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Sample records for oxidative lung injury

  1. Nitric oxide and hyperoxic acute lung injury

    PubMed Central

    Liu, Wen-wu; Han, Cui-hong; Zhang, Pei-xi; Zheng, Juan; Liu, Kan; Sun, Xue-jun

    2016-01-01

    Hyperoxic acute lung injury (HALI) refers to the damage to the lungs secondary to exposure to elevated oxygen partial pressure. HALI has been a concern in clinical practice with the development of deep diving and the use of normobaric as well as hyperbaric oxygen in clinical practice. Although the pathogenesis of HALI has been extensively studied, the findings are still controversial. Nitric oxide (NO) is an intercellular messenger and has been considered as a signaling molecule involved in many physiological and pathological processes. Although the role of NO in the occurrence and development of pulmonary diseases including HALI has been extensively studied, the findings on the role of NO in HALI are conflicting. Moreover, inhalation of NO has been approved as a therapeutic strategy for several diseases. In this paper, we briefly summarize the role of NO in the pathogenesis of HALI and the therapeutic potential of inhaled NO in HALI. PMID:27867474

  2. OXIDATIVE STRESS PARTICIPATES IN PARTICULATE MATTER (PM) INDUCED LUNG INJURY

    EPA Science Inventory

    Oxidative stress participates in particulate matter (PM) induced acute lung injury.
    Elizabeth S. Roberts1, Judy L. Richards2, Kevin L. Dreher2. 1College of Veterinary Medicine, NC State University, Raleigh, NC, 2US Environmental Protection Agency, NHEERL, RTP, NC.
    Epidemiol...

  3. OXIDATIVE STRESS PARTICIPATES IN PARTICULATE MATTER (PM) INDUCED LUNG INJURY

    EPA Science Inventory

    Oxidative stress participates in particulate matter (PM) induced acute lung injury.
    Elizabeth S. Roberts1, Judy L. Richards2, Kevin L. Dreher2. 1College of Veterinary Medicine, NC State University, Raleigh, NC, 2US Environmental Protection Agency, NHEERL, RTP, NC.
    Epidemiol...

  4. Nitric Oxide as a Mediator of Oxidant Lung Injury Due to Paraquat

    NASA Astrophysics Data System (ADS)

    Berisha, Hasan I.; Pakbaz, Hedayatollah; Absood, Afaf; Said, Sami I.

    1994-08-01

    At low concentrations, nitric oxide is a physiological transmitter, but in excessive concentrations it may cause cell and tissue injury. We report that in acute oxidant injury induced by the herbicide paraquat in isolated guinea pig lungs, nitric oxide synthesis was markedly stimulated, as evidenced by increased levels of cyclic GMP in lung perfusate and of nitrite and L-citrulline production in lung tissue. All signs of injury, including increased airway and perfusion pressures, pulmonary edema, and protein leakage into the airspaces, were dose-dependently attenuated or totally prevented by either N^G-nitro-L-arginine methyl ester or N^ω-nitro-L-arginine, selective and competitive inhibitors of nitric oxide synthase. Protection was reversed by excess L-arginine but not by its enantiomer D-arginine. When blood was added to the lung perfusate, the paraquat injury was moderated or delayed as it was when paraquat was given to anesthetized guinea pigs. The rapid onset of injury and its failure to occur in the absence of Ca2+ suggest that constitutive rather than inducible nitric oxide synthase was responsible for the stimulated nitric oxide synthesis. The findings indicate that nitric oxide plays a critical role in the production of lung tissue injury due to paraquat, and it may be a pathogenetic factor in other forms of oxidant tissue injury.

  5. Nitrofurantoin: evidence for the oxidant injury of lung parenchymal cells.

    PubMed

    Martin, W J

    1983-04-01

    Nitrofurantoin, a commonly used urinary antiseptic, is associated with significant pulmonary toxicity. This study used a 51Cr rat lung explant cytotoxicity assay to demonstrate that nitrofurantoin (10(-3) M), when incubated with lung parenchymal cells for 12 h at 37 degrees C, resulted in significant lung cell injury (cytotoxic index of 43 +/- 2). This injury could be reduced (p less than 0.05) by several antioxidants, including superoxide dismutase, 300 U/ml (37 +/- 2); catalase, 1,100 U/ml (27 +/- 2); alpha tocopherol, 10 micrograms/ml (30 +/- 2); ascorbic acid 50 micrograms/ml (37 +/- 2); ethanol, 0.1% (35 +/- 2); dimethyl sulfoxide, 1.0% (37 +/- 2). Additionally, the nitrofurantoin-induced injury could be accelerated in the presence of hyperoxia (95% O2) from 45 +/- 2 to 62 +/- 1, p less than 0.01. These data suggest that nitrofurantoin can directly injure lung parenchymal cells, probably through oxidant mechanisms, and this might suggest alternative approaches in the evaluation and therapy of patients with this disorder.

  6. Hyaluronan mediates airway hyperresponsiveness in oxidative lung injury

    PubMed Central

    Lazrak, Ahmed; Creighton, Judy; Yu, Zhihong; Komarova, Svetlana; Doran, Stephen F.; Aggarwal, Saurabh; Emala, Charles W.; Stober, Vandy P.; Trempus, Carol S.; Garantziotis, Stavros

    2015-01-01

    Chlorine (Cl2) inhalation induces severe oxidative lung injury and airway hyperresponsiveness (AHR) that lead to asthmalike symptoms. When inhaled, Cl2 reacts with epithelial lining fluid, forming by-products that damage hyaluronan, a constituent of the extracellular matrix, causing the release of low-molecular-weight fragments (L-HA, <300 kDa), which initiate a series of proinflammatory events. Cl2 (400 ppm, 30 min) exposure to mice caused an increase of L-HA and its binding partner, inter-α-trypsin-inhibitor (IαI), in the bronchoalveolar lavage fluid. Airway resistance following methacholine challenge was increased 24 h post-Cl2 exposure. Intratracheal administration of high-molecular-weight hyaluronan (H-HA) or an antibody against IαI post-Cl2 exposure decreased AHR. Exposure of human airway smooth muscle (HASM) cells to Cl2 (100 ppm, 10 min) or incubation with Cl2-exposed H-HA (which fragments it to L-HA) increased membrane potential depolarization, intracellular Ca2+, and RhoA activation. Inhibition of RhoA, chelation of intracellular Ca2+, blockade of cation channels, as well as postexposure addition of H-HA, reversed membrane depolarization in HASM cells. We propose a paradigm in which oxidative lung injury generates reactive species and L-HA that activates RhoA and Ca2+ channels of airway smooth muscle cells, increasing their contractility and thus causing AHR. PMID:25747964

  7. Oxidative Stress and Lung Ischemia-Reperfusion Injury

    PubMed Central

    Ferrari, Renata Salatti; Andrade, Cristiano Feijó

    2015-01-01

    Ischemia-reperfusion (IR) injury is directly related to the formation of reactive oxygen species (ROS), endothelial cell injury, increased vascular permeability, and the activation of neutrophils and platelets, cytokines, and the complement system. Several studies have confirmed the destructiveness of the toxic oxygen metabolites produced and their role in the pathophysiology of different processes, such as oxygen poisoning, inflammation, and ischemic injury. Due to the different degrees of tissue damage resulting from the process of ischemia and subsequent reperfusion, several studies in animal models have focused on the prevention of IR injury and methods of lung protection. Lung IR injury has clinical relevance in the setting of lung transplantation and cardiopulmonary bypass, for which the consequences of IR injury may be devastating in critically ill patients. PMID:26161240

  8. Effect of ozone oxidative preconditioning in preventing early radiation-induced lung injury in rats.

    PubMed

    Bakkal, B H; Gultekin, F A; Guven, B; Turkcu, U O; Bektas, S; Can, M

    2013-09-01

    Ionizing radiation causes its biological effects mainly through oxidative damage induced by reactive oxygen species. Previous studies showed that ozone oxidative preconditioning attenuated pathophysiological events mediated by reactive oxygen species. As inhalation of ozone induces lung injury, the aim of this study was to examine whether ozone oxidative preconditioning potentiates or attenuates the effects of irradiation on the lung. Rats were subjected to total body irradiation, with or without treatment with ozone oxidative preconditioning (0.72 mg/kg). Serum proinflammatory cytokine levels, oxidative damage markers, and histopathological analysis were compared at 6 and 72 h after total body irradiation. Irradiation significantly increased lung malondialdehyde levels as an end-product of lipoperoxidation. Irradiation also significantly decreased lung superoxide dismutase activity, which is an indicator of the generation of oxidative stress and an early protective response to oxidative damage. Ozone oxidative preconditioning plus irradiation significantly decreased malondialdehyde levels and increased the activity of superoxide dismutase, which might indicate protection of the lung from radiation-induced lung injury. Serum tumor necrosis factor alpha and interleukin-1 beta levels, which increased significantly following total body irradiation, were decreased with ozone oxidative preconditioning. Moreover, ozone oxidative preconditioning was able to ameliorate radiation-induced lung injury assessed by histopathological evaluation. In conclusion, ozone oxidative preconditioning, repeated low-dose intraperitoneal administration of ozone, did not exacerbate radiation-induced lung injury, and, on the contrary, it provided protection against radiation-induced lung damage.

  9. Inhaled nitric oxide exacerbated phorbol-induced acute lung injury in rats.

    PubMed

    Lin, Hen I; Chu, Shi Jye; Hsu, Kang; Wang, David

    2004-01-01

    In this study, we determined the effect of inhaled nitric oxide (NO) on the acute lung injury induced by phorbol myristate acetate (PMA) in isolated rat lung. Typical acute lung injury was induced successfully by PMA during 60 min of observation. PMA (2 microg/kg) elicited a significant increase in microvascular permeability, (measured using the capillary filtration coefficient Kfc), lung weight gain, lung weight/body weight ratio, pulmonary arterial pressure (PAP) and protein concentration of the bronchoalveolar lavage fluid. Pretreatment with inhaled NO (30 ppm) significantly exacerbated acute lung injury. All of the parameters reflective of lung injury increased significantly except PAP (P<0.05). Coadministration of Nomega-nitro-L-arginine methyl ester (L-NAME) (5 mM) attenuated the detrimental effect of inhaled NO in PMA-induced lung injury, except for PAP. In addition, L-NAME (5 mM) significantly attenuated PMA-induced acute lung injury except for PAP. These experimental data suggest that inhaled NO significantly exacerbated acute lung injury induced by PMA in rats. L-NAME attenuated the detrimental effect of inhaled NO.

  10. Inhaled nitric oxide aggravates phosgene model of acute lung injury.

    PubMed

    Li, Wen-Li; Hai, Chun-Xu; Pauluhn, Jürgen

    2011-11-01

    The principal acute mode of action of inhaled phosgene gas is related to an increase alveolar fluid exudation under pathologic conditions. This paper considers some aspects in modeling phosgene-induced acute lung injury (ALI) in an acute rat bioassay and whether edema formation can be modulated by inhaled nitric oxide (iNO). Protein analysis in bronchoalveolar lavage (BAL) fluid is amongst the most sensitive method to quantify the phosgene-induced non-cardiogenic, pulmonary high-permeability edema following acute inhalation exposure. Maximum concentrations in BAL-protein occur within one day postexposure, typically within a latency period up to about 15 h as a consequence of an increasingly exhausted lymphatic drainage. An almost similar sensitivity was given by the functional endpoint 'enhanced pause (Penh)' when measured by non-invasive whole-body barometric plethysmography over a time period of 20 h. The magnitude of edema formation follows a concentration x time (C¹xt) relationship, although animal model-specific deviations may occur at very short exposure durations (1-20 min) due to a rodent-specific, reflexively induced transient decreased ventilation. This has to be accounted for when simulating accidental exposure scenarios to study the mechanisms involved in pharmacological modulation of fluid transport in this type of ALI. Therefore, a special focus has to be given to the dosimetry of inhaled phosgene, otherwise any change in effect magnitude, as a result of under-dosing of phosgene, may be misconceived as promising therapy. This study demonstrates that accidental exposures can be modeled best in rats by exposure durations of at least 20-30 min. Lung function measurements (Penh) show that pathophysiological effects appear to occur concomitant with the exposure to phosgene; however, its full clinical manifestation requires a gross imbalance of pulmonary fluid clearance. When applying this concept, post-phosgene exposure iNO at 1.5 ppm × 6 h or

  11. Indium oxide (In2O3) nanoparticles induce progressive lung injury distinct from lung injuries by copper oxide (CuO) and nickel oxide (NiO) nanoparticles.

    PubMed

    Jeong, Jiyoung; Kim, Jeongeun; Seok, Seung Hyeok; Cho, Wan-Seob

    2016-04-01

    Indium is an essential element in the manufacture of liquid crystal displays and other electronic devices, and several forms of indium compounds have been developed, including nanopowders, films, nanowires, and indium metal complexes. Although there are several reports on lung injury caused by indium-containing compounds, the toxicity of nanoscale indium oxide (In2O3) particles has not been reported. Here, we compared lung injury induced by a single exposure to In2O3 nanoparticles (NPs) to that caused by benchmark high-toxicity nickel oxide (NiO) and copper oxide (CuO) NPs. In2O3 NPs at doses of 7.5, 30, and 90 cm(2)/rat (50, 200, and 600 µg/rat) were administered to 6-week-old female Wistar rats via pharyngeal aspiration, and lung inflammation was evaluated 1, 3, 14, and 28 days after treatment. Neutrophilic inflammation was observed on day 1 and worsened until day 28, and severe pulmonary alveolar proteinosis (PAP) was observed on post-aspiration days 14 and 28. In contrast, pharyngeal aspiration of NiO NPs showed severe neutrophilic inflammation on day 1 and lymphocytic inflammation with PAP on day 28. Pharyngeal aspiration of CuO NPs showed severe neutrophilic inflammation on day 1, but symptoms were completely resolved after 14 days and no PAP was observed. The dose of In2O3 NPs that produced progressive neutrophilic inflammation and PAP was much less than the doses of other toxic particles that produced this effect, including crystalline silica and NiO NPs. These results suggest that occupational exposure to In2O3 NPs can cause severe lung injury.

  12. Propofol attenuates oxidant-induced acute lung injury in an isolated perfused rabbit-lung model.

    PubMed

    Yumoto, Masato; Nishida, Osamu; Nakamura, Fujio; Katsuya, Hirotada

    2005-01-01

    Reactive oxygen species have been strongly implicated in the pathogenesis of acute lung injury (ALI). Some animal studies suggest that free radical scavengers inhibit the onset of oxidant-induced ALI. Propofol (2,6-diisopropylphenol) is chemically similar to phenol-based free radical scavengers such as the endogenous antioxidant vitamin E. Both in vivo and in vitro studies have suggested that propofol has antioxidant potential. We hypothesized that propofol may attenuate ALI by acting as a free-radical scavenger. We investigated the effects of propofol on oxidant-induced ALI induced by purine and xanthine oxidase (XO), in isolated perfused rabbit lung, in two series of experiments. In series 1, we examined the relationship between the severity of ALI and the presence of hydrogen peroxide (H2O2). In series 2, we evaluated the effects of propofol on attenuating ALI and the dose dependence of these effects. The lungs were perfused for 90 min, and we evaluated the effects on the severity of ALI by monitoring the pulmonary capillary filtration coefficient (Kfc), pulmonary arterial pressure (Ppa), and the pulmonary capillary hydrostatic pressure (Ppc). In series 1, treatment with catalase (an H2O2 scavenger) prior to the addition of purine and XO resulted in complete prevention of ALI, suggesting that H2O2 may be involved closely in the pathogenesis of ALI. In series 2, pretreatment with propofol at concentrations in excess of 0.5 mM significantly inhibited the increases in the Kfc values, and that in excess of 0.75 mM significantly inhibited the increase in the Ppa values. Propofol attenuates oxidant-induced ALI in an isolated perfused rabbit lung model, probably due to its antioxidant action.

  13. Nanoparticles, Lung Injury, and the Role of Oxidant Stress

    PubMed Central

    Madl, Amy K.; Plummer, Laurel E.; Carosino, Christopher; Pinkerton, Kent E.

    2015-01-01

    The emergence of engineered nanoscale materials has provided significant advancements in electronic, biomedical, and material science applications. Both engineered nanoparticles and nanoparticles derived from combustion or incidental processes exhibit a range of physical and chemical properties, which have been shown to induce inflammation and oxidative stress in biologic systems. Oxidative stress reflects the imbalance between the generation of reaction oxygen species (ROS) and the biochemical mechanisms to detoxify and repair resulting damage of reactive intermediates. This review examines current research incidental and engineered nanoparticles in terms of their health effects on the lungs and mechanisms by which oxidative stress via physicochemical characteristics influence toxicity or biocompatibility. Although oxidative stress has generally been thought of as an adverse biological outcome, this review will also briefly discuss some of the potential emerging technologies to use nanoparticle-induced oxidative stress to treat disease in a site specific fashion. PMID:24215442

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

    SciTech Connect

    Salama, Samir A.; Omar, Hany A.; Maghrabi, Ibrahim A.; AlSaeed, Mohammed S.; EL-Tarras, Adel E.

    2014-01-01

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

  15. Selective phosphodiesterase 3 inhibitor olprinone attenuates meconium-induced oxidative lung injury.

    PubMed

    Mokra, Daniela; Drgova, Anna; Pullmann, Rudolf; Calkovska, Andrea

    2012-06-01

    Since inflammation and oxidation play a key role in the pathophysiology of neonatal meconium aspiration syndrome, various anti-inflammatory drugs have been tested in the treatment. This study evaluated whether the phosphodiesterase (PDE) 3 inhibitor olprinone can alleviate meconium-induced inflammation and oxidative lung injury. Oxygen-ventilated rabbits intratracheally received 4 ml/kg of meconium (25 mg/ml) or saline. Thirty minutes after meconium/saline instillation, meconium-instilled animals were treated by intravenous olprinone (0.2 mg/kg) or were left without treatment. All animals were oxygen-ventilated for an additional 5 h. A bronchoalveolar lavage (BAL) of the left lungs was performed and differential leukocyte count in the sediment was estimated. The right lungs were used to determine lung edema by wet/dry weight ratio, as well as to detect oxidative damage to the lungs. In the lung tissue homogenate, total antioxidant status (TAS) was determined. In isolated lung mitochondria, the thiol group content, conjugated dienes, thiobarbituric acid-reactive substances (TBARS), dityrosine, lysine-lipid peroxidation products, and activity of cytochrome c oxidase (COX) were estimated. To evaluate the effects of meconium instillation and olprinone treatment on the systemic level, TBARS and TAS were determined in the blood plasma, as well. Meconium instillation increased the relative numbers of neutrophils and eosinophils in the BAL fluid, increased edema formation and concentrations of oxidation markers, and decreased TAS. Treatment with olprinone reduced the numbers of polymorphonuclears in the BAL fluid, decreased the formation of most oxidation markers in the lungs, reduced lung edema and prevented a decrease in TAS in the lung homogenate compared to non-treated animals. In the blood plasma, olprinone decreased TBARS and increased TAS compared to the non-treated group. Conclusion, the selective PDE3 inhibitor olprinone has shown potent antioxidative and anti

  16. Oxidative Stress Mediates Radiation Lung Injury by Inducing Apoptosis

    SciTech Connect

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

    2012-06-01

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

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

    PubMed Central

    SEPEHR, REYHANEH; AUDI, SAID H.; MALEKI, SEPIDEH; STANISZEWSKI, KEVIN; EIS, ANNIE L.; KONDURI, GIRIJA G.; RANJI, MAHSA

    2014-01-01

    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. PMID:24672581

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

    PubMed

    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.

  19. Resolution of experimental lung injury by Monocyte-derived inducible nitric oxide synthase (iNOS)

    PubMed Central

    D’Alessio, Franco R.; Tsushima, Kenji; Aggarwal, Neil R.; Mock, Jason R.; Eto, Yoshiki; Garibaldi, Brian T.; Files, Daniel C.; Avalos, Claudia R.; Rodriguez, Jackie V.; Waickman, Adam T.; Reddy, Sekhar P.; Pearse, David B.; Sidhaye, Venkataramana K.; Hassoun, Paul M.; Crow, Michael T.; King, Landon S.

    2012-01-01

    While early events in the pathogenesis of acute lung injury (ALI) have been defined, little is known about mechanisms mediating resolution. To search for determinants of resolution, we exposed wild type (WT) mice to intratracheal lipopolysacaccharide (i.t. LPS) and assessed the response at intervals to day 10, when injury had resolved. Inducible nitric oxide synthase (iNOS) was significantly upregulated in the lung at day 4 after LPS. When iNOS−/− mice were exposed to i.t. LPS, early lung injury was attenuated, however recovery was markedly impaired compared to wild type (WT) mice. iNOS−/− mice had increased mortality and sustained increases in markers of lung injury. Adoptive transfer of WT (iNOS+/+) bone marrow-derived monocytes or direct adenoviral gene delivery of iNOS into injured iNOS−/− mice restored resolution of ALI. Irradiated bone marrow chimeras confirmed the protective effects of myeloid-derived iNOS, but not of epithelial iNOS. Alveolar macrophages exhibited sustained expression of co-signalling molecule CD86 in iNOS−/− mice compared to WT mice. Antibody-mediated blockade of CD86 in iNOS−/− mice improved survival and enhanced resolution of lung inflammation. Our findings show that monocyte-derived iNOS plays a pivotal role in mediating resolution of ALI by modulating lung immune responses, thus facilitating clearance of alveolar inflammation and promoting lung repair. PMID:22844117

  20. Pentoxifylline attenuates nitrogen mustard-induced acute lung injury, oxidative stress and inflammation.

    PubMed

    Sunil, Vasanthi R; Vayas, Kinal N; Cervelli, Jessica A; Malaviya, Rama; Hall, LeRoy; Massa, Christopher B; Gow, Andrew J; Laskin, Jeffrey D; Laskin, Debra L

    2014-08-01

    Nitrogen mustard (NM) is a toxic alkylating agent that causes damage to the respiratory tract. Evidence suggests that macrophages and inflammatory mediators including tumor necrosis factor (TNF)α contribute to pulmonary injury. Pentoxifylline is a TNFα inhibitor known to suppress inflammation. In these studies, we analyzed the ability of pentoxifylline to mitigate NM-induced lung injury and inflammation. Exposure of male Wistar rats (150-174 g; 8-10 weeks) to NM (0.125 mg/kg, i.t.) resulted in severe histopathological changes in the lung within 3d of exposure, along with increases in bronchoalveolar lavage (BAL) cell number and protein, indicating inflammation and alveolar-epithelial barrier dysfunction. This was associated with increases in oxidative stress proteins including lipocalin (Lcn)2 and heme oxygenase (HO)-1 in the lung, along with pro-inflammatory/cytotoxic (COX-2(+) and MMP-9(+)), and anti-inflammatory/wound repair (CD163+ and Gal-3(+)) macrophages. Treatment of rats with pentoxifylline (46.7 mg/kg, i.p.) daily for 3d beginning 15 min after NM significantly reduced NM-induced lung injury, inflammation, and oxidative stress, as measured histologically and by decreases in BAL cell and protein content, and levels of HO-1 and Lcn2. Macrophages expressing COX-2 and MMP-9 also decreased after pentoxifylline, while CD163+ and Gal-3(+) macrophages increased. This was correlated with persistent upregulation of markers of wound repair including pro-surfactant protein-C and proliferating nuclear cell antigen by Type II cells. NM-induced lung injury and inflammation were associated with alterations in the elastic properties of the lung, however these were largely unaltered by pentoxifylline. These data suggest that pentoxifylline may be useful in treating acute lung injury, inflammation and oxidative stress induced by vesicants.

