deterioration of other physiological,biochemical parameters mentioned above. Conclusion Pretreatment with α1-AT could attenuate endotoxin-induced lung injury in rabbits.Those beneficial effects of α1-AT might be due in part to the inhibitory effect on neutrophil elastase.

  12. Cannabidiol, a non-psychotropic plant-derived cannabinoid, decreases inflammation in a murine model of acute lung injury: role for the adenosine A(2A) receptor.

    Ribeiro, Alison; Ferraz-de-Paula, Viviane; Pinheiro, Milena L; Vitoretti, Luana B; Mariano-Souza, Domenica P; Quinteiro-Filho, Wanderley M; Akamine, Adriana T; Almeida, Vinícius I; Quevedo, João; Dal-Pizzol, Felipe; Hallak, Jaime E; Zuardi, Antônio W; Crippa, José A; Palermo-Neto, João

    2012-03-05

    Acute lung injury is an inflammatory condition for which treatment is mainly supportive because effective therapies have not been developed. Cannabidiol, a non-psychotropic cannabinoid component of marijuana (Cannabis sativa), has potent immunosuppressive and anti-inflammatory properties. Therefore, we investigated the possible anti-inflammatory effect of cannabidiol in a murine model of acute lung injury. Analysis of total inflammatory cells and differential in bronchoalveolar lavage fluid was used to characterize leukocyte migration into the lungs; myeloperoxidase activity of lung tissue and albumin concentration in the bronchoalveolar lavage fluid were analyzed by colorimetric assays; cytokine/chemokine production in the bronchoalveolar lavage fluid was also analyzed by Cytometric Bead Arrays and Enzyme-Linked Immunosorbent Assay (ELISA). A single dose of cannabidiol (20mg/kg) administered prior to the induction of LPS (lipopolysaccharide)-induced acute lung injury decreases leukocyte (specifically neutrophil) migration into the lungs, albumin concentration in the bronchoalveolar lavage fluid, myeloperoxidase activity in the lung tissue, and production of pro-inflammatory cytokines (TNF and IL-6) and chemokines (MCP-1 and MIP-2) 1, 2, and 4days after the induction of LPS-induced acute lung injury. Additionally, adenosine A(2A) receptor is involved in the anti-inflammatory effects of cannabidiol on LPS-induced acute lung injury because ZM241385 (4-(2-[7-Amino-2-(2-furyl)[1,2,4]triazolo[2,3-a][1,3,5]triazin-5-ylamino]ethyl)phenol) (a highly selective antagonist of adenosine A(2A) receptor) abrogated all of the anti-inflammatory effects of cannabidiol previously described. Thus, we show that cannabidiol has anti-inflammatory effects in a murine model of acute lung injury and that this effect is most likely associated with an increase in the extracellular adenosine offer and signaling through adenosine A(2A) receptor.

  13. Proceedings of the Workshop on Acute Lung Injury and Pulmonary Edema Held in Aberdeen Proving Ground, Maryland on 4-5 May 1989

    1989-11-01

    with side effects, including pulmonary edema . The objective of this study was to determine if the pulmonary edema was cardiogenic or noncardio- genic...Proeedings ~FL gof the .1Workshop on Acute Lung Injury and Pulmonary Edema 4-5 May 1989a Aberdeen Proving Ground, Maryland I7 21 Sponsored by the...TITLE (include Security Classification) (U) Proceedings of the" Workshop on Acute Lung Injury and Pulmonary Edema , May 1989 12. PERSONAL AUTHOR(S) David

  14. Plantamajoside ameliorates lipopolysaccharide-induced acute lung injury via suppressing NF-κB and MAPK activation.

    Wu, Haichong; Zhao, Gan; Jiang, Kangfeng; Chen, Xiuying; Zhu, Zhe; Qiu, Changwei; Li, Chengye; Deng, Ganzhen

    2016-06-01

    Despite developments in the knowledge and therapy of acute lung injury in recent decades, mortality remains high, and there is usually a lack of effective therapy. Plantamajoside, a major ingredient isolated from Plantago asiatica L. (Plantaginaceae), has been reported to have potent anti-inflammatory properties. However, the effect of plantamajoside on lipopolysaccharide (LPS)-induced acute lung injury (ALI) in mice has not been investigated. The present study aimed to reveal the potential mechanism responsible for the anti-inflammatory effects of plantamajoside on LPS-induced acute lung injury in mice and in RAW264.7 cells. The results of histopathological changes as well as the lung wet-to-dry ratio and myeloperoxidase (MPO) activity showed that plantamajoside ameliorated the lung injury that was induced by LPS. qPCR and ELISA assays demonstrated that plantamajoside suppressed the production of IL-1β, IL-6 and TNF-α in a dose-dependent manner. TLR4 is an important sensor in LPS infection. Molecular studies showed that the expression of TLR4 was inhibited by plantamajoside administration. Further study was conducted on nuclear factor (NF)-κB and mitogen-activated protein kinase (MAPK) using pathways using western blots. The results showed that plantamajoside inhibited the phosphorylation of IκBα, p65, p38, JNK and ERK. All results indicated that plantamajoside has protective effect on LPS-induced ALI in mice and in RAW264.7 cells. Thus, plantamajoside may be a potential therapy for the treatment of pulmonary inflammation.

  15. Recombinant osteopontin attenuates hyperoxia-induced acute lung injury through inhibiting nuclear factor kappa B and matrix metalloproteinases 2 and 9

    Zhang Xiangfeng; Liu Fen; Zhu Guangfa; Wang Zengzhi

    2014-01-01

    Background Exposure of adult mice to more than 95% O2 produces a lethal injury by 72 hours.Nuclear factor kappa B (NF-κB) is a transcriptional factor that plays a key role in the modulation of cytokine networks during hyperoxia-induced acute lung injury (ALl).Osteopontin (OPN) is a phosphorylated glycoprotein produced principally by macrophages.Studies have reported that exogenous OPN can maintain the integrity of the cerebral microvascular basement membrane and reduce brain damage through inhibiting NF-κB activities in the brain after subarachnoid hemorrhage.However,it is not clear whether OPN can reduce lung injury during ALl by inhibiting transcriptional signal pathways of NF-κB and consequent inhibition of infiammatory cytokines.Thus we examined the effects and mechanisms of recombinant OPN (r-OPN) on ALl.Methods Ninety-six mice were randomly divided into phosphate buffered saline (PBS) and r-OPN groups.Mice were put in an oxygen chamber (>95% O2) and assessed for lung injury at 24,48,and 72 hours.Expressions of NF-κB,matrix metalloproteinases 2 and 9 (MMP-2 and MMP-9),and tissue inhibitors of MMP-2 and MMP-9 (TIMP-1,TIMP-2) mRNA in lungs were examined with RT-PCR.Expression and distribution of NF-κB protein in lungs were measured with immunohistochemistry.Results Exposure to hyperoxia for 72 hours induced more severe lung injury in the PBS group compared with the r-OPN group.Expression of NF-κB mRNA in the PBS group exposed to hyperoxia for 48 and 72 hours was significantly higher than the r-OPN group (P <0.05).With 72-hour exposure,expression of TIMP-1 mRNA in the r-OPN group was significantly higher than that of the PBS group (P <0.05).Expression of TIMP-2 mRNA in the r-OPN group at 48 and 72 hours was significantly higher than those in the PBS group (P <0.05).After 72-hour exposure,expression of NF-κB protein in airway epithelium in the PBS group was significantly higher than that in the r-OPN group (P <0.05).Conclusion r-OPN can

  16. Cerium Oxide Nanoparticles Induced Toxicity in Human Lung Cells: Role of ROS Mediated DNA Damage and Apoptosis

    Sandeep Mittal

    2014-01-01

    Full Text Available Cerium oxide nanoparticles (CeO2 NPs have promising industrial and biomedical applications. In spite of their applications, the toxicity of these NPs in biological/physiological environment is a major concern. Present study aimed to understand the molecular mechanism underlying the toxicity of CeO2 NPs on lung adenocarcinoma (A549 cells. After internalization, CeO2 NPs caused significant cytotoxicity and morphological changes in A549 cells. Further, the cell death was found to be apoptotic as shown by loss in mitochondrial membrane potential and increase in annexin-V positive cells and confirmed by immunoblot analysis of BAX, BCl-2, Cyt C, AIF, caspase-3, and caspase-9. A significant increase in oxidative DNA damage was found which was confirmed by phosphorylation of p53 gene and presence of cleaved poly ADP ribose polymerase (PARP. This damage could be attributed to increased production of reactive oxygen species (ROS with concomitant decrease in antioxidant “glutathione (GSH” level. DNA damage and cell death were attenuated by the application of ROS and apoptosis inhibitors N-acetyl-L- cysteine (NAC and Z-DEVD-fmk, respectively. Our study concludes that ROS mediated DNA damage and cell cycle arrest play a major role in CeO2 NPs induced apoptotic cell death in A549 cells. Apart from beneficial applications, these NPs also impart potential harmful effects which should be properly evaluated prior to their use.

  17. Protective effect of erdosteine metabolite I against hydrogen peroxide-induced oxidative DNA-damage in lung epithelial cells.

    Marabini, Laura; Calò, Rossella; Braga, Pier Carlo

    2011-01-01

    It has been shown that the mucolytic agent erdosteine (N-carboxymethylthio-acetyl-homocysteine thiolactone, CAS 84611-23-4) has anti-inflammatory and anti-oxidant properties, and an active metabolite I (MET I) containing pharmacologically active sulphydryl group has been found to have a free radical scavenging activity. The aim of this study was to assess the ability of erdosteine metabolite I to protect A549 human lung adenocarcinoma cell against hydrogen peroxide (H2O2)-mediated oxidative stress and oxidative DNA damage. When A549 cells were pre-treated with the active metabolite I (2.5-5-10 microg/ml) for 10-30 min and then exposed to H2O2 (1-4 mM) for two additional hours at 37 degrees C, 5% at CO2, the intracellular peroxide production, reflected by dichlorofluorescein (DCF) fluorescence, decreased in a concentration-dependent manner. Furthermore, using a comet assay as an indicator for oxidative DNA damage, it was found that the metabolite I prevented damage to cells exposed to shortterm H2O2 treatment. The data suggest that this compound is effective in preventing H2O2-induced oxidative stress and DNA damage in A549 cells. The underlying mechanisms involve the scavenging of intracellular reactive oxygen species (ROS).

  18. Acute myocardial infarction mimicking squamous cell lung cancer with bone metastases due to hypercalcemia: a case report

    FANG Chong-feng; XU Geng; CHEN Yang-xin

    2010-01-01

    @@ Acute myocardial infarction (AMI), the most severe coronary artery disease, is one of the most frequent cardiac emergencies, and early diagnosis and treatment are very important to decrease the subsequent cardiac adverse events such as malignant arrhythmia and sudden cardiac death. But in fact, lots of diseases are similar to AMI in clinical practice, of which the most common are myocarditis, pulmonary embolism in department of cardiology. Here we report a case of AMI-like squamous cell lung cancer with bone metastases.

  19. Differential diagnosis of acute miliary pulmonary tuberculosis from widespread-metastatic cancer for postoperative lung cancer patients: two cases

    Zhao, Wei; Tian, Yuke; Peng, Feng; Long, Jianlin; Liu, Lan; Lu, You

    2017-01-01

    Pulmonary infections and lung cancer can resemble each other on radiographic images, which makes it difficult to diagnosis accurately and apply an appropriate therapy. Here we report two cases that two postoperative patients with lung adenocarcinoma developed diffuse nodules in bilateral lungs in a month which needed to be distinguished between metastatic malignancies and infectious diseases. Although there are much similarities in disease characteristics of two cases, patient in case one was diagnosed as acute miliary pulmonary tuberculosis (TB) while patient in case two was diagnosed as metastatic disease. The symptoms and pulmonary foci on CT scan of patient in case one improved distinctly after the immediate anti-TB treatment, but the disease of patient in case two progressed after chemotherapy. These findings caution us that differential diagnosis is crucial and have significance in guiding clinical work.

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

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

    2003-12-01

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

  1. Elevated mRNA levels of CTLA-4, FoxP3, and granzyme B in BAL, but not in blood, during acute rejection of lung allografts

    Madsen, Caroline B; Nørgaard, Astrid; Iversen, Martin

    2010-01-01

    expression and acute rejection is still being debated. Some studies have been performed on blood samples from lung-transplanted patients, while others have investigated the local immune response in the lungs by analysing broncho-alveolar-lavage (BAL) fluids or biopsies. Biopsies are considered the gold...

  2. Acute lung inflammation in Klebsiella pneumoniae B5055-induced pneumonia and sepsis in BALB/c mice: a comparative study.

    Kumar, Vijay; Chhibber, Sanjay

    2011-10-01

    Lungs play an important role in the body's defense against a variety of pathogens, but this network of immune system-mediated defense can be deregulated during acute pulmonary infections. The present study compares acute lung inflammation occurring during Klebsiella pneumoniae B5055-induced pneumonia and sepsis in BALB/c mice. Pneumonia was induced by intranasal instillation of bacteria (10(4) cfu), while sepsis was developed by placing the fibrin-thrombin clot containing known amount of bacteria (10(2) cfu) into the peritoneal cavity of animals. Mice with sepsis showed 100% mortality within five post-infection days, whereas all the animals with pneumonia survived. In animals suffering from K. pneumoniae B5055-induced pneumonia, all the inflammatory parameters (TNF-α, IL-1α, MPO, MDA, and NO) were found to be maximum till third post-infection day, after that, a decline was observed, whereas in septic animals, all the above-mentioned markers of inflammation kept on increasing. Histopathological study showed presence of alternatively activated alveolar macrophages (or foam cells) in lungs of mice with pneumonia after third post-infection day, which might have contributed to the induction of resolution of inflammation, but no such observation was made in lungs of septic mice. Hence, during pneumonia, controlled activation of macrophages may lead to resolution of inflammation.

  3. Acute and subacute non-infectious lung diseases. Usefulness of HRCT for evaluation of activity especially in follow-up

    Johkoh, Takeshi; Tomiyama, Noriyuki; Honda, Osamu [Osaka Univ., Suita (Japan). Medical School] (and others)

    2000-08-01

    The purpose of this study was to survey the usefulness of high-resolution CT (HRCT) for the evaluation of activity in acute and subacute non-infectious diffuse infiltrative lung diseases before and after corticosteroid treatment. Sequential HRCT images and chest radiographs obtained before and after treatment were retrospectively evaluated in 33 patients with acute or subacute non-infectious diffuse infiltrative lung diseases. All these patients were histologically confirmed to have pulmonary Inflammation and to have responded to treatment with corticosteroid. Radiographic and CT scores were correlated with the degree of dyspnea and the results of arterial blood gas analysis using Spearman's rank-correlation coefficient. On follow-up HRCT, the profusion score of areas with increased attenuation was significantly correlated with arterial oxygen tension (PaO{sub 2}) (p=.003, r=-.53) and the alveolar-arterial oxygen tension difference (AaDO{sub 2}) (p=.001, r=.57). No other correlation was found after treatment. Nodular and linear opacities were more commonly seen on follow-up chest radiographs and HRCT images than on initial ones. HRCT is useful for the evaluation of disease activity in acute and subacute non-infectious infiltrative lung diseases before and after treatment if paying special attention to the profusion of ground-glass attenuation. Even if pretreatment HRCT has not been performed, posttreatment HRCT should be examined. (author)

  4. Calpain inhibitor attenuated optic nerve damage in acute optic neuritis in rats

    Das, Arabinda; Guyton, M. Kelly; Smith, Amena; Wallace, Gerald; McDowell, Misty L.; Matzelle, Denise D.; Ray, Swapan K.; Banik, Naren L.

    2012-01-01

    Optic neuritis (ON), which is an acute inflammatory autoimmune demyelinating disease of the central nervous system (CNS), often occurs in multiple sclerosis (MS). ON is an early diagnostic sign in most MS patients caused by damage to the optic nerve leading to visual dysfunction. Various features of both MS and ON can be studied following induction of experimental autoimmune encephalomyelitis (EAE), an animal model of MS, in Lewis rats. Inflammation and cell death in the optic nerve, with subsequent damage to the retinal ganglion cells in the retina, are thought to correlate with visual dysfunction. Thus, characterizing the pathophysiological changes that lead to visual dysfunction in EAE animals may help develop novel targets for therapeutic intervention. We treated EAE animals with and without the calpain inhibitor calpeptin (CP). Our studies demonstrated that the Ca2+-activated neutral protease calpain was upregulated in the optic nerve following induction of EAE at the onset of clinical signs (OCS) of the disease and these changes were attenuated following treatment with CP. These reductions correlated with decreases in inflammation (cytokines, iNOS, COX-2, NF-κB), and microgliosis (i.e. activated microglia). We observed that calpain inhibition reduced astrogliosis (reactive astroglia) and expression of aquaporin 4 (AQP4). The balance of Th1/Th2 cytokine production and also expression of the Th1-related CCR5 and CXCR3 chemokine receptors influence many pathological processes and play both causative and protective roles in neuron damage. Our data indicated that CP suppressed cytokine imbalances. Also, Bax:Bcl-2 ratio, production of tBid, PARP-1, expression and activities of calpain and caspases, and internucleosomal DNA fragmentation were attenuated after treatment with CP. Our results demonstrated that CP decreased demyelination [loss of myelin basic protein (MBP)] and axonal damage [increase in dephosphorylated neurofilament protein (de-NFP), and also

  5. Mucoactive effects of naringin in lipopolysaccharide-induced acute lung injury mice and beagle dogs.

    Chen, Yan; Wu, Hao; Nie, Yi-chu; Li, Pei-bo; Shen, Jian-gang; Su, Wei-wei

    2014-07-01

    Our previous study has demonstrated that naringin attenuates EGF-induced MUC5AC hypersecretion in A549 cells by suppressing the cooperative activities of MAPKs/AP-1 and IKKs/IκB/NF-κB signaling pathways. However, the volume of airway mucus is determined by two factors including the number of mucous cells and capacity of mucus secretion. The aim of the present study is to explore the mucoactive effects of naringin in lipopolysaccharide (LPS)-induced acute lung injury (ALI) mice and beagle dogs. The results demonstrated that naringin of 12.4 mg/kg treatment significantly decreased LPS-induced enhancement of sputum volume and pulmonary inflammation, remarkably increased the subglottic sputum volume and solids content in sputum of lower trachea, while partially, but not fully, significantly increased the elasticity and viscosity of sputum in lower trachea of beagle dogs. Moreover, the MUC5AC content in BALF and goblet-cells in large airways of LPS-induced ALI mice were significantly attenuated by dexamethasone (5 mg/kg), ambroxol (25 mg/kg), and naringin (15, 60 mg/kg). However, the goblet-cells hyperplasia in small airways induced by LPS was only significantly inhibited by dexamethasone and naringin (60 mg/kg). In conclusion, naringin exhibits mucoactive effects through multiple targets which including reduction of goblet cells hyperplasia and mucus hypersecretion, as well as promotion of sputum excretion.

  6. The impact of intravenous fat emulsion administration in acute lung injury.

    Lekka, Marilena E; Liokatis, Stamatis; Nathanail, Christos; Galani, Vasiliki; Nakos, George

    2004-03-01

    The aim of this study was to evaluate the effect of parenteral nutrition containing medium- and long-chain triglycerides on the function of the respiratory system and to investigate mechanisms involved in this process. We studied 13 patients with acute respiratory distress syndrome (ARDS), 8 receiving lipid and 5 placebo, and 6 without ARDS, receiving lipid. Bronchoalveolar lavage (BAL) was performed before and 1 hour after administration of lipid or placebo. In patients with ARDS, lipid administration resulted in deterioration of oxygenation (Pa(O(2))/FI(O(2)): from 129 +/- 37 to 95 +/- 42), compliance of respiratory system (from 39.2 +/- 12 to 33.1 +/- 9.2 ml/cm H(2)O), and pulmonary vascular resistance (from 258 +/- 47 to 321 +/- 58 dyne x s x cm(-5)). In the BAL fluid of the same group, an increase in total protein and phospholipid concentrations, phospholipase activities, platelet-activating factor and neutrophils, as well as alterations in BAL lipid profile were observed. No significant changes were observed in the control or in the ARDS-Placebo groups. In conclusion, this study indicates that administration of medium- and long-chain triglycerides in patients with ARDS causes alterations in lung function and hemodynamics. Inflammatory cells, possibly activated by lipids, release phospholipase A(2) and platelet-activating factor, enhancing edema formation, inflammation, and surfactant alterations.

  7. A clinical study of multiple trauma combined with acute lung injury

    Tao Liang; Yong-Fu Ma; Jian Zhu; Dao-Xi Wang; Yang Liu

    2016-01-01

    Objective: To study the changes of the contents of inflammatory mediators in serum of polytrauma patients with acute lung injury (ALI) and their correlation with the disease. Methods: Patients suffering from multiple trauma combined with ALI were selected as ALI group (n=54). Patients suffering from multiple trauma without ALI were considered as the control group (n=117). The severity of the disease of patients in the two groups was assessed. Arterial blood was extracted for blood gas analysis. Venous blood was extracted to detect the contents of inflammatory mediators tumor necrosis factor-a, interleukin-1b (IL-1b), IL-10, granulocyte-macrophage colony stimulating factor, NO, endothelin-1. Results: The scores of injury severity score [(25.42 ± 3.58) vs. (17.03 ± 2.25)], systemic inflammatory response syndrome [(3.85 ± 0.52) vs. (2.20 ± 0.36)] and acute physiology and chronic health evaluation II [(92.63 ± 11.04) vs. (60.46 ± 8.87)] in patients in ALI group were all significantly higher than those in the control group and its correcting shock time [(8.39 ± 1.05) vs. (5.15 ± 0.72) h] was longer than that of the control group. The amount of blood transfusion [(674.69 ± 93.52) vs. (402.55 ± 57.65) mL] was greater than that in the control group. The contents of the arterial partial pressure of oxygen [(76.65 ± 9.68) vs. (86.51 ± 10.56) mmHg], arterial blood pressure of carbon dioxide [(27.76 ± 4.82) vs. (36.78 ± 5.82) mmHg] and arterial partial pressure of oxygen/fraction of inspired oxygen [(236.94 ± 36.49) vs. (353.95 ± 47.76)] were all significantly lower than those in the control group. The contents of serum tumor necrosis factor-a, IL-1b, IL-10, granulocyte-macrophage colony stimulating factor, NO and endothelin-1 were obviously higher than those of control group and also positively correlated with the scores of injury severity score, systemic inflammatory response syndrome and acute physiology and chronic health evaluation II.

  8. A clinical study of multiple trauma combined with acute lung injury

    Tao Liang

    2016-11-01

    Full Text Available Objective: To study the changes of the contents of inflammatory mediators in serum of polytrauma patients with acute lung injury (ALI and their correlation with the disease. Methods: Patients suffering from multiple trauma combined with ALI were selected as ALI group (n = 54. Patients suffering from multiple trauma without ALI were considered as the control group (n = 117. The severity of the disease of patients in the two groups was assessed. Arterial blood was extracted for blood gas analysis. Venous blood was extracted to detect the contents of inflammatory mediators tumor necrosis factor-a, interleukin-1b (IL-1b, IL-10, granulocyte-macrophage colony stimulating factor, NO, endothelin-1. Results: The scores of injury severity score [(25.42 ± 3.58 vs. (17.03 ± 2.25], systemic inflammatory response syndrome [(3.85 ± 0.52 vs. (2.20 ± 0.36] and acute physiology and chronic health evaluation II [(92.63 ± 11.04 vs. (60.46 ± 8.87] in patients in ALI group were all significantly higher than those in the control group and its correcting shock time [(8.39 ± 1.05 vs. (5.15 ± 0.72 h] was longer than that of the control group. The amount of blood transfusion [(674.69 ± 93.52 vs. (402.55 ± 57.65 mL] was greater than that in the control group. The contents of the arterial partial pressure of oxygen [(76.65 ± 9.68 vs. (86.51 ± 10.56 mmHg], arterial blood pressure of carbon dioxide [(27.76 ± 4.82 vs. (36.78 ± 5.82 mmHg] and arterial partial pressure of oxygen/fraction of inspired oxygen [(236.94 ± 36.49 vs. (353.95 ± 47.76] were all significantly lower than those in the control group. The contents of serum tumor necrosis factor-a, IL-1b, IL- 10, granulocyte-macrophage colony stimulating factor, NO and endothelin-1 were obviously higher than those of control group and also positively correlated with the scores of injury severity score, systemic inflammatory response syndrome and acute physiology and chronic health evaluation II. Conclusions

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

    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.

  10. ESR investigation of the oxidative damage in lungs caused by asbestos and air pollution particles

    Kadiiska, M. B.; Ghio, A. J.; Mason, R. P.

    2004-05-01

    Exposure to asbestos and air pollution particles can be associated with increased human morbidity and mortality. However, the molecular mechanism of lung injuries remains unknown. It has been postulated that the in vivo toxicity results from the catalysis of free radical generation. Using electron spin resonance (ESR) in conjunction with the spin trap α-(4-pyridyl-1-oxide)- N- tert-butylnitrone (4-POBN) we previously investigated in vivo free radical production by rats treated with intratracheal instillation of asbestos (crocidolite fibers) and an emission source air pollution particle (oil fly ash). In this report we compare the effect of two different exposures on the type of free radicals they induce in in vivo animal model. Twenty-four hours after the exposure, ESR spectroscopy of the chloroform extract from lungs of animals exposed to either asbestos or oil fly ash gave a spectrum consistent with a carbon-centered radical adduct ( aN=15.01 G and aH=2.46 G). To test whether free radical formation occurred in vivo and not in vitro, a number of control experiments were performed. Combinations (both individually and together) of asbestos or oil fly ash and 4-POBN were added to lung homogenate of unexposed rats prior to chloroform extraction. No detectable ESR signal resulted. To exclude the possibility of ex vivo free radical generation, asbestos or oil fly ash was added to lung homogenate of an animal treated with 4-POBN. Also, 4-POBN was added to lung homogenate from rats instilled with asbestos or oil fly ash. Neither system produced radical adducts, indicating that the ESR signal detected in the lung extracts of the treated animals must be produced in vivo and not ex vivo or in vitro. In conclusion, ESR analysis of lung tissue demonstrated that both exposures produce lipid-derived radical metabolites despite their different composition and structure. Analogously, both exposures provide evidence of in vivo enhanced lipid peroxidation. Furthermore, it is

  11. The Effects of Dexamethasone and L-NAME on Acute Lung Injury in Rats with Lung Contusion.

    Kozan, Ahmet; Kilic, Nermin; Alacam, Hasan; Guzel, Ahmet; Guvenc, Tolga; Acikgoz, Mehmet

    2016-10-01

    The therapeutic efficiency of an anti-inflammatory agent, dexamethasone (DXM), and a nitric oxide synthase (NOS) inhibitor, Nitro-L-arginine methyl ester (L-NAME), in lung tissue injury after lung contusion was investigated. Serum levels of tumor necrosis factor-alpha (TNF-α), interleukin-10 (IL-10), YKL-40, an inflammatory peptide, inducible NOS (iNOS), and Clara cell protein 16 (CC-16) were evaluated. Immunohistochemical analyses were also performed, and the lung tissue was examined histopathologically. The study consisted of eight groups of Sprague-Dawley rats (n = 10 in each group), weighing 250-300 g: (1) control, (2) contusion, (3) control + DXM, (4) contusion + DXM, (5) control + L-NAME (6) contusion + L-NAME, (7) control + DXM + L-NAME, and (8) contusion + DXM + L-NAME. A previously developed lung contusion model was used, in addition to the control group. The rats were administered DXM and L-NAME intraperitoneally (i.p.) at doses of 15 and 60 mg/kg/day, respectively. DXM and L-NAME administration decreased the iNOS level in the contusion groups. DXM increased the levels of YKL-40 and IL-10 in both the control and contusion groups, with higher levels in the contusion groups. L-NAME increased the serum level of IL-10 in the lung contusion groups. DXM increased the synthesis of CC-16 in the control and contusion groups. The combined use of a high-dose steroid and NOS inhibitor resulted in the death of the rats. Steroids can increase the level of cytokines, such as YKL-40 and IL-10, and the synthesis of CC-16 and prevent pneumonia, ALI/ARDS, and sepsis in lung contusion.

  12. Regulation on the expression of Clara cell secretory protein in the lungs of the rats with acute lung injury by growth hormone

    MIN Jia; LUO Fo-quan; ZHAO Wei-lu

    2012-01-01

    Background Clara cell secretory protein (CC16) is an important lung derived protective factor and may play an important role on the pathogenesis of acute lung injury (ALl) induced by endotoxemia.Growth hormone (GH) is an important anabolism hormone secreted by GH cells of the hypophysis.Pravious research showed that GH would significantly exacerbate ALl induced by endotoxemia,but the mechanism is not very clear yet.Whether the effects are related to CC16 or not is undetermined.Methods One hundred and twelve male Sprague-Dawley rats were randomly divided into an ALl group and a GH group.The rats in the two groups were subdivided into seven subgroups,according to injection with lipopolysaccharides (LPS) or not,then according to different intervals of time after LPS injection; 0 hour (pre-injection of LPS,acted as control group),0.5 hour,1 hour,2 hours,4 hours,6 hours and 24 hours for subgroups.Pulmonary alveolar septa area density (PASAD) and ploymorphonuclear cells (PMN) in the lungs were analyzed morphometrically.The levels of tumor necrosis factor (TNF) and interleukin 6 (1L-6) were determined by radioimmunoassay.To analyze the expression and activation of nuclear factor kappa B (NF-kB),the numbers of NF-kB positive cells in lungs were counted after immunofluorescence staining.and the levels of NF-KB inhibitory protein-α (1KB-α) in lung homogenates of rats were detected by Western blotting.The expression levels of CC16 mRNA in lungs of the rats with ALl were determined by semi-quantitative reverse transcription polymerase chain reaction (RT-PCR).The levels of CC16 protein in lung homogenates were detected by Western blotting.Results Half an hour after LPS injury both the PASAD and PMN numbers in lungs of the rats with ALl began to increase significantly and peaked at 6-hour post-injury.They then began to recover and reached normal levels at 24-hour post-injury.Both the PASAD and PMN numbers in the GH group increased more significantly than those in the ALl group

  13. Long-term effects of severe acute malnutrition on lung function in Malawian children: a cohort study.

    Lelijveld, Natasha; Kerac, Marko; Seal, Andrew; Chimwezi, Emmanuel; Wells, Jonathan C; Heyderman, Robert S; Nyirenda, Moffat J; Stocks, Janet; Kirkby, Jane

    2017-04-01

    Early nutritional insults may increase risk of adult lung disease. We aimed to quantify the impact of severe acute malnutrition (SAM) on spirometric outcomes 7 years post-treatment and explore predictors of impaired lung function.Spirometry and pulse oximetry were assessed in 237 Malawian children (median age: 9.3 years) who had been treated for SAM and compared with sibling and age/sex-matched community controls. Spirometry results were expressed as z-scores based on Global Lung Function Initiative reference data for the African-American population.Forced expiratory volume in 1 s (FEV1) and forced vital capacity (FVC) were low in all groups (mean FEV1 z-score: -0.47 for cases, -0.48 for siblings, -0.34 for community controls; mean FVC z-score: -0.32, -0.38, and -0.15 respectively). There were no differences in spirometric or oximetry outcomes between SAM survivors and controls. Leg length was shorter in SAM survivors but inter-group sitting heights were similar. HIV positive status or female sex was associated with poorer FEV1, by 0.55 and 0.31 z-scores, respectively.SAM in early childhood was not associated with subsequent reduced lung function compared to local controls. Preservation of sitting height and compromised leg length suggest "thrifty" or "lung-sparing" growth. Female sex and HIV positive status were identified as potentially high-risk groups.