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

    PubMed

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

    2010-04-05

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

  2. Role of inhaled nitric oxide in ischaemia-reperfusion injury in the perfused rabbit lung.

    PubMed

    Ishibe, Y; Liu, R; Ueda, M; Mori, K; Miura, N

    1999-09-01

    We have tested if inhaled nitric oxide (NO) is beneficial in ischaemia-reperfusion (IR) lung injury using an isolated perfused rabbit lung model. Ischaemia for 60 min was followed by reperfusion and ventilation with nitric oxide 40 ppm (n = 6) or without nitric oxide ventilation (n = 6) for 60 min. In the control group (n = 6), the lungs were perfused continuously for 120 min. Permeability coefficient (Kfc) and vascular resistance (PVR) were measured serially for 60 min after reperfusion. We also determined the left lung W/D ratio and measured nitric oxide metabolites (NOx) and cGMP concentrations in bronchoalveolar lavage (BAL) fluid from the right lung. IR increased Kfc, PVR and W/D followed by decreased cGMP. Ventilation with nitric oxide restored these changes by preventing the decrease in cGMP. Differences in NOx concentrations in BAL fluid between the control and IR groups were not statistically significant. Our results indicate that IR impaired pulmonary vascular function and resulted in microvascular constriction and leakage. Ventilation with nitric oxide from the beginning of the reperfusion period improved pulmonary dysfunction such as vasoconstriction and capillary leak by restoring cGMP concentrations.

  3. Ibuprofen prevents oxidant lung injury and in vitro lipid peroxidation by chelating iron.

    PubMed Central

    Kennedy, T P; Rao, N V; Noah, W; Michael, J R; Jafri, M H; Gurtner, G H; Hoidal, J R

    1990-01-01

    Because ibuprofen protects from septic lung injury, we studied the effect of ibuprofen in oxidant lung injury from phosgene. Lungs from rabbits exposed to 2,000 ppm-min phosgene were perfused with Krebs-Henseleit buffer at 50 ml/min for 60 min. Phosgene caused no increase in lung generation of cyclooxygenase metabolites and no elevation in pulmonary arterial pressure, but markedly increased transvascular fluid flux (delta W = 31 +/- 5 phosgene vs. 8 +/- 1 g unexposed, P less than 0.001), permeability to albumin (125I-HSA) lung leak index 0.274 +/- 0.035 phosgene vs. 0.019 +/- 0.001 unexposed, P less than 0.01; 125I-HSA lavage leak index 0.352 +/- 0.073 phosgene vs. 0.008 +/- 0.001 unexposed, P less than 0.01), and lung malondialdehyde (50 +/- 7 phosgene vs. 24 +/- 0.7 mumol/g dry lung unexposed, P less than 0.01). Ibuprofen protected lungs from phosgene (delta W = 10 +/- 2 g; lung leak index 0.095 +/- 0.013; lavage leak index 0.052 +/- 0.013; and malondialdehyde 16 +/- 3 mumol/g dry lung, P less than 0.01). Because iron-treated ibuprofen failed to protect, we studied the effect of ibuprofen in several iron-mediated reactions in vitro. Ibuprofen attenuated generation of .OH by a Fenton reaction and peroxidation of arachidonic acid by FeCl3 and ascorbate. Ibuprofen also formed iron chelates that lack the free coordination site required for iron to be reactive. Thus, ibuprofen may prevent iron-mediated generation of oxidants or iron-mediated lipid peroxidation after phosgene exposure. This suggests a new mechanism for ibuprofen's action. PMID:2173723

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

    PubMed

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

    2017-05-01

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

  5. Nitric oxide synthase 3 contributes to ventilator-induced lung injury

    PubMed Central

    Vaporidi, Katerina; Francis, Roland C.; Bloch, Kenneth D.

    2010-01-01

    Nitric oxide synthase (NOS) depletion or inhibition reduces ventilator-induced lung injury (VILI), but the responsible mechanisms remain incompletely defined. The aim of this study was to elucidate the role of endothelial NOS, NOS3, in the pathogenesis of VILI in an in vivo mouse model. Wild-type and NOS3-deficient mice were ventilated with high-tidal volume (HVT; 40 ml/kg) for 4 h, with and without adding NO to the inhaled gas. Additional wild-type mice were pretreated with tetrahydrobiopterin and ascorbic acid, agents that can prevent NOS-generated superoxide production. Arterial blood gas tensions, histology, and lung mechanics were evaluated after 4 h of HVT ventilation. The concentration of protein, IgM, cytokines, malondialdehyde, and 8-isoprostane were measured in bronchoalveolar lavage fluid (BALF). Myeloperoxidase activity, total and oxidized glutathione levels, and NOS-derived superoxide production were measured in lung tissue homogenates. HVT ventilation induced VILI in wild-type mice, as reflected by decreased lung compliance, increased concentrations of protein and cytokines in BALF, and oxidative stress. All indices of VILI were ameliorated in NOS3-deficient mice. Augmenting pulmonary NO levels by breathing NO during mechanical ventilation did not increase lung injury in NOS3-deficient mice. HVT ventilation increased NOS-inhibitable superoxide production in lung extracts from wild-type mice but not in those from NOS3-deficient mice. Administration of tetrahydrobiopterin and ascorbic acid ameliorated VILI in wild-type mice. Our results indicate that NOS3 contributes to ventilator-induced lung injury via increased production of superoxide. PMID:20453164

  6. An endothelial TLR4-VEGFR2 pathway mediates lung protection against oxidant-induced injury

    PubMed Central

    Takyar, Seyedtaghi; Zhang, Yi; Haslip, Maria; Jin, Lei; Shan, Peiying; Zhang, Xuchen; Lee, Patty J.

    2015-01-01

    TLR4 deficiency causes hypersusceptibility to oxidant-induced injury. We investigated the role of TLR4 in lung protection, using used bone marrow chimeras; cell-specific transgenic modeling; and lentiviral delivery in vivo to knock down or express TLR4 in various lung compartments; and lung-specific VEGF transgenic mice to investigate the effect of TLR4 on VEGF-mediated protection. C57/BL6 mice were exposed to 100% oxygen in an enclosed chamber and assessed for survival and lung injury. Primary endothelial cells were stimulated with recombinant VEGF and exposed to hyperoxia or hydrogen peroxide. Endothelium-specific expression of human TLR4 (as opposed to its expression in epithelium or immune cells) increased the survival of TLR4-deficent mice in hyperoxia by 24 h and decreased LDH release and lung cell apoptosis after 72 h of exposure by 30%. TLR4 expression was necessary and sufficient for the protective effect of VEGF in the lungs and in primary endothelial cells in culture. TLR4 knockdown inhibited VEGF signaling through VEGF receptor 2 (VEGFR2), Akt, and ERK pathways in lungs and primary endothelial cells and decreased the availability of VEGFR2 at the cell surface. These findings demonstrate a novel mechanism through which TLR4, an innate pattern receptor, interacts with an endothelial survival pathway.—Takyar, S., Zhang, Y., Haslip, M., Jin L., Shan P., Zhang, X., Lee, P. J. An endothelial TLR4-VEGFR2 pathway mediates lung protection against oxidant-induced injury. PMID:26655705

  7. Long term ethanol consumption leads to lung tissue oxidative stress and injury.

    PubMed

    Das, Subir Kumar; Mukherjee, Sukhes

    2010-01-01

    Alcohol abuse is a systemic disorder. The deleterious health effects of alcohol consumption may result in irreversible organ damage. By contrast, there currently is little evidence for the toxicity of chronic alcohol use on lung tissue. Hence, in this study we investigated long term effects of ethanol in the lung. Though body weight of rats increased significantly with duration of exposure compared to its initial weight, but there was no significant change in relative weight (g/100 g body weight) of lung due to ethanol exposure. The levels of thiobarbituric acid reactive substances (TBARS), nitrite, protein carbonyl, oxidized glutathione (GSSG), redox ratio (GSSG/GSH) and GST activity elevated; while reduced glutathione (GSH) level and activities of glutathione reductase (GR), glutathione peroxidase (GPx), catalase, superoxide dismutase (SOD) and Na(+)K(+) ATPase reduced significantly with duration of ethanol exposure in the lung homogenate compared to the control group. Total matrix metalloproteinase activity elevated in the lung homogenate with time of ethanol consumption. Histopathologic examination also demonstrated that severity of lung injury enhanced with duration of ethanol exposure. 16-18 weeks old male albino Wistar strain rats weighing 200-220 g were fed with ethanol (1.6 g/ kg body weight/ day) up to 36 weeks. At the end of the experimental period, blood samples were collected from reteroorbital plexus to determine blood alcohol concentration, and the animals were sacrificed. Various oxidative stress related biochemical parameters, total matrix metalloproteinase activity and histopathologic examinations of the lung tissues were performed. Results of this study indicate that long term ethanol administration aggravates systemic and local oxidative stress, which may be associated with lung tissue injury.

  8. An endothelial TLR4-VEGFR2 pathway mediates lung protection against oxidant-induced injury.

    PubMed

    Takyar, Seyedtaghi; Zhang, Yi; Haslip, Maria; Jin, Lei; Shan, Peiying; Zhang, Xuchen; Lee, Patty J

    2016-03-01

    TLR4 deficiency causes hypersusceptibility to oxidant-induced injury. We investigated the role of TLR4 in lung protection, using used bone marrow chimeras; cell-specific transgenic modeling; and lentiviral delivery in vivo to knock down or express TLR4 in various lung compartments; and lung-specific VEGF transgenic mice to investigate the effect of TLR4 on VEGF-mediated protection. C57/BL6 mice were exposed to 100% oxygen in an enclosed chamber and assessed for survival and lung injury. Primary endothelial cells were stimulated with recombinant VEGF and exposed to hyperoxia or hydrogen peroxide. Endothelium-specific expression of human TLR4 (as opposed to its expression in epithelium or immune cells) increased the survival of TLR4-deficent mice in hyperoxia by 24 h and decreased LDH release and lung cell apoptosis after 72 h of exposure by 30%. TLR4 expression was necessary and sufficient for the protective effect of VEGF in the lungs and in primary endothelial cells in culture. TLR4 knockdown inhibited VEGF signaling through VEGF receptor 2 (VEGFR2), Akt, and ERK pathways in lungs and primary endothelial cells and decreased the availability of VEGFR2 at the cell surface. These findings demonstrate a novel mechanism through which TLR4, an innate pattern receptor, interacts with an endothelial survival pathway.

  9. Biomarkers for oxidative stress in acute lung injury induced in rabbits submitted to different strategies of mechanical ventilation

    USDA-ARS?s Scientific Manuscript database

    Oxidative damage has been said to play an important role in pulmonary injury, which is associated with the development and progression of acute respiratory distress syndrome (ARDS). We aimed to identify biomarkers to determine the oxidative stress in an animal model of acute lung injury (ALI) using ...

  10. A crucial role of nitric oxide in acute lung injury secondary to the acute necrotizing pancreatitis.

    PubMed

    Cheng, Shi; Yan, Wen-Mao; Yang, Bin; Shi, Jing-dong; Song, Mao-min; Zhao, Yuqian

    2010-04-01

    To investigate the role of nitric oxide (NO) in acute lung inflammation and injury secondary to acute necrotizing pancreatitis (ANP), 5% sodium taurocholate was retrogradely injected into the biliopancreatic duct of rats to ANP model. These ANP rats were given L-Arginine (L-Arg, 100 mg/kg), L-NAME (10 mg/kg), or their combination by intraperitoneal injection 30 min prior to ANP induction. At 1, 3, 6, and 12 hours after ANP induction, lung NO production, and inducible NO synthase (iNOS) expression were measured. Lung histopathological changes, bronchoalveolar lavage (BAL) protein concentration, proinflammatory mediators tumor necrotic factor alpha (TNF-alpha), and lung tissue myeloperoxidase (MPO) activity were examined. Results showed that NO production and iNOS mRNA expression in alveolar macrophages (AMs) were significantly increased along with significant increases in lung histological abnormalities and BAL proteins in the ANP group, all of which were further enhanced by pretreatment with L-Arg and attenuated by pretreatment with L-NAME, respectively. These markers were slightly attenuated by pretreatment with combination of L-Arg + L-NAME, suggesting that NO is required for initiating the acute lung damage in ANP rats, and also that L-Arg-enhanced lung injury is mediated by its NO generation rather than its direct effect. MPO activity and TNF-alpha expression in lung were upregulated in the ANP rats and further enhanced by pretreatment with L-Arg and attenuated by pretreatment with L-NAME, respectively. These results suggest that overproduction of NO mediated by iNOS in the lung is required for the acute lung inflammation and damage secondary to ANP.

  11. [A experiment research of beryllium oxide induced oxidative lung injury and the protective effects of LBP in rats].

    PubMed

    Liu, Zhihong; Zhang, Qingfeng; Wang, Yao; Wei, Conghui; Yan, Qing; Gong, Aihong; Guo, Xiong

    2015-07-01

    To explore beryllium oxide induced oxidative lung injury and the protective effects of LBP. Intoxication of animals were induced by once intratracheal injection and LBP intervention by intragastric administration. The content of HIF-1, VEGF and HO-1 of lung tissues were measured by kits. The pathological changes of lung tissue were showed by pathological section. The changes of lung ultrastructure were observed by electron microscope. Pathological changes of the lung tissue in beryllium oxide exposure group rats were in line with the characteristics of beryllium disease in human. Compared with the control group, HO-1 was increased in beryllium oxide exposure 40 d group and low doses of LBP group, compared with the control group, HO-1 was increased in beryllium oxide exposure 80d group and LBP treatment groups (P < 0.05 or P < 0.01). Compared with the control group, HIF-1 was increased in beryllium oxide exposure 40 d group, LBP treatment groups, beryllium oxide exposure 60 d and 80 d groups (P < 0.05 or P < 0.01). Compared with the control group, VEGF was increased of all phases, especially in beryllium oxide exposure 40d and 80 groups, LBP treatment groups and beryllium oxide exposure 60 d (P < 0.05 or P < 0.01). The content of HO-1 of beryllium oxide exposure group was higher than the LBP treatment for 40d group but below LBP treatment for 80 d group (P < 0.05). The content of HIF1 of beryllium oxide exposure group was higher than high dose of LBP treatment for 60d group and LBP treatment for 80 d group (P < 0.01). The content of VEGF of beryllium oxide exposure group was higher than LBP treatment for 40 d group and high dose of LBP treatment for 60 d (P < 0.05 or P < 0.01). BeO can cause abnormal expression of related genes of lung tissue in rats, LBP has protective effects on BeO caused lung injury.

  12. Combined exogenous surfactant and inhaled nitric oxide therapy for lung ischemia-reperfusion injury in minipigs.

    PubMed

    Warnecke, G; Strüber, M; Fraud, S; Hohlfeld, J M; Haverich, A

    2001-05-15

    The combined application of exogenous surfactant and inhaled nitric oxide was evaluated for prevention of ischemia-reperfusion injury of the lung. Left lungs were selectively perfused in 18 minipigs in situ with cold preservation solution. After 90 min of warm ischemia, the lungs were reperfused and the right pulmonary artery and bronchus were ligated (control group, n=6). Exogenous surfactant was instilled via bronchoscopy during ischemia (surfactant group, n=6). In a third group, surfactant was applied, followed by administration of inhaled nitric oxide (surfactant+NO group, n=6). Hemodynamic and respiratory parameters were recorded for 7 hr, and bronchoalveolar lavage fluid (BALF) was obtained before and after reperfusion for measurement of surface tension, small aggregate/large aggregate ratio, protein and phospholipid contents, and a differential cell count. Control group animals survived for 3.7+/-1.4 hr. In both surfactant-treated groups, five out of six animals survived the observation period (P<0.001). Dynamic compliance of the lung was decreased in control animals (P<0.001). In the surfactant+NO group, arterial PO2 was higher than in both other groups (P<0.001). BALF cell count and histology showed reduced neutrophil infiltration in surfactant+NO-treated lungs. Surface tension assessed in BALF with a pulsating bubble surfactometer was severely impaired in control animals (gammamin, 14.82+/-9.95 mN/m), but maintained in surfactant-treated (gammamin, 1.11+/-0.56 mN/m) and surfactant+NO-treated animals (gammamin, 3.90+/-2.35 mN/m, P=0.02). Administration of exogenous surfactant in lung reperfusion injury results in improved lung compliance. The addition of inhaled NO improves arterial oxygenation and reduces neutrophil extravasation compared with surfactant treatment alone.

  13. Endothelial Nitric Oxide Synthase Deficient Mice Are Protected from Lipopolysaccharide Induced Acute Lung Injury

    PubMed Central

    Gross, Christine M.; Rafikov, Ruslan; Kumar, Sanjiv; Aggarwal, Saurabh; Ham III, P. Benson; Meadows, Mary Louise; Cherian-Shaw, Mary; Kangath, Archana; Sridhar, Supriya; Lucas, Rudolf; Black, Stephen M.

    2015-01-01

    Lipopolysaccharide (LPS) derived from the outer membrane of gram-negative bacteria induces acute lung injury (ALI) in mice. This injury is associated with lung edema, inflammation, diffuse alveolar damage, and severe respiratory insufficiency. We have previously reported that LPS-mediated nitric oxide synthase (NOS) uncoupling, through increases in asymmetric dimethylarginine (ADMA), plays an important role in the development of ALI through the generation of reactive oxygen and nitrogen species. Therefore, the focus of this study was to determine whether mice deficient in endothelial NOS (eNOS-/-) are protected against ALI. In both wild-type and eNOS-/- mice, ALI was induced by the intratracheal instillation of LPS (2 mg/kg). After 24 hours, we found that eNOS-/-mice were protected against the LPS mediated increase in inflammatory cell infiltration, inflammatory cytokine production, and lung injury. In addition, LPS exposed eNOS-/- mice had increased oxygen saturation and improved lung mechanics. The protection in eNOS-/- mice was associated with an attenuated production of NO, NOS derived superoxide, and peroxynitrite. Furthermore, we found that eNOS-/- mice had less RhoA activation that correlated with a reduction in RhoA nitration at Tyr34. Finally, we found that the reduction in NOS uncoupling in eNOS-/- mice was due to a preservation of dimethylarginine dimethylaminohydrolase (DDAH) activity that prevented the LPS-mediated increase in ADMA. Together our data suggest that eNOS derived reactive species play an important role in the development of LPS-mediated lung injury. PMID:25786132

  14. Ukrain (NSC 631570) ameliorates intestinal ischemia-reperfusion-induced acute lung injury by reducing oxidative stress

    PubMed Central

    Kocak, Cengiz; Kocak, Fatma Emel; Akcilar, Raziye; Akcilar, Aydin; Savran, Bircan; Zeren, Sezgin; Bayhan, Zulfu; Bayat, Zeynep

    2016-01-01

    Intestinal ischemia-reperfusion (I/R) causes severe destruction in remote organs. Lung damage is a frequently seen complication after intestinal I/R. Ukrain (NSC 631570) is a synthetic thiophosphate derivative of alkaloids from the extract of the celandine (Chelidonium majus L.) plant. We investigated the effect of Ukrain in animals with lung injury induced by intestinal I/R. Adult male Spraque-Dawley rats were randomly divided into four groups: control, Ukrain, I/R, I/R with Ukrain. Before intestinal I/R was induced, Ukrain was administered intraperitoneally at a dose of 7.0 mg/body weight. After 1 h ischemia and 2 h reperfusion period, lung tissues were excised. Tissue levels of total oxidative status (TOS), total antioxidant status (TAS) were measured and oxidative stress indices (OSI) were calculated. Lung tissues were also examined histopathologically. TOS and OSI levels markedly increased and TAS levels decreased in the I/R group compared to the control group (P < 0.05). TOS and OSI levels markedly decreased and TAS levels increased in the I/R with Ukrain group compared with the group subjected to IR only (P < 0.05). Severe hemorrhage, alveolar septal thickening, and leukocyte infiltration were observed in the I/R group. In the I/R with Ukrain group, morphologic changes occurring as a result of lung damage attenuated and histopathological scores reduced compared to the I/R group (P < 0.05). Our results suggest that Ukrain pretreatment could reduce lung injury induced by intestinal I/R induced via anti-inflammatory and antioxidant effects. PMID:26773189

  15. Carvacrol and Pomegranate Extract in Treating Methotrexate-Induced Lung Oxidative Injury in Rats

    PubMed Central

    Şen, Hadice Selimoğlu; Şen, Velat; Bozkurt, Mehtap; Türkçü, Gül; Güzel, Abdulmenap; Sezgi, Cengizhan; Abakay, Özlem; Kaplan, Ibrahim

    2014-01-01

    Background This study was designed to evaluate the effects of carvacrol (CRV) and pomegranate extract (PE) on methotrexate (MTX)-induced lung injury in rats. Material/Methods A total of 32 male rats were subdivided into 4 groups: control (group I), MTX treated (group II), MTX+CRV treated (group III), and MTX+PE treated (group IV). A single dose of 73 mg/kg CRV was administered intraperitoneally to rats in group III on Day 1 of the investigation. To group IV, a dose of 225 mg/kg of PE was administered via orogastric gavage once daily over 7 days. A single dose of 20 mg/kg of MTX was given intraperitoneally to groups II, III, and IV on Day 2. The total duration of experiment was 8 days. Malondialdehyde (MDA), total oxidant status (TOS), total antioxidant capacity (TAC), and oxidative stress index (OSI) were measured from rat lung tissues and cardiac blood samples. Results Serum and lung specimen analyses demonstrated that MDA, TOS, and OSI levels were significantly greater in group II relative to controls. Conversely, the TAC level was significantly reduced in group II when compared to the control group. Pre-administering either CRV or PE was associated with decreased MDA, TOS, and OSI levels and increased TAC levels compared to rats treated with MTX alone. Histopathological examination revealed that lung injury was less severe in group III and IV relative to group II. Conclusions MTX treatment results in rat lung oxidative damage that is partially counteracted by pretreatment with either CRV or PE. PMID:25326861

  16. Prevention of ischemia-reperfusion lung injury by inhaled nitric oxide in neonatal piglets.

    PubMed

    Barbotin-Larrieu, F; Mazmanian, M; Baudet, B; Détruit, H; Chapelier, A; Libert, J M; Dartevelle, P; Hervé, P

    1996-03-01

    Lung ischemia-reperfusion results in a decrease in the release of nitric oxide (NO) by the pulmonary endothelium. NO may have lung-protective effects by decreasing neutrophil accumulation in the lung. We tested whether NO inhalation would attenuate reperfusion-induced endothelial dysfunction and increases in microvascular permeability and total pulmonary vascular resistance (RT) by preventing neutrophil lung accumulation. After baseline determinations of RT, coefficient of filtration (Kfc), and circulating neutrophil counts, isolated neonatal piglet lungs were subjected to a 1-h period of ischemia followed by a 1-h period of blood reperfusion and reventilation with or without addition of NO (10 ppm). NO prevented reperfusion-induced increases in RT and Kfc, as well as the decrease in circulating neutrophils. After reperfusion, increases in Kfc were correlated with decreases in circulating neutrophils. NO prevented reperfusion-induced decrease in endothelium-dependent relaxation in precontracted pulmonary arterial rings. This demonstrates that inhaled NO prevents microvascular injury, endothelial dysfunction, and pulmonary neutrophil accumulation in a neonatal piglet model of lung ischemia-reperfusion.

  17. Influence of glutathione-S-transferase (GST) inhibition on lung epithelial cell injury: role of oxidative stress and metabolism.