  14. 15-deoxy-△12,14-prostaglandin J2 ameliorates endotoxin-induced acute lung injury in rats

    Liu Dong; Geng Zhilong; Zhu Wankun; Wang Huiwen; Chen Ye; Liang Juan

    2014-01-01

    Background A proinflammatory milieu emerging in the lung due to neutrophil accumulation and activation is a key in the pathogenesis of acute lung injury (ALI).15-deoxy-△12,14-prostaglandin J2 (15d-PGJ2),one of the terminal products of the cyclooxygenase-2 pathway,is known to be the endogenous ligand of peroxisome proliferator-activated receptor y (PPAR-y) with multiple physiological properties.Growing evidence indicates that 15d-PGJ2 has anti-inflammatory,antiproliferative,cytoprotective and pro-resolving effects.We investigated whether 15d-PGJ2 has a protective effect against endotoxin-induced acute lung injury in rats.Methods Twenty-four male Wistar rats were randomly assigned into four groups (n=6 per group):sham+vehicle group,sham+15d-PGJ2 group,LPS+vehicle group,and LPS+15d-PGJ2 group.The rats were given either lipopolysaccharide (LPS,6 mg/kg intravenously) or saline,and pretreated with 15d-PGJ2 (0.3 mg/kg intravenously) or its vehicle (dimethyl sulphoxide) 30 minutes before LPS.Histological alterations,wet/dry weight (W/D) ratio and myeloperoxidase (MPO) activity as well as tumor necrosis factor (TNF)-α and cytokine-induced neutrophil chemoattractant-1 (CINC-1) levels were determined in lung tissues four hours after LPS injection.Immunohistochemical analysis for intercellular adhesion molecule-1 (ICAM-1) expression and Western blotting analysis for nuclear factor (NF)-κB p65 translocation and IκBα protein levels were also studied.Results 15d-PGJ2 pretreatment significantly attenuated LPS-induced lung injury,and reduced the increased W/D ratio,MPO activity,TNF-α,CINC-1 levels,and ICAM-1 expression in the lung.15d-PGJ2 also suppressed the nuclear NF-ΚB p65 translocation and increased cytosolic IKBα levels.Conclusions 15d-PGJ2 protects against endotoxin-induced acute lung injury,most likely through the reduction of proinflammatory protein levels during endotoxemia subsequent to the inhibition of NF-ΚB activation.

  15. A novel fluorinated stilbene exerts hepatoprotective properties in CCl(4)-induced acute liver damage.

    Rivera, Horacio; Morales-Ríos, Martha S; Bautista, Wendy; Shibayama, Mineko; Tsutsumi, Víctor; Muriel, Pablo; Pérez-Álvarez, Víctor

    2011-10-01

    There has been a recently increase in the development of novel stilbene-based compounds with in vitro anti-inflamatory properties. For this study, we synthesized and evaluated the anti-inflammatory properties of 2 fluorinated stilbenes on carbon tetrachloride (CCl₄)-induced acute liver damage. To achieve this, CCl₄ (4 g·kg(-1), per os) was administered to male Wistar rats, followed by either 2-fluoro-4'-methoxystilbene (FME) or 2,3-difluoro-4'-methoxystilbene (DFME) (10 mg·kg(-1), per os). We found that although both of the latter compounds prevented cholestatic damage (γ-glutamyl transpeptidase activity), only DFME showed partial but consistent results in the prevention of necrosis, as assessed by both alanine aminotransferase activity and histological analysis. Since inflammatory responses are mediated by cytokines, mainly tumour necrosis factor α (TNF-α), we used the Western blot technique to determine the action of FME and DFME on the expression level of this cytokine. The observed increase in the level of TNF-α caused by CCl₄ administration was only prevented by treatment with DFME, in agreement with our biochemical findings. This result was confirmed by measuring interleukin-6 (IL-6) levels, since the expression of this protein depends on the level of TNF-α. In this case, DFME completely blocked the CCl₄-induced increase of IL-6. Our results suggest that DFME possesses greater anti-inflammatory properties in vivo than FME. DFME constitutes a possible therapeutic agent for liver disease and could serve as a template for structure optimization.

  16. Relationship between serum S-100 protein level and ischemic damage degree in patients with acute cerebral infarction

    HE Ming-li; XU Bing-chao; HUANG Guo-sheng

    2005-01-01

    Objective: To investigate the time course of serum S-100 concentrations of patients with acute cerebral infarction,and their relation with the clinical data and the prognosis. Methods: Serum S-100 levels were serially determined in 35 patients with acute cerebral infarction within 12 h, at 24 h and day 2, 3, 4, 5,7 and 10 after acute cerebral infarction and in 20 age- and sex-matched control subjects. An S-100 content assay was performed using a two-site radioimmunoassay technique. The clinical status was assessed using NIH Stroke Scale. The functional deficit at 4 weeks after acute cerebral infarction was scored using the modified Rankin scale. A cranial computed tomography was performed initially. Results: Elevated concentrations of S100 (>0.2 μg/L) were observed in 29 of 36 patients with acute cerebral infarction,but none of the control subjects. The S-100 peak levels were at day 2 and 3 after acute cerebral infarction and were significantly high in those patients with severe neurological deficit at admission, with extensive infarction or with space-occupying effect of ischemic edema as compared with the rest of the populations. Conclusion: Serum S-100 level assay can be used as a peripheral marker of ischemic brain damage, and may be helpful for evaluation of therapeutic effects in acute ischemic stroke.

  17. Xanthohumol ameliorates lipopolysaccharide (LPS)-induced acute lung injury via induction of AMPK/GSK3β-Nrf2 signal axis.

    Lv, Hongming; Liu, Qinmei; Wen, Zhongmei; Feng, Haihua; Deng, Xuming; Ci, Xinxin

    2017-03-02

    Abundant natural flavonoids can induce nuclear factor-erythroid 2 related factor 2 (Nrf2) and/or AMP-activated protein kinase (AMPK) activation, which play crucial roles in the amelioration of various inflammation- and oxidative stress-induced diseases, including acute lung injury (ALI). Xanthohumol (Xn), a principal prenylflavonoid, possesses anti-inflammation and anti-oxidant activities. However, whether Xn could protect from LPS-induced ALI through inducing AMPK/Nrf2 activation and its downstream signals, are still poorly elucidated. Accordingly, we focused on exploring the protective effect of Xn in the context of ALI and the involvement of underlying molecular mechanisms. Our findings indicated that Xn effectively alleviated lung injury by reduction of lung W/D ratio and protein levels, neutrophil infiltration, MDA and MPO formation, and SOD and GSH depletion. Meanwhile, Xn significantly lessened histopathological changes, reactive oxygen species (ROS) generation, several cytokines secretion, and iNOS and HMGB1 expression, and inhibited Txnip/NLRP3 inflammasome and NF-κB signaling pathway activation. Additionally, Xn evidently decreased t-BHP-stimulated cell apoptosis, ROS generation and GSH depletion but increased various anti-oxidative enzymes expression regulated by Keap1-Nrf2/ARE activation, which may be associated with AMPK and GSK3β phosphorylation. However, Xn-mediated inflammatory cytokines and ROS production, histopathological changes, Txnip/NLRP3 inflammasome and NF-κB signaling pathway in WT mice were remarkably abrogated in Nrf2(-/-) mice. Our experimental results firstly provided a support that Xn effectively protected LPS-induced ALI against oxidative stress and inflammation damage which are largely dependent upon upregulation of the Nrf2 pathway via activation of AMPK/GSK3β, thereby suppressing LPS-activated Txnip/NLRP3 inflammasome and NF-κB signaling pathway.

  18. Importin-α7 is required for enhanced influenza A virus replication in the alveolar epithelium and severe lung damage in mice.

    Resa-Infante, Patricia; Thieme, René; Ernst, Thomas; Arck, Petra C; Ittrich, Harald; Reimer, Rudolph; Gabriel, Gülsah

    2014-07-01

    Influenza A viruses recruit components of the nuclear import pathway to enter the host cell nucleus and promote viral replication. Here, we analyzed the role of the nuclear import factor importin-α7 in H1N1 influenza virus pulmonary tropism by using various ex vivo imaging techniques (magnetic resonance imaging, confocal laser scanning microscopy, and correlative light-electron microscopy). We infected importin-α7 gene-deficient (α7(-/-)) mice with a recombinant H1N1 influenza virus and compared the in vivo viral kinetics with those in wild-type (WT) mice. In WT mice, influenza virus replication in the bronchial and alveolar epithelium already occurred a few days after infection. Accordingly, extensive mononuclear infiltration and alveolar destruction were present in the lungs of infected WT mice, followed by 100% lethality. Conversely, in α7(-/-) mice, virus replication was restricted mostly to the bronchial epithelium with marginal alveolar infection, resulting in significantly reduced lung damage and enhanced animal survival. To investigate the host immune response during alveolar virus replication, we studied the role of primary macrophages in virus propagation and clearance. The ability of macrophages to support or clear the virus infection, as well as the host cellular immune responses, did not significantly differ between WT and α7(-/-) mice. However, cytokine and chemokine responses were generally elevated in WT mice, likely reflective of increased viral replication in the lung. In summary, these data show that a cellular factor, importin-α7, is required for enhanced virus replication in the alveolar epithelium, resulting in elevated cytokine and chemokine levels, extensive mononuclear infiltration, and thus, severe pneumonia and enhanced virulence in mice. Importance: Influenza A viruses are respiratory pathogens that may cause pneumonia in humans. Viral infection and replication in the alveoli of the respiratory tract are believed to be crucial for

  19. Mechanism of Action of Lung Damage Caused by a Nanofilm Spray Product

    Larsen, Søren T.; Dallot, Constantin; Larsen, Susan W;

    2014-01-01

    techniques and by identification of the binding interaction. Inhalation of the aerosolized product gave rise to increased airway resistance in the mice, as evident from the decreased expiratory flow rate. The toxic effect of the waterproofing spray product included interaction with the pulmonary surfactants....... More specifically, the active film-forming components in the spray product, perfluorinated siloxanes, inhibited the function of the lung surfactant due to non-covalent interaction with surfactant protein B, a component which is crucial for the stability and persistence of the lung surfactant film...... and identification of toxicological targets are important to perform rational and cost-effective toxicological studies. Thus, because the pulmonary surfactant system appears to be an important toxicological target for waterproofing spray products, study of surfactant inhibition could be included in toxicological...

  20. Ameliorative effect of Matricaria chamomilla .L on paraquat: Induced oxidative damage in lung rats

    Akram Ranjbar; Fariba Mohsenzadeh; Abdolkarim Chehregani; Farzad Khajavi; Seyed-Mostafa Hossini Zijoud; Hassan Ghasemi,

    2014-01-01

    Background: Herbal medicines have been long used for antioxidant properties. The purpose of this study was to investigate the effect of hydroalcholic extract Matricaria chamomilla. L (M. chamomilla) against Paraquat (PQ) induced pulmonary injury in association with its antioxidant activity. Materials and Methods: Effective doses of PQ (5 mg/kg/day) and M. chamomilla (50 mg/kg/day) were administered alone or in combination for 7 days. At the end of the experiment, lung tissue of the animals wa...

  1. Therapeutic effect of intravenous infusion of perfluorocarbon emulsion on LPS-induced acute lung injury in rats.

    Shike Hou

    Full Text Available Acute lung injury (ALI and its more severe form, acute respiratory distress syndrome (ARDS are the leading causes of death in critical care. Despite extensive efforts in research and clinical medicine, mortality remains high in these diseases. Perfluorocarbon (PFC, a chemical compound known as liquid ventilation medium, is capable of dissolving large amounts of physiologically important gases (mainly oxygen and carbon dioxide. In this study we aimed to investigate the effect of intravenous infusion of PFC emulsion on lipopolysaccharide (LPS induced ALI in rats and elucidate its mechanism of action. Forty two Wistar rats were randomly divided into three groups: 6 rats were treated with saline solution by intratracheal instillation (control group, 18 rats were treated with LPS by intratracheal instillation (LPS group and the other 18 rats received PFC through femoral vein prior to LPS instillation (LPS+PFC group. The rats in the control group were sacrificed 6 hours later after saline instillation. At 2, 4 and 6 hours of exposure to LPS, 6 rats in the LPS group and 6 rats in LPS+PFC group were sacrificed at each time point. By analyzing pulmonary pathology, partial pressure of oxygen in the blood (PaO2 and lung wet-dry weight ratio (W/D of each rat, we found that intravenous infusion of PFC significantly alleviated acute lung injury induced by LPS. Moreover, we showed that the expression of pulmonary myeloperoxidase (MPO, intercellular adhesion molecule-1 (ICAM-1 of endothelial cells and CD11b of polymorphonuclear neutrophils (PMN induced by LPS were significantly decreased by PFC treatment in vivo. Our results indicate that intravenous infusion of PFC inhibits the infiltration of PMNs into lung tissue, which has been shown as the core pathogenesis of ALI/ARDS. Thus, our study provides a theoretical foundation for using intravenous infusion of PFC to prevent and treat ALI/ARDS in clinical practice.

  2. Therapeutic effect of intravenous infusion of perfluorocarbon emulsion on LPS-induced acute lung injury in rats.

    Hou, Shike; Ding, Hui; Lv, Qi; Yin, Xiaofeng; Song, Jianqi; Landén, Ning Xu; Fan, Haojun

    2014-01-01

    Acute lung injury (ALI) and its more severe form, acute respiratory distress syndrome (ARDS) are the leading causes of death in critical care. Despite extensive efforts in research and clinical medicine, mortality remains high in these diseases. Perfluorocarbon (PFC), a chemical compound known as liquid ventilation medium, is capable of dissolving large amounts of physiologically important gases (mainly oxygen and carbon dioxide). In this study we aimed to investigate the effect of intravenous infusion of PFC emulsion on lipopolysaccharide (LPS) induced ALI in rats and elucidate its mechanism of action. Forty two Wistar rats were randomly divided into three groups: 6 rats were treated with saline solution by intratracheal instillation (control group), 18 rats were treated with LPS by intratracheal instillation (LPS group) and the other 18 rats received PFC through femoral vein prior to LPS instillation (LPS+PFC group). The rats in the control group were sacrificed 6 hours later after saline instillation. At 2, 4 and 6 hours of exposure to LPS, 6 rats in the LPS group and 6 rats in LPS+PFC group were sacrificed at each time point. By analyzing pulmonary pathology, partial pressure of oxygen in the blood (PaO2) and lung wet-dry weight ratio (W/D) of each rat, we found that intravenous infusion of PFC significantly alleviated acute lung injury induced by LPS. Moreover, we showed that the expression of pulmonary myeloperoxidase (MPO), intercellular adhesion molecule-1 (ICAM-1) of endothelial cells and CD11b of polymorphonuclear neutrophils (PMN) induced by LPS were significantly decreased by PFC treatment in vivo. Our results indicate that intravenous infusion of PFC inhibits the infiltration of PMNs into lung tissue, which has been shown as the core pathogenesis of ALI/ARDS. Thus, our study provides a theoretical foundation for using intravenous infusion of PFC to prevent and treat ALI/ARDS in clinical practice.

  3. Ameliorative effect of Matricaria chamomilla.L on paraquat: Induced oxidative damage in lung rats

    Akram Ranjbar

    2014-01-01

    Full Text Available Background: Herbal medicines have been long used for antioxidant properties. The purpose of this study was to investigate the effect of hydroalcholic extract Matricaria chamomilla. L (M. chamomilla against Paraquat (PQ induced pulmonary injury in association with its antioxidant activity. Materials and Methods: Effective doses of PQ (5 mg/kg/day and M. chamomilla (50 mg/kg/day were administered alone or in combination for 7 days. At the end of the experiment, lung tissue of the animals was separated. The activity of enzymatic scavengers such as glutathione peroxidase (GPx and superoxide dismutase (SOD, lipid peroxidation (LPO and total antioxidant power (TAP were measured. Results: In these samples, the LPO, SOD, and GPx were higher in the PQ group as compared with controls. M. chamomilla extract ameliorated LPO, SOD, GPx and increased TAP in plasma and lung tissue of PQ induced changes. Co administration of PQ with M. chamomilla improved LPO and SOD, and GPx. Conclusion: M. chamomilla as natural antioxidant may be considered beneficial for the protection oxidative lung injury in PQ poisoning.

  4. Cys C, BUN and sCr level in patients with early renal damage of acute glomerulonephritis

    Hong Zhang; Ge Xu

    2016-01-01

    Objective:To explore the levels of Cys C, BUN and sCr in patients of early renal damage of acute glomerulonephritis.Methods: A total of 90 cases with acute glomerulonephritis treated in Nephrology Department of our hospital from May 2013 to May 2015 were randomly selected, among whom 32 cases of AKI1 stage (A group), 28 cases of AKI2 stage (B group) and 30 cases of AKI3 stage (C group), and 35 cases of healthy volunteers receiving routine physical examination in our hospital during the same period were selected as control group. Cystatin C (Cys C), blood urea nitrogen (BUN) and serum creatinine (sCr) were detected, and acute physiology and chronic health status score (APACHEⅡ scoring) was conducted in all research subjects. The correlation of APACHEⅡ scores with Cys C, BUN and sCr levels was analyzed respectively.Results: The differences in Cys C, BUN and sCr levels and APACHEⅡ scores among groups were statistically significant (P=0.000); there was significant positive correlation between APACHEⅡ scores and levels of Cys C, BUN and sCr of three groups of patients with acute glomerulonephritis (r>0.00), and the differences were statistically significant (P<0.05); in the diagnosis of early renal damage in patients with acute glomerulonephritis, the areas of Cys C, BUN and sCr under ROC curve were 0.946, 0.832 and 0.896, respectively.Conclusions: Cys C, BUN and sCr levels significantly increase with the increase of early renal damage of acute glomerulonephritis, both sensitivity and specificity of Cys C level are higher, and it has higher clinical application value.

  5. Sonic Hedgehog Signaling: Evidence for Its Protective Role in Endotoxin Induced Acute Lung Injury in Mouse Model.

    Xing Chen

    Full Text Available To investigate the protective role of the sonic hedgehog (SHH signaling associated with a lipopolysaccharide (LPS-induced acute lung injury (ALI in a mouse model.Male BALB/c mice were randomly divided into four groups: control, LPS, LPS-cyclopamine group and cyclopamine group. ALI was induced by LPS ip injection (5 mg/kg. The sonic hedgehog inhibitor cyclopamine (50 mg/kg was given to the LPS-cyclopamine group at 30 min after LPS injection as well as normal mice as control. Lung injury was observed histologically in hematoxylin and eosin (HE stained tissue sections, semi-quantified by lung tissue injury score, and the lung tissue mass alteration was measured by wet to dry weight ratio (W/D. mRNA expression levels of TNF-α, SHH, Patched (PTC and GLI1 in lung tissue were studied with real time quantitative PCR (RT-PCR, while the protein expression of SHH and GLI1 was determined by western blot analysis.Lung tissue injury score, thickness of alveolar septa, W/D, and TNF-α mRNA expression levels were significantly higher in the ALI mice than the normal mice (P<0.05. The mRNA expression levels of SHH, PTC, and GLI1 in the ALI mice were significantly higher at 12h and 24h after LPS injection, but not at the 6h time point. Protein production of SHH and GLI1 at 6h, 12h, and 24h in the lungs of ALI mice significantly increased, in a time-dependent manner, compared with that in normal mice. Cyclopamine alone has no effect on pathological changes in normal mice. Intervention with cyclopamine in ALI mice led to a reduction in mRNA levels of SHH, PTC, and GLI1 as well as SHH and GLI1 protein levels; meanwhile, the pathological injury scores of lung tissues, thickness of alveolar septa, W/D, and mRNA expression levels of TNF-α increased compared with mice receiving LPS only.The SHH signaling pathway was activated in response to LPS-induced ALI, and up-regulation of SHH expression could alleviate lung injury and be involved in the repair of injured lung

  6. Adipose Tissue-Derived Stem Cells Reduce Acute and Chronic Kidney Damage in Mice.

    Marina Burgos-Silva

    Full Text Available Acute and chronic kidney injuries (AKI and CKI constitute syndromes responsible for a large part of renal failures, and are today still associated with high mortality rates. Given the lack of more effective therapies, there has been intense focus on the use stem cells for organ protective and regenerative effects. Mesenchymal stem cells (MSCs have shown great potential in the treatment of various diseases of immune character, although there is still debate on its mechanism of action. Thus, for a greater understanding of the role of MSCs, we evaluated the effect of adipose tissue-derived stem cells (AdSCs in an experimental model of nephrotoxicity induced by folic acid (FA in FVB mice. AdSC-treated animals displayed kidney functional improvement 24h after therapy, represented by reduced serum urea after FA. These data correlated with cell cycle regulation and immune response modulation via reduced chemokine expression and reduced neutrophil infiltrate. Long-term analyses, 4 weeks after FA, indicated that AdSC treatment reduced kidney fibrosis and chronic inflammation. These were demonstrated by reduced interstitial collagen deposition and tissue chemokine and cytokine expression. Thus, we concluded that AdSC treatment played a protective role in the framework of nephrotoxic injury via modulation of inflammation and cell cycle regulation, resulting in reduced kidney damage and functional improvement, inhibiting organ fibrosis and providing long-term immune regulation.

  7. Toll-Like Receptor-9 (TLR9) is Requisite for Acute Inflammatory Response and Injury Following Lung Contusion.

    Suresh, Madathilparambil V; Thomas, Bivin; Dolgachev, Vladislav A; Sherman, Matthew A; Goldberg, Rebecca; Johnson, Mark; Chowdhury, Aulina; Machado-Aranda, David; Raghavendran, Krishnan

    2016-10-01

    Lung contusion (LC) is a significant risk factor for the development of acute respiratory distress syndrome. Toll-like receptor 9 (TLR9) recognizes specific unmethylated CpG motifs, which are prevalent in microbial but not vertebrate genomic DNA, leading to innate and acquired immune responses. TLR9 signaling has recently been implicated as a critical component of the inflammatory response following lung injury. The aim of the present study was to evaluate the contribution of TLR9 signaling to the acute physiologic changes following LC. Nonlethal unilateral closed-chest LC was induced in TLR9 (-/-) and wild-type (WT) mice. The mice were sacrificed at 5, 24, 48, and 72-h time points. The extent of injury was assessed by measuring bronchoalveolar lavage, cells (cytospin), albumin (permeability injury), and cytokines (inflammation). Following LC, only the TLR9 (-/-) mice showed significant reductions in the levels of albumin; release of pro-inflammatory cytokines IL-1β, IL-6, and Keratinocyte chemoattractant; production of macrophage chemoattractant protein 5; and recruitment of alveolar macrophages and neutrophil infiltration. Histological evaluation demonstrated significantly worse injury at all-time points for WT mice. Macrophages, isolated from TLR9 (-/-) mice, exhibited increased phagocytic activity at 24 h after LC compared with those isolated from WT mice. TLR9, therefore, appears to be functionally important in the development of progressive lung injury and inflammation following LC. Our findings provide a new framework for understanding the pathogenesis of lung injury and suggest blockade of TLR9 as a new therapeutic strategy for the treatment of LC-induced lung injury.

  8. Cooperation between Monocyte-Derived Cells and Lymphoid Cells in the Acute Response to a Bacterial Lung Pathogen.

    Andrew S Brown

    2016-06-01

    Full Text Available Legionella pneumophila is the causative agent of Legionnaires' disease, a potentially fatal lung infection. Alveolar macrophages support intracellular replication of L. pneumophila, however the contributions of other immune cell types to bacterial killing during infection are unclear. Here, we used recently described methods to characterise the major inflammatory cells in lung after acute respiratory infection of mice with L. pneumophila. We observed that the numbers of alveolar macrophages rapidly decreased after infection coincident with a rapid infiltration of the lung by monocyte-derived cells (MC, which, together with neutrophils, became the dominant inflammatory cells associated with the bacteria. Using mice in which the ability of MC to infiltrate tissues is impaired it was found that MC were required for bacterial clearance and were the major source of IL12. IL12 was needed to induce IFNγ production by lymphoid cells including NK cells, memory T cells, NKT cells and γδ T cells. Memory T cells that produced IFNγ appeared to be circulating effector/memory T cells that infiltrated the lung after infection. IFNγ production by memory T cells was stimulated in an antigen-independent fashion and could effectively clear bacteria from the lung indicating that memory T cells are an important contributor to innate bacterial defence. We also determined that a major function of IFNγ was to stimulate bactericidal activity of MC. On the other hand, neutrophils did not require IFNγ to kill bacteria and alveolar macrophages remained poorly bactericidal even in the presence of IFNγ. This work has revealed a cooperative innate immune circuit between lymphoid cells and MC that combats acute L. pneumophila infection and defines a specific role for IFNγ in anti-bacterial immunity.

  9. Cooperation between Monocyte-Derived Cells and Lymphoid Cells in the Acute Response to a Bacterial Lung Pathogen.

    Brown, Andrew S; Yang, Chao; Fung, Ka Yee; Bachem, Annabell; Bourges, Dorothée; Bedoui, Sammy; Hartland, Elizabeth L; van Driel, Ian R

    2016-06-01

    Legionella pneumophila is the causative agent of Legionnaires' disease, a potentially fatal lung infection. Alveolar macrophages support intracellular replication of L. pneumophila, however the contributions of other immune cell types to bacterial killing during infection are unclear. Here, we used recently described methods to characterise the major inflammatory cells in lung after acute respiratory infection of mice with L. pneumophila. We observed that the numbers of alveolar macrophages rapidly decreased after infection coincident with a rapid infiltration of the lung by monocyte-derived cells (MC), which, together with neutrophils, became the dominant inflammatory cells associated with the bacteria. Using mice in which the ability of MC to infiltrate tissues is impaired it was found that MC were required for bacterial clearance and were the major source of IL12. IL12 was needed to induce IFNγ production by lymphoid cells including NK cells, memory T cells, NKT cells and γδ T cells. Memory T cells that produced IFNγ appeared to be circulating effector/memory T cells that infiltrated the lung after infection. IFNγ production by memory T cells was stimulated in an antigen-independent fashion and could effectively clear bacteria from the lung indicating that memory T cells are an important contributor to innate bacterial defence. We also determined that a major function of IFNγ was to stimulate bactericidal activity of MC. On the other hand, neutrophils did not require IFNγ to kill bacteria and alveolar macrophages remained poorly bactericidal even in the presence of IFNγ. This work has revealed a cooperative innate immune circuit between lymphoid cells and MC that combats acute L. pneumophila infection and defines a specific role for IFNγ in anti-bacterial immunity.

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

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

    2010-08-01

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

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

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

    2012-09-01

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

  12. PAMAM Nanoparticles Promote Acute Lung Injury by Inducing Autophagic Cell Death through the Akt-TSC2-mTOR Signaling Pathway

    Chenggang Li; Haolin Liu; Yang Sun; Hongliang Wang; Feng Guo; Shuan Rao; Jiejie Deng; Yanli Zhang; Yufa Miao; Chenying Guo; Jie Meng; Xiping Chen; Limin Li; Dangsheng Li; Haiyan Xu; Heng Wang; Bo Li; Chengyu Jiang

    2009-01-01

    Nanotechnology is an important and emerging industry with a projected annual market of around one trillion US dollars by 2011–2015. Concerns about the toxicity of nanomaterials in humans, however, have recently been raised. Although studies of nanoparticle toxicity have focused on lung disease the molecular link between nanoparticle exposure and lung injury remained unclear. In this report, we show that cationic Starburst polyamidoamine dendrimer (PAMAM), a class of nanomaterials that are being widely developed for clinical applications can induce acute lung injury in vivo. PAMAM triggers autophagic cell death by deregulating the Akt-TSC2-mTOR signaling pathway. The autophagy inhibitor 3-methyladenine rescued PAMAM dendrimer-induced cell death and ameliorated acute lung injury caused by PAMAM in mice. Our data provide a molecular explanation for nanoparticle-induced lung injury, and suggest potential remedies to address the growing concerns of nanotechnology safety.

  13. Lung function

    2005-01-01

    2005200 The effect of body position changes on lung function, lung CT imaging and pathology in an oleic acid induced acute lung injury model. JI Xin-ping (戢新平), et al. Dept Emergency, 1st Affili Hosp, China Med Univ, Shenyang 110001. Chin J Tuberc Respir Dis, 2005;28(1) :33-36. Objective: To study the effect of body position changes on lung mechanics, oxygenation, CT images and pathology in an oleic acid-induced acute lung injury (ALl) model. Methods: The study groups con-

  14. Acute Esophagus Toxicity in Lung Cancer Patients After Intensity Modulated Radiation Therapy and Concurrent Chemotherapy

    Kwint, Margriet [Department of Radiation Oncology, The Netherlands Cancer Institute-Antoni van Leeuwenhoek Hospital, Amsterdam (Netherlands); Uyterlinde, Wilma [Department of Thoracic Oncology, The Netherlands Cancer Institute-Antoni van Leeuwenhoek Hospital, Amsterdam (Netherlands); Nijkamp, Jasper; Chen, Chun; Bois, Josien de; Sonke, Jan-Jakob [Department of Radiation Oncology, The Netherlands Cancer Institute-Antoni van Leeuwenhoek Hospital, Amsterdam (Netherlands); Heuvel, Michel van den [Department of Thoracic Oncology, The Netherlands Cancer Institute-Antoni van Leeuwenhoek Hospital, Amsterdam (Netherlands); Knegjens, Joost; Herk, Marcel van [Department of Radiation Oncology, The Netherlands Cancer Institute-Antoni van Leeuwenhoek Hospital, Amsterdam (Netherlands); Belderbos, Jose, E-mail: j.belderbos@nki.nl [Department of Radiation Oncology, The Netherlands Cancer Institute-Antoni van Leeuwenhoek Hospital, Amsterdam (Netherlands)

    2012-10-01

    Purpose: The purpose of this study was to investigate the dose-effect relation between acute esophageal toxicity (AET) and the dose-volume parameters of the esophagus after intensity modulated radiation therapy (IMRT) and concurrent chemotherapy for patients with non-small cell lung cancer (NSCLC). Patients and Methods: One hundred thirty-nine patients with inoperable NSCLC treated with IMRT and concurrent chemotherapy were prospectively analyzed. The fractionation scheme was 66 Gy in 24 fractions. All patients received concurrently a daily dose of cisplatin (6 mg/m Superscript-Two ). Maximum AET was scored according to Common Toxicity Criteria 3.0. Dose-volume parameters V5 to V70, D{sub mean} and D{sub max} of the esophagus were calculated. A logistic regression analysis was performed to analyze the dose-effect relation between these parameters and grade {>=}2 and grade {>=}3 AET. The outcome was compared with the clinically used esophagus V35 prediction model for grade {>=}2 after radical 3-dimensional conformal radiation therapy (3DCRT) treatment. Results: In our patient group, 9% did not experience AET, and 31% experienced grade 1 AET, 38% grade 2 AET, and 22% grade 3 AET. The incidence of grade 2 and grade 3 AET was not different from that in patients treated with CCRT using 3DCRT. The V50 turned out to be the most significant dosimetric predictor for grade {>=}3 AET (P=.012). The derived V50 model was shown to predict grade {>=}2 AET significantly better than the clinical V35 model (P<.001). Conclusions: For NSCLC patients treated with IMRT and concurrent chemotherapy, the V50 was identified as most accurate predictor of grade {>=}3 AET. There was no difference in the incidence of grade {>=}2 AET between 3DCRT and IMRT in patients treated with concurrent chemoradiation therapy.