    PubMed

    Fletcher, Marianne E; Boshier, Piers R; Wakabayashi, Kenji; Keun, Hector C; Smolenski, Ryszard T; Kirkham, Paul A; Adcock, Ian M; Barton, Paul J; Takata, Masao; Marczin, Nandor

    2015-06-15

    Oxidant-mediated tissue injury is key to the pathogenesis of acute lung injury. Glutathione-S-transferases (GSTs) are important detoxifying enzymes that catalyze the conjugation of glutathione with toxic oxidant compounds and are associated with acute and chronic inflammatory lung diseases. We hypothesized that attenuation of cellular GST enzymes would augment intracellular oxidative and metabolic stress and induce lung cell injury. Treatment of murine lung epithelial cells with GST inhibitors, ethacrynic acid (EA), and caffeic acid compromised lung epithelial cell viability in a concentration-dependent manner. These inhibitors also potentiated cell injury induced by hydrogen peroxide (H2O2), tert-butyl-hydroperoxide, and hypoxia and reoxygenation (HR). SiRNA-mediated attenuation of GST-π but not GST-μ expression reduced cell viability and significantly enhanced stress (H2O2/HR)-induced injury. GST inhibitors also induced intracellular oxidative stress (measured by dihydrorhodamine 123 and dichlorofluorescein fluorescence), caused alterations in overall intracellular redox status (as evidenced by NAD(+)/NADH ratios), and increased protein carbonyl formation. Furthermore, the antioxidant N-acetylcysteine completely prevented EA-induced oxidative stress and cytotoxicity. Whereas EA had no effect on mitochondrial energetics, it significantly altered cellular metabolic profile. To explore the physiological impact of these cellular events, we used an ex vivo mouse-isolated perfused lung model. Supplementation of perfusate with EA markedly affected lung mechanics and significantly increased lung permeability. The results of our combined genetic, pharmacological, and metabolic studies on multiple platforms suggest the importance of GST enzymes, specifically GST-π, in the cellular and whole lung response to acute oxidative and metabolic stress. These may have important clinical implications. Copyright © 2015 the American Physiological Society.

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

    SciTech Connect

    Malaviya, Rama; Venosa, Alessandro; Hall, LeRoy; Gow, Andrew J.; Sinko, Patrick J.; Laskin, Jeffrey D.; Laskin, Debra L.

    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

  19. Oxidative lipidomics of hyperoxic acute lung injury: mass spectrometric characterization of cardiolipin and phosphatidylserine peroxidation

    PubMed Central

    Tyurin, Vladimir A.; Kaynar, A. Murat; Kapralova, Valentyna I.; Wasserloos, Karla; Li, Jin; Mosher, Mackenzie; Wright, Lindsay; Wipf, Peter; Watkins, Simon; Pitt, Bruce R.; Kagan, Valerian E.

    2010-01-01

    Reactive oxygen species have been shown to play a significant role in hyperoxia-induced acute lung injury, in part, by inducing apoptosis of pulmonary endothelium. However, the signaling roles of phospholipid oxidation products in pulmonary endothelial apoptosis have not been studied. Using an oxidative lipidomics approach, we identified individual molecular species of phospholipids involved in the apoptosis-associated peroxidation process in a hyperoxic lung. C57BL/6 mice were killed 72 h after exposure to hyperoxia (100% oxygen). We found that hyperoxia-induced apoptosis (documented by activation of caspase-3 and -7 and histochemical terminal deoxynucleotidyl transferase dUTP-mediated nick-end labeling staining of pulmonary endothelium) was accompanied by nonrandom oxidation of pulmonary lipids. Two anionic phospholipids, mitochondria-specific cardiolipin (CL) and extramitochondrial phosphatidylserine (PS), were the two major oxidized phospholipids in hyperoxic lung. Using electrospray ionization mass spectrometry, we identified several oxygenation products in CL and PS. Quantitative assessments revealed a significant decrease of CL and PS molecular species containing C18:2, C20:4, C22:5, and C22:6 fatty acids. Similarly, exposure of mouse pulmonary endothelial cells (MLEC) to hyperoxia (95% oxygen; 72 h) resulted in activation of caspase-3 and -7 and significantly decreased the content of CL molecular species containing C18:2 and C20:4 as well as PS molecular species containing C22:5 and C22:6. Oxygenated molecular species were found in the same two anionic phospholipids, CL and PS, in MLEC exposed to hyperoxia. Treatment of MLEC with a mitochondria-targeted radical scavenger, a conjugate of hemi-gramicidin S with nitroxide, XJB-5-131, resulted in significantly lower oxidation of both CL and PS and a decrease in hyperoxia-induced changes in caspase-3 and -7 activation. We speculate that cytochrome c driven oxidation of CL and PS is associated with the signaling

  20. Oxidative Lipidomics of γ-Radiation-Induced Lung Injury: Mass Spectrometric Characterization of Cardiolipin and Phosphatidylserine Peroxidation

    PubMed Central

    Tyurina, Yulia Y.; Tyurin, Vladimir A.; Kapralova, Valentyna I.; Wasserloos, Karla; Mosher, Mackenzie; Epperly, Michael W.; Greenberger, Joel S.; Pitt, Bruce R.; Kagan, Valerian E.

    2011-01-01

    Oxidative damage plays a significant role in the pathogenesis of γ-radiation-induced lung injury. Endothelium is a preferred target for early radiation-induced damage and apoptosis. Given the newly discovered role of oxidized phospholipids in apoptotic signaling, we performed oxidative lipidomics analysis of phospholipids in irradiated mouse lungs and cultured mouse lung endothelial cells. C57BL/6NHsd female mice were subjected to total-body irradiation (10 Gy, 15 Gy) and euthanized 24 h thereafter. Mouse lung endothelial cells were analyzed 48 h after γ irradiation (15 Gy). We found that radiation-induced apoptosis in vivo and in vitro was accompanied by non-random oxidation of phospholipids. Cardiolipin and phosphatidylserine were the major oxidized phospholipids, while more abundant phospholipids (phosphatidylcholine, phosphatidylethanolamine) remained non-oxidized. Electrospray ionization mass spectrometry analysis revealed the formation of cardiolipin and phosphatidylserine oxygenated molecular species in the irradiated lung and cells. Analysis of fatty acids after hydrolysis of cardiolipin and phosphatidylserine by phospholipase A2 revealed the presence of mono-hydroperoxy and/or mono-hydroxy/mono-epoxy, mono-hydroperoxy/mono-oxo molecular species of linoleic acid. We speculate that cyt c-driven oxidations of cardiolipin and phosphatidylserine associated with the execution of apoptosis in pulmonary endothelial cells are important contributors to endothelium dysfunction in γ-radiation-induced lung injury. PMID:21338246

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

    PubMed

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

    2015-01-01

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

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

    PubMed Central

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

    2015-01-01

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

  3. Nitric oxide mediates lung injury induced by ischemia-reperfusion in rats.

    PubMed

    Kao, Shang Jyh; Peng, Tai-Chu; Lee, Ru Ping; Hsu, Kang; Chen, Chao-Fuh; Hung, Yu-Kuen; Wang, David; Chen, Hsing I

    2003-01-01

    Nitric oxide (NO) has been reported to play a role in lung injury (LI) induced by ischemia-reperfusion (I/R). However, controversy exists as to the potential beneficial or detrimental effect of NO. In the present study, an in situ, perfused rat lung model was used to study the possible role of NO in the LI induced by I/R. The filtration coefficient (Kfc), lung weight gain (LWG), protein concentration in the bronchoalveolar lavage (PCBAL), and pulmonary arterial pressure (PAP) were measured to evaluate the degree of pulmonary hypertension and LI. I/R resulted in increased Kfc, LWG, and PCBAL. These changes were exacerbated by inhalation of NO (20-30 ppm) or 4 mM L-arginine, an NO precursor. The permeability increase and LI caused by I/R could be blocked by exposure to 5 mM N omega-nitro-L-arginine methyl ester (L-NAME; a nonspecific NO synthase inhibitor), and this protective effect of L-NAME was reversed with NO inhalation. Inhaled NO prevented the increase in PAP caused by I/R, while L-arginine had no such effect. L-NAME tended to diminish the I/R-induced elevation in PAP, but the suppression was not statistically significant when compared to the values in the I/R group. These results indicate that I/R increases Kfc and promotes alveolar edema by stimulating endogenous NO synthesis. Exogenous NO, either generated from L-arginine or delivered into the airway, is apparently also injurious to the lung following I/R. Copyright 2003 National Science Council, ROC and S. Karger AG, Basel

  4. Effects of an endogenous nitric oxide synthase inhibitor on phorbol myristate acetate-induced acute lung injury in rats.

    PubMed

    Lin, Hen I; Chu, Shi Jye; Wang, David; Chen, Hsing I; Hsu, Kang

    2003-01-01

    1. In the present study, we determined whether the endogenous nitric oxide (NO) synthase (NOS) inhibitor Nomega-nitro-l-arginine methyl ester (l-NAME) could ameliorate the acute lung injury (ALI) induced by phorbol myristate acetate (PMA) in rat isolated lung. 2. Typical ALI was induced successfully by PMA during 60 min of observation. At 2 micro g/kg, PMA elicited a significant increase in microvascular permeability (measured using the capillary filtration coefficient Kfc), lung weight gain, lung weight/bodyweight ratio, pulmonary arterial pressure (PAP) and protein concentration of bronchoalveolar lavage fluid. 3. Pretreatment with the NOS inhibitor l-NAME (5 mmol/L) significantly attenuated ALI. None of the parameters reflective of lung injury showed significant increase, except for PAP (P < 0.001). The addition of l-arginine (4 mmol/L) blocked the protective effective of l-NAME. Pretreatment with l-arginine exacerbated PMA-induced lung injury. 4. These data suggest that l-NAME significantly ameliorates ALI induced by PMA in rats, indicating that endogenous NO plays a key role in the development of lung oedema in PMA-induced lung injury.

  5. Role of Nitric Oxide Isoforms in Vascular and Alveolar Development and Lung Injury in Vascular Endothelial Growth Factor Overexpressing Neonatal Mice Lungs.

    PubMed

    Syed, Mansoor A; Choo-Wing, Rayman; Homer, Robert J; Bhandari, Vineet

    2016-01-01

    The role of vascular endothelial growth factor (VEGF)-induced 3 different nitric oxide synthase (NOS) isoforms in lung development and injury in the newborn (NB) lung are not known. We hypothesized that VEGF-induced specific NOS pathways are critical regulators of lung development and injury. We studied NB wild type (WT), lung epithelial cell-targeted VEGF165 doxycycline-inducible overexpressing transgenic (VEGFTG), VEGFTG treated with a NOS1 inhibitor (L-NIO), VEGFTG x NOS2-/- and VEGFTG x NOS3+/- mice in room air (RA) for 7 postnatal (PN) days. Lung morphometry (chord length), vascular markers (Ang1, Ang2, Notch2, vWF, CD31 and VE-cadherin), cell proliferation (Ki67), vascular permeability, injury and oxidative stress markers (hemosiderin, nitrotyrosine and 8-OHdG) were evaluated. VEGF overexpression in RA led to increased chord length and vascular markers at PN7, which were significantly decreased to control values in VEGFTG x NOS2-/- and VEGFTG x NOS3+/- lungs. However, we found no noticeable effect on chord length and vascular markers in the VEGFTG / NOS1 inhibited group. In the NB VEGFTG mouse model, we found VEGF-induced vascular permeability in the NB murine lung was partially dependent on NOS2 and NOS3-signaling pathways. In addition, the inhibition of NOS2 and NOS3 resulted in a significant decrease in VEGF-induced hemosiderin, nitrotyrosine- and 8-OHdG positive cells at PN7. NOS1 inhibition had no significant effect. Our data showed that the complete absence of NOS2 and partial deficiency of NOS3 confers protection against VEGF-induced pathologic lung vascular and alveolar developmental changes, as well as injury markers. Inhibition of NOS1 does not have any modulating role on VEGF-induced changes in the NB lung. Overall, our data suggests that there is a significant differential regulation in the NOS-mediated effects of VEGF overexpression in the developing mouse lung.

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

    PubMed Central

    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

  7. The protective role of MnTBAP in Oxidant-mediated injury and inflammation following Lung Contusion

    PubMed Central

    Suresh, Madathilparambil V; Yu, Bi; Lakshminrusimha, Satyan; Machado-Aranda, D; Talarico, Nicholas; Zeng, Lixia; Davidson, Bruce A.; Pennathur, Subramaniam; Raghavendran, Krishnan

    2013-01-01

    Background Lung contusion (LC) is a unique direct and focal insult that is considered a major risk factor for initiation of acute lung injury (ALI) and acute respiratory distress syndrome (ARDS). We have recently shown that consumption of Nitric oxide (NO)(due to excess superoxide) resulting in peroxynitrite formation leads to diminished vascular reactivity after LC. Here, we set to determine if superoxide scavenger Mn (III) tetrakis (4-benzoic acid) porphyrin chloride (MnTBAP) plays a protective role in alleviating acute inflammatory response and injury in LC. Methods Non-lethal closed-chest bilateral lung contusion was induced in a rodent model. Administration of superoxide dismutase (SOD) mimetic-MnTBAP, concurrently with LC in rats was performed and bronchoalveolar lavage (BAL) and lung samples were analyzed for degree of injury and inflammation at 5 and 24 h following the insult. The extent of injury was assessed by the measurement of cells and albumin with cytokine levels in the BAL and lungs. Lung samples were subjected to H&E and superoxide staining with dihydro-ethidium (DHE). Protein-bound dityrosine and nitrotyrosine levels were quantified in lung tissue by tandem mass spectrometry. Results The degree of lung injury after LC as determined by BAL albumin levels were significantly reduced in the MnTBAP administered rats at all the time points, when compared to the corresponding controls. The release of pro-inflammatory cytokines and BAL neutrophils were significantly lower in the MnTBAP administered rats after LC. Pathological examination revealed that administration of MnTBAP reduced tissue damage with decreased necrosis and neutrophil-rich exudate at the 24 h time point. Staining for superoxide anions showed significantly higher intensity in the lung samples from LC group compared to LC+ MnTBAP. Liquid chromatography/tandem mass spectrometry [HPLC/MS/MS] revealed that MnTBAP treatment significantly attenuated dityrosine and nitrotyrosine levels

  8. Lung injury and lung cancer caused by cigarette smoke-induced oxidative stress: Molecular mechanisms and therapeutic opportunities involving the ceramide-generating machinery and epidermal growth factor receptor.

    PubMed

    Goldkorn, Tzipora; Filosto, Simone; Chung, Samuel

    2014-11-20

    Chronic obstructive pulmonary disease (COPD) and lung cancer are frequently caused by tobacco smoking. However, these diseases present opposite phenotypes involving redox signaling at the cellular level. While COPD is characterized by excessive airway epithelial cell death and lung injury, lung cancer is caused by uncontrolled epithelial cell proliferation. Notably, epidemiological studies have demonstrated that lung cancer incidence is significantly higher in patients who have preexisting emphysema/lung injury. However, the molecular link and common cell signaling events underlying lung injury diseases and lung cancer are poorly understood. This review focuses on studies of molecular mechanism(s) underlying smoking-related lung injury (COPD) and lung cancer. Specifically, the role of the ceramide-generating machinery during cigarette smoke-induced oxidative stress leading to both apoptosis and proliferation of lung epithelial cells is emphasized. Over recent years, it has been established that ceramide is a sphingolipid playing a major role in lung epithelia structure/function leading to lung injury in chronic pulmonary diseases. However, new and unexpected findings draw attention to its potential role in lung development, cell proliferation, and tumorigenesis. To address this dichotomy in detail, evidence is presented regarding several protein targets, including Src, p38 mitogen-activated protein kinase, and neutral sphingomyelinase 2, the major sphingomyelinase that controls ceramide generation during oxidative stress. Furthermore, their roles are presented not only in apoptosis and lung injury but also in enhancing cell proliferation, lung cancer development, and resistance to epidermal growth factor receptor-targeted therapy for treating lung cancer.

  9. An Endothelial Hsp70-TLR4 Axis Limits Nox3 Expression and Protects Against Oxidant Injury in Lungs

    PubMed Central

    Zhang, Yi; Shan, Peiying; Srivastava, Anup; Jiang, Ge; Zhang, Xuchen

    2016-01-01

    Abstract Aims: Oxidants play a critical role in the pathogenesis of acute lung injury (ALI). Nox3 is a novel member of the NADPH oxidase (Nox) family of oxidant-generating enzymes, which our laboratory had previously identified to be induced in the lungs of TLR4−/− mice. However, the physiologic role of Nox3 induction in lungs and its precise relationship to TLR4 are unknown. Furthermore, the cell compartment involved and the signaling mechanisms of Nox3 induction are unknown. Results: We identified that Nox3 is regulated by heat shock protein 70 (Hsp70) signaling via a TLR4-Trif-signal transducer and activator of transcription 3 (Stat3) pathway and that Nox3 induction leads to increased oxidant injury and death in mice and lung endothelial cells. We generated Nox3−/−/TLR4−/− double knockout mice, endothelial-targeting lentiviral silencing constructs, and endothelial-targeted Stat3−/− mice to specifically demonstrate that Nox3 induction is responsible for the pro-oxidant, proapoptotic phenotype of TLR4−/− mice. We also show that an endothelial Hsp70-TLR4-Trif-Stat3 axis is required to suppress deleterious Nox3 induction. Innovation: To date, a physiologic role for Nox3 in oxidant-induced ALI has not been identified. In addition, we generated unique double knockout mice and endothelial-targeted lentiviral silencing constructs to specifically demonstrate the role of a TLR4 signaling pathway in regulating pro-oxidant generation. Conclusions: We identified an endothelial TLR4-Trif antioxidant pathway that leads to the inhibition of a novel NADPH oxidase, Nox3, in lungs and lung endothelial cells. We also identified the role of a TLR4 ligand, Hsp70, in suppressing Nox3 in basal and pro-oxidant conditions. These studies identify potentially new therapeutic targets in oxidant-induced ALI. Antioxid. Redox Signal. 24, 991–1012. PMID:26905942

  10. Effectiveness of nitric oxide during spontaneous breathing in experimental lung injury.

    PubMed

    Dembinski, Rolf; Hochhausen, Nadine; Terbeck, Sandra; Bickenbach, Johannes; Stadermann, Frederik; Rossaint, Rolf; Kuhlen, Ralf

    2010-04-01

    Inhaled nitric oxide (iNO) improves gas exchange in about 60% of patients with acute respiratory distress syndrome (ARDS). Recruitment of atelectatic lung areas may improve responsiveness and preservation of spontaneous breathing (SB) may cause recruitment. Accordingly, preservation of SB may improve effectiveness of iNO. To test this hypothesis, iNO was evaluated in experimental acute lung injury (ALI) during SB. In 24 pigs with ALI, effects of 10 ppm iNO were evaluated during controlled mechanical ventilation (CMV) and SB in random order. Preservation of SB was provided by 4 different modes: Unassisted SB was enabled by biphasic positive airway pressure (BIPAP), moderate inspiratory assist was provided by pressure support (PS) and volume-assured pressure support (VAPS), maximum assist was ensured by assist control (A/C). Statistical analysis did not reveal gas exchange improvements due to SB alone. Significant gas exchange improvements due to iNO were only achieved during unassisted SB with BIPAP (P <.05) but not during CMV or assisted SB. The authors conclude that effectiveness of iNO may be improved by unassisted SB during BIPAP but not by assisted SB. Thus combined iNO and unassisted SB is possibly most effective to improve gas exchange in severe hypoxemic ARDS.

  11. Protective effects of hydrogen sulfide inhalation on oxidative stress in rats with cotton smoke inhalation-induced lung injury

    PubMed Central

    HAN, ZHI-HAI; JIANG, YI; DUAN, YUN-YOU; WANG, XIAO-YANG; HUANG, YAN; FANG, TING-ZHENG

    2015-01-01

    The aim of the present study was to investigate the mechanism by which hydrogen sulfide (H2S) inhalation protects against oxidative stress in rats with cotton smoke inhalation-induced lung injury. A total of 24 male Sprague-Dawley rats were separated randomly into four groups, which included the control, H2S, smoke and smoke + H2S groups. A rat model of cotton smoke inhalation-induced lung injury was established following inhalation of 30% oxygen for 6 h. In addition, H2S (80 ppm) was inhaled by the rats in the H2S and smoke + H2S groups for 6 h following smoke or sham-smoke inhalation. Enzyme-linked immunosorbent assays were performed to measure various indices in the rat lung homogenate, while the levels of nuclear factor (NF)-κBp65 in the lung tissue of the rats were determined and semiquantitatively analyzed using immunohistochemistry. In addition, quantitative fluorescence polymerase chain reaction was employed to detect the mRNA expression of inducible nitric oxide synthase (iNOS) in the rat lung tissue. The concentrations of malondialdehyde (MDA), nitric oxide (NO), inducible iNOS and NF-κBp65, as well as the sum-integrated optical density of NF-κBp65 and the relative mRNA expression of iNOS, in the rat lung tissue from the smoke + H2S group were significantly lower when compared with the smoke group. The concentrations of MDA, NO, iNOS and NF-κBp65 in the H2S group were comparable to that of the control group. Therefore, inhalation of 80 ppm H2S may reduce iNOS mRNA transcription and the production of iNOS and NO in rats by inhibiting NF-κBp65 activation, subsequently decreasing oxidative stress and cotton smoke inhalation-induced lung injury. PMID:26170929

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

    PubMed

    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.

  13. Time course changes of oxidative stress and inflammation in hyperoxia-induced acute lung injury in rats

    PubMed Central

    Yu, Shouli; Shi, Min; Liu, Changting; Liu, Qinghui; Guo, Jun; Yu, Senyang; Jiang, Tingshu

    2015-01-01

    Objective(s): Therapies with high levels of oxygen are commonly used in the management of critical care. However, prolonged exposure to hyperoxia can cause acute lung injury. Although oxidative stress and inflammation are purported to play an important role in the pathogenesis of acute lung injury, the exact mechanisms are still less known in the hyperoxic acute lung injury (HALI). Materials and Methods: In this study, we investigated the time course changes of oxidative stress and inflammation in lung tissues of rats exposed to >95% oxygen for 12-60 hr. Results: We found that at 12 hr after hyperoxia challenge, the activities of superoxide dismutase and glutathione peroxidase were significantly reduced with remarkably increased lipid peroxidation. At 12 hr, NF-κB p65 expression was also upregulated, but Iκ-Bα expression showed a remarkable decline. Significant production of inflammatory mediators, e.g, interleukin-1β, occurred 24 hr after hyperoxia exposure. In addition, the expression of intracellular adhesion molecule 1 expression and the activity of myeloperoxidase were significantly increased at 24 hr with a peak at 48 hr. Conclusion: Our data support that hyperoxia-induced oxidative damage and NF-κB pathway activation implicate in the early phase of HALI pathogenesis. PMID:25810882

  14. Anti-inflammatory and Anti-oxidative Effects of Dexpanthenol on Lipopolysaccharide Induced Acute Lung Injury in Mice.

    PubMed

    Li-Mei, Wan; Jie, Tan; Shan-He, Wan; Dong-Mei, Meng; Peng-Jiu, Yu

    2016-10-01

    The aim of this study is to investigate the effects of dexpanthenol in a model of acute lung injury (ALI) induced by lipopolysaccharides (LPS). Lung injury was induced by exposure to atomized LPS. Mice were randomly divided into four groups: control group; Dxp (500 mg/kg) group; LPS group; LPS + Dxp (500 mg/kg) group. The effects of dexpanthenol on LPS-induced neutrophil recruitment, cytokine levels, total protein concentration, myeloperoxidase (MPO), malondialdehyde (MDA), superoxide dismutase (SOD), and glutathione (GSH) contents were examined. Additionally, lung tissue was examined by histology to investigate the changes in pathology in the presence and absence of dexpanthenol. In LPS-challenged mice, dexpanthenol significantly improved lung edema. Dexpanthenol also markedly inhibited the LPS-induced neutrophiles influx, protein leakage, and release of TNF-α and IL-6 in bronchoalveolar lavage fluid (BALF). Furthermore, dexpanthenol attenuated MPO activity and MDA contents and increased SOD and GSH activity in the LPS-challenged lung tissue. These data suggest that dexpanthenol protects mice from LPS-induced acute lung injury by its anti-inflammatory and anti-oxidative activities.

  15. Dexmedetomidine attenuates lipopolysaccharide-induced acute lung injury by inhibiting oxidative stress, mitochondrial dysfunction and apoptosis in rats.