  15. Lung ventilation strategies for acute respiratory distress syndrome: a systematic review and network meta-analysis.

    Wang, Changsong; Wang, Xiaoyang; Chi, Chunjie; Guo, Libo; Guo, Lei; Zhao, Nana; Wang, Weiwei; Pi, Xin; Sun, Bo; Lian, Ailing; Shi, Jinghui; Li, Enyou

    2016-03-09

    To identify the best lung ventilation strategy for acute respiratory distress syndrome (ARDS), we performed a network meta-analysis. The Cochrane Central Register of Controlled Trials, EMBASE, MEDLINE, CINAHL, and the Web of Science were searched, and 36 eligible articles were included. Compared with higher tidal volumes with FiO2-guided lower positive end-expiratory pressure [PEEP], the hazard ratios (HRs) for mortality were 0.624 (95% confidence interval (CI) 0.419-0.98) for lower tidal volumes with FiO2-guided lower PEEP and prone positioning and 0.572 (0.34-0.968) for pressure-controlled ventilation with FiO2-guided lower PEEP. Lower tidal volumes with FiO2-guided higher PEEP and prone positioning had the greatest potential to reduce mortality, and the possibility of receiving the first ranking was 61.6%. Permissive hypercapnia, recruitment maneuver, and low airway pressures were most likely to be the worst in terms of all-cause mortality. Compared with higher tidal volumes with FiO2-guided lower PEEP, pressure-controlled ventilation with FiO2-guided lower PEEP and lower tidal volumes with FiO2-guided lower PEEP and prone positioning ventilation are associated with lower mortality in ARDS patients. Lower tidal volumes with FiO2-guided higher PEEP and prone positioning ventilation and lower tidal volumes with pressure-volume (P-V) static curve-guided individual PEEP are potential optimal strategies for ARDS patients.

  16. Emodin Ameliorates LPS-Induced Acute Lung Injury, Involving the Inactivation of NF-κB in Mice

    Min Xiao

    2014-10-01

    Full Text Available Acute lung injury (ALI and its severe manifestation of acute respiratory distress syndrome (ARDS are well-known illnesses. Uncontrolled and self-amplified pulmonary inflammation lies at the center of the pathology of this disease. Emodin, the bio-active coxund of herb Radix rhizoma Rhei, shows potent anti-inflammatory properties through inactivation of nuclear factor-κB (NF-κB. The aim of this study was to evaluate the effect of emodin on lipopolysaccharide (LPS-induced ALI in mice, and its potential bio-mechanism. In our study, BALB/c mice were stimulated with LPS to induce ALI. After 72 h of LPS stimulation, pulmonary pathological changes, lung injury scores, pulmonary edema, myeloperoxidase (MPO activity, total cells, neutrophils, macrophages, TNF-α, IL-6 and IL-1β in bronchoalveolar lavage fluid (BALF, and MCP-1 and E-selectin expression were notably attenuated by emodin in mice. Meanwhile, our data also revealed that emodin significantly inhibited the LPS-enhanced the phosphorylation of NF-κB p65 and NF-κB p65 DNA binding activity in lung. Our data indicates that emodin potently inhibits LPS-induced pulmonary inflammation, pulmonary edema and MCP-1 and E-selectin expression, and that these effects were very likely mediated by inactivation of NF-κB in mice. These results suggest a therapeutic potential of emodin as an anti-inflammatory agent for ALI/ARDS treatment.

  17. Understanding Lung Deposition of Alpha-1 Antitrypsin in Acute Experimental Mouse Lung Injury Model Using Fluorescence Microscopy

    Mengmeng Wang

    2016-01-01

    Full Text Available Human plasma-derived α1-antitrypsin (AAT delivered by intravenous infusion is used as augmentation therapy in patients with emphysema who have a genetic mutation resulting in deficiency of AAT. Inhalation is an alternative route of administration that can potentially increase the efficacy and convenience of treatment. This study was conducted to determine whether delivery to the lungs, initially via the intratracheal (IT route of administration, would deliver efficacious levels of a recombinant AAT (rAAT to the site of action in the lungs in mice. 125I-radiolabeled rAAT, fluorophore-conjugated rAAT (rAAT-Alexa488, and NE680 (neutrophil elastase 680, a silent fluorescent substrate of neutrophil elastase which fluoresces in the near-infrared range upon activation by neutrophil elastase were used to characterize the pharmacokinetics and tissue distribution profile, distribution of rAAT within the lung, and efficacy of rAAT to inhibit neutrophil elastase at the site of action, respectively. The study has demonstrated that rAAT was able to gain access to locations where neutrophil elastase was localized. The histochemical quantification of rAAT activity relative to dose at the site of action provided here will improve confidence in predicting the human dose via the inhalation route.

  18. Combined action of influenza virus and Staphylococcus aureus panton-valentine leukocidin provokes severe lung epithelium damage.

    Niemann, Silke; Ehrhardt, Christina; Medina, Eva; Warnking, Kathrin; Tuchscherr, Lorena; Heitmann, Vanessa; Ludwig, Stephan; Peters, Georg; Löffler, Bettina

    2012-10-01

    Staphylococcus aureus necrotizing pneumonia is a life-threatening disease that is frequently preceded by influenza infection. The S. aureus toxin Panton-Valentine leukocidin (PVL) is most likely causative for necrotizing diseases, but the precise pathogenic mechanisms of PVL and a possible contribution of influenza virus remain to be elucidated. In this study, we present a model that explains how influenza virus and PVL act together to cause necrotizing pneumonia: an influenza infection activates the lung epithelium to produce chemoattractants for neutrophils. Upon superinfection with PVL-expressing S. aureus, the recruited neutrophils are rapidly killed by PVL, resulting in uncontrolled release of neutrophil proteases that damage the airway epithelium. The host counteracts this pathogen strategy by generating PVL-neutralizing antibodies and by neutralizing the released proteases via protease inhibitors present in the serum. These findings explain why necrotizing infections mainly develop in serum-free spaces (eg, pulmonary alveoli) and open options for new therapeutic approaches.

  19. Comparative DNA damage and transcriptomic effects of engineered nanoparticles in human lung cells in vitro

    A series of six titanium dioxide and two cerium oxide engineered nanomaterials were assessed for their ability to induce cytotoxicity, reactive oxygen species (ROS), various types of DNA damage, and transcriptional changes in human respiratory BEAS-2B cells exposed in vitro at se...

  20. Retrospective review of thoracic neural damage during lung ablation - what the interventional radiologist needs to know about neural thoracic anatomy

    Palussiere, Jean, E-mail: j.palussiere@bordeaux.unicancer.fr [Institut Bergonie, Department of Interventional Radiology (France); Canella, Mathieu [Centre Hospitalier Pau, Department of Radiology (France); Cornelis, Francois; Catena, Vittorio; Descat, Edouard [Institut Bergonie, Department of Interventional Radiology (France); Brouste, Veronique [Institut Bergonie, Clinical and Epidemiological Research Unit (France); Montaudon, Michel [CHU Haut Leveque, Department of Radiology (France)

    2013-12-15

    Background and Purpose: Radiofrequency ablation (RFA) is associated with low neural morbidity compared with surgery, which commonly causes debilitating long-term pain. The purpose was to review the thoracic neural anatomy relevant to percutaneous RFA and to retrospectively review symptomatic nerve injury after lung RFA at our institution. Materials and Methods: We retrospectively examined all symptomatic nerve injuries occurring after computed tomography (CT)-guided RFA treatment of lung tumors for 462 patients/509 procedures/708 lesions treated at our large tertiary referral centre during 10 years. Results: Eight patients experienced neurological complications after heating during the RFA procedure. These complications occurred in the phrenic (n = 1), brachial (n = 3), left recurrent (n = 1), and intercostal nerves (n = 2) and the stellate ganglion (n = 1). Three were grade 2, four grade 3 and one grade 4 injuries (CTCAE v3). Conclusion: Although rare, neurological complications can occur after RFA, and they can occasionally be severe. To prevent these complications, it is important for the interventional radiologist to be aware of the anatomy of nervous structures and to attempt to identify nerves on CT scans during the RFA procedure. Creating a pneumothorax can be useful to avoid nerve damage and related clinical complications.

  1. Inhalation exposure to chloramine T induces DNA damage and inflammation in lung of Sprague-Dawley rats.

    Shim, Ilseob; Seo, Gyun-Baek; Oh, Eunha; Lee, Mimi; Kwon, Jung-Taek; Sul, Donggeun; Lee, Byung-Woo; Yoon, Byung-Il; Kim, Pilje; Choi, Kyunghee; Kim, Hyun-Mi

    2013-01-01

    Chloramine T has been widely used as a disinfectant in many areas such as kitchens, laboratories and hospitals. It has been also used as a biocide in air fresheners and deodorants which are consumer products; however, little is known about its toxic effects by inhalation route. This study was performed to identify the subacute inhalation toxicity of chloramine T under whole-body inhalation exposure conditions. Male and female groups of rats were exposed to chloramine T at concentrations of 0.2, 0.9 and 4.0 mg/m³ for 6 hr/day, 5 days/week during 4 weeks. After 28-day repeated inhalation of chloramine T, there were dose-dependently significant DNA damage in the rat tissues evaluated and inflammation was histopathologically noted around the terminal airways of the lung in both genders. As a result of the expression of three types of antioxidant enzymes (SOD-2, GPx-1, PRX-1) in rat's lung after exposure, there was no significant change of all antioxidant enzymes in the male and female rats. The results showed that no observed adverse effect level (NOAEL) was 0.2 mg/m³ in male rats and 0.9 mg/m³ in female rats under the present experimental condition.

  2. Distending Pressure Did Not Activate Acute Phase or Inflammatory Responses in the Airways and Lungs of Fetal, Preterm Lambs.

    Rebecca Y Petersen

    Full Text Available Mechanical ventilation at birth causes airway injury and lung inflammation in preterm sheep. Continuous positive airway pressure (CPAP is being increasingly used clinically to transition preterm infants at birth.To test if distending pressures will activate acute phase reactants and inflammatory changes in the airways of fetal, preterm lambs.The head and chest of fetal lambs at 128±1 day GA were surgically exteriorized. With placental circulation intact, fetal lambs were then randomized to one of five 15 minute interventions: PEEP of 0, 4, 8, 12, or 16 cmH2O. Recruitment volumes were recorded. Fetal lambs remained on placental support for 30 min after the intervention. The twins of each 0 cmH2O animal served as controls. Fetal lung fluid (FLF, bronchoalveolar lavage fluid (BAL, right mainstem bronchi and peripheral lung tissue were evaluated for inflammation.Recruitment volume increased from 0.4±0.04 mL/kg at 4 cmH2O to 2.4±0.3 mL/kg at 16 cmH2O. The lambs were surfactant deficient, and all pressures were below the opening inflection pressure on pressure-volume curve. mRNA expression of early response genes and pro-inflammatory cytokines did not increase in airway tissue or lung tissue at any pressure compared to controls. FLF and BAL also did not have increases in early response proteins. No histologic changes or Egr-1 activation was present at the pressures used.Distending pressures as high as 16 cmH2O did not recruit lung volume at birth and did not increase markers of injury in the lung or airways in non-breathing preterm fetal sheep.

  3. Parasite burden and CD36-mediated sequestration are determinants of acute lung injury in an experimental malaria model.

    Fiona E Lovegrove

    2008-05-01

    Full Text Available Although acute lung injury (ALI is a common complication of severe malaria, little is known about the underlying molecular basis of lung dysfunction. Animal models have provided powerful insights into the pathogenesis of severe malaria syndromes such as cerebral malaria (CM; however, no model of malaria-induced lung injury has been definitively established. This study used bronchoalveolar lavage (BAL, histopathology and gene expression analysis to examine the development of ALI in mice infected with Plasmodium berghei ANKA (PbA. BAL fluid of PbA-infected C57BL/6 mice revealed a significant increase in IgM and total protein prior to the development of CM, indicating disruption of the alveolar-capillary membrane barrier-the physiological hallmark of ALI. In contrast to sepsis-induced ALI, BAL fluid cell counts remained constant with no infiltration of neutrophils. Histopathology showed septal inflammation without cellular transmigration into the alveolar spaces. Microarray analysis of lung tissue from PbA-infected mice identified a significant up-regulation of expressed genes associated with the gene ontology categories of defense and immune response. Severity of malaria-induced ALI varied in a panel of inbred mouse strains, and development of ALI correlated with peripheral parasite burden but not CM susceptibility. Cd36(-/- mice, which have decreased parasite lung sequestration, were relatively protected from ALI. In summary, parasite burden and CD36-mediated sequestration in the lung are primary determinants of ALI in experimental murine malaria. Furthermore, differential susceptibility of mouse strains to malaria-induced ALI and CM suggests that distinct genetic determinants may regulate susceptibility to these two important causes of malaria-associated morbidity and mortality.

  4. An improved method for the isolation of rat alveolar type II lung cells: Use in the Comet assay to determine DNA damage induced by cigarette smoke.

    Dalrymple, Annette; Ordoñez, Patricia; Thorne, David; Dillon, Debbie; Meredith, Clive

    2015-06-01

    Smoking is a cause of serious diseases, including lung cancer, emphysema, chronic bronchitis and heart disease. DNA damage is thought to be one of the mechanisms by which cigarette smoke (CS) initiates disease in the lung. Indeed, CS induced DNA damage can be measured in vitro and in vivo. The potential of the Comet assay to measure DNA damage in isolated rat lung alveolar type II epithelial cells (AEC II) was explored as a means to include a genotoxicity end-point in rodent sub-chronic inhalation studies. In this study, published AEC II isolation methods were improved to yield viable cells suitable for use in the Comet assay. The improved method reduced the level of basal DNA damage and DNA repair in isolated AEC II. CS induced DNA damage could also be quantified in isolated cells following a single or 5 days CS exposure. In conclusion, the Comet assay has the potential to determine CS or other aerosol induced DNA damage in AEC II isolated from rodents used in sub-chronic inhalation studies.

  5. Biological Signatures of Brain Damage Associated with High Serum Ferritin Levels in Patients with Acute Ischemic Stroke and Thrombolytic Treatment

    Mónica Millán

    2008-01-01

    Full Text Available Background and purpose: Increased body iron stores have been related to greater oxidative stress and brain injury in clinical and experimental cerebral ischemia and reperfusion. We aimed to investigate the biological signatures of excitotoxicity, inflammation and blood brain barrier disruption potentially associated with high serum ferritin levels-related damage in acute stroke patients treated with i.v. t-PA.

  6. CCK1-Receptor Stimulation Protects Against Gut Mediator-Induced Lung Damage During Endotoxemia

    Friederike Eisner

    2013-12-01

    Full Text Available Background/Aims: Cholecystokinin 1-receptor (CCK1-R activation by long chain fatty acid (LCFA absorption stimulates vago-vagal reflex pathways in the brain stem. The present study determines whether this reflex also activates the cholinergic anti-inflammatory pathway, a pathway known to modulate cytokine release during endotoxemia. Methods:Mesenteric lymph was obtained from wild type (WT and CCK1-R knockout (CCK1-R-/- mice intraperitoneally challenged with Lipopolysaccharid (LPS (endotoxemic lymph, EL and intestinally infused with vehicle or LCFA-enriched solution. The lymph was analyzed for TNFα, IL-6 and IL-10 concentration and administered to healthy recipient mice via jugular infusion. Alveolar wall thickness, myeloperoxidase (MPO and TUNEL positive cells were determined in lung tissue of recipient mice. Results: LCFA infusion in WT mice reduced TNFα concentration in EL by 49% compared to vehicle infusion, but had no effect in CCK1-R-/- mice. EL significantly increased the alveolar wall thickness, the number of MPO-positive and TUNEL-positive cells compared to control lymph administration. LCFA infusion in WT, but not in CCK1R-/- mice, significantly reduced these pathological effects of EL. Conclusion: During endotoxemia enteral LCFA absorption reduces TNFα release into mesenteric lymph and attenuates histomorphologic parameters of lung dysfunction. Failure to elicit this effect in CCK1R-/- mice demonstrates that anti-inflammatory properties of LCFAs are mediated through CCK1-Rs.