    PubMed

    Fu, Chunlai; Dai, Xingui; Yang, You; Lin, Mengxiang; Cai, Yeping; Cai, Shaoxi

    2017-01-01

    Previous studies have identified that dexmedetomidine (DEX) treatment can ameliorate the acute lung injury (ALI) induced by lipopolysaccharide and ischemia-reperfusion. However, the molecular mechanisms by which DEX ameliorates lung injury remain unclear. The present study investigated whether DEX, which has been reported to exert effects on oxidative stress, mitochondrial permeability transition pores and apoptosis in other disease types, can exert protective effects in lipopolysaccharide (LPS)‑induced ALI by inhibiting oxidative stress, mitochondrial dysfunction and mitochondrial‑dependent apoptosis. It was revealed that LPS‑challenged rats exhibited significant lung injury, characterized by the deterioration of histopathology, vascular hyperpermeability, wet‑to‑dry weight ratio and oxygenation index (PaO2/FIO2), which was attenuated by DEX treatment. DEX treatment inhibited LPS‑induced mitochondrial dysfunction, as evidenced by alleviating the cellular ATP and mitochondrial membrane potential in vitro. In addition, DEX treatment markedly prevented the LPS‑induced mitochondrial‑dependent apoptotic pathway in vitro (increases of cell apoptotic rate, cytosolic cytochrome c, and caspase 3 activity) and in vivo (increases of |terminal deoxynucleotidyl transferase dUTP nick‑end labeling positive cells, cleaved caspase 3, Bax upregulation and Bcl‑2 downregulation). Furthermore, DEX treatment markedly attenuated LPS‑induced oxidative stress, as evidenced by downregulation of cellular reactive oxygen species in vitro and lipid peroxides in serum. Collectively, the present results demonstrated that DEX ameliorates LPS‑induced ALI by reducing oxidative stress, mitochondrial dysfunction and mitochondrial-dependent apoptosis.

  16. Dexmedetomidine attenuates lipopolysaccharide-induced acute lung injury by inhibiting oxidative stress, mitochondrial dysfunction and apoptosis in rats

    PubMed Central

    Fu, Chunlai; Dai, Xingui; Yang, You; Lin, Mengxiang; Cai, Yeping; Cai, Shaoxi

    2016-01-01

    Previous studies have identified that dexmedetomidine (DEX) treatment can ameliorate the acute lung injury (ALI) induced by lipopolysaccharide and ischemia-reperfusion. However, the molecular mechanisms by which DEX ameliorates lung injury remain unclear. The present study investigated whether DEX, which has been reported to exert effects on oxidative stress, mitochondrial permeability transition pores and apoptosis in other disease types, can exert protective effects in lipopolysaccharide (LPS)-induced ALI by inhibiting oxidative stress, mitochondrial dysfunction and mitochondrial-dependent apoptosis. It was revealed that LPS-challenged rats exhibited significant lung injury, characterized by the deterioration of histopathology, vascular hyperpermeability, wet-to-dry weight ratio and oxygenation index (PaO2/FIO2), which was attenuated by DEX treatment. DEX treatment inhibited LPS-induced mitochondrial dysfunction, as evidenced by alleviating the cellular ATP and mitochondrial membrane potential in vitro. In addition, DEX treatment markedly prevented the LPS-induced mitochondrial-dependent apoptotic pathway in vitro (increases of cell apoptotic rate, cytosolic cytochrome c, and caspase 3 activity) and in vivo (increases of |terminal deoxynucleotidyl transferase dUTP nick-end labeling positive cells, cleaved caspase 3, Bax upregulation and Bcl-2 downregulation). Furthermore, DEX treatment markedly attenuated LPS-induced oxidative stress, as evidenced by downregulation of cellular reactive oxygen species in vitro and lipid peroxides in serum. Collectively, the present results demonstrated that DEX ameliorates LPS-induced ALI by reducing oxidative stress, mitochondrial dysfunction and mitochondrial-dependent apoptosis. PMID:27959438

  17. H2S Attenuates LPS-Induced Acute Lung Injury by Reducing Oxidative/Nitrative Stress and Inflammation.

    PubMed

    Zhang, Hong-Xia; Liu, Shu-Juan; Tang, Xiao-Lu; Duan, Guo-Li; Ni, Xin; Zhu, Xiao-Yan; Liu, Yu-Jian; Wang, Chang-Nan

    2016-01-01

    Hydrogen sulfide (H2S), known as the third endogenous gaseous transmitter, has received increasing attention because of its diverse effects, including angiogenesis, vascular relaxation and myocardial protection.We aimed to investigate the role of H2S in oxidative/nitrative stress and inflammation in acute lung injury (ALI) induced by endotoxemia. Male ICR mice were divided in six groups: (1) Control group; (2) GYY4137treatment group; (3) L-NAME treatment group; (4) lipopolysaccharide (LPS) treatment group; (5) LPS with GYY4137 treatment group; and (6) LPS with L-NAME treatment group. The lungs were analysed by histology, NO production in the mouse lungs determined by modified Griess (Sigma-Aldrich) reaction, cytokine levels utilizing commercialkits, and protein abundance by Western blotting. GYY4137, a slowly-releasing H2S donor, improved the histopathological changes in the lungs of endotoxemic mice. Treatment with NG-nitro-L-arginine methyl ester (L-NAME), a nitric oxide synthase (NOS) inhibitor, increased anti-oxidant biomarkers such as thetotal antioxidant capacity (T-AOC) and theactivities of catalase (CAT) and superoxide dismutase (SOD) but decreased a marker of peroxynitrite (ONOO-) action and 3-nitrotyrosine (3-NT) in endotoxemic lung. L-NAME administration also suppressed inflammation in endotoxemic lung, as evidenced by the decreased pulmonary levels of interleukin (IL)-6, IL-8, and myeloperoxidase (MPO) and the increased level of anti-inflammatory cytokine IL-10. GYY4137 treatment reversed endotoxin-induced oxidative/nitrative stress, as evidenced by a decrease in malondialdehyde (MDA), hydrogenperoxide (H2O2) and 3-NT and an increase in the antioxidant biomarker ratio of reduced/oxidized glutathione(GSH/GSSG ratio) and T-AOC, CAT and SOD activity. GYY4137 also attenuated endotoxin-induced lung inflammation. Moreover, treatment with GYY4137 inhibited inducible NOS (iNOS) expression and nitric oxide (NO) production in the endotoxemia lung. GYY4137

  18. Biomarkers of Lung Injury

    EPA Science Inventory

    Unlike the hepatic, cardiovascular, nervous, or excretory organ systems, where there .ls a strong contribution of host factors or extracellular biochemical milieu in causing organ damage, the causes of lung injuries and subsequent diseases are primarily from direct environmental ...

  19. Biomarkers of Lung Injury

    EPA Science Inventory

    Unlike the hepatic, cardiovascular, nervous, or excretory organ systems, where there .ls a strong contribution of host factors or extracellular biochemical milieu in causing organ damage, the causes of lung injuries and subsequent diseases are primarily from direct environmental ...

  20. Role of Nitric Oxide Isoforms in Vascular and Alveolar Development and Lung Injury in Vascular Endothelial Growth Factor Overexpressing Neonatal Mice Lungs

    PubMed Central

    Syed, Mansoor A.; Choo-Wing, Rayman; Homer, Robert J.; Bhandari, Vineet

    2016-01-01

    Background The role of vascular endothelial growth factor (VEGF)-induced 3 different nitric oxide synthase (NOS) isoforms in lung development and injury in the newborn (NB) lung are not known. We hypothesized that VEGF-induced specific NOS pathways are critical regulators of lung development and injury. Methodology We studied NB wild type (WT), lung epithelial cell-targeted VEGF165 doxycycline-inducible overexpressing transgenic (VEGFTG), VEGFTG treated with a NOS1 inhibitor (L-NIO), VEGFTG x NOS2-/- and VEGFTG x NOS3+/- mice in room air (RA) for 7 postnatal (PN) days. Lung morphometry (chord length), vascular markers (Ang1, Ang2, Notch2, vWF, CD31 and VE-cadherin), cell proliferation (Ki67), vascular permeability, injury and oxidative stress markers (hemosiderin, nitrotyrosine and 8-OHdG) were evaluated. Results VEGF overexpression in RA led to increased chord length and vascular markers at PN7, which were significantly decreased to control values in VEGFTG x NOS2−/− and VEGFTG x NOS3+/- lungs. However, we found no noticeable effect on chord length and vascular markers in the VEGFTG / NOS1 inhibited group. In the NB VEGFTG mouse model, we found VEGF-induced vascular permeability in the NB murine lung was partially dependent on NOS2 and NOS3-signaling pathways. In addition, the inhibition of NOS2 and NOS3 resulted in a significant decrease in VEGF-induced hemosiderin, nitrotyrosine- and 8-OHdG positive cells at PN7. NOS1 inhibition had no significant effect. Conclusion Our data showed that the complete absence of NOS2 and partial deficiency of NOS3 confers protection against VEGF-induced pathologic lung vascular and alveolar developmental changes, as well as injury markers. Inhibition of NOS1 does not have any modulating role on VEGF-induced changes in the NB lung. Overall, our data suggests that there is a significant differential regulation in the NOS-mediated effects of VEGF overexpression in the developing mouse lung. PMID:26799210

  1. AMP-activated protein kinase deficiency reduces ozone-induced lung injury and oxidative stress in mice

    PubMed Central

    2011-01-01

    Background Acute ozone exposure causes lung oxidative stress and inflammation leading to lung injury. At least one mechanism underlying the lung toxicity of ozone involves excessive production of reactive oxygen and nitrogen intermediates such as peroxynitrite. In addition and beyond its major prooxidant properties, peroxynitrite may nitrate tyrosine residues altering phosphorylation of many protein kinases involved in cell signalling. It was recently proposed that peroxynitrite activates 5'-AMP-activated kinase (AMPK), which regulates metabolic pathways and the response to cell stress. AMPK activation as a consequence of ozone exposure has not been previously evaluated. First, we tested whether acute ozone exposure in mice would impair alveolar fluid clearance, increase lung tissue peroxynitrite production and activate AMPK. Second, we tested whether loss of AMP-activated protein kinase alpha1 subunit in mouse would prevent enhanced oxidative stress and lung injury induced by ozone exposure. Methods Control and AMPKα1 deficient mice were exposed to ozone at a concentration of 2.0 ppm for 3 h in glass cages. Evaluation was performed 24 h after ozone exposure. Alveolar fluid clearance (AFC) was evaluated using fluorescein isothiocyanate tagged albumin. Differential cell counts, total protein levels, cytokine concentrations, myeloperoxidase activity and markers of oxidative stress, i.e. malondialdehyde and peroxynitrite, were determined in bronchoalveolar lavage (BAL) and lung homogenates (LH). Levels of AMPK-Thr172 phosphorylation and basolateral membrane Na(+)-K(+)-ATPase abundance were determined by Western blot. Results In control mice, ozone exposure induced lung inflammation as evidence by increased leukocyte count, protein concentration in BAL and myeloperoxidase activity, pro-inflammatory cytokine levels in LH. Increases in peroxynitrite levels (3 vs 4.4 nM, p = 0.02) and malondialdehyde concentrations (110 vs 230 μmole/g wet tissue) were detected in LH

  2. Oxidative stress and lung injury induced by short-term exposure to wood smoke in guinea pigs.

    PubMed

    Ramos, Carlos; Pedraza-Chaverri, José; Becerril, C; Cisneros, J; González-Ávila, G; Rivera-Rosales, R; Sommer, B; Medina-Campos, O N; Montaño, M

    2013-11-01

    Oxidative stress and lung injury induced by short-term exposure to wood smoke were evaluated in guinea pigs through cell profile, bronchoalveolar lavage (BAL), conventional histology and immunohistochemistry (4-hydroxynonenal, 3-nitrotyrosine, Mn-superoxide dismutase, heme oxygenase-1); malondialdehyde and 4-hydroxynonenal concentration, Mn-superoxide dismutase, glutathione reductase, glutathione peroxidase, and catalase activities in plasma, lung and BAL. Total cells increased in BAL, and the percentage of macrophages, neutrophils and lymphocytes augmented (72-96 h). Histopathological examination of lung tissues showed mild thickening of membranous bronchiole walls, infiltration of foamy macrophages and polymorphonuclear leukocytes in bronchial, bronchiolar and intraalveolar spaces. Goblet cell hyperplasia was also observed in bronchial and bronchiolar epithelia. Plasma malondialdehyde concentration was increased at all times, while 4-hydroxynonenal was increased only in plasma and BAL after 24 h. Plasma glutathione reductase activity increased at 24 and 72 h, BAL glutathione peroxidase activity decreased at 72 and 96 h, whereas catalase activity increased in plasma at 72 h, and decreased in BAL at 24 h. Immunostaining intensity to 4-hydroxynonenal, 3-nitrotyrosine, Mn-superoxide dismutase and heme oxygenase-1 was enhanced mainly in macrophages, bronchial/bronchiolar epithelial cells and type II pneumocytes after 72-96 h of wood smoke exposure. Overall, short-term exposure to wood smoke induces alterations in oxidative/antioxidant state in lung and airway injury, similar to those observed in humans with domestic exposure.

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

    SciTech Connect

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

    2012-05-15

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

  4. Effect of inhaled nitric oxide on pulmonary hemodynamics after acute lung injury in dogs

    SciTech Connect

    Romand, J.A.; Pinsky, M.R.; Firestone, L.; Zar, H.A.; Lancaster, J.R. Jr. )

    1994-03-01

    Increased pulmonary vascular resistance (PVR) and mismatch in ventilation-to-perfusion ratio characterize acute lung injury (ALI). Pulmonary arterial pressure (Ppa) decreases when nitric oxide (NO) is inhaled during hypoxic pulmonary vasoconstriction (HPV); thus NO inhalation may reduce PVR and improve gas exchange in ALI. The authors studied the hemodynamic and gas exchange effects of NO inhalation during HPV and then ALI in eight anesthetized open-chest mechanically ventilated dogs. Right atrial pressure, Ppa, and left ventricular and arterial pressures were measured, and cardiac output was estimated by an aortic flow probe. Shunt and dead space were also estimated. The effect of 5-min exposures to 0, 17, 28, 47, and 0 ppm inhaled NO was recorded during hyperoxia, hypoxia, and oleic acid-induced ALI. During ALI, partial [beta]-adrenergic blockage (propanolol, 0.15 mg/kg iv) was induced and 74 ppm NO was inhaled. Nitrosylhemoglobin (NO-Hb) and methemoglobin (MetHb) levels were measured. During hyperoxia, NO inhalation had no measurable effects. Hypoxia increased Ppa and calculated PVR, both of which decreased with 17 ppm NO. ALI decreased arterial Po[sub 2] and increased airway pressure, shunt, and dead space ventilation. Ppa and PVR were greater during ALI than during hyperoxia. NO inhalation had no measurable effect during ALI before or after [beta]-adrenergic blockage. MetHb remained low, and NO-Hb was unmeasurable. Bolus infusion of nitroglycerin (15 [mu]g) induced an immediate decrease in Ppa and PVR during ALI. Short-term NO inhalation does not affect PVR or gas exchange in dogs with oleic acid-induced ALI, nor does it increase NO-Hb or MetHb. In contrast, NO can diminish hypoxia-induced elevations in pulmonary vascular tone. These data suggest that NO inhalation selectively dilates the pulmonary circulation and specifically reduces HPV but not oleic acid-induced increases in pulmonary vasomotor tone. 28 refs., 3 figs., 2 tabs.

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

    PubMed

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

    2016-02-01

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

  6. 4-Methoxyestradiol-induced oxidative injuries in human lung epithelial cells

    SciTech Connect

    Cheng Yahsin; Chang, Louis W.; Cheng Lichuan; Tsai, M.-H.; Lin Pinpin . E-mail: pplin@nhri.org.tw

    2007-05-01

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

  7. [Oxidative and anti-oxidative effects of ambroxol on acute hydrochloric acid-induced lung injury in rats].

    PubMed

    Zhao, Shuang-ping; Guo, Qu-lian; Wang, Rui-ke; Wang, E

    2004-10-01

    To evaluate the protective effect of ambroxol on acute hydrochloric acid-induced lung injury in rats. Thirty pathogen-free SD rats were randomly divided into 3 groups: Group A (n=10) served as control group, and received intracheal instillation of normal saline (NS, pH5.3, 1.2 ml/kg) with pre-treatment of intraperitoneal NS; Group B (n=10) received intracheal instillation of hydrochloric acid /NS (pH1.25, 1.2 ml/kg) with pre-treatment of intraperitoneal NS; and Group C received intracheal instillation of hydrochloric acid /NS (pH1.25, 1.2 ml/kg) with pre-treatment of intraperitoneal ambroxol (50 mg/kg/d, 3 days). Five hours after the instillation of the injury vehicle, the arterial gas was examined, the levels of superoxide dismutase (SOD), malondialdehyde (MDA) in the blood and homogenate of harvested lung were assayed respectively. PaO2 in Group B was significantly lower than that in Group A and C (P < 0.01), and pH and PaCO2 in the 3 groups had little difference (P > 0.05). MDA in the lungs of Group B increased obviously, and levels of SOD in the lung and blood decreased significantly in Group B (Group B vs Group A, P < 0.01). Levels of SOD of Group C in the lung and blood were markedly higher than those of Group B (P < 0.01), MDA of Group C was obviously lower than that of Group B (P < 0.01), and MDA of blood in the 3 groups had no significant difference (P > 0.05). Ambroxol can inhibit lipid peroxidation and increase antioxidant activity, which may be one of the mechanisms in protecting lung tissue from hydrochloric acid-induced injury.

  8. The role of the Src family of tyrosine kinases after oxidant-induced lung injury in vivo.

    PubMed

    Khadaroo, Rachel G; He, Ruijuan; Parodo, Jean; Powers, Kinga A; Marshall, John C; Kapus, Andras; Rotstein, Ori D

    2004-08-01

    Patients sustaining major trauma are predisposed to the development of organ dysfunction. We have shown that oxidant stress generated by hemorrhagic shock/resuscitation (S/R) in rodents increases lipopolysaccharide (LPS)-induced lung injury and translocation of nuclear factor kappa B (NF-kappaB) in alveolar macrophages (AMs). In addition, using a cellular model, we have shown that priming with oxidants reprograms LPS signaling through an Src-dependent pathway. In the present studies, we hypothesize that oxidant priming by S/R in vivo involves Src family kinases. Rats were bled to a mean arterial pressure of 40 mmHg and maintained for 1 hour, then resuscitated with shed blood and equal volume of Ringer's lactate. In some studies, animals received the antioxidant NAC (0.5 g/kg) or a Src family inhibitor, PP2 (0.1 or 0.2 mg/kg), before resuscitation. LPS was given intratracheally (30 mg/kg) for 4 hours. AMs were lavaged, and total cell counts were determined. AMs were also obtained at end resuscitation and exposed to LPS (0.1 microg/mL) from 0 to 60 minutes. Activation of Hck, an Src family kinase, was analyzed by Western blot using a phosphospecific antibody. Nuclear extracts were obtained to examine NF-kappaB translocation. S/R caused a rise in Src family activity compared with sham animals as shown by the phosphorylation of Hck. This was prevented by treating the animals during resuscitation with NAC. The LPS-induced NF-kappaB translocation in AMs after shock/resuscitation was 3-fold higher than in sham AMs treated with LPS. This augmented translocation was prevented by pretreating the animals with PP2 before resuscitation. In a parallel fashion, PP2 pretreatment reduced the absolute lung neutrophil sequestration. Oxidant stress generated during S/R in vivo causes Src family kinase activation in AMs. Inhibition of Src activation by PP2 attenuates AM priming for increased LPS responsiveness after hemorrhagic shock and causes a modest reduction in lung injury

  9. Inhaled nitric oxide alleviates hyperoxia suppressed phosphatidylcholine synthesis in endotoxin-induced injury in mature rat lungs

    PubMed Central

    Gong, Xiaohui; Guo, Chunbao; Huang, Shibing; Sun, Bo

    2006-01-01

    Background We investigated efficacy of inhaled nitric oxide (NO) in modulation of metabolism of phosphatidylcholine (PC) of pulmonary surfactant and in anti-inflammatory mechanism of mature lungs with inflammatory injury. Methods Healthy adult rats were divided into a group of lung inflammation induced by i.v. lipopolysaccharides (LPS) or a normal control (C) for 24 h, and then exposed to: room air (Air), 95% oxygen (O), NO (20 parts per million, NO), both O and NO (ONO) as subgroups, whereas [3H]-choline was injected i.v. for incorporation into PC of the lungs which were processed subsequently at 10 min, 4, 8, 12 and 24 h, respectively, for measurement of PC synthesis and proinflammatory cytokine production. Results LPS-NO subgroup had the lowest level of labeled PC in total phospholipids and disaturated PC in bronchoalveolar lavage fluid and lung tissue (decreased by 46–59%), along with the lowest activity of cytidine triphosphate: phosphocholine cytidylyltransferase (-14–18%) in the lungs, compared to all other subgroups at 4 h (p < 0.01), but not at 8 and 12 h. After 24-h, all LPS-subgroups had lower labeled PC than the corresponding C-subgroups (p < 0.05). LPS-ONO had higher labeled PC in total phospholipids and disaturated PC, activity of cytidylyltransferase, and lower activity of nuclear transcription factor-κB and expression of proinflammatory cytokine mRNA, than that in the LPS-O subgroup (p < 0.05). Conclusion In LPS-induced lung inflammation in association with hyperoxia, depressed PC synthesis and enhanced proinflammatory cytokine production may be alleviated by iNO. NO alone only transiently suppressed the PC synthesis as a result of lower activity of cytidylyltransferase. PMID:16403237

  10. Gene expression profile of oxidative stress in the lung of inbred mice after intestinal ischemia/reperfusion injury.

    PubMed

    Ikejiri, Adauto Tsutomu; Somaio Neto, Frederico; Chaves, José Carlos; Bertoletto, Paulo Roberto; Teruya, Roberto; Bertoletto, Eduardo Rodrigues; Taha, Murched Omar; Fagundes, Djalma José

    2014-03-01

    To determine the gene expression profile associated with oxidative stress and antioxidant defense in the lung tissue of mice subjected to intestinal ischemia and reperfusion. Twelve male, inbred mice (C57BL/6) were randomly assigned to one of two groups. The control group (CG) underwent anesthesia and laparotomy and was observed for 120 minutes; the ischemia/reperfusion group (IRG) was subjected to anesthesia, laparotomy, and ischemia of the small intestine for 60 minutes and to 60 minutes of reperfusion. A pool of six mice from each group was subjected to a reverse transcription-quantitative polymerase chain reaction (RT-qPCR) to analyze the oxidative stress and antioxidant defense genes. All genes that were up-regulated or down-regulated greater than three-fold, based on the algorithm [2^(ΔΔCt)], were considered to be biologically meaningful. Out of a total of 84 genes in the lung that are related to oxidative stress, 67 (79.7%) were up-regulated and 17 (20.2%) were down-regulated. Only two genes (2.3%), Lpo (lactoperoxidase) (+3.51) and Gpx4 (glutathione peroxidase) (+4.10), were expressed above the three-fold threshold, while none of the down-regulated genes were expressed outside of this threshold. The intestinal ischemia/reperfusion injury promoted a gene expression profile consisting of the positive expression of oxidative genes in a remote organ. This suggests that activate signaling pathways are implicated in both cell survival and the maintenance of genome integrity in the lung.