  7. Smart imaging of acute lung injury: exploration of myeloperoxidase activity using in vivo endoscopic confocal fluorescence microscopy.

    Chagnon, Frédéric; Bourgouin, Alexandra; Lebel, Réjean; Bonin, Marc-André; Marsault, Eric; Lepage, Martin; Lesur, Olivier

    2015-09-15

    The pathophysiology of acute lung injury (ALI) is well characterized, but its real-time assessment at bedside remains a challenge. When patients do not improve after 1 wk despite supportive therapies, physicians have to consider open lung biopsy (OLB) to identify the process(es) at play. Sustained inflammation and inadequate repair are often observed in this context. OLB is neither easy to perform in a critical setting nor exempt from complications. Herein, we explore intravital endoscopic confocal fluorescence microscopy (ECFM) of the lung in vivo combined with the use of fluorescent smart probe(s) activated by myeloperoxidase (MPO). MPO is a granular enzyme expressed by polymorphonuclear neutrophils (PMNs) and alveolar macrophages (AMs), catalyzing the synthesis of hypoclorous acid, a by-product of hydrogen peroxide. Activation of these probes was first validated in vitro in relevant cells (i.e., AMs and PMNs) and on MPO-non-expressing cells (as negative controls) and then tested in vivo using three rat models of ALI and real-time intravital imaging with ECFM. Semiquantitative image analyses revealed that in vivo probe-related cellular/background fluorescence was associated with corresponding enhanced lung enzymatic activity and was partly prevented by specific MPO inhibition. Additional ex vivo phenotyping was performed, confirming that fluorescent cells were neutrophil elastase(+) (PMNs) or CD68(+) (AMs). This work is a first step toward "virtual biopsy" of ALI without OLB.

  8. Role of CC chemokines (macrophage inflammatory protein-1 beta, monocyte chemoattractant protein-1, RANTES) in acute lung injury in rats

    Bless, N M; Huber-Lang, M; Guo, R F

    2000-01-01

    were cloned, the proteins were expressed, and neutralizing Abs were developed. mRNA and protein expression for MIP-1 beta and MCP-1 were up-regulated during the inflammatory response, while mRNA and protein expression for RANTES were constitutive and unchanged during the inflammatory response...... that in chemokine-dependent inflammatory responses in lung CC chemokines do not necessarily demonstrate redundant function.......The role of the CC chemokines, macrophage inflammatory protein-1 beta (MIP-1 beta), monocyte chemotactic peptide-1 (MCP-1), and RANTES, in acute lung inflammatory injury induced by intrapulmonary deposition of IgG immune complexes injury in rats was determined. Rat MIP-1 beta, MCP-1, and RANTES...

  9. Tobacco Smoke Activates Human Papillomavirus 16 p97 Promoter and Cooperates with High-Risk E6/E7 for Oxidative DNA Damage in Lung Cells

    Muñoz, Juan P.; Chnaiderman, Jonás; Urzúa, Ulises; León, Oscar; Tornesello, Maria L.; Corvalán, Alejandro H.; Soto-Rifo, Ricardo; Aguayo, Francisco

    2015-01-01

    We have previously shown a functional interaction between human papillomavirus type 16 (HPV-16) E6 and E7 oncoproteins and cigarette smoke condensate (CSC) in lung cells suggesting cooperation during carcinogenesis. The molecular mechanisms of such interaction, however, remain to be elucidated. Here we first present evidence showing that cigarette smoke condensate (CSC) has the ability to activate the HPV-16 p97 promoter by acting on the long control region (LCR) in lung epithelial cells. Interestingly, we observed that CSC-induced p97 promoter activation occurs in a dose-dependent manner in both tumor A-549 (lung adenocarcinoma), H-2170 (bronchial carcinoma), SiHa or Hela (cervical carcinoma) cells but not in non-tumor BEAS-2B (bronchial) or NL-20 (alveolar) lung cells unless they ectopically expressed the HPV-16 E6 and E7 oncogenes. In addition, we also observed a significant increase of primary DNA damage in tumor and non-tumor CSC-treated lung cells expressing HPV-16 E6 and E7 oncogenes suggesting a cooperative effect in this process, even though the contribution of E7 was significantly higher. Taken together, our results strongly suggest that tobacco smoke is able to induce the activation of the HPV-16 p97 promoter in cooperation with HPV-16 E6 and E7 oncogenes that, in turn, sensitize lung cells to tobacco smoke-induced DNA damage. PMID:25830243

  10. Partial liquid ventilation decreases tissue and serum tumor necrosis factor-α concentrations in acute lung injury model of immature piglet induced by oleic acid

    ZHU Yao-bin; FAN Xiang-ming; LI Xiao-feng; LI Zhi-qiang; WANG Qiang; SUN Li-zhong; LIU Ying-long

    2012-01-01

    Background Pediatric patients are susceptible to lung injury.Acute lung injury in children often results in high mortality.Partial liquid ventilation (PLV) has been shown to markedly improve oxygenation and reduce histologic evidence of injury in a number of lung injury models.This study was designed to examine the hypothesis that PLV would attenuate the production of local and systemic tumor necrosis factor (TNF)-α in an immature piglet model of acute lung injury induced by oleic acid (OA).Methods Twelve Chinese immature piglets were induced acute lung injury by OA.The animals were randomly assigned to two groups of six animals,(1) conventional mechanical ventilation (MV) group and (2) PLV with 10 ml/kg FC-77 group.Results Compared with MV group,the PLV group had better cardiopulmonary variables (P <0.05).These variables included heart rate,mean blood pressure,blood pH,partial pressure of arterial oxygen (PaO2),PaO2/inspired O2 fraction (FiO2) and partial pressure of arterial carbon dioxide (PaCO2).PLV reduced TNF-α levels both in plasma and tissue compared with MV group (P <0.05).Conclusion PLV provides protective effects against TNF-a response in OA-induced acute lung injury in immature piglets.

  11. Vitamin D deficiency contributes to vascular damage in sustained ischemic acute kidney injury.

    de Bragança, Ana C; Volpini, Rildo A; Mehrotra, Purvi; Andrade, Lúcia; Basile, David P

    2016-07-01

    Reductions in renal microvasculature density and increased lymphocyte activity may play critical roles in the progression of chronic kidney disease (CKD) following acute kidney injury (AKI) induced by ischemia/reperfusion injury (IRI). Vitamin D deficiency is associated with tubulointerstitial damage and fibrosis progression following IRI-AKI We evaluated the effect of vitamin D deficiency in sustained IRI-AKI, hypothesizing that such deficiency contributes to the early reduction in renal capillary density or alters the lymphocyte response to IRI Wistar rats were fed vitamin D-free or standard diets for 35 days. On day 28, rats were randomized into four groups: control, vitamin D deficient (VDD), bilateral IRI, and VDD+IRI Indices of renal injury and recovery were evaluated for up to 7 days following the surgical procedures. VDD rats showed reduced capillary density (by cablin staining), even in the absence of renal I/R. In comparison with VDD and IRI rats, VDD+IRI rats manifested a significant exacerbation of capillary rarefaction as well as higher urinary volume, kidney weight/body weight ratio, tissue injury scores, fibroblast-specific protein-1, and alpha-smooth muscle actin. VDD+IRI rats also had higher numbers of infiltrating activated CD4(+) and CD8(+) cells staining for interferon gamma and interleukin-17, with a significant elevation in the Th17/T-regulatory cell ratio. These data suggest that vitamin D deficiency impairs renal repair responses to I/R injury, exacerbates changes in renal capillary density, as well as promoting fibrosis and inflammation, which may contribute to the transition from AKI to CKD.

  12. The acute toxicity of iron and copper: biomolecule oxidation and oxidative damage in rat liver.

    Boveris, Alberto; Musacco-Sebio, Rosario; Ferrarotti, Nidia; Saporito-Magriñá, Christian; Torti, Horacio; Massot, Francisco; Repetto, Marisa G

    2012-11-01

    The transition metals iron (Fe) and copper (Cu) are needed at low levels for normal health and at higher levels they become toxic for humans and animals. The acute liver toxicity of Fe and Cu was studied in Sprague Dawley male rats (200 g) that received ip 0-60 mg/kg FeCl(2) or 0-30 mg/kg CuSO(4). Dose and time-responses were determined for spontaneous in situ liver chemiluminescence, phospholipid lipoperoxidation, protein oxidation and lipid soluble antioxidants. The doses linearly defined the tissue content of both metals. Liver chemiluminescence increased 4 times and 2 times after Fe and Cu overloads, with half maximal responses at contents (C(50%)) of 110 μgFe/g and 42 μgCu/g liver, and with half maximal time responses (t(1/2)) of 4h for both metals. Phospholipid peroxidation increased 4 and 1.8 times with C(50%) of 118 μg Fe/g and 45 μg Cu/g and with t(1/2) of 7h and 8h. Protein oxidation increased 1.6 times for Fe with C(50%) at 113 μg Fe/g and 1.2 times for Cu with 50 μg Cu/g and t(1/2) of 4h and 5h respectively. The accumulation of Fe and Cu in liver enhanced the rate of free radical reactions and produced oxidative damage. A similar free radical-mediated process, through the formation HO(•) and RO(•) by a Fenton-like homolytic scission of H(2)O(2) and ROOH, seems to operate as the chemical mechanism for the liver toxicity of both metals.

  13. Fish oil-supplemented parenteral nutrition could alleviate acute lung injury, modulate immunity, and reduce inflammation in rats with abdominal sepsis.

    Li, Xiaolong; Zhang, Xianxiang; Yang, Enqin; Zhang, Nanyang; Cao, Shougen; Zhou, Yanbing

    2015-09-01

    The objectives were to confirm that intravenous fish oil (FO) emulsions could alleviate acute lung injury, modulate immunity, and reduce inflammation in rats with abdominal sepsis and to explore the mechanisms of these effects. Thirty-six adult male Sprague-Dawley rats were divided into 4 groups randomly. Two days after central venous catheterization, rats were subjected to cecal ligation and puncture to produce abdominal sepsis. Rats were assigned to receive normal saline or total parenteral nutrition (TPN) containing standard soybean oil emulsions or FO-supplemented TPN at the onset of sepsis for 5 days. A sham operation and control treatment were performed in control group rats. Acute lung injury scores, peripheral blood lymphocyte subsets, plasma cytokines, and Foxp3 expression in the spleen were determined. Compared with the normal saline and TPN without FO, FO-supplemented TPN beneficially altered the distributions of the T-lymphocyte subsets and downregulated the acute lung injury scores, plasma cytokines, and expression of Foxp3 due to sepsis. Fish oil-supplemented TPN can decrease acute lung injury scores, alleviate histopathology, reduce the bacterial load in the peritoneal lavage fluid, modulate the lymphocyte subpopulation in the peripheral blood, downregulate Foxp3 expression in the spleen, and reduce plasma cytokines, which means that FO-supplemented TPN can alleviate acute lung injury, modulate immunity, and reduce inflammation in rats with abdominal sepsis.

  14. Aerosolized alpha-tocopherol ameliorates acute lung injury following combined burn and smoke inhalation injury in sheep.

    Morita, Naoki; Traber, Maret G; Enkhbaatar, Perenlei; Westphal, Martin; Murakami, Kazunori; Leonard, Scott W; Cox, Robert A; Hawkins, Hal K; Herndon, David; Traber, Lillian D; Traber, Daniel L

    2006-03-01

    Victims of fire accidents who sustain both thermal injury to the skin and smoke inhalation have gross evidence of oxidant injury. Therefore, we hypothesized that delivery of vitamin E, an oxygen superoxide scavenger, directly into the airway would attenuate acute lung injury postburn and smoke inhalation. Sheep (N = 17 female, 35 +/- 5 kg) were divided into 3 groups: (1) injured, then nebulized with vitamin E (B&S, Vitamin E, n = 6); (2) injured, nebulized with saline (B&S, Saline, n = 6); and (3) not injured, not treated (Sham, n = 5). While under deep anesthesia with isoflurane, the sheep were subjected to a flame burn (40% total body surface area, 3rd degree) and inhalation injury (48 breaths of cotton smoke, Ringer lactate solution (4 mL/kg/%burn/24 h) and placed on a ventilator [positive end-expiratory pressure (PEEP) = 5 cm H2O, tidal volume = 15 mL/kg] for 48 h. B&S injury halved the lung alpha-tocopherol concentrations (0.9 +/- 0.1 nmol/g) compared with sham-injured animals (1.5 +/- 0.3), whereas vitamin E treatment elevated the lung alpha-tocopherol concentrations (7.40 +/- 2.61) in the injured animals. B&S injury decreased pulmonary gas exchange (PaO2/FiO2 ratios) from 517 +/- 15 at baseline to 329 +/- 49 at 24 h and to 149 +/- 32 at 48 h compared with sham ratios of 477 +/- 14, 536 +/- 48, and 609 +/- 49, respectively. Vitamin E treatment resulted in a significant improvement of pulmonary gas exchange; ratios were 415 +/- 34 and 283 +/- 42 at 24 and 48 h, respectively. Vitamin E nebulization therapy improved the clinical responses to burn and smoke inhalation-induced acute lung injury.

  15. A comparison of biologically variable ventilation to recruitment manoeuvres in a porcine model of acute lung injury

    Rector Edward S

    2004-11-01

    Full Text Available Abstract Background Biologically variable ventilation (return of physiological variability in rate and tidal volume using a computer-controller was compared to control mode ventilation with and without a recruitment manoeuvre – 40 cm H2O for 40 sec performed hourly; in a porcine oleic acid acute lung injury model. Methods We compared gas exchange, respiratory mechanics, and measured bronchoalveolar fluid for inflammatory cytokines, cell counts and surfactant function. Lung injury was scored by light microscopy. Pigs received mechanical ventilation (FIO2 = 0.3; PEEP 5 cm H2O in control mode until PaO2 decreased to 60 mm Hg with oleic acid infusion (PaO2/FIO2 2O was added after injury. Animals were randomized to one of the 3 modes of ventilation and followed for 5 hr after injury. Results PaO2 and respiratory system compliance was significantly greater with biologically variable ventilation compared to the other 2 groups. Mean and mean peak airway pressures were also lower. There were no differences in cell counts in bronchoalveolar fluid by flow cytometry, or interleukin-8 and -10 levels between groups. Lung injury scoring revealed no difference between groups in the regions examined. No differences in surfactant function were seen between groups by capillary surfactometry. Conclusions In this porcine model of acute lung injury, various indices to measure injury or inflammation did not differ between the 3 approaches to ventilation. However, when using a low tidal volume strategy with moderate levels of PEEP, sustained improvements in arterial oxygen tension and respiratory system compliance were only seen with BVV when compared to CMV or CMV with a recruitment manoeuvre.

  16. Cordyceps Militaris Alleviates Severity of Murine Acute Lung Injury Through miRNAs-Mediated CXCR2 Inhibition

    Sheng Liu

    2015-07-01

    Full Text Available Background/Aims: Acute lung injury (ALI and acute respiratory distress syndrome (ARDS are lethal diseases in humans, and the current treatments have limited therapeutic effects. Cordyceps militaris (CM is a caterpillar-grown traditional medicinal mushroom, and has been used as a natural invigorant for longevity, endurance, and vitality in China. Recently, purified extracts from CM have been shown to have beneficial effects on various diseases including cancer. Nevertheless, a role of CM in ALI has not been examined previously. Methods: Here, we used a bleomycin-induced ALI model to study the effects of CM on the severity of ALI in mice. The levels of CXCR2, a receptor for Interleukin 8 (IL-8 in pulmonary microvascular endothelial cells, were examined in different experimental groups. The levels of microRNA (miR-1321 and miR-3188 were also examined in lung samples and in CM. Adeno-associated viruses carrying miR-1321 and miR-3188 were injected into bleomycin-treated mice for evaluation their effects on the severity of ALI. Results: CM treatment significantly alleviated the severity of bleomycin-induced ALI in mice. The increases in lung CXCR2 by bleomycin were significantly reduced by CM at protein level, but not at mRNA level. CM contained high levels of 2 miRNAs (miR-1321 and miR-3188 that target 3'-UTR of CXCR2 mRNA to inhibit its expression. Overexpression of miR-1321 and miR-3188 in mouse lung through AAV-mediated gene therapy mimicked the effects of CM. Conclusion: CM may alleviate severity of murine ALI through miRNAs-mediated CXCR2 inhibition.