  11. Stress preconditioning attenuates oxidative injury to the alveolar epithelium of the lung following haemorrhage in rats

    PubMed Central

    Pittet, J F; Lu, L N; Geiser, T; Lee, H; Matthay, M A; Welch, W J

    2002-01-01

    Inhibition of cAMP-dependent stimulation of vectorial fluid transport across the alveolar epithelium following haemorrhagic shock is mediated by reactive nitrogen species released within the airspaces of the lung. We tested here the hypothesis that the prior activation of the cellular heat shock or stress response, via exposure to either heat or geldanamycin, would attenuate the release of airspace nitric oxide (NO) responsible for the shock-mediated failure of the alveolar epithelium to respond to catecholamines in rats. Rats were haemorrhaged to a mean arterial pressure of 30–35 mmHg for 60 min, and then resuscitated with a 4 % albumin solution. Alveolar fluid clearance was measured by change in concentration of a protein solution instilled into the airspaces 5 h after the onset of haemorrhage. Stress preconditioning restored the cAMP-mediated upregulation of alveolar liquid clearance after haemorrhage. The protective effect of stress preconditioning was mediated in part by a decrease in the expression of iNOS in the lung. Specifically, stress preconditioning decreased the production of nitrite by endotoxin-stimulated alveolar macrophages removed from haemorrhaged rats or by A549 and rat alveolar epithelial type II cell monolayers stimulated with cytomix (a mixture of TNF-α, IL-1β and IFN-γ) for 24 h. In summary, these results provide the first in vivo evidence that stress preconditioning restores a normal fluid transport capacity of the alveolar epithelium in the early phase following haemorrhagic shock by attenuating NO-mediated oxidative stress to the lung epithelium. PMID:11790821

  12. Hyperoxic Acute Lung Injury

    PubMed Central

    Kallet, Richard H; Matthay, Michael A

    2013-01-01

    Prolonged breathing of very high FIO2 (FIO2 ≥ 0.9) uniformly causes severe hyperoxic acute lung injury (HALI) and, without a reduction of FIO2, is usually fatal. The severity of HALI is directly proportional to PO2 (particularly above 450 mm Hg, or an FIO2 of 0.6) and exposure duration. Hyperoxia produces extraordinary amounts of reactive O2 species that overwhelms natural antioxidant defenses and destroys cellular structures through several pathways. Genetic predisposition has been shown to play an important role in HALI among animals, and some genetics-based epidemiologic research suggests that this may be true for humans as well. Clinically, the risk of HALI likely occurs when FIO2exceeds 0.7, and may become problematic when FIO2 exceeds 0.8 for an extended period of time. Both high-stretch mechanical ventilation and hyperoxia potentiate lung injury and may promote pulmonary infection. During the 1960s, confusion regarding the incidence and relevance of HALI largely reflected such issues as the primitive control of FIO2, the absence of PEEP, and the fact that at the time both ALI and ventilator-induced lung injury were unknown. The advent of PEEP and precise control over FIO2, as well as lung-protective ventilation, and other adjunctive therapies for severe hypoxemia, has greatly reduced the risk of HALI for the vast majority of patients requiring mechanical ventilation in the 21st century. However, a subset of patients with very severe ARDS requiring hyperoxic therapy is at substantial risk for developing HALI, therefore justifying the use of such adjunctive therapies. PMID:23271823

  13. Science review: Redox and oxygen-sensitive transcription factors in the regulation of oxidant-mediated lung injury: role for nuclear factor-κB

    PubMed Central

    Haddad, John J

    2002-01-01

    The primary role of pulmonary airways is to conduct air to the alveolar epithelium, where gas exchange can efficiently occur. Injuries to airways resulting from inhalation of airborne pollutants and parenteral exposure to ingested pollutants that cause oxidative stress have the potential to interfere with this process. A progressive rise of oxidative stress due to altered reduction–oxidation (redox) homeostasis appears to be one of the hallmarks of the processes that regulate gene transcription in lung physiology and pathophysiology. Reactive metabolites serve as signaling messengers for the evolution and perpetuation of the inflammatory process that is often associated with cell death and degeneration. Redox-sensitive transcription factors are often associated with the development and progression of many human disease states and inflammatory-related injury, particularly of the lung. The present review elaborates on the role of the redox-sensitive and oxygen-sensitive transcription factor NF-κB in mediating lung injury. Changes in the pattern of gene expression through regulatory transcription factors are crucial components of the machinery that determines cellular responses to oxidative and redox perturbations. Additionally, the discussion of the possible therapeutic approaches of antioxidants, thiol-related compounds and phosphodiesterase inhibitors as anti-inflammatory agents will thereby help understand the oxidant/redox-mediated lung injury mechanisms. PMID:12493069

  14. OXIDATIVE STRESS PARTICIPATES IN ACUTE LUNG INJURY AND ACTIVATION OF MITOGEN ACTIVATED PROTEIN KINASES (MAPK) FOLLOWING AIR POLLUTION PARTICLE EXPOSURE (PM)

    EPA Science Inventory

    OXIDATIVE STRESS PARTICIPATES IN ACUTE LUNG INJURY AND ACTIVATION OF MITOGEN ACTIVATED PROTEIN KINASES (MAPK) FOLLOWING AIR POLLUTION PARTICLE EXPOSURE (PM). E S Roberts1, R Jaskot2, J Richards2, and K L Dreher2. 1College of Veterinary Medicine, NC State University, Raleigh, NC a...

  15. OXIDATIVE STRESS PARTICIPATES IN ACUTE LUNG INJURY AND ACTIVATION OF MITOGEN ACTIVATED PROTEIN KINASES (MAPK) FOLLOWING AIR POLLUTION PARTICLE EXPOSURE (PM)

    EPA Science Inventory

    OXIDATIVE STRESS PARTICIPATES IN ACUTE LUNG INJURY AND ACTIVATION OF MITOGEN ACTIVATED PROTEIN KINASES (MAPK) FOLLOWING AIR POLLUTION PARTICLE EXPOSURE (PM). E S Roberts1, R Jaskot2, J Richards2, and K L Dreher2. 1College of Veterinary Medicine, NC State University, Raleigh, NC a...

  16. Potential Biochemical Mechanisms of Lung Injury in Diabetes

    PubMed Central

    Zheng, Hong; Wu, Jinzi; Jin, Zhen; Yan, Liang-Jun

    2017-01-01

    Accumulating evidence has shown that the lung is one of the target organs for microangiopathy in patients with either type 1 or type 2 diabetes mellitus (DM). Diabetes is associated with physiological and structural abnormalities in the diabetic lung concurrent with attenuated lung function. Despite intensive investigations in recent years, the pathogenic mechanisms of diabetic lung injury remain largely elusive. In this review, we summarize currently postulated mechanisms of diabetic lung injury. We mainly focus on the pathogenesis of diabetic lung injury that implicates key pathways, including oxidative stress, non-enzymatic protein glycosylation, polyol pathway, NF-κB pathway, and protein kinase c pathway. We also highlight that while numerous studies have mainly focused on tissue or cell damage in the lung, studies focusing on mitochondrial dysfunction in the diabetic lung have remained sketchy. Hence, further understanding of mitochondrial mechanisms of diabetic lung injury should provide invaluable insights into future therapeutic approaches for diabetic lung injury. PMID:28203478

  17. Novel insights into phosgene-induced acute lung injury in rats: role of dysregulated cardiopulmonary reflexes and nitric oxide in lung edema pathogenesis.

    PubMed

    Li, Wenli; Liu, Fangfang; Wang, Chen; Truebel, Hubert; Pauluhn, Juergen

    2013-02-01

    Phosgene gas is a lower respiratory tract irritant. As such, it stimulates nociceptive vagal C-fiber-related reflexes in a dose-rate and concentration × exposure duration (C × t)-dependent manner. In rats, this reflex is characterized by extended apnea time periods, bradycardia, and hypothermia. Although inhalation exposures at nonlethal C × t products show rapid reversibility of reflexively induced changes in respiratory patterns, lethal C × t products seem to cause prolonged stimulation after discontinued exposure to phosgene. This observation has been taken as indirect evidence that phosgene-induced lethal lung edema is likely to be associated with a dysfunctional neurogenic control of cardiopulmonary and microvascular physiology. In order to verify this hypothesis, data from respiratory function measurements during and after the inhalation exposure to phosgene gas were compared with time-course measurements of cardiac function over 20 h post-phosgene exposure. These data were complemented by time-course analyses of nitric oxide (NO(e)) and carbon dioxide in exhaled breath, including time-dependent changes of extravasated protein in bronchoalveolar lavage fluid and hemoglobin in blood. The nitric oxidase synthetase inhibitors L-NAME and L-NIL were used to further elucidate the role of NO(e) in this type of acute lung injury and whether its analysis can serve as an early biomarker of pulmonary injury. Collectively, the sequence and time course of pathological events in phosgene-induced lung edema appear to suggest that overstimulated, continued sensorimotor vagal reflexes affect cardiopulmonary hemodynamics. A continued parasympathetic tone appears to be involved in this etiopathology.

  18. Role of pulmonary artery reactivity and nitric oxide in injury and inflammation following lung contusion.

    PubMed

    Lakshminrusimha, Satyan; Suresh, Madathilparambil V; Knight, Paul R; Gugino, Sylvia F; Davidson, Bruce A; Helinski, Jadwiga D; Nielsen, Lori C; Russell, James A; Yu, Bi; Zeng, Lixia; Pennathur, Subramaniam; Raghavendran, Krishnan

    2013-03-01

    The mechanisms contributing to hypoxia in lung contusion (LC) remain unclear and not temporally associated with the peak onset of acute inflammation. We investigated the role of oxidative stress in alteration of pulmonary arterial (PA) reactivity following LC. In addition, the role of antioxidants in reversing this process was examined. PaO2 and PA reactivity were measured in rats subjected to bilateral LC. Rings were pretreated with a nitric oxide synthase (NOS) inhibitor, L-nitro arginine (10(-3) M), or PEG-superoxide dismutase (SOD) and PEG-catalase (CAT), or both (L-nitro arginine + SOD/CAT). Rings were constricted with norepinephrine and relaxed with an NOS agonist (A23187) or NO donor (SNAP [S-nitrosyl amino penicillamine]). Immunochemical and mass spectrometric quantification for nitrotyrosine was performed. Rats were hypoxemic at 4 h after contusion compared with controls, but recovered by 24 h (PaO(2)/FIO(2) ratio: baseline, 443 ± 28; 4 h, 288 ± 46; and 24 h, 417 ± 23). Pulmonary arterial constriction to NOS inhibition and relaxation to A23187 were impaired 4 h after LC. Pulmonary arterial relaxation to SNAP was decreased at 4 and 24 h after LC. These alterations in PA reactivity were reversed by SOD/CAT pretreatment. SOD1 and 2 mRNA were upregulated, and soluble guanylyl cyclase mRNA was downregulated 24 h after LC. Immunohistochemistry and mass spectrometry revealed that levels of 3-nitrotyrosine were increased markedly at 4 h following LC consistent with superoxide generation and formation of peroxynitrite. Collectively, these data suggest that consumption of NO due to excess superoxide resulting in peroxynitrite formation leads to diminished vascular reactivity following LC.

  19. [Ischemia-reperfusion injury after lung transplantation].

    PubMed

    Gennai, Stéphane; Pison, Christophe; Briot, Raphaël

    2014-09-01

    Lung ischemia-reperfusion is characterized by diffuse alveolar damage arising from the first hours after transplantation. The first etiology of the primary graft dysfunction in lung is ischemia-reperfusion. It is burdened by an important morbi-mortality. Lung ischemia-reperfusion increases the oxidative stress, inactivates the sodium pump, increases the intracellular calcium, leads to cellular death and the liberation of pro-inflammatory mediators. Researches relative to the reduction of the lung ischemia-reperfusion injuries are numerous but few of them found a place in common clinical practice, because of an insufficient level of proofs. Ex vivolung evaluation is a suitable technique in order to evaluate therapeutics supposed to limit lung ischemia-reperfusion injuries.

  20. Biomarkers in acute lung injury.

    PubMed

    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.

  1. The protective role of MnTBAP in oxidant-mediated injury and inflammation in a rat model of lung contusion.

    PubMed

    Suresh, Madathilparambil V; Yu, Bi; Lakshminrusimha, Satyan; Machado-Aranda, David; Talarico, Nicholas; Zeng, Lixia; Davidson, Bruce A; Pennathur, Subramaniam; Raghavendran, Krishnan

    2013-11-01

    Lung contusion (LC) is a unique direct and focal insult that is considered a major risk factor for the initiation of acute lung injury and acute respiratory distress syndrome. We have shown recently that consumption of nitric oxide (due to excess superoxide) resulting in peroxynitrite formation leads to decreased vascular reactivity after LC. In this study, we set out to determine whether the superoxide scavenger Mn (III) tetrakis (4-benzoic acid) porphyrin chloride (MnTBAP) plays a protective role in alleviating acute inflammatory response and injury in LC. Nonlethal, closed-chest, bilateral LC was induced in a rodent model. Administration of the superoxide dismutase mimetic MnTBAP concurrently in LC in rats was performed, and bronchoalveolar lavage (BAL) and lung samples were analyzed for degree of injury and inflammation at 5 and 24 h after the insult. The extent of injury was assessed by the measurement of cells and albumin with cytokine levels in the BAL and lungs. Lung samples were subjected to H&E and superoxide staining with dihydro-ethidium. Protein-bound dityrosine and nitrotyrosine levels were quantified in lung tissue by tandem mass spectrometry. The degrees of lung injury after LC as determined by BAL albumin levels were significantly decreased in the MnTBAP-administered rats at all the time points when compared to the corresponding controls. The release of proinflammatory cytokines and BAL neutrophils was significantly less in the rats administered MnTBAP after LC. Administration of MnTBAP decreased tissue damage and decreased necrosis and neutrophil-rich exudate at the 24-h time point. Staining for superoxide anions showed significantly greater intensity in the lung samples from the LC group compared to the LC+ MnTBAP group. High-performance liquid chromatography/tandem mass spectrometry revealed that MnTBAP treatment significantly attenuated dityrosine and nitrotyrosine levels, consistent with decreased oxidant injury. Superoxide dismutase mimetic

  2. Role of Pulmonary Artery Reactivity and Nitric Oxide in Injury and Inflammation following Lung Contusion

    PubMed Central

    Lakshminrusimha, Satyan; Suresh, Madathilparambil V; Knight, Paul R.; Gugino, Sylvia F.; Davidson, Bruce A.; Helinski, Jadwiga D.; Nielsen, Lori C.; Russell, James A.; Yu, Bi; Zeng, Lixia; Pennathur, Subramaniam; Raghavendran, Krishnan

    2013-01-01

    Rationale The mechanisms contributing to hypoxia in lung contusion remain unclear and not temporally associated with the peak onset of acute inflammation. Objective We investigated the role of oxidative stress in alteration of pulmonary arterial (PA) reactivity following LC. Additionally, the role of antioxidants in reversing this process was examined. Methods PaO2 and PA reactivity were measured in rats subjected to bilateral LC. Rings were pretreated with a NO synthase (NOS) inhibitor, L-nitro arginine (LNA 10−3 M) or PEG-superoxide dismutase (SOD) and PEG-catalase (CAT) or both (LNA+SOD/CAT). Rings were constricted with norepinephrine (NE) and relaxed with an NOS agonist (A23187) or NO donor (SNAP). Immunochemical and mass spectrometric quantification for nitrotyrosine were performed. Results Rats were hypoxemic at 4h post-contusion compared to controls, but recovered by 24h (PaO2/FiO2 ratio: baseline- 443±28, 4h-288±46 and 24h-417±23). PA constriction to NOS inhibition and relaxation to A23187 were impaired 4h after LC. PA relaxation to SNAP was decreased at 4h and 24h after LC. These alterations in PA reactivity were reversed by SOD/CAT pretreatment. SOD1 and 2 mRNA was up-regulated and soluble guanylyl cyclase (sGC) mRNA was down-regulated 24h after LC. IHC and mass spectrometry revealed that levels of 3-nitrotyrosine were increased markedly at 4h following LC consistent with superoxide generation and formation of peroxynitrite. Conclusion Collectively, this data suggests that consumption of NO due to excess superoxide resulting in peroxynitrite formation leads to diminished vascular reactivity following LC. PMID:23364426

  3. Brain injury requires lung protection

    PubMed Central

    Lopez-Aguilar, Josefina

    2015-01-01

    The paper entitled “The high-mobility group protein B1-Receptor for advanced glycation endproducts (HMGB1-RAGE) axis mediates traumatic brain injury (TBI)-induced pulmonary dysfunction in lung transplantation” published recently in Science Translational Medicine links lung failure after transplantation with alterations in the axis HMGB1-RAGE after TBI, opening a new field for exploring indicators for the early detection of patients at risk of developing acute lung injury (ALI). The lung is one of the organs most vulnerable to the inflammatory cascade triggered by TBI. HMGB1 is an alarm in that can be released from activated immune cells in response to tissue injury. Increased systemic HMGB1 concentration correlates with poor lung function before and after lung transplant, confirming its role in acute ALI after TBI. HMGB1 exerts its influence by interacting with several receptors, including the RAGE receptor. RAGE also plays an important role in the onset of innate immune inflammatory responses, and systemic levels of RAGE are strongly associated with ALI and clinical outcomes in ventilator-induced lung injury. RAGE ligation to HMGB1 triggers the amplification of the inflammatory cascade involving nuclear factor-κB (NF-κB) activation. Identifying early biomarkers that mediate pulmonary dysfunction will improve outcomes not only in lung transplantation, but also in other scenarios. These novel findings show that upregulation of the HMGB1-RAGE axis plays an important role in brain-lung crosstalk. PMID:26046092

  4. Protective Effects of Dioscin against Lipopolysaccharide-Induced Acute Lung Injury through Inhibition of Oxidative Stress and Inflammation

    PubMed Central

    Yao, Hong; Sun, Yiping; Song, Shasha; Qi, Yan; Tao, Xufeng; Xu, Lina; Yin, Lianhong; Han, Xu; Xu, Youwei; Li, Hua; Sun, Huijun; Peng, Jinyong

    2017-01-01

    The protective effects of dioscin, a natural steroidal saponin from some medicinal plants including Dioscorea nipponica Makino, against lipopolysaccharide (LPS)- induced acute liver and renal damages have been reported in our previous works. However, the actions of dioscin against LPS-induced acute lung injury (ALI) is still unknown. In the present study, we investigated the effects and mechanisms of dioscin against LPS-induced ALI in vitro and in vivo. The results showed that dioscin obviously inhibited cell proliferation and markedly decreased reactive oxidative species level in 16HBE cells treated by LPS. In addition, dioscin significantly protected LPS-induced histological changes, inhibited the infiltration of inflammatory cells, as well as decreased the levels of MDA, SOD, NO and iNOS in mice and rats (p < 0.05). Mechanistically, dioscin significantly decreased the protein levels of TLR4, MyD88, TRAF6, TKB1, TRAF3, phosphorylation levels of PI3K, Akt, IκBα, NF-κB, and the mRNA levels of IL-1β, IL-6, and TNF-α against oxidative stress and inflammation (p < 0.05). Dioscin significantly reduced the overexpression of TLR4, and obviously down-regulated the levels of MyD88, TRAF6, TKB1, TRAF3, p-PI3K, p-Akt, p-IκBα, and p-NF-κB. These findings provide new perspectives for the study of ALI. Dioscin has protective effects on LPS-induced ALI via adjusting TLR4/MyD88- mediated oxidative stress and inflammation, which should be a potent drug in the treatment of ALI. PMID:28377715

  5. Contribution of neutrophils to acute lung injury.

    PubMed

    Grommes, Jochen; Soehnlein, Oliver

    2011-01-01

    Treatment of acute lung injury (ALI) and its most severe form, acute respiratory distress syndrome (ARDS), remain unsolved problems of intensive care medicine. ALI/ARDS are characterized by lung edema due to increased permeability of the alveolar-capillary barrier and subsequent impairment of arterial oxygenation. Lung edema, endothelial and epithelial injury are accompanied by an influx of neutrophils into the interstitium and broncheoalveolar space. Hence, activation and recruitment of neutrophils are regarded to play a key role in progression of ALI/ARDS. Neutrophils are the first cells to be recruited to the site of inflammation and have a potent antimicrobial armour that includes oxidants, proteinases and cationic peptides. Under pathological circumstances, however, unregulated release of these microbicidal compounds into the extracellular space paradoxically can damage host tissues. This review focuses on the mechanisms of neutrophil recruitment into the lung and on the contribution of neutrophils to tissue damage in ALI.

  6. Lung Injury After One-Lung Ventilation: A Review of the Pathophysiologic Mechanisms Affecting the Ventilated and the Collapsed Lung.

    PubMed

    Lohser, Jens; Slinger, Peter

    2015-08-01

    Lung injury is the leading cause of death after thoracic surgery. Initially recognized after pneumonectomy, it has since been described after any period of 1-lung ventilation (OLV), even in the absence of lung resection. Overhydration and high tidal volumes were thought to be responsible at various points; however, it is now recognized that the pathophysiology is more complex and multifactorial. All causative mechanisms known to trigger ventilator-induced lung injury have been described in the OLV setting. The ventilated lung is exposed to high strain secondary to large, nonphysiologic tidal volumes and loss of the normal functional residual capacity. In addition, the ventilated lung experiences oxidative stress, as well as capillary shear stress because of hyperperfusion. Surgical manipulation and/or resection of the collapsed lung may induce lung injury. Re-expansion of the collapsed lung at the conclusion of OLV invariably induces duration-dependent, ischemia-reperfusion injury. Inflammatory cytokines are released in response to localized injury and may promote local and contralateral lung injury. Protective ventilation and volatile anesthesia lessen the degree of injury; however, increases in biochemical and histologic markers of lung injury appear unavoidable. The endothelial glycocalyx may represent a common pathway for lung injury creation during OLV, because it is damaged by most of the recognized lung injurious mechanisms. Experimental therapies to stabilize the endothelial glycocalyx may afford the ability to reduce lung injury in the future. In the interim, protective ventilation with tidal volumes of 4 to 5 mL/kg predicted body weight, positive end-expiratory pressure of 5 to 10 cm H2O, and routine lung recruitment should be used during OLV in an attempt to minimize harmful lung stress and strain. Additional strategies to reduce lung injury include routine volatile anesthesia and efforts to minimize OLV duration and hyperoxia.

  7. The therapeutic effects of anti-oxidant and anti-inflammatory drug quercetin on aspiration-induced lung injury in rats.

    PubMed

    Yilmaz, Mehmet Ziya; Guzel, Aygul; Torun, Aysun Caglar; Okuyucu, Ali; Salis, Osman; Karli, Rifat; Gacar, Ayhan; Guvenc, Tolga; Paksu, Sule; Urey, Volkan; Murat, Naci; Alacam, Hasan

    2014-04-01

    Aspiration pneumonitis refers to acute chemical lung injury caused by aspiration of sterile gastric contents. The aim of this study was to evaluate the role of quercetin (QC) in acid aspiration-induced lung injury in rats. Twenty-eight female Sprague-Dawley rats were used and divided into the following groups (n = 7): sham (aspirated normal saline, S), hydrochloric acid (aspirated HCl), S plus treatment with QC (S + QC), and HCl plus treatment with QC (HCl + QC). After aspiration, the treatment groups received QC 60 mg/kg/day intraperitoneally once a day for 7 days. As a result of acid aspiration, an increase was observed in the levels of serum clara cell protein-16 (CC-16) and advanced oxidation protein products, whereas there was a decrease in serum thiobarbituric acid-reactive substances, superoxide dismutase (SOD), and catalase levels. There was a significant decrease in peribronchial inflammatory cell infiltration, alveolar septal infiltration, alveolar edema, and alveolar exudate scores, except in the alveolar histiocytes in the HCl + QC group. The expression of nitric oxide synthase, which increased after aspiration in the HCl group, showed a statistically significant decrease after the QC treatment. After the treatment with QC, an increase in the serum SOD level was observed, whereas a significant decrease was determined in the serum CC-16 level relative to that of the aspiration group (HCl). The antioxidant QC is effective in the treatment of lung injury following acid aspiration and can be used as a serum CC-16 biomarker in predicting the severity of oxidative lung injury.

  8. Ventilator-induced Lung Injury

    PubMed Central

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

    2016-01-01

    It is well established that mechanical ventilation can injure the lung, producing an entity known as ventilator-induced lung injury (VILI). There are various forms of VILI, including volutrauma (i.e., injury caused by overdistending the lung), atelectrauma (injury due to repeated opening/closing of lung units), and biotrauma (release of mediators that can induce lung injury or aggravate pre-existing injury, potentially leading to multiple organ failure). Experimental data in the pediatric context are in accord with the importance of VILI, and appear to show age-related susceptibility to VILI, although a conclusive link between use of large Vts and mortality has not been demonstrated in this population. The relevance of VILI in the pediatric intensive care unit population is thus unclear. Given the physiological and biological differences in the respiratory systems of infants, children, and adults, it is difficult to directly extrapolate clinical practice from adults to children. This Critical Care Perspective analyzes the relevance of VILI to the pediatric population, and addresses why pediatric patients might be less susceptible than adults to VILI. PMID:25003705

  9. Association between inflammatory mediators and response to inhaled nitric oxide in a model of endotoxin-induced lung injury

    PubMed Central

    Trachsel, Sebastien; Deby-Dupont, Ginette; Maurenbrecher, Edwige; Nys, Monique; Lamy, Maurice; Hedenstierna, Göran

    2008-01-01

    Introduction Inhaled nitric oxide (INO) allows selective pulmonary vasodilation in acute respiratory distress syndrome and improves PaO2 by redistribution of pulmonary blood flow towards better ventilated parenchyma. One-third of patients are nonresponders to INO, however, and it is difficult to predict who will respond. The aim of the present study was to identify, within a panel of inflammatory mediators released during endotoxin-induced lung injury, specific mediators that are associated with a PaO2 response to INO. Methods After animal ethics committee approval, pigs were anesthetized and exposed to 2 hours of endotoxin infusion. Levels of cytokines, prostanoid, leucotriene and endothelin-1 (ET-1) were sampled prior to endotoxin exposure and hourly thereafter. All animals were exposed to 40 ppm INO: 28 animals were exposed at either 4 hours or 6 hours and a subgroup of nine animals was exposed both at 4 hours and 6 hours after onset of endotoxin infusion. Results Based on the response to INO, the animals were retrospectively placed into a responder group (increase in PaO2 ≥ 20%) or a nonresponder group. All mediators increased with endotoxin infusion although no significant differences were seen between responders and nonresponders. There was a mean difference in ET-1, however, with lower levels in the nonresponder group than in the responder group, 0.1 pg/ml versus 3.0 pg/ml. Moreover, five animals in the group exposed twice to INO switched from responder to nonresponder and had decreased ET-1 levels (3.0 (2.5 to 7.5) pg/ml versus 0.1 (0.1 to 2.1) pg/ml, P < 0.05). The pulmonary artery pressure and ET-1 level were higher in future responders to INO. Conclusions ET-1 may therefore be involved in mediating the response to INO. PMID:18954441

  10. Radionuclide injury to the lung.

    PubMed Central

    Dagle, G E; Sanders, C L

    1984-01-01

    Radionuclide injury to the lung has been studied in rats, hamsters, dogs, mice and baboons. Exposure of the lung to high dose levels of radionuclides produces a spectrum of progressively more severe functional and morphological changes, ranging from radiation pneumonitis and fibrosis to lung tumors. These changes are somewhat similar for different species. Their severity can be related to the absorbed radiation dose (measured in rads) produced by alpha, beta or gamma radiation emanating from various deposited radionuclides. The chemicophysical forms of radionuclides and spatial-temporal factors are also important variables. As with other forms of injury to the lung, repair attempts are highlighted by fibrosis and proliferation of pulmonary epithelium. Lung tumors are the principal late effect observed in experimental animals following pulmonary deposition of radionuclides at dose levels that do not result in early deaths from radiation pneumonitis or fibrosis. The predominant lung tumors described have been of epithelial origin and have been classified, in decreasing frequency of occurrence, as adenocarcinoma, bronchioloalveolar carcinoma, epidermoid carcinomas and combined epidermoid and adenocarcinoma. Mesothelioma and fibrosarcoma have been observed in rats, but less commonly in other species. Hemangiosarcomas were frequency observed in dogs exposed to beta-gamma emitters, and occasionally in rats exposed to alpha emitters. These morphologic changes in the lungs of experimental animals were reviewed and issues relevant to the prediction of human hazards discussed. PMID:6376095

  11. Selective inducible nitric oxide synthase (iNOS) inhibition attenuates remote acute lung injury in a model of ruptured abdominal aortic aneurysm.

    PubMed

    Harkin, Denis W; Rubin, Barry B; Romaschin, Alex; Lindsay, Thomas F

    2004-08-01

    Abdominal aortic aneurysm rupture is associated with a systemic inflammatory response syndrome and acute lung injury. Using a selective inducible nitric oxide synthase (iNOS) inhibitor, N(6)-(iminoethyl)-lysine (L-NIL), we explored the role of iNOS in the early pro-inflammatory signaling and acute lung injury in experimental abdominal aortic aneurysm rupture. Anesthetized rats were randomized to sham control or shock and clamp (s + c) groups, which underwent one hour of hemorrhagic shock, followed by 45 minutes of supramesenteric aortic clamping, and then two hours resuscitated reperfusion. Animals in s + c were randomized to receive intravenous L-NIL at 50 microg/kg/h or saline at the start of reperfusion. Pulmonary permeability to (125)I-labeled albumin, myeloperoxidase (MPO) activity, cytokine levels, and semi-quantitative RT-PCR for mRNA were indicators of microvascular permeability, leuco-sequestration, and pro-inflammatory signaling, respectively. Lung permeability index were significantly increased in s + c compared to sham (4.43 +/- 0.96 versus 1.30 +/- 0.17, P < 0.01), and attenuated by L-NIL treatment (2.14 +/- 0.70, P < 0.05). Lung tissue MPO activity was significantly increased in s + c compared to sham (2.80 +/- 0.32 versus 1.03 +/- 0.29, P < 0.002), and attenuated by L-NIL treatment (1.50 +/- 0.20, P < 0.007). Lung tissue iNOS activity was significantly increased in s + c compared to sham animals (P < 0.05), and attenuated by L-NIL treatment (P < 0.05). Lung tissue iNOS mRNA was upregulated 8-fold in s + c compared to sham (P < 0.05). Data represents mean +/- standard error mean, comparisons with ANOVA. These data suggest that in our model of ruptured abdominal aortic aneurysm iNOS plays a crucial role in reperfusion lung injury. Selective inhibition of iNOS during early reperfusion prevents neutrophil mediated acute lung injury.

  12. NMDA Receptor Antagonist Attenuates Bleomycin-Induced Acute Lung Injury

    PubMed Central

    Li, Yang; Liu, Yong; Peng, XiangPing; Liu, Wei; Zhao, FeiYan; Feng, DanDan; Han, JianZhong; Huang, YanHong; Luo, SiWei; Li, Lian; Yue, Shao Jie; Cheng, QingMei; Huang, XiaoTing; Luo, ZiQiang

    2015-01-01

    Background Glutamate is a major neurotransmitter in the central nervous system (CNS). Large amount of glutamate can overstimulate N-methyl-D-aspartate receptor (NMDAR), causing neuronal injury and death. Recently, NMDAR has been reported to be found in the lungs. The aim of this study is to examine the effects of memantine, a NMDAR channel blocker, on bleomycin-induced lung injury mice. Methods C57BL/6 mice were intratracheally injected with bleomycin (BLM) to induce lung injury. Mice were randomized to receive saline, memantine (Me), BLM, BLM plus Me. Lungs and BALF were harvested on day 3 or 7 for further evaluation. Results BLM caused leukocyte infiltration, pulmonary edema and increase in cytokines, and imposed significant oxidative stress (MDA as a marker) in lungs. Memantine significantly mitigated the oxidative stress, lung inflammatory response and acute lung injury caused by BLM. Moreover, activation of NMDAR enhances CD11b expression on neutrophils. Conclusions Memantine mitigates oxidative stress, lung inflammatory response and acute lung injury in BLM challenged mice. PMID:25942563

  13. Mice Deficient in the Gene for Cytochrome P450 (CYP)1A1 Are More Susceptible Than Wild-Type to Hyperoxic Lung Injury: Evidence for Protective Role of CYP1A1 Against Oxidative Stress

    PubMed Central

    Wang, Lihua; Wang, Gangduo; Couroucli, Xanthi I.; Shivanna, Binoy; Welty, Stephen E.; Barrios, Roberto; Khan,  M. Firoze; Nebert, Daniel W.; Roberts, L. Jackson; Moorthy, Bhagavatula

    2014-01-01

    Hyperoxia contributes to acute lung injury in diseases such as acute respiratory distress syndrome in adults and bronchopulmonary dysplasia in premature infants. Cytochrome P450 (CYP)1A1 has been shown to modulate hyperoxic lung injury. The mechanistic role(s) of CYP1A1 in hyperoxic lung injury in vivo is not known. In this investigation, we hypothesized that Cyp1a1(–/–) mice would be more susceptible to hyperoxic lung injury than wild-type (WT) mice, and that the protective role of CYP1A1 is in part due to CYP1A1-mediated decrease in the levels of reactive oxygen species-mediated lipid hydroperoxides, e.g., F2-isoprostanes/isofurans, leading to attenuation of oxidative damage. Eight- to ten-week-old male WT (C57BL/6J) or Cyp1a1(–/–) mice were exposed to hyperoxia (>95% O2) or room air for 24–72 h. The Cyp1a1(–/–) mice were more susceptible to oxygen-mediated lung damage and inflammation than WT mice, as evidenced by increased lung weight/body weight ratio, lung injury, neutrophil infiltration, and augmented expression of IL-6. Hyperoxia for 24–48 h induced CYP1A expression at the mRNA, protein, and enzyme levels in liver and lung of WT mice. Pulmonary F2-isoprostane and isofuran levels were elevated in WT mice after hyperoxia for 24 h. On the other hand, Cyp1a1(–/–) mice showed higher levels after 48–72 h of hyperoxia exposure compared to WT mice. Our results support the hypothesis that CYP1A1 protects against hyperoxic lung injury by decreasing oxidative stress. Future research could lead to the development of novel strategies for prevention and/or treatment of acute lung injury. PMID:24893714

  14. Alcohol and lung injury and immunity.

    PubMed

    Yeligar, Samantha M; Chen, Michael M; Kovacs, Elizabeth J; Sisson, Joseph H; Burnham, Ellen L; Brown, Lou Ann S

    2016-09-01

    Annually, excessive alcohol use accounts for more than $220 billion in economic costs and 80,000 deaths, making excessive alcohol use the third leading lifestyle-related cause of death in the US. Patients with an alcohol-use disorder (AUD) also have an increased susceptibility to respiratory pathogens and lung injury, including a 2-4-fold increased risk of acute respiratory distress syndrome (ARDS). This review investigates some of the potential mechanisms by which alcohol causes lung injury and impairs lung immunity. In intoxicated individuals with burn injuries, activation of the gut-liver axis drives pulmonary inflammation, thereby negatively impacting morbidity and mortality. In the lung, the upper airway is the first checkpoint to fail in microbe clearance during alcohol-induced lung immune dysfunction. Brief and prolonged alcohol exposure drive different post-translational modifications of novel proteins that control cilia function. Proteomic approaches are needed to identify novel alcohol targets and post-translational modifications in airway cilia that are involved in alcohol-dependent signal transduction pathways. When the upper airway fails to clear inhaled pathogens, they enter the alveolar space where they are primarily cleared by alveolar macrophages (AM). With chronic alcohol ingestion, oxidative stress pathways in the AMs are stimulated, thereby impairing AM immune capacity and pathogen clearance. The epidemiology of pneumococcal pneumonia and AUDs is well established, as both increased predisposition and illness severity have been reported. AUD subjects have increased susceptibility to pneumococcal pneumonia infections, which may be due to the pro-inflammatory response of AMs, leading to increased oxidative stress. Copyright © 2016 Elsevier Inc. All rights reserved.

  15. Teduglutide, a glucagon-like peptide 2 analogue: a novel protective agent with anti-apoptotic and anti-oxidant properties in mice with lung injury.

    PubMed

    Arda-Pirincci, Pelin; Oztay, Fusun; Bayrak, Bertan Boran; Yanardag, Refiye; Bolkent, Sehnaz

    2012-12-01

    Teduglutide is a long-acting synthetic analogue of human glucagon-like peptide-2 (GLP-2). GLP-2 regulates cell proliferation and apoptosis as well as normal physiology in the gastrointestinal tract. In the present study, possible cytoprotective and reparative effects of teduglutide were analyzed on a mouse model with lung injury induced by tumor necrosis factor-alpha (TNF-α) and actinomycin D (Act D). BALB/c mice were divided into six groups: control mice (I), mice injected intraperitoneally with 15 μg/kg TNF-α (II), 800 μg/kg Act D (III), Act D 2 min prior to TNF-α administration with the same doses (IV), mice injected subcutaneously with 200 μg/kg teduglutide every 12h for 10 consecutive days (V), and mice given Act D 2 min prior to TNF-α administration on day 11 after receiving teduglutide for 10 days (VI). The TNF-α/Act D administration made the lung a sensitive organ to damage. Mice lung subjected to TNF-α/Act D were characterized by the disruption of alveolar wall, induced pulmonary endothelial/epithelial cell apoptosis and expression of active caspase-3. These mice exhibited an increase in lipid peroxidation, glutathione levels, and activities of myeloperoxidase, superoxide dismutase, catalase, glutathione peroxidase and xanthine oxidase, as well as reduced tissue factor and sodium-potassium/ATPase activities. Teduglutide pretreatment regressed the structural damage, cell apoptosis and oxidative stress by reducing lipid peroxidation in mice received TNF-α/Act D. GLP-2 receptors were present on the cell membrane of type II pneumocytes and interstitial cells. Thus, teduglutide can be suggested as a novel protective agent, which possesses anti-apoptotic and anti-oxidant properties, against lung injury.

  16. Lung injury and recovery after exposure to blast overpressure.

    PubMed

    Chavko, Mikulas; Prusaczyk, W Keith; McCarron, Richard M

    2006-10-01

    A critical immediate determinant of survival after exposure to blast overpressure (BOP) is pulmonary damage, but mechanisms of injury and the course of recovery are not well understood. The objective of this study was to characterize the progression of oxidative and inflammatory responses in lungs as well as the activation of consequent protective mechanisms after exposure to medium intensity BOP. Rats were exposed to a moderate (approximately 120 kPa) level of BOP in a pneumatically driven shock tube. At different times (2-192 hours) after exposure, lungs were examined for pathologic signs of injury, markers of inflammatory responses, and indicators of oxidative and nitrative damage. The results showed a postblast activation of inflammatory response (increase of myeloperoxidase activity, CINC-1, ICAM-1, and iNOS), increase in protein oxidation and nitration, and development of gross diffused hemorrhage in lungs. The initial phase of lung damage that peaked at 24 to 48 hours after exposure to BOP was followed by gradual dissolution of inflammation and oxidation that were complete by 192 hours. Resolution of morphologic damage and inflammation in lungs concurred with activation of expression of antioxidant enzymes heme oxygenase-1 (HO-1) and manganese superoxide dismutase (MnSOD). Plasma level of gelsolin, a marker of acute lung damage was decreased at 24 hours postblast and later returned to the control level. The study shows the role of adaptive anti-oxidant and anti- inflammatory mechanisms in lung recovery after injury caused by exposure to BOP.

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

    SciTech Connect

    Ono, Koichi; Koizumi, Tomonobu; Tsushima, Kenji; Yoshikawa, Sumiko; Yokoyama, Toshiki; Nakagawa, Rikimaru; Obata, Toru

    2009-10-16

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

  18. Adiponectin protects against hyperoxic lung injury and vascular leak

    PubMed Central

    Sliman, Sean M.; Patel, Rishi B.; Cruff, Jason P.; Kotha, Sainath R.; Newland, Christie A.; Schrader, Carrie A.; Sherwani, Shariq I.; Gurney, Travis O.; Magalang, Ulysses J.; Parinandi, Narasimham L.

    2014-01-01

    Adiponectin (Ad), an adipokine exclusively secreted by the adipose tissue, has emerged as a paracrine metabolic regulator as well as a protectant against oxidative stress. Pharmacological approaches of protecting against clinical hyperoxic lung injury during oxygen therapy/treatment are limited. Earlier, we have reported that Ad inhibits the NADPH oxidase-catalyzed formation of superoxide from molecular oxygen in human neutrophils. Having this as the premise, we conducted studies to determine whether (i) exogenous Ad would protect against the hyperoxia-induced barrier dysfunction in the lung endothelial cells (ECs) in vitro and (ii) endogenously synthesized Ad would protect against hyperoxic lung injury in wild type (WT) and Ad-overexpressing transgenic (AdTg) mice in vivo. The results demonstrated that exogenous Ad protected against the hyperoxia-induced oxidative stress, loss of glutathione (GSH), cytoskeletal reorganization, barrier dysfunction, and leak in the lung ECs in vitro. Furthermore, the hyperoxia-induced lung injury, vascular leak, and lipid peroxidation were significantly attenuated in AdTg mice in vivo. Also, AdTg mice exhibited elevated levels of total thiols and GSH in the lungs as compared to WT mice. For the first time, our studies demonstrated that Ad protected against the hyperoxia-induced lung damage apparently through attenuation of oxidative stress and modulation of thiol-redox status. PMID:22183615

  19. Lung injury-dependent oxidative status and chymotrypsin-like activity of skeletal muscles in hamsters with experimental emphysema

    PubMed Central

    2013-01-01

    Background Peripheral skeletal muscle is altered in patients suffering from emphysema and chronic obstructive pulmonary disease (COPD). Oxidative stress have been demonstrated to participate on skeletal muscle loss of several states, including disuse atrophy, mechanical ventilation, and chronic diseases. No evidences have demonstrated the occurance in a severity manner. Methods We evaluated body weight, muscle loss, oxidative stress, and chymotrypsin-like proteolytic activity in the gastrocnemius muscle of emphysemic hamsters. The experimental animals had 2 different severities of lung damage from experimental emphysema induced by 20 mg/mL (E20) and 40 mg/mL (E40) papain. Results The severity of emphysema increased significantly in E20 (60.52 ± 2.8, p < 0.05) and E40 (52.27 ± 4.7; crossed the alveolar intercepts) groups. As compared to the control group, there was a reduction on body (171.6 ± 15.9 g) and muscle weight (251.87 ± 24.87 mg) in the E20 group (157.5 ± 10.3 mg and 230.12 ± 23.52 mg, for body and muscle weight, respectively), which was accentuated in the E40 group (137.4 ± 7.2 g and 197.87 ± 10.49 mg, for body and muscle weight, respectively). Additionally, the thiobarbituric acid reactive substances (TBARS), tert-butyl hydroperoxide-initiated chemiluminescence (CL), carbonylated proteins, and chymotrypsin-like proteolytic activity were elevated in the E40 group as compared to the E20 group (p < 0.05 for all comparisons). The severity of emphysema significantly correlated with the progressive increase in CL (r = −0.95), TBARS (r = −0.98), carbonyl proteins (r = −0.99), and chymotrypsin-like proteolytic activity (r = −0.90). Furthermore, augmentation of proteolytic activity correlated significantly with CL (r = 0.97), TBARS (r = 0.96), and carbonyl proteins (r = 0.91). Conclusions Taken together, the results of the present study suggest that muscle atrophy observed in this model of emphysema is mediated by increased muscle chymotrypsin

  20. Visualizing the Propagation of Acute Lung Injury

    PubMed Central

    Cereda, Maurizio; Xin, Yi; Meeder, Natalie; Zeng, Johnathan; Jiang, YunQing; Hamedani, Hooman; Profka, Harrilla; Kadlecek, Stephen; Clapp, Justin; Deshpande, Charuhas G.; Wu, Jue; Gee, James C.; Kavanagh, Brian P.; Rizi, Rahim R.

    2015-01-01

    Background Mechanical ventilation worsens acute respiratory distress syndrome (ARDS), but this secondary ‘ventilator-associated’ injury is variable and difficult to predict. We aimed to visualize the propagation of such ventilator-induced injury, in the presence (and absence) of a primary underlying lung injury, and to determine the predictors of propagation. Methods Anesthetized rats (n=20) received acid aspiration (HCl) followed by ventilation with moderate tidal volume (VT). In animals surviving ventilation for at least two hours, propagation of injury was quantified using serial computed tomography (CT). Baseline lung status was assessed by oxygenation, lung weight, and lung strain (VT/expiratory lung volume). Separate groups of rats without HCl aspiration were ventilated with large (n=10) or moderate (n=6) VT. Results In 15 rats surviving longer than two hours, CT opacities spread outwards from the initial site of injury. Propagation was associated with higher baseline strain (propagation vs. no propagation, mean ± SD: 1.52 ± 0.13 vs. 1.16 ± 0.20, p<0.01), but similar oxygenation and lung weight. Propagation did not occur where baseline strain <1.29. In healthy animals, large VT caused injury that was propagated inwards from the lung periphery; in the absence of preexisting injury, propagation did not occur where strain was <2.0. Conclusions Compared with healthy lungs, underlying injury causes propagation to occur at a lower strain threshold and, it originates at the site of injury; this suggests that tissue around the primary lesion is more sensitive. Understanding how injury is propagated may ultimately facilitate a more individualized monitoring or management. PMID:26536308

  1. Angiotensin receptor blockade attenuates cigarette smoke-induced lung injury and rescues lung architecture in mice.

    PubMed

    Podowski, Megan; Calvi, Carla; Metzger, Shana; Misono, Kaori; Poonyagariyagorn, Hataya; Lopez-Mercado, Armando; Ku, Therese; Lauer, Thomas; McGrath-Morrow, Sharon; Berger, Alan; Cheadle, Christopher; Tuder, Rubin; Dietz, Harry C; Mitzner, Wayne; Wise, Robert; Neptune, Enid

    2012-01-01

    Chronic obstructive pulmonary disease (COPD) is a prevalent smoking-related disease for which no disease-altering therapies currently exist. As dysregulated TGF-β signaling associates with lung pathology in patients with COPD and in animal models of lung injury induced by chronic exposure to cigarette smoke (CS), we postulated that inhibiting TGF-β signaling would protect against CS-induced lung injury. We first confirmed that TGF-β signaling was induced in the lungs of mice chronically exposed to CS as well as in COPD patient samples. Importantly, key pathological features of smoking-associated lung disease in patients, e.g., alveolar injury with overt emphysema and airway epithelial hyperplasia with fibrosis, accompanied CS-induced alveolar cell apoptosis caused by enhanced TGF-β signaling in CS-exposed mice. Systemic administration of a TGF-β-specific neutralizing antibody normalized TGF-β signaling and alveolar cell death, conferring improved lung architecture and lung mechanics in CS-exposed mice. Use of losartan, an angiotensin receptor type 1 blocker used widely in the clinic and known to antagonize TGF-β signaling, also improved oxidative stress, inflammation, metalloprotease activation and elastin remodeling. These data support our hypothesis that inhibition of TGF-β signaling through angiotensin receptor blockade can attenuate CS-induced lung injury in an established murine model. More importantly, our findings provide a preclinical platform for the development of other TGF-β-targeted therapies for patients with COPD.