  17. Evaluation of N-acetylcysteine and methylprednisolone as therapies for oxygen and acrolein-induced lung damage

    Critchley, J.A.J.H. (Univ. of Edinburgh (England)); Beeley, J.M.; Clark, R.J.; Buchanan, J.D. (Royal Naval Hospital Hoslar, Gosport (England)); Summerfield, M.; Bell, S. (Admiralty Research Establishment, Alverstoke (England)); Spurlock, M.S.; Edginton, J.A.G. (Chemical Defence Establishment, Porton Down (England))

    1990-04-01

    Reactive oxidizing species are implicated in the etiology of a range of inhalational pulmonary injuries. Consequently, various free radical scavengers have been tested as potential prophylactic agents. The sulfydryl compound, N-acetylcysteine (NAC) is the only such compound clinically available for use in realistic dosages, and it is well established as an effective antidote for the hepatic and renal toxicity of paracetamol. Another approach in pulmonary injury prophylaxis is methylprednisolone therapy. The authors evaluated NAC and methylprednisolone in two rats models of inhalation injury: 40-hr exposure to >97% oxygen at 1.1 bar and 15-min exposure to acrolein vapor (210 ppm). The increases in lung wet/dry weight ratios, seen with both oxygen and acrolein toxicity were reduced with both treatments. However, with oxygen, NAC therapy was associated with considerably increased mortality and histological changes. Furthermore, IP NAC administration resulted in large volumes of ascitic fluid. With acrolein, IV, NAC had no significant effect on mortality or pulmonary histological damage. Methylprednisolone had no beneficial effects on either the mortality or histological damage observed in either toxicity model. They caution against the ad hoc use of NAC in the management of inhalational pulmonary injury.

  18. The critical role of myeloperoxidase in Streptococcus pneumoniae clearance and tissue damage during mouse acute otitis media.

    Xiang, Yun; Jin, Chunfang; Wang, Wei; Wang, Zimeng; Huang, Yifei; Fan, Fangmei; Ma, Yurong; Zhang, Xuemei; Xu, Wenchun; Yin, Yibing; He, Yujuan

    2017-04-01

    We have recently reported that neutrophils play a pivotal role in innate defense against Streptococcus pneumoniae ( Spn) during mouse acute otitis media (AOM). However, the underlying mechanism remains unclear. By constructing models of pneumococcal AOM in C57BL/6 mice and using a specific inhibitor in vivo, we investigated the role of myeloperoxidase (MPO), one of the most important protein components of neutrophils. Experiment results showed a significant increase in MPO production of the recruited neutrophils in Spn-infected mice. Neutrophils killed Spn in a MPO-dependent manner. MPO facilitated the generation of reactive oxygen species (ROS), and consequently promoted Spn clearance at an early stage and exacerbated tissue damage. Moreover, MPO induced neutrophil apoptosis and necrosis, which, in turn, worsened tissue damage. In summary, our study demonstrates that neutrophil MPO plays a paradoxical role in bacterial clearance and tissue damage in pneumococcal AOM.

  19. Usefulness of a selective neutrophil elastase inhibitor, sivelestat, in acute lung injury patients with sepsis

    Miyoshi S

    2013-04-01

    Full Text Available Seigo Miyoshi,1 Hironobu Hamada,1,2 Ryoji Ito,1 Hitoshi Katayama,1 Kazunori Irifune,1 Toshimitsu Suwaki,3 Norihiko Nakanishi,4 Takanori Kanematsu,5 Kentaro Dote,6 Mayuki Aibiki,7 Takafumi Okura,1 Jitsuo Higaki1 1Department of Integrated Medicine and Informatics, Ehime University, Graduate School of Medicine, Toon, 2Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, 3Department of Respiratory Medicine, Sumitomo Besshi Hospital, Niihama, 4Department of Respiratory Medicine, Ehime Prefectural Central Hospital, Matsuyama, 5Department of Respiratory Medicine, Matsuyama Red Cross Hospital, Matsuyama, 6Intensive Care Division, Ehime University Hospital, Toon, 7Department of Emergency Medicine, School of Medicine, Ehime University, Toon, Japan Background: Neutrophil elastase plays a crucial role in the development of acute lung injury (ALI in patients with systemic inflammatory response syndrome (SIRS. The clinical efficacy of the neutrophil elastase inhibitor, sivelestat, for patients with ALI associated with SIRS has not been convincingly demonstrated. The aim of this study was to determine if there are clinical features of patients with this condition that affect the efficacy of sivelestat. Methods: This was a retrospective study of 110 ALI patients with SIRS. Clinical information, including the etiology of ALI, the number of organs failing, scoring systems for assessing the severity of illness, and laboratory data, was collected at the time of diagnosis. Information on the number of ventilator-free days (VFDs and changes in PaO2/FIO2 (ΔP/F before and 7 days after the time of ALI diagnosis was also collected. The effect of sivelestat on ALI patients was also examined based on whether they had sepsis and whether their initial serum procalcitonin level was ≥0.5 ng/mL. Results: There were 70 patients who were treated with sivelestat and 40 control patients. VFDs and ΔP/F were significantly higher in the treated

  20. LPS-induced lung inflammation in marmoset monkeys - an acute model for anti-inflammatory drug testing.

    Sophie Seehase

    Full Text Available Increasing incidence and substantial morbidity and mortality of respiratory diseases requires the development of new human-specific anti-inflammatory and disease-modifying therapeutics. Therefore, new predictive animal models that closely reflect human lung pathology are needed. In the current study, a tiered acute lipopolysaccharide (LPS-induced inflammation model was established in marmoset monkeys (Callithrix jacchus to reflect crucial features of inflammatory lung diseases. Firstly, in an ex vivo approach marmoset and, for the purposes of comparison, human precision-cut lung slices (PCLS were stimulated with LPS in the presence or absence of the phosphodiesterase-4 (PDE4 inhibitor roflumilast. Pro-inflammatory cytokines including tumor necrosis factor-alpha (TNF-α and macrophage inflammatory protein-1 beta (MIP-1β were measured. The corticosteroid dexamethasone was used as treatment control. Secondly, in an in vivo approach marmosets were pre-treated with roflumilast or dexamethasone and unilaterally challenged with LPS. Ipsilateral bronchoalveolar lavage (BAL was conducted 18 hours after LPS challenge. BAL fluid was processed and analyzed for neutrophils, TNF-α, and MIP-1β. TNF-α release in marmoset PCLS correlated significantly with human PCLS. Roflumilast treatment significantly reduced TNF-α secretion ex vivo in both species, with comparable half maximal inhibitory concentration (IC(50. LPS instillation into marmoset lungs caused a profound inflammation as shown by neutrophilic influx and increased TNF-α and MIP-1β levels in BAL fluid. This inflammatory response was significantly suppressed by roflumilast and dexamethasone. The close similarity of marmoset and human lungs regarding LPS-induced inflammation and the significant anti-inflammatory effect of approved pharmaceuticals assess the suitability of marmoset monkeys to serve as a promising model for studying anti-inflammatory drugs.

  1. Corticosteroid treatment ameliorates acute lung injury induced by 2009 swine origin influenza A (H1N1 virus in mice.

    Chenggang Li

    Full Text Available BACKGROUND: The 2009 influenza pandemic affected people in almost all countries in the world, especially in younger age groups. During this time, the debate over whether to use corticosteroid treatment in severe influenza H1N1 infections patients resurfaced and was disputed by clinicians. There is an urgent need for a susceptible animal model of 2009 H1N1 infection that can be used to evaluate the pathogenesis and the therapeutic effect of corticosteroid treatment during infection. METHODOLOGY/PRINCIPAL FINDINGS: We intranasally inoculated two groups of C57BL/6 and BALB/c mice (using 4- or 6-to 8-week-old mice to compare the pathogenesis of several different H1N1 strains in mice of different ages. Based on the results, a very susceptible 4-week-old C57BL/6 mouse model of Beijing 501 strain of 2009 H1N1 virus infection was established, showing significantly elevated lung edema and cytokine levels compared to controls. Using our established animal model, the cytokine production profile and lung histology were assessed at different times post-infection, revealing increased lung lesions in a time-dependent manner. In additional,the mice were also treated with dexamethasone, which significantly improved survival rate and lung lesions in infected mice compared to those in control mice. Our data showed that corticosteroid treatment ameliorated acute lung injury induced by the 2009 A/H1N1 virus in mice and suggested that corticosteroids are valid drugs for treating 2009 A/H1N1 infection. CONCLUSIONS/SIGNIFICANCE: Using the established, very susceptible 2009 Pandemic Influenza A (H1N1 mouse model, our studies indicate that corticosteroids are a potential therapeutic remedy that may address the increasing concerns over future 2009 A/H1N1 pandemics.

  2. I-FABP as biomarker for the early diagnosis of acute mesenteric ischemia and resultant lung injury.

    Rachel G Khadaroo

    Full Text Available Acute mesenteric ischemia (AMI is a life-threatening condition that can result in multiple organ injury and death. A timely diagnosis and treatment would have a significant impact on the morbidity and mortality in high-risk patient population. The purpose of this study was to investigate if intestinal fatty acid binding protein (I-FABP and α-defensins can be used as biomarkers for early AMI and resultant lung injury. C57BL/6 mice were subjected to intestinal ischemia by occlusion of the superior mesenteric artery. A time course of intestinal ischemia from 0.5 to 3 h was performed and followed by reperfusion for 2 h. Additional mice were treated with N-acetyl-cysteine (NAC at 300 mg/kg given intraperitoneally prior to reperfusion. AMI resulted in severe intestinal injury characterized by neutrophil infiltrate, myeloperoxidase (MPO levels, cytokine/chemokine levels, and tissue histopathology. Pathologic signs of ischemia were evident at 1 h, and by 3 h of ischemia, the full thickness of the intestine mucosa had areas of coagulative necrosis. It was noted that the levels of α-defensins in intestinal tissue peaked at 1 h and I-FABP in plasma peaked at 3 h after AMI. Intestinal ischemia also resulted in lung injury in a time-dependent manner. Pretreatment with NAC decreased the levels of intestinal α-defensins and plasma I-FABP, as well as lung MPO and cytokines. In summary, the concentrations of intestinal α-defensins and plasma I-FABP predicted intestinal ischemia prior to pathological evidence of ischemia and I-FABP directly correlated with resultant lung injury. The antioxidant NAC reduced intestinal and lung injury induced by AMI, suggesting a role for oxidants in the mechanism for distant organ injury. I-FABP and α-defensins are promising biomarkers, and may guide the treatment with antioxidant in early intestinal and distal organ injury.

  3. Effect of penehyclidine hydrochloride on patients with acute lung injury and its mechanisms

    LI Bai-qiang; SUN Hai-chen; NIE Shi-nan; SHAO Dan-bing; LIU Hong-mei; QIAN Xiao-ming

    2010-01-01

    Objective: To assess the effects of penehyclidine hydrochloride on patients with acute lung injury (ALI), to observe the expression of Toll-like receptor 4 (TLR4) on the peripheral monocytes of ALI patients and changes of inflammatory & anti-inflammatory cytokines and to investigate the mechanism of TLR4 in ALI.Methods: Forty-five patients with ALI were randomly divided into penehyclidine hydrochloride treatment group (P group, n=21) and conventional treatment group (control group, C group, n=24). Patients in both groups received conventional treatment, including active treatment of the primary disease, respiratory support, nutritional support and fluid management therapy, while those in P group were given penehyclidine hydrochloride (1 mg, im, q. 12 h) in addition.The TLR4 expression of 20 healthy volunteers were detected.The clinical effect, average length of stay in ICU and hospital,values of PaO2 and PaO2/FiO2, expression of TLR4 on the surface of peripheral blood mononuclear cells and some serum cytokines were evaluated for 48 h.Results: The general conditions of the two groups were improved gradually and PaO2 increased progressively.Compared with 0 h, PaO2 and PaO2/FiO2 at 6, 12, 24 and 48 h after treatment were significantly increased (P<0.05). The improvement in P group was obviously greater than that in C group (P<0.05). The average length of hospitalization showed no difference between the two groups, but penehyclidine hydrochloride significantly decreased the average length of stay in ICU (t=3.485, P<0.01). The expression of TLR4 in two groups were both obviously higher than that of healthy volunteers (P<0.01). It decreased significantly at 24 h (t=2.032, P<0.05) and 48 h (t=3.620, P<0.01)and was lower in P group than in C group. The patients who showed a higher level of TLR4 expression in early stage had a worse prognosis and most of them developed acute respiratory distress syndrome (ARDS). The incidence of ARDS was 23.8% in P group and 29

  4. Effect and mechanism of acute graft versus host disease on early diffuse murine lung injury following allogeneic stem cell transplantation

    2009-01-01

    To explore the effect and pathogenssis of acute graft-versus-host disease (aGVHD) on early diffuse lung injury in allogeneic hematopoietic stem cell transplantation (allo-HSCT), we established an aGVHD model of C57BL/6→BALB/c mice. Chest computed tomography (CT) scans, histopathology and the levels of cytokines including tumor necrosis factor α (TNFα) and Interferon (IFNγ) in lungs were dynamically detected in recipient mice after transplantation. The incidence of aGVHD was respectively 0%, 0% and 100% in simple irradiation group (A), syngeneic transplant group(B) and allogeneic transplant group (C). Chest CT scans of recipient mice were normal in 3 groups on days +3 and +7 after transplantation. CT showed that two of ten mice had bilateral lung diffuse infiltrate on day +12 (on the brink of death) in group A and 6 of 10 mice had bilateral lung diffuse infiltrate on day +14 (3 d after aGVHD occurring) in group C, and were normal on days +12 and +14 in group B after transplantation. Histopathology of lungs in the 3 groups was similar, consisting of minor interstitial pneumonitis on day +3. Group A showed edema, hyperplasia of epithelial cells and widened alveolar interval on day +7, and epithelial cell necrosis, lymphocyte infiltration, hemorrhage, protein leakage, and local consolidation on day +12. The histopathology of group B showed slight edema of epithelial cells on +7 day, which were slighter than that on day +3, and virtually normal on day +14. The histopathology in group C was characterized by the significant expansion and congestion of capillaries, and lymphocyte infiltration on day +7, the acute pneumonitis was present involving tissue edema, lymphocyte and macrophage infiltration, protein leakage and perivascular inflammation on day +14. In group A, the levels of TNFα were lower on day +7 than on day +3. In group B, the levels of TNFα attained a peak on day +3, which decreased on days +7 and +14. In group C, the levels of TNFα were highest on day

  5. Effect of pentoxifylline on lung inflammation and gas exchange in a sepsis-induced acute lung injury model

    I.S. Oliveira-Junior

    2006-11-01

    Full Text Available Experimental models of sepsis-induced pulmonary alterations are important for the study of pathogenesis and for potential intervention therapies. The objective of the present study was to characterize lung dysfunction (low PaO2 and high PaCO2, and increased cellular infiltration, protein extravasation, and malondialdehyde (MDA production assessed in bronchoalveolar lavage in a sepsis model consisting of intraperitoneal (ip injection of Escherichia coli and the protective effects of pentoxifylline (PTX. Male Wistar rats (weighing between 270 and 350 g were injected ip with 10(7 or 10(9 CFU/100 g body weight or saline and samples were collected 2, 6, 12, and 24 h later (N = 5 each group. PaO2, PaCO2 and pH were measured in blood, and cellular influx, protein extravasation and MDA concentration were measured in bronchoalveolar lavage. In a second set of experiments either PTX or saline was administered 1 h prior to E. coli ip injection (N = 5 each group and the animals were observed for 6 h. Injection of 10(7 or 10(9 CFU/100 g body weight of E. coli induced acidosis, hypoxemia, and hypercapnia. An increased (P < 0.05 cell influx was observed in bronchoalveolar lavage, with a predominance of neutrophils. Total protein and MDA concentrations were also higher (P < 0.05 in the septic groups compared to control. A higher tumor necrosis factor-alpha (P < 0.05 concentration was also found in these animals. Changes in all parameters were more pronounced with the higher bacterial inoculum. PTX administered prior to sepsis reduced (P < 0.05 most functional alterations. These data show that an E. coli ip inoculum is a good model for the induction of lung dysfunction in sepsis, and suitable for studies of therapeutic interventions.