  2. Angiotensin receptor blockade attenuates cigarette smoke–induced lung injury and rescues lung architecture in mice

    PubMed Central

    Podowski, Megan; Calvi, Carla; Metzger, Shana; Misono, Kaori; Poonyagariyagorn, Hataya; Lopez-Mercado, Armando; Ku, Therese; Lauer, Thomas; McGrath-Morrow, Sharon; Berger, Alan; Cheadle, Christopher; Tuder, Rubin; Dietz, Harry C.; Mitzner, Wayne; Wise, Robert; Neptune, Enid

    2011-01-01

    Chronic obstructive pulmonary disease (COPD) is a prevalent smoking-related disease for which no disease-altering therapies currently exist. As dysregulated TGF-β signaling associates with lung pathology in patients with COPD and in animal models of lung injury induced by chronic exposure to cigarette smoke (CS), we postulated that inhibiting TGF-β signaling would protect against CS-induced lung injury. We first confirmed that TGF-β signaling was induced in the lungs of mice chronically exposed to CS as well as in COPD patient samples. Importantly, key pathological features of smoking-associated lung disease in patients, e.g., alveolar injury with overt emphysema and airway epithelial hyperplasia with fibrosis, accompanied CS-induced alveolar cell apoptosis caused by enhanced TGF-β signaling in CS-exposed mice. Systemic administration of a TGF-β–specific neutralizing antibody normalized TGF-β signaling and alveolar cell death, conferring improved lung architecture and lung mechanics in CS-exposed mice. Use of losartan, an angiotensin receptor type 1 blocker used widely in the clinic and known to antagonize TGF-β signaling, also improved oxidative stress, inflammation, metalloprotease activation and elastin remodeling. These data support our hypothesis that inhibition of TGF-β signaling through angiotensin receptor blockade can attenuate CS-induced lung injury in an established murine model. More importantly, our findings provide a preclinical platform for the development of other TGF-β–targeted therapies for patients with COPD. PMID:22182843

  3. Acute Lung Injury after Phosgene Inhalation

    PubMed Central

    Lim, Sung-Chul; Yang, Ju-Yeoul; Jang, An-Soo; Park, Yong-Uk; Kim, Young-Chul; Choi, In-Seon; Park, Kyung-Ok

    1996-01-01

    Phosgene (COCl2) is a colorless oxidant gas which is heavier than air and the lethal exposure dose (LC50) in humans is 500 ppm/min. This gas was originally manufactured as an agent for chemical warfare during World War I and there had been a great deal of studies on phosgene poisoning during the early years of industrial use. It is still widely used in the synthesis of chemicals and plastics. In the modern era, however, phosgene poisoning is relatively uncommon except in accidental exposures. In Korea, there has been no report about lung injury from phosgene inhalation. We present a clinical experience with six patients accidentally exposed to phosgene. PMID:8882481

  4. Hydrogen water alleviates lung injury induced by one-lung ventilation.

    PubMed

    Wu, Qifei; Zhang, Jingyao; Wan, Yong; Song, Sidong; Zhang, Yong; Zhang, Guangjian; Liu, Chang; Fu, Junke

    2015-12-01

    With the development of thoracic surgeries, one-lung ventilation (OLV) has been routinely used to facilitate surgical exposure. However, OLV can cause lung injury during the surgical process and becomes an important factor affecting the outcomes. To date, effective treatments for the prevention of lung injury caused by OLV are lacking. Hydrogen has been demonstrated to have effective protection against tissue injuries caused by oxidative stress, inflammation, and apoptosis. This study investigated the efficacy of hydrogen water consumption on the prevention of lung injury induced by OLV in rats. Male Sprague-Dawley rats (n = 32, 240-260 g) were divided randomly into the following four groups: sham group, sham + H2 group, OLV group, OLV + H2 group. The rats drank hydrogen water or degassed hydrogen water for 4 wk before the operation and received OLV for 60 min and two-lung ventilation for 60 min. Lung tissues were assayed for wet-to-dry ratio, oxidative stress variables, proinflammatory cytokines, and hematoxylin-eosin staining. Hydrogen water consumption reduced wet-to-dry weight ratio, malondialdehyde and myeloperoxidase activity and decreased the concentration of TNF-α, IL-1β, and IL-6 in the lung tissues compared with sham group and sham + H2 group. Hydrogen water consumption further attenuated NF-κB activation and caused histopathologic alterations. Our data demonstrated that hydrogen water consumption ameliorated OLV-induced lung injury, and it may exert its protective role by its anti-inflammation, antioxidation and reducing NF-κB activity in the lung tissues. Copyright © 2015 Elsevier Inc. All rights reserved.

  5. Corilagin Attenuates Aerosol Bleomycin-Induced Experimental Lung Injury

    PubMed Central

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

    2014-01-01

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

  6. Combined effect of low-dose nitric oxide gas inhalation with partial liquid ventilation on hemodynamics, pulmonary function, and gas exchange in acute lung injury of newborn piglets.

    PubMed Central

    Choi, Chang Won; Hwang, Jong Hee; Chang, Yun Sil; Park, Won Soon

    2003-01-01

    We conducted a randomized animal study to determine whether there is a cumulative effect on hemodynamics, pulmonary function, and gas exchange when low-dose nitric oxide (NO) is added to partial liquid ventilation (PLV) in acute lung injury. Eighteen newborn piglets were saline-lavaged repeatedly, and randomly divided into two groups: PLV with perfluorocarbon group (n=8) and lavage only (control) group (n=10). Perfluorodecalin (30 mL/kg) was instilled into the endotracheal tube for 30 min, followed by 5-10 mL/kg/hr. Fifteen minutes after the completion of perfluorodecalin dosing, NO (10 ppm) was added to the inspiratory gas in an "on/off" manner. Perfluorodecalin instillation produced a significant improvement in gas exchange, pulmonary mechanics, shunt, and pulmonary arterial pressure (PAP). The addition of NO produced a further significant improvement in PaO2 and PAP. The "on/off" response to NO was seen apparently in PAP, PaO2, dynamic compliance, and shunt. All the variables in control group were remained at near the after-lavage levels without significant improvements until the end of the experiment. We concluded that NO might have a cumulative effect on gas exchange when combined with PLV, and this might be attributable to deceased PAP and V/Q mismatching. PMID:14676437

  7. Lung Oxidative Damage by Hypoxia

    PubMed Central

    Araneda, O. F.; Tuesta, M.

    2012-01-01

    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. PMID:22966417

  8. Lung oxidative damage by hypoxia.

    PubMed

    Araneda, O F; Tuesta, M

    2012-01-01

    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. Nicotinamide Exacerbates Hypoxemia in Ventilator-Induced Lung Injury Independent of Neutrophil Infiltration

    PubMed Central

    Jones, Heather D.; Yoo, Jeena; Crother, Timothy R.; Kyme, Pierre; Ben-Shlomo, Anat; Khalafi, Ramtin; Tseng, Ching W.; Parks, William C.; Arditi, Moshe

    2015-01-01

    Background Ventilator-induced lung injury is a form of acute lung injury that develops in critically ill patients on mechanical ventilation and has a high degree of mortality. Nicotinamide phosphoribosyltransferase is an enzyme that is highly upregulated in ventilator-induced lung injury and exacerbates the injury when given exogenously. Nicotinamide (vitamin B3) directly inhibits downstream pathways activated by Nicotinamide phosphoribosyltransferase and is protective in other models of acute lung injury. Methods We administered nicotinamide i.p. to mice undergoing mechanical ventilation with high tidal volumes to study the effects of nicotinamide on ventilator-induced lung injury. Measures of injury included oxygen saturations and bronchoalveolar lavage neutrophil counts, protein, and cytokine levels. We also measured expression of nicotinamide phosophoribosyltransferase, and its downstream effectors Sirt1 and Cebpa, Cebpb, Cebpe. We assessed the effect of nicotinamide on the production of nitric oxide during ventilator-induced lung injury. We also studied the effects of ventilator-induced lung injury in mice deficient in C/EBPε. Results Nicotinamide treatment significantly inhibited neutrophil infiltration into the lungs during ventilator-induced lung injury, but did not affect protein leakage or cytokine production. Surprisingly, mice treated with nicotinamide developed significantly worse hypoxemia during mechanical ventilation. This effect was not linked to increases in nitric oxide production or alterations in expression of Nicotinamide phosphoribosyl transferase, Sirt1, or Cebpa and Cebpb. Cebpe mRNA levels were decreased with either nicotinamide treatment or mechanical ventilation, but mice lacking C/EBPε developed the same degree of hypoxemia and ventilator-induced lung injury as wild-type mice. Conclusions Nicotinamide treatment during VILI inhibits neutrophil infiltration of the lungs consistent with a strong anti-inflammatory effect, but

  10. NOS-2 Inhibition in Phosgene-Induced Acute Lung Injury.

    PubMed

    Filipczak, Piotr T; Senft, Albert P; Seagrave, JeanClare; Weber, Waylon; Kuehl, Philip J; Fredenburgh, Laura E; McDonald, Jacob D; Baron, Rebecca M

    2015-07-01

    Phosgene exposure via an industrial or warfare release produces severe acute lung injury (ALI) with high mortality, characterized by massive pulmonary edema, disruption of epithelial tight junctions, surfactant dysfunction, and oxidative stress. There are no targeted treatments for phosgene-induced ALI. Previous studies demonstrated that nitric oxide synthase 2 (NOS-2) is upregulated in the lungs after phosgene exposure; however, the role of NOS-2 in the pathogenesis of phosgene-induced ALI remains unknown. We previously demonstrated that NOS-2 expression in lung epithelium exacerbates inhaled endotoxin-induced ALI in mice, mediated partially through downregulation of surfactant protein B (SP-B) expression. Therefore, we hypothesized that a selective NOS-2 inhibitor delivered to the lung epithelium by inhalation would mitigate phosgene-induced ALI. Inhaled phosgene produced increases in bronchoalveolar lavage fluid protein, histologic lung injury, and lung NOS-2 expression at 24 h. Administration of the selective NOS-2 inhibitor 1400 W via inhalation, but not via systemic delivery, significantly attenuated phosgene-induced ALI and preserved epithelial barrier integrity. Furthermore, aerosolized 1400 W augmented expression of SP-B and prevented downregulation of tight junction protein zonula occludens 1 (ZO-1), both critical for maintenance of normal lung physiology and barrier integrity. We also demonstrate for the first time that NOS-2-derived nitric oxide downregulates the ZO-1 expression at the transcriptional level in human lung epithelial cells, providing a novel target for ameliorating vascular leak in ALI. Our data demonstrate that lung NOS-2 plays a critical role in the development of phosgene-induced ALI and suggest that aerosolized NOS-2 inhibitors offer a novel therapeutic strategy for its treatment. © The Author 2015. Published by Oxford University Press on behalf of the Society of Toxicology. All rights reserved. For Permissions, please e

  11. NOS-2 Inhibition in Phosgene-Induced Acute Lung Injury

    PubMed Central

    Filipczak, Piotr T.; Senft, Albert P.; Seagrave, JeanClare; Weber, Waylon; Kuehl, Philip J.; Fredenburgh, Laura E.; McDonald, Jacob D.; Baron, Rebecca M.

    2015-01-01

    Phosgene exposure via an industrial or warfare release produces severe acute lung injury (ALI) with high mortality, characterized by massive pulmonary edema, disruption of epithelial tight junctions, surfactant dysfunction, and oxidative stress. There are no targeted treatments for phosgene-induced ALI. Previous studies demonstrated that nitric oxide synthase 2 (NOS-2) is upregulated in the lungs after phosgene exposure; however, the role of NOS-2 in the pathogenesis of phosgene-induced ALI remains unknown. We previously demonstrated that NOS-2 expression in lung epithelium exacerbates inhaled endotoxin-induced ALI in mice, mediated partially through downregulation of surfactant protein B (SP-B) expression. Therefore, we hypothesized that a selective NOS-2 inhibitor delivered to the lung epithelium by inhalation would mitigate phosgene-induced ALI. Inhaled phosgene produced increases in bronchoalveolar lavage fluid protein, histologic lung injury, and lung NOS-2 expression at 24 h. Administration of the selective NOS-2 inhibitor 1400 W via inhalation, but not via systemic delivery, significantly attenuated phosgene-induced ALI and preserved epithelial barrier integrity. Furthermore, aerosolized 1400 W augmented expression of SP-B and prevented downregulation of tight junction protein zonula occludens 1 (ZO-1), both critical for maintenance of normal lung physiology and barrier integrity. We also demonstrate for the first time that NOS-2-derived nitric oxide downregulates the ZO-1 expression at the transcriptional level in human lung epithelial cells, providing a novel target for ameliorating vascular leak in ALI. Our data demonstrate that lung NOS-2 plays a critical role in the development of phosgene-induced ALI and suggest that aerosolized NOS-2 inhibitors offer a novel therapeutic strategy for its treatment. PMID:25870319

  12. Curcumin protects bleomycin-induced lung injury in rats.

    PubMed

    Venkatesan, N; Punithavathi, V; Chandrakasan, G

    1997-01-01

    The present study was designed to determine the protective effects of curcumin against bleomycin (BLM)-induced inflammatory and oxidant lung injury. The data indicate that BLM-mediated lung injury resulted in increases in lung lavage fluid biomarkers such as total protein, angiotensin-converting enzyme (ACE), lactate dehydrogenase (LDH), N-acetyl-beta-D-glucosaminidase (NAG), lipid peroxidation (LPO) products, superoxide dismutase (SOD) and catalase. Bleomycin administration also resulted in increased levels of malondialdehyde (MDA) in bronchoalveolar lavage fluid (BALF) and bronchoalveolar lavage (BAL) cells and greater amounts of alveolar macrophage (AM) superoxide dismutase activity. By contrast, lower levels of reduced glutathione (GSH) were observed in lung lavage fluid, BAL cells and AM. Stimulated superoxide anion and hydrogen peroxide release by AM from BLM rats were found to be higher. Curcumin treatment resulted in a significant reduction in lavage fluid biomarkers. In addition, curcumin treatment resulted in the restoration of antioxidant status in BLM rats. These data suggest that curcumin treatment reduces the development of BLM-induced inflammatory and oxidant activity. Therefore, curcumin offers the potential for a novel pharmacological approach in the suppression of drug or chemical-induced lung injury.

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

    PubMed

    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.

  14. Tranilast ameliorates cyclophosphamide-induced lung injury and nephrotoxicity.

    PubMed

    Said, Eman; Elkashef, Wagdi F; Abdelaziz, Rania R

    2016-04-01

    The world-wide increase in cancer incidence imposes a corresponding significant increase in the use of chemotherapeutic agents. Nephrotoxicity is a side effect frequently encountered with cyclophosphamide (CP), which is also well-known to cause acute and chronic lung toxicities. The current study focuses on the evaluation of the potential protective efficacy of tranilast against acute and subacute CP-induced lung and kidney injuries in male Swiss Albino mice. Intraperitoneal CP significantly impaired oxidant/anti-oxidant balance and increased inflammatory cell count in bronchoalveolar lavage fluid, serum creatinine, blood urea nitrogen (BUN), tumor necrosis factor-α (TNF-α) and lactate dehydrogenase (LDH) levels, with significant impairment of lung and kidney architectures. Tranilast taken orally for 8 and 14 days significantly enhanced mice anti-oxidant defense mechanisms; it increased lung and kidney SOD activity, GSH content and reduced lipid peroxidation. Tranilast significantly reduced serum creatinine and BUN. Furthermore, it decreased accumulation of inflammatory cells in the lungs. Serum TNF-α, LDH, total lung and kidney protein contents significantly declined as well. Histopathological examination revealed concomitant significant tissue recovery. Such results show a significant protective potential of tranilast against deleterious lung and kidney damage induced by CP, probably by enhancing host antioxidant defense mechanism, decreasing cytotoxicity, and decreasing expression of inflammatory cytokines.

  15. Ozone therapy ameliorates paraquat-induced lung injury in rats.

    PubMed

    Kaldirim, Umit; Uysal, Bulent; Yuksel, Ramazan; Macit, Enis; Eyi, Yusuf E; Toygar, Mehmet; Tuncer, Salim K; Ardic, Sukru; Arziman, Ibrahim; Aydin, Ibrahim; Oztas, Yesim; Karslioglu, Yildirim; Topal, Turgut

    2014-12-01

    Paraquat (PQ) overdose can cause acute lung injury and death. Ozone therapy (OT) was previously demonstrated to alleviate inflammation and necrosis in various pathologies. We therefore hypothesized that OT has ameliorative and preventive effects on PQ-induced lung damage due to anti-inflammatory and antioxidants properties. Sprague-Dawley rats (n = 24) were separated into three groups: sham, PQ, and PQ+OT groups. 15 mg/kg PQ was administered intraperitoneally in PQ and PQ+OT groups to induce experimental lung injury. One hour after PQ treatment, PQ+OT group was administered a single dose of ozone-oxygen mixture (1 mg/kg/day) by intraperitoneal route for four consecutive days. The animals were sacrificed on fifth day after PQ administration. Blood samples and lung tissues were collected to evaluate the inflammatory processes, antioxidant defense and pulmonary damage. Serum lactate dehydrogenase (LDH) and neopterin levels, tissue oxidative stress parameters, total TGF-β1 levels, and histological injury scores in PQ+OT group were significantly lower than PQ group (P<0.05, PQ vs. PQ+OT). Total antioxidant capacity in PQ+OT group was significantly higher than PQ group (P < 0.05, PQ+OT vs. PQ). These findings suggest that outcome in PQ-induced lung injury may be improved by using OT as an adjuvant therapy.

  16. L-arginine attenuates acute lung injury after smoke inhalation and burn injury in sheep.

    PubMed

    Murakami, Kazunori; Enkhbaatar, Perenlei; Yu, Yong-Ming; Traber, Lillian D; Cox, Robert A; Hawkins, Hal K; Tompkins, Ronald G; Herndon, David; Traber, Daniel L

    2007-10-01

    Thermal injury results in reduced plasma levels of arginine (Arg). With reduced Arg availability, NOS produces superoxide instead of NO. We hypothesized that Arg supplementation after burn and smoke inhalation (B + S) injury would attenuate the acute insult to the lungs and, thus, protect pulmonary function. Seventeen Suffolk ewes (n = 17) were randomly divided into three groups: (1) sham injury group (n = 6), (2) B + S injury plus saline treatment (n = 6), and (3) B + S injury plus L-ARG infusion at 57 mg.kg(-1).h(-1) (n = 5). Burn and smoke inhalation injury was induced by standardized procedures, including a 40% area full thickness flame burn combined with 48 breaths of smoke from burning cottons. All animals were immediately resuscitated by Ringer solution and supported by mechanical ventilation for 48 h, during which various variables of pulmonary function were monitored. The results demonstrated that Arg treatment attenuated the decline of plasma Arg concentration after B + S injury. A higher plasma Arg concentration was associated with a less decline in Pao2/Fio2 ratio and a reduced extent of airway obstruction after B + S injury. Histopathological examinations also indicated a remarkably reduced histopathological scores associated with B + S injury. Nitrotyrosine stain in lung tissue was positive after B + S injury, but was significantly reduced in the group with Arg. Therefore, L-Arg supplementation improved gas exchange and pulmonary function in ovine after B + S injury via its, at least in part, effect on reduction of oxidative stress through the peroxynitrite pathway.

  17. Prolonged Injury and Altered Lung Function after Ozone Inhalation in Mice with Chronic Lung Inflammation

    PubMed Central

    Groves, Angela M.; Gow, Andrew J.; Massa, Christopher B.; Laskin, Jeffrey D.

    2012-01-01

    Surfactant protein–D (Sftpd) is a pulmonary collectin important in down-regulating macrophage inflammatory responses. In these experiments, we analyzed the effects of chronic macrophage inflammation attributable to loss of Sftpd on the persistence of ozone-induced injury, macrophage activation, and altered functioning in the lung. Wild-type (Sftpd+/+) and Sftpd−/− mice (aged 8 wk) were exposed to air or ozone (0.8 parts per million, 3 h). Bronchoalveolar lavage (BAL) fluid and tissue were collected 72 hours later. In Sftpd−/− mice, but not Sftpd+/+ mice, increased BAL protein and nitrogen oxides were observed after ozone inhalation, indicating prolonged lung injury and oxidative stress. Increased numbers of macrophages were also present in BAL fluid and in histologic sections from Sftpd−/− mice. These cells were enlarged and foamy, suggesting that they were activated. This conclusion was supported by findings of increased BAL chemotactic activity, and increased expression of inducible nitric oxide synthase in lung macrophages. In both Sftpd+/+ and Sftpd−/− mice, inhalation of ozone was associated with functional alterations in the lung. Although these alterations were limited to central airway mechanics in Sftpd+/+ mice, both central airway and parenchymal mechanics were modified by ozone exposure in Sftpd−/− mice. The most notable changes were evident in resistance and elastance spectra and baseline lung function, and in lung responsiveness to changes in positive end-expiratory pressure. These data demonstrate that a loss of Sftpd is associated with prolonged lung injury, oxidative stress, and macrophage accumulation and activation in response to ozone, and with more extensive functional changes consistent with the loss of parenchymal integrity. PMID:22878412

  18. DEPLETION OF IRON AND ASCORBATE IN RODENTS DIMINISHES LUNG INJURY AFTER SILICA

    EPA Science Inventory

    Exposures of the lung to iron chelates can be associated with an injury. The catalysis of oxygen-based free radicals is postulated to participate in this injury. Such oxidant generation by mineral oxide particles can be dependent on availability of both iron and a reductant. We t...

  19. DEPLETION OF IRON AND ASCORBATE IN RODENTS DIMINISHES LUNG INJURY AFTER SILICA

    EPA Science Inventory

    Exposures of the lung to iron chelates can be associated with an injury. The catalysis of oxygen-based free radicals is postulated to participate in this injury. Such oxidant generation by mineral oxide particles can be dependent on availability of both iron and a reductant. We t...

  20. Transfusion-related acute lung injury.

    PubMed

    Jawa, Randeep S; Anillo, Sergio; Kulaylat, Mahmoud N

    2008-01-01

    Transfusion-related acute lung injury (TRALI) refers to a clinical syndrome of acute lung injury that occurs in a temporal relationship with the transfusion of blood products. Because of the difficulty in making its diagnosis, TRALI is often underreported. Three not necessarily mutually exclusive hypotheses have been described to explain its etiogenesis: antibody mediated, non-antibody mediated, and two hit mechanisms. Treatment is primarily supportive and includes supplemental oxygen. Diuretics are generally not indicated, as hypovolemia should be avoided. Compared with many other forms of acute lung injury, including the acute respiratory distress syndrome, TRALI is generally transient, reverses spontaneously, and carries a better prognosis. A variety of prevention strategies have been proposed, ranging from restrictive transfusion strategies to using plasma derived only from males.

  1. Senegenin Ameliorate Acute Lung Injury Through Reduction of Oxidative Stress and Inhibition of Inflammation in Cecal Ligation and Puncture-Induced Sepsis Rats.

    PubMed

    Liu, Chun-Hong; Zhang, Wei-Dong; Wang, Jian-Jie; Feng, Shan-Dan

    2016-04-01

    The purpose of this study was to assess the protective effect of senegenin on acute lung injury (ALI) in rats induced by sepsis. Rat ALI model was reproduced by cecal ligation and puncture (CLP). All rats were randomly divided into five groups: group 1 (control), group 2 (CLP), group 3 (CLP + senegenin 15 mg/kg), group 4 (CLP + senegenin 30 mg/kg), and group 5 (CLP + senegenin 60 mg/kg). CLP + senegenin groups received senegenin by gavage daily for consecutive 5 days, respectively, while the mice in control and CLP 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 lung tissue myeloperoxidase (MPO), malondialdehyde (MDA), superoxide dismutase (SOD), and glutathione (GSH) were determined. Meanwhile, the nuclear factor-kappa B (NF-κB) activation, tumor necrosis factor-alpha (TNF-α), and interleukin-1β (IL-1β) levels were studied. The results demonstrated that senegenin treatment significantly attenuated CLP-induced lung injury, including reduction of lung wet/dry weight ratio, protein leak, infiltration of leukocytes, and MPO activity. In addition, senegenin markedly decreased MDA content and increased SOD activity and GSH level. Serum levels of TNF-α and IL-1β were also decreased by senegenin administration. Furthermore, senegenin administration inhibited the nuclear translocation of NF-κB in the lungs. These findings indicate that senegenin exerts protective effects on CLP-induced septic rats. Senegenin may be a potential therapeutic agent against sepsis.

  2. Sex-specific differences in hyperoxic lung injury in mice: Implications for acute and chronic lung disease in humans

    SciTech Connect

    Lingappan, Krithika; Jiang, Weiwu; Wang, Lihua; Couroucli, Xanthi I.; Barrios, Roberto; Moorthy, Bhagavatula

    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.

  3. Acute lung injury after thoracic surgery.

    PubMed

    Eichenbaum, Kenneth D; Neustein, Steven M

    2010-08-01

    In this review, the authors discussed criteria for diagnosing ALI; incidence, etiology, preoperative risk factors, intraoperative management, risk-reduction strategies, treatment, and prognosis. The anesthesiologist needs to maintain an index of suspicion for ALI in the perioperative period of thoracic surgery, particularly after lung resection on the right side. Acute hypoxemia, imaging analysis for diffuse infiltrates, and detecting a noncardiogenic origin for pulmonary edema are important hallmarks of acute lung injury. Conservative intraoperative fluid administration of neutral to slightly negative fluid balance over the postoperative first week can reduce the number of ventilator days. Fluid management may be optimized with the assistance of new imaging techniques, and the anesthesiologist should monitor for transfusion-related lung injuries. Small tidal volumes of 6 mL/kg and low plateau pressures of < or =30 cmH2O may reduce organ and systemic failure. PEEP may improve oxygenation and increases organ failure-free days but has not shown a mortality benefit. The optimal mode of ventilation has not been shown in perioperative studies. Permissive hypercapnia may be needed in order to reduce lung injury from positive-pressure ventilation. NO is not recommended as a treatment. Strategies such as bronchodilation, smoking cessation, steroids, and recruitment maneuvers are unproven to benefit mortality although symptomatically they often have been shown to help ALI patients. Further studies to isolate biomarkers active in the acute setting of lung injury and pharmacologic agents to inhibit inflammatory intermediates may help improve management of this complex disease.

  4. Endothelin antagonists: new bullets against lung injury?

    PubMed

    Leeman, Marc

    2005-06-01

    Acute lung injury is a syndrome of inflammation and of increased permeability of the blood-gas barrier. Endothelins are thought to exert proinflammatory effects. Kuklin and colleagues show that the endothelin receptor antagonist tezosentan reduces pulmonary edema in endotoxemic sheep, in parallel with a prevention of protein kinase C-alpha activation. In turn, the level of some cytokines increased after tezosentan treatment. Whether these contrasting effects of endothelin blockade on inflammatory mechanisms have clinical relevance and whether these agents might benefit patients with acute lung injury is unknown.

  5. Biomarkers of Lung Injury in Cardiothoracic Surgery

    PubMed Central

    Engels, Gerwin Erik; van Oeveren, Willem

    2015-01-01

    Diagnosis of pulmonary dysfunction is currently almost entirely based on a vast series of physiological changes, but comprehensive research is focused on determining biomarkers for early diagnosis of pulmonary dysfunction. Here we discuss the use of biomarkers of lung injury in cardiothoracic surgery and their ability to detect subtle pulmonary dysfunction in the perioperative period. Degranulation products of neutrophils are often used as biomarker since they have detrimental effects on the pulmonary tissue by themselves. However, these substances are not lung specific. Lung epithelium specific proteins offer more specificity and slowly find their way into clinical studies. PMID:25866435

  6. Quantitation of nitrotyrosine levels in lung sections of patients and animals with acute lung injury.

    PubMed Central

    Haddad, I Y; Pataki, G; Hu, P; Galliani, C; Beckman, J S; Matalon, S

    1994-01-01

    Activated alveolar macrophages and epithelial type II cells release both nitric oxide and superoxide which react at near diffusion-limited rate (6.7 x 10(9) M-1s-1) to form peroxynitrite, a potent oxidant capable of damaging the alveolar epithelium and pulmonary surfactant. Peroxynitrite, but not nitric oxide or superoxide, readily nitrates phenolic rings including tyrosine. We quantified the presence of nitrotyrosine in the lungs of patients with the adult respiratory distress syndrome (ARDS) and in the lungs of rats exposed to hyperoxia (100% O2 for 60 h) using quantitative immunofluorescence. Fresh frozen or paraffin-embedded lung sections were incubated with a polyclonal antibody to nitrotyrosine, followed by goat anti-rabbit IgG coupled to rhodamine. Sections from patients with ARDS (n = 5), or from rats exposed to hyperoxia (n = 4), exhibited a twofold increase of specific binding over controls. This binding was blocked by the addition of an excess amount of nitrotyrosine and was absent when the nitrotyrosine antibody was replaced with nonimmune IgG. In additional experiments we demonstrated nitrotyrosine formation in rat lung sections incubated in vitro with peroxynitrite, but not nitric oxide or reactive oxygen species. These data suggest that toxic levels of peroxynitrite may be formed in the lungs of patients with acute lung injury. Images PMID:7989597

  7. Effects of High-Intensity Swimming on Lung Inflammation and Oxidative Stress in a Murine Model of DEP-Induced Injury.

    PubMed

    Ávila, Leonardo C M; Bruggemann, Thayse R; Bobinski, Franciane; da Silva, Morgana Duarte; Oliveira, Regiane Carvalho; Martins, Daniel Fernandes; Mazzardo-Martins, Leidiane; Duarte, Marta Maria Medeiros Frescura; de Souza, Luiz Felipe; Dafre, Alcir; Vieira, Rodolfo de Paula; Santos, Adair Roberto Soares; Bonorino, Kelly Cattelan; Hizume Kunzler, Deborah de C

    2015-01-01

    Studies have reported that exposure to diesel exhaust particles (DEPs) induces lung inflammation and increases oxidative stress, and both effects are susceptible to changes via regular aerobic exercise in rehabilitation programs. However, the effects of exercise on lungs exposed to DEP after the cessation of exercise are not clear. Therefore, the aim of this study was to evaluate the effects of high-intensity swimming on lung inflammation and oxidative stress in mice exposed to DEP concomitantly and after exercise cessation. Male Swiss mice were divided into 4 groups: Control (n = 12), Swimming (30 min/day) (n = 8), DEP (3 mg/mL-10 μL/mouse) (n = 9) and DEP+Swimming (n = 8). The high-intensity swimming was characterized by an increase in blood lactate levels greater than 1 mmoL/L between 10th and 30th minutes of exercise. Twenty-four hours after the final exposure to DEP, the anesthetized mice were euthanized, and we counted the number of total and differential inflammatory cells in the bronchoalveolar fluid (BALF), measured the lung homogenate levels of IL-1β, TNF-α, IL-6, INF-ϫ, IL-10, and IL-1ra using ELISA, and measured the levels of glutathione, non-protein thiols (GSH-t and NPSH) and the antioxidant enzymes catalase and glutathione peroxidase (GPx) in the lung. Swimming sessions decreased the number of total cells (p<0.001), neutrophils and lymphocytes (p<0.001; p<0.05) in the BALF, as well as lung levels of IL-1β (p = 0.002), TNF-α (p = 0.003), IL-6 (p = 0.0001) and IFN-ϫ (p = 0.0001). However, the levels of IL-10 (p = 0.01) and IL-1ra (p = 0.0002) increased in the swimming groups compared with the control groups, as did the CAT lung levels (p = 0.0001). Simultaneously, swimming resulted in an increase in the GSH-t and NPSH lung levels in the DEP group (p = 0.0001 and p<0.002). We concluded that in this experimental model, the high-intensity swimming sessions decreased the lung inflammation and oxidative stress status during DEP-induced lung

  8. Effects of High-Intensity Swimming on Lung Inflammation and Oxidative Stress in a Murine Model of DEP-Induced Injury

    PubMed Central

    Ávila, Leonardo C. M.; Bruggemann, Thayse R.; Bobinski, Franciane; da Silva, Morgana Duarte; Oliveira, Regiane Carvalho; Martins, Daniel Fernandes; Mazzardo-Martins, Leidiane; Duarte, Marta Maria Medeiros Frescura; de Souza, Luiz Felipe; Dafre, Alcir; Vieira, Rodolfo de Paula; Santos, Adair Roberto Soares; Bonorino, Kelly Cattelan; Hizume Kunzler, Deborah de C.

    2015-01-01

    Studies have reported that exposure to diesel exhaust particles (DEPs) induces lung inflammation and increases oxidative stress, and both effects are susceptible to changes via regular aerobic exercise in rehabilitation programs. However, the effects of exercise on lungs exposed to DEP after the cessation of exercise are not clear. Therefore, the aim of this study was to evaluate the effects of high-intensity swimming on lung inflammation and oxidative stress in mice exposed to DEP concomitantly and after exercise cessation. Male Swiss mice were divided into 4 groups: Control (n = 12), Swimming (30 min/day) (n = 8), DEP (3 mg/mL—10 μL/mouse) (n = 9) and DEP+Swimming (n = 8). The high-intensity swimming was characterized by an increase in blood lactate levels greater than 1 mmoL/L between 10th and 30th minutes of exercise. Twenty-four hours after the final exposure to DEP, the anesthetized mice were euthanized, and we counted the number of total and differential inflammatory cells in the bronchoalveolar fluid (BALF), measured the lung homogenate levels of IL-1β, TNF-α, IL-6, INF-ϫ, IL-10, and IL-1ra using ELISA, and measured the levels of glutathione, non-protein thiols (GSH-t and NPSH) and the antioxidant enzymes catalase and glutathione peroxidase (GPx) in the lung. Swimming sessions decreased the number of total cells (p<0.001), neutrophils and lymphocytes (p<0.001; p<0.05) in the BALF, as well as lung levels of IL-1β (p = 0.002), TNF-α (p = 0.003), IL-6 (p = 0.0001) and IFN-ϫ (p = 0.0001). However, the levels of IL-10 (p = 0.01) and IL-1ra (p = 0.0002) increased in the swimming groups compared with the control groups, as did the CAT lung levels (p = 0.0001). Simultaneously, swimming resulted in an increase in the GSH-t and NPSH lung levels in the DEP group (p = 0.0001 and p<0.002). We concluded that in this experimental model, the high-intensity swimming sessions decreased the lung inflammation and oxidative stress status during DEP-induced lung

  9. Interactions between PBEF and oxidative stress proteins-a potential new mechanism underlying PBEF in the pathogenesis of acute lung injury

    PubMed Central

    Zhang, Li Qin; Adyshev, Djanybek M.; Singleton, Patrick; Li, Hailong; Cepeda, Javier; Huang, Sheng-You; Zou, Xiaoqin; Verin, Alexander D.; Tu, Jiancheng; Garcia, Joe G.N.; Ye, Shui Qing

    2008-01-01

    Identification of pre-B-cell colony-enhancing factor (PBEF) interacting partners may reveal new molecular mechanisms of PBEF in the pathogenesis of acute lung injury (ALI). The interactions between PBEF and NADH dehydrogenase subunit 1(ND1), ferritin light chain and interferon induced transmembrane 3 (IFITM3) in human pulmonary vascular endothelial cells were identified and validated. ND1, ferritin and IFITM3 are involved in oxidative stress and inflammation. Overexpression of PBEF increased its interactions and intracellular oxidative stress, which can be attenuated by rotenone. The interaction modeling between PBEF and ND1 is consistent with the corresponding experimental finding. These interactions may underlie a novel role of PBEF in the pathogenesis of ALI. Structured summary MINT-6538697: PBEF (uniprotkb:P43490) physically interacts (MI:0218) with NADH1 (uniprotkb:P03886) by two hybrid (MI:0018) MINT-6538811, MINT-6538868: PBEF (uniprotkb:P43490) physically interacts (MI:0218) with interferon-induced transmembra (uniprotkb:Q01628) by anti bait coimmunoprecipitation (MI:0006) MINT-6538787, MINT-6538841: PBEF (uniprotkb:P43490) physically interacts (MI:0218) with NADH1 (uniprotkb:P03886) by anti bait coimmunoprecipitation (MI:0006) MINT-6538755: PBEF (uniprotkb:P43490) physically interacts (MI:0218) with gamma-glutamil-transferase (uniprotkb:P19440) by two hybrid (MI:0018) MINT-6538799, MINT-6538862: PBEF (uniprotkb:P43490) physically interacts (MI:0218) with Ferritin light chain (uniprotkb:P02792) by anti bait coimmunoprecipitation (MI:0006) MINT-6538769: PBEF (uniprotkb:P43490) physically interacts (MI:0218) with E2L6 (uniprotkb:O14933) by two hybrid (MI:0018) MINT-6538741: PBEF (uniprotkb:P43490) physically interacts (MI:0218) with Adenosine A2aR (uniprotkb:P29274) by two hybrid (MI:0018) MINT-6538727: PBEF (uniprotkb:P43490) physically interacts (MI:0218) with interferon-induced transmembra (uniprotkb:Q01628) by two hybrid (MI:0018) MINT-6538712: PBEF

  10. Smoke Inhalation Lung Injury: An Update

    PubMed Central

    Demling, Robert H.

    2008-01-01

    Objectives: The purpose of this study is to present a multifaceted, definitive review of the past and current status of smoke inhalation injury. History along with current understanding of anatomical, physiology, and biologic components will be discussed. Methods: The literature has been reviewed from the early onset of the concept of smoke inhalation in the 1920s to our current understanding as of 2007. Results: The results indicate that the current pathophysiologic concept is of a disease process that leads to immediate and delayed pulmonary injury best managed by aggressive physiologic support. Management approaches for the biochemical changes have not kept up with current knowledge. The lung injury process is activated by toxins in the smoke's gas and particle components and perpetuated by a resulting lung inflammation. This inflammatory process becomes self-perpetuating through the activation of a large number of inflammatory cascades. In addition, smoke injury leads to significant systemic abnormalities injuring other organs and accentuating the burn injury process and subsequently leading to mediator-induced cellular injury leading potentially to multisystem organ failure. Conclusions: Smoke inhalation injury results in the anatomic finding of denuded and sometimes sloughed airways mucosa. Physiologic findings include small airways containing fibrin casts of mucosa and neutrophils. Airway hyper-reactivity results as well, leading to further decreased collapse, causing obstruction. PMID:18552974

  11. Induction of cellular antioxidant defense by amifostine improves ventilator-induced lung injury.

    PubMed

    Fu, Panfeng; Murley, Jeffrey S; Grdina, David J; Birukova, Anna A; Birukov, Konstantin G

    2011-12-01

    To test the hypothesis that preconditioning animals with amifostine improves ventilator-induced lung injury via induction of antioxidant defense enzymes. Mechanical ventilation at high tidal volume induces reactive oxygen species production and oxidative stress in the lung, which plays a major role in the pathogenesis of ventilator-induced lung injury. Amifostine attenuates oxidative stress and improves lipopolysaccharide-induced lung injury by acting as a direct scavenger of reactive oxygen and nitrogen species. This study tested effects of chronic amifostine administration on parameters of oxidative stress, lung barrier function, and inflammation associated with ventilator-induced lung injury. Randomized and controlled laboratory investigation in mice and cell culture. University laboratory. C57BL/6J mice. Mice received once-daily dosing with amifostine (10-100 mg/kg, intraperitoneal injection) 3 days consecutively before high tidal volume ventilation (30 mL/kg, 4 hrs) at day 4. Pulmonary endothelial cell cultures were exposed to pathologic cyclic stretching (18% equibiaxial stretch) and thrombin in a previously verified two-hit model of in vitro ventilator-induced lung injury. Three-day amifostine preconditioning before high tidal volume attenuated high tidal volume-induced protein and cell accumulation in the alveolar space judged by bronchoalveolar lavage fluid analysis, decreased Evans Blue dye extravasation into the lung parenchyma, decreased biochemical parameters of high tidal volume-induced tissue oxidative stress, and inhibited high tidal volume-induced activation of redox-sensitive stress kinases and nuclear factor-kappa B inflammatory cascade. These protective effects of amifostine were associated with increased superoxide dismutase 2 expression and increased superoxide dismutase and catalase enzymatic activities in the animal and endothelial cell culture models of ventilator-induced lung injury. Amifostine preconditioning activates lung tissue

  12. Neurological outcome after experimental lung injury.

    PubMed

    Bickenbach, Johannes; Biener, Ingeborg; Czaplik, Michael; Nolte, Kay; Dembinski, Rolf; Marx, Gernot; Rossaint, Rolf; Fries, Michael

    2011-12-15

    We examined the influences of acute lung injury and hypoxia on neurological outcome. Functional performance was assessed using a neurocognitive test and a neurologic deficit score (NDS) five days before. On experimental day, mechanically ventilated pigs were randomized to hypoxia only (HO group, n=5) or to acute lung injury (ALI group, n=5). Hemodynamics, respiratory mechanics, systemic cytokines and further physiologic variables were obtained at baseline, at the time of ALI, 2, 4 and 8h thereafter. Subsequently, injured lungs were recruited and animals weaned from the ventilator. Neurocognitive testing was re-examined for five days. Then, brains were harvested for neurohistopathology. After the experiment, neurocognitive performance was significantly worsened and the NDS increased in the ALI group. Histopathology revealed no significant differences. Oxygenation was comparable between groups although significantly higher inspiratory pressures occured after ALI. Cytokines showed a trend towards higher levels after ALI. Neurocognitive compromise after ALI seems due to a more pronounced inflammatory response and complex mechanical ventilation.

  13. Surfactant for Pediatric Acute Lung Injury

    PubMed Central

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

    2008-01-01

    Synopsis 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 on reviewing clinical studies of surfactant therapy in pediatric and adult patients with 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, including the multifaceted pathology of inflammatory lung injury, the effectiveness of surfactant delivery in injured lungs, and composition-based activity differences among clinical exogenous surfactant preparations. PMID:18501754

  14. Immersing lungs in hydrogen-rich saline attenuates lung ischaemia-reperfusion injury.

    PubMed

    Takahashi, Mamoru; Chen-Yoshikawa, Toyofumi F; Saito, Masao; Tanaka, Satona; Miyamoto, Ei; Ohata, Keiji; Kondo, Takeshi; Motoyama, Hideki; Hijiya, Kyoko; Aoyama, Akihiro; Date, Hiroshi

    2017-03-01

    Anti-oxidant effects of hydrogen have been reported in studies examining ischaemia-reperfusion injury (IRI). In this study, we evaluated the therapeutic efficacy of immersing lungs in hydrogen-rich saline on lung IRI. Lewis rats were divided into three groups: (i) sham, (ii) normal saline and (iii) hydrogen-rich saline. In the first experiment, the left thoracic cavity was filled with either normal saline or hydrogen-rich saline for 1 h. Then, we measured the hydrogen concentration in the left lung using a sensor gas chromatograph ( N = 3 per group). In the second experiment, lung IRI was induced by occlusion of the left pulmonary hilum for 1 h, followed by reperfusion for 3 h. During the ischaemic period, the left thoracic cavity was filled with either normal saline or hydrogen-rich saline. After reperfusion, we assessed lung function, histological changes and cytokine production ( N = 5-7 per group). Immersing lungs in hydrogen-rich saline resulted in an elevated hydrogen concentration in the lung (6.9 ± 2.9 μmol/1 g lung). After IRI, pulmonary function (pulmonary compliance and oxygenation levels) was significantly higher in the hydrogen-rich saline group than in the normal saline group ( P  < 0.05). Similarly, pro-inflammatory cytokine levels (interleukin-1β and interleukin-6) in the left lung were significantly lower in the hydrogen-rich saline group than in the normal saline group ( P  < 0.05). Immersing lungs in hydrogen-rich saline delivered hydrogen into the lung and consequently attenuated lung IRI. Hydrogen-rich solution appears to be a promising approach to managing lung IRI.

  15. Thioredoxin-Related Mechanisms in Hyperoxic Lung Injury in Mice

    PubMed Central

    Tipple, Trent E.; Welty, Stephen E.; Rogers, Lynette K.; Hansen, Thomas N.; Choi, Young-Eun; Kehrer, James P.; Smith, Charles V.

    2007-01-01

    Reduction of glutathione disulfide (GSSG) to glutathione (GSH) by glutathione reductase (GR) enhances the efficiency of GSH-dependent antioxidant activities. However, GR-deficient (a1Neu) mice are less susceptible to acute lung injury from continuous exposure to > 95% O2 (96 h: 6.9 ± 0.1 g right lung/kg body versus room air 3.6 ± 0.3) than are C3H/HeN control mice (10.6 ± 1.3 versus 4.2 ± 0.3, P < 0.001). a1Neu mice have greater hepatic thioredoxin (Trx)1 and Trx2 levels than do C3H/HeN mice, suggesting compensation for the absence of GR. a1Neu mice exposed to hyperoxia for 96 hours showed lower levels of inflammatory infiltrates in lungs than did similarly exposed C3H/HeN mice. Pretreatment with aurothioglucose (ATG), a thioredoxin reductase (TrxR) inhibitor, exacerbated the effects of hyperoxia on lung injury in a1Neu mice (11.6 ± 0.8, P < 0.001), but attenuated hyperoxic lung edema and inflammation in C3H/HeN mice (6.3 ± 0.4, P < 0.001). No consistent alterations were observed in lung GSH contents or liver GSH or GSSG levels after ATG pretreatment. The data suggest that modulation of Trx/TrxR systems might provide therapeutically useful alterations of cellular resistance to oxidant stresses. The protective effects of ATG against hyperoxic lung injury could prove to be particularly useful therapeutically. PMID:17575077

  16. Lung inflation with hydrogen during the cold ischemia phase decreases lung graft injury in rats.

    PubMed

    Liu, Rongfang; Fang, Xianhai; Meng, Chao; Xing, Jingchun; Liu, Jinfeng; Yang, Wanchao; Li, Wenzhi; Zhou, Huacheng

    2015-09-01

    Hydrogen has antioxidant and anti-inflammatory effects on lung ischemia-reperfusion injury when it is inhaled by donor or/and recipient. This study examined the effects of lung inflation with 3% hydrogen during the cold ischemia phase on lung graft function in rats. The donor lung was inflated with 3% hydrogen, 40% oxygen, and 57% nitrogen at 5 mL/kg, and the gas was replaced every 20 min during the cold ischemia phase for 2 h. In the control group, the donor lung was inflated with 40% oxygen and 60% nitrogen at 5 mL/kg. The recipient was euthanized 2 h after orthotropic lung transplantation. The hydrogen concentration in the donor lung during the cold ischemia phase was 1.99-3%. The oxygenation indices in the arterial blood and pulmonary vein blood were improved in the hydrogen group. The inflammation response indices, including lung W/D ratio, the myeloperoxidase activity in the grafts, and the levels of IL-8 and TNF-α in serum, were significantly lower in the hydrogen group (5.2 ± 0.8, 0.76 ± 0.32 U/g, 340 ± 84 pg/mL, and 405 ± 115 pg/mL, respectively) than those in the control group (6.5 ± 0.7, 1.1 ± 0.5 U/g, 443 ± 94 pg/mL, and 657 ± 96 pg/mL, respectively (P < 0.05), and the oxidative stress indices, including the superoxide dismutase activity and the level of malonaldehyde in lung grafts were improved after hydrogen application. Furthermore, the lung injury score determined by histopathology, the cell apoptotic index, and the caspase-3 protein expression in lung grafts were decreased after hydrogen treatment, and the static pressure-volume curve of lung graft was improved by hydrogen inflation. In conclusion, lung inflation with 3% hydrogen during the cold ischemia phase alleviated lung graft injury and improved graft function.

  17. Lung inflation with hydrogen during the cold ischemia phase decreases lung graft injury in rats

    PubMed Central

    Liu, Rongfang; Fang, Xianhai; Meng, Chao; Xing, Jingchun; Liu, Jinfeng; Yang, Wanchao

    2015-01-01

    Hydrogen has antioxidant and anti-inflammatory effects on lung ischemia–reperfusion injury when it is inhaled by donor or/and recipient. This study examined the effects of lung inflation with 3% hydrogen during the cold ischemia phase on lung graft function in rats. The donor lung was inflated with 3% hydrogen, 40% oxygen, and 57% nitrogen at 5 mL/kg, and the gas was replaced every 20 min during the cold ischemia phase for 2 h. In the control group, the donor lung was inflated with 40% oxygen and 60% nitrogen at 5 mL/kg. The recipient was euthanized 2 h after orthotropic lung transplantation. The hydrogen concentration in the donor lung during the cold ischemia phase was 1.99–3%. The oxygenation indices in the arterial blood and pulmonary vein blood were improved in the hydrogen group. The inflammation response indices, including lung W/D ratio, the myeloperoxidase activity in the grafts, and the levels of IL-8 and TNF-α in serum, were significantly lower in the hydrogen group (5.2 ± 0.8, 0.76 ± 0.32 U/g, 340 ± 84 pg/mL, and 405 ± 115 pg/mL, respectively) than those in the control group (6.5 ± 0.7, 1.1 ± 0.5 U/g, 443 ± 94 pg/mL, and 657 ± 96 pg/mL, respectively (P < 0.05), and the oxidative stress indices