  6. Acute damage by naphthalene triggers expression of the neuroendocrine marker PGP9.5 in airway epithelial cells

    Poulsen, T.T.; Naizhen, X.; Linnoila, R.I.

    2008-01-01

    Protein Gene Product 9.5 (PGP9.5) is highly expressed in nervous tissue. Recently PGP9.5 expression has been found to be upregulated in the pulmonary epithelium of smokers and in non-small cell lung cancer, suggesting that it also plays a role in carcinogen-inflicted lung epithelial injury...... airways compared to controls, indicating that the rise in PGP9.5 in the airway epithelium is related to downregulation of p27(Kip1). This study is the first to specifically identify the carcinogen naphthalene as an inducer of PGP9.5 expression in non-neuroendocrine epithelium after acute lung injury...... and carcinogenesis. We investigated the expression of PGP9.5 in mice in response to two prominent carcinogens found in tobacco smoke: Naphthalene and 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK). By immunostaining, we found that PGP9.5 protein was highly expressed throughout the airway epithelium in the days...

  7. Aging promotes pro-fibrotic matrix production and increases fibrocyte recruitment during acute lung injury.

    Sueblinvong, Viranuj; Neveu, Wendy A; Neujahr, David C; Mills, Stephen T; Rojas, Mauricio; Roman, Jesse; Guidot, David M

    2014-01-01

    Fibrotic lung diseases increase with age. Previously we determined that senescence increases tissue expression of fibronectin EDA (Fn-EDA) and decreases fibroblast expression of Thy-1, and that fibrocytes contribute to fibrosis following bleomycin-induced lung injury in mice. In this study we hypothesized that fibroblasts lacking Thy-1 expression produce an extracellular matrix that promotes fibrocyte retention and myofibroblast transdifferentiation, thereby promoting fibrogenesis. Young and old mice were treated with bleomycin intratracheally; fibrocytes in the bone marrow, blood, and lungs were quantified, and lung fibroblast Thy-1 expression assessed. Bone marrow-derived fibrocytes were cultured on matrices derived from Thy-1(+) or Thy-1(-) fibroblasts ± the pro-fibrotic cytokine TGFβ1. Older mice had more fibrocytes in their bone marrows at baseline and more fibrocytes in their lungs following bleomycin treatment. In parallel, lung fibroblasts in older mice had lower expression of Thy-1 at baseline that increased transiently 7 days after bleomycin treatment but then rapidly waned such that 14 days after bleomycin treatment Thy-1 expression was again markedly lower. Fibrocytes cultured on matrices derived from Thy-1(-) fibroblasts + TGFβ1 had increased gene expression for collagen type 1, fibronectin, Fn-EDA, and α-smooth muscle actin. In parallel, whereas the matrices derived from Thy-1(-) fibroblasts stimulated phosphorylation of Akt in cultured fibrocytes, the matrices derived from Thy-1(+) fibroblasts induced apoptosis. These findings suggest that senescence increases fibrocyte recruitment to the lung following injury and that loss of Thy-1 expression by lung fibroblasts promotes fibrocyte retention and myofibroblast trans-differentiation that renders the "aging lung" susceptible to fibrosis.

  8. Immunomodulatory Effect of Chinese Herbal Medicine Formula Sheng-Fei-Yu-Chuan-Tang in Lipopolysaccharide-Induced Acute Lung Injury Mice

    Chia-Hung Lin; Ching-Hua Yeh; Li-Jen Lin; Shulhn-Der Wang; Jen-Shu Wang; Shung-Te Kao

    2013-01-01

    Traditional Chinese medicine formula Sheng-Fei-Yu-Chuan-Tang (SFYCT), consisting of 13 medicinal plants, was used to treat patients with lung diseases. This study investigated the immunoregulatory effect of SFYCT on intratracheal lipopolysaccharides- (LPS-) challenged acute lung injury (ALI) mice. SFYCT attenuated pulmonary edema, macrophages, and neutrophils infiltration in the airways. SFYCT decreased inflammatory cytokines, including tumor necrosis factor- α (TNF α ), interleukin-1 β , and...

  9. Experimental study of acute lung injury induced by different tidal volume ventilation in rats

    ZHANG Xin-ri; DU Yong-cheng; JIANG Hong-ying; XU Jian-ying; XU Yong-jian

    2005-01-01

    @@ Mechanical ventilation (MV) is a dual blade sward which if misused could lead to lung injury, called ventilator induced lung injury (VILI). Pathogenesis of VILI is very complex with various manifestations, which is the focus in MV field in recent years.1 In our research, the rats were ventilated with different tidal volume, then the pathological changes of the lungs were observed under macroscopy, light and electronic microscope, and various laboratory tests in blood and bronchoalveolar lavage fluid (BALF) were also carried out in order to probe further the pathologic characteristics and the pathogenesis of VILI.

  10. Blocking Cyclic Adenosine Diphosphate Ribose-mediated Calcium Overload Attenuates Sepsis-induced Acute Lung Injury in Rats

    Qian-yi Peng; Yu Zou; Li-Na Zhang; Mei-Lin Ai; Wei Liu; Yu-Hang Ai

    2016-01-01

    Background:Acute lung injury (ALI) is a common complication of sepsis that is associated with high mortality.Intracellular Ca2+ overload plays an important role in the pathophysiology of sepsis-induced ALI,and cyclic adenosine diphosphate ribose (cADPR) is an important regulator of intracellular Ca2+ mobilization.The cluster of differentiation 38 (CD38)/cADPR pathway has been found to play roles in multiple inflammatory processes but its role in sepsis-induced ALI is still unknown.This study aimed to investigate whether the CD38/cADPR signaling pathway is activated in sepsis-induced ALI and whether blocking cADPR-mediated calcium overload attenuates ALI.Methods:Septic rat models were established by cecal ligation and puncture (CLP).Rats were divided into the sham group,the CLP group,and the CLP+ 8-bromo-cyclic adenosine diphosphate ribose (8-Br-cADPR) group.Nicotinamide adenine dinucleotide (NAD+),cADPR,CD38,and intracellular Ca2+ levels in the lung tissues were measured at 6,12,24,and 48 h after CLP surgery.Lung histologic injury,tumor necrosis factor (TNF)-α,malondialdehyde (MDA) levels,and superoxide dismutase (SOD) activities were measured.Results:NAD+,cADPR,CD38,and intracellular Ca2+ levels in the lungs of septic rats increased significantly at 24 h after CLP surgery.Treatment with 8-Br-cADPR,a specific inhibitor of cADPR,significantly reduced intracellular Ca2+ levels (P =0.007),attenuated lung histological injury (P =0.023),reduced TNF-α and MDA levels (P < 0.001 and P =0.002,respectively) and recovered SOD activity (P =0.031) in the lungs of septic rats.Conclusions:The CD38/cADPR pathway is activated in the lungs of septic rats,and blocking cADPR-mediated calcium overload with 8-Br-cADPR protects against sepsis-induced ALI.

  11. Suppression of the DNA damage response in acute myeloid leukemia versus myelodysplastic syndrome.

    Boehrer, S; Adès, L; Tajeddine, N; Hofmann, W K; Kriener, S; Bug, G; Ottmann, O G; Ruthardt, M; Galluzzi, L; Fouassier, C; Tailler, M; Olaussen, K A; Gardin, C; Eclache, V; de Botton, S; Thepot, S; Fenaux, P; Kroemer, G

    2009-06-04

    The molecular mechanisms responsible for the evolution from the preleukemic entities of low-risk myelodysplastic syndrome (MDS) to the less favorable forms of high-risk MDS, as well as those enabling transformation to acute myeloid leukemia (AML), are still incompletely understood. Abundant evidence from solid tumors demonstrates that preneoplastic lesions activate signaling pathways of a DNA damage response (DDR), which functions as an 'anticancer barrier' hindering tumorigenesis. Testing the hypothesis that subgroups of MDS and AML differ with respect to DDR, we first assessed markers of DDR (phosphorylation of ATM, Chk-1, Chk-2 and H2AX) in cell lines representing different entities of MDS (P39, MOLM-13) and AML (MV4-11, KG-1) before and after gamma-irradiation. Although gamma-irradiation induced apoptosis and G(2)/M arrest and a concomitant increase in the phosphorylation of ATM, Chk-1 and H2AX in MDS-derived cell lines, this radiation response was attenuated in the AML-derived cell lines. It is noteworthy that KG-1, but not P39 cells exhibit signs of an endogenous activation of the DDR. Similarly, we found that the frequency of P-ATM(+) cells detectable in bone marrow (BM) biopsies increased in samples from patients with AML as compared with high-risk MDS samples and significantly correlated with the percentage of BM blasts. In contrast, the frequency of gamma-H2AX(+) cells was heterogeneous in all subgroups of AML and MDS. Whereas intermediate-1 MDS samples contained as little P-Chk-1 and P-Chk-2 as healthy controls, staining for both checkpoint kinases increased in intermediate-2 and high-risk MDS, yet declined to near-to-background levels in AML samples. Thus the activation of Chk-1 and Chk-2 behaves in accord with the paradigm established for solid tumors, whereas ATM is activated during and beyond transformation. In conclusion, we demonstrate the heterogeneity of the DDR response in MDS and AML and provide evidence for its selective suppression in AML

  12. Relationship between Acute Organophosphorus Pesticide Poisoning and Damages Induced by Free Radicals

    2002-01-01

    Objective To study the relationship between abnormal reactions of free radicals in bodies of patients with acute organophosphorus pesticide poisoning (AOPP) and damages induced by free radicals. Methods 58 AOPP patients and 58 healthy adult volunteers (HAV) were enrolled in an independent samples control design, in which spectrophotometric methods were used to determine the concentrations of nitric oxide (NO) and lipoperoxides (LPO) in plasma, and LPO in erythrocytes, vitamin C (VC), vitamin E (VE) and b-carotene (b-CAR) in plasma as well as activities of superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GSH-Px) and acetylcholinesterase (AChE) in erythrocytes. Results Compared with the average values of every biochemical parameter in the HAV group, the average values of LPO in plasma and in erythrocytes, and NO in plasma in the AOPP group were significantly increased (P=0.000001), while the average values of VC, VE, a-CAR in plasma as well as SOD, CAT, GSH-Px and AChE in erythrocytes in the AOPP group were significantly decreased (P=0.000001). The findings of Pearson product-moment correlation analysis between the value of AChE in erythrocytes and the values of above biochemical parameters for 58 AOPP patients showed that there was a significant linear negative correlation between AChE in erythrocytes and LPO, NO in plasma, and LPO in erythrocytes (P=0.000001~0.001319), while there was a significant linear positive correlation between AChE in erythrocytes and VC, VE, a-CAR in plasma as well as SOD, CAT, GSH-Px in erythrocytes (P=0.000013~0.000824). The results of discriminant analysis of above chemical parameters for 58 AOPP patients and 58 HAV suggested that the correct rates of discriminant analysis were increased to 100 % when the values of AChE and LPO in plasma and in erythrocytes, or AChE and others, were jointly used for the discriminant analysis. Conclusion The findings of the present study suggest that a series of free radical

  13. A specific phospholipase C activity regulates phosphatidylinositol levels in lung surfactant of patients with acute respiratory distress syndrome.

    Spyridakis, Spyros; Leondaritis, George; Nakos, George; Lekka, Marilena E; Galanopoulou, Dia

    2010-03-01

    Lung surfactant (LS) is a lipid-rich material lining the inside of the lungs. It reduces surface tension at the liquid/air interface and thus, it confers protection of the alveoli from collapsing. The surface-active component of LS is dipalmitoyl-phosphatidylcholine, while anionic phospholipids such as phosphatidylinositol (PtdIns) and primarily phosphatidylglycerol are involved in the stabilization of the LS monolayer. The exact role of PtdIns in this system is not well-understood; however, PtdIns levels change dramatically during the acute respiratory distress syndrome (ARDS) evolution. In this report we present evidence of a phosphoinositide-specific phospholipase C (PI-PLC) activity in bronchoalveolar lavage (BAL) fluid, which may regulate PtdIns levels. Characterization of this extracellular activity showed specificity for PtdIns and phosphatidylinositol 4,5-bisphosphate, sharing the typical substrate concentration-, pH-, and calcium-dependencies with mammalian PI-PLCs. Fractionation of BAL fluid showed that PI-PLC did not co-fractionate with large surfactant aggregates, but it was found mainly in the soluble fraction. Importantly, analysis of BAL samples from control subjects and from patients with ARDS showed that the PI-PLC specific activity was decreased by 4-fold in ARDS samples concurrently with the increase in BAL PtdIns levels. Thus, we have identified for the first time an extracellular PI-PLC enzyme activity that may be acutely involved in the regulation of PtdIns levels in LS.

  14. Nitrative DNA damage induced by multi-walled carbon nanotube via endocytosis in human lung epithelial cells

    Guo, Feiye, E-mail: zhizi0269@doc.medic.mie-u.ac.jp [Department of Environmental and Molecular Medicine, Mie University Graduate School of Medicine, 2-174 Edobashi, Tsu, Mie, 514-8507 (Japan); Ma, Ning, E-mail: maning@suzuka-u.ac.jp [Faculty of Health Science, Suzuka University of Medical Science, 1001-1 Kishioka-cho, Suzuka, Mie, 510-0293 (Japan); Horibe, Yoshiteru, E-mail: violinteru@yahoo.co.jp [Department of Environmental and Molecular Medicine, Mie University Graduate School of Medicine, 2-174 Edobashi, Tsu, Mie, 514-8507 (Japan); Kawanishi, Shosuke, E-mail: kawanisi@suzuka-u.ac.jp [Faculty of Pharmaceutical Sciences, Suzuka University of Medical Science, 3500-3 Minami-Tamagaki-cho, Suzuka, Mie, 513-8670 (Japan); Murata, Mariko, E-mail: mmurata@doc.medic.mie-u.ac.jp [Department of Environmental and Molecular Medicine, Mie University Graduate School of Medicine, 2-174 Edobashi, Tsu, Mie, 514-8507 (Japan); Hiraku, Yusuke, E-mail: y-hiraku@doc.medic.mie-u.ac.jp [Department of Environmental and Molecular Medicine, Mie University Graduate School of Medicine, 2-174 Edobashi, Tsu, Mie, 514-8507 (Japan)

    2012-04-15

    Carbon nanotube (CNT) has a promising usage in the field of material science for industrial purposes because of its unique physicochemical property. However, intraperitoneal administration of CNT was reported to cause mesothelioma in experimental animals. Chronic inflammation may contribute to carcinogenesis induced by fibrous materials. 8-Nitroguanine is a mutagenic DNA lesion formed during inflammation and may play a role in CNT-induced carcinogenesis. In this study, we examined 8-nitroguanine formation in A549 human lung alveolar epithelial cells treated with multi-walled CNT (MWCNT) by fluorescent immunocytochemistry. Both MWCNTs with diameter of 20–30 nm (CNT20) and 40–70 nm (CNT40) significantly induced 8-nitroguanine formation at 5 and 10 μg/ml (p < 0.05), which persisted for 24 h, although there was no significant difference in DNA-damaging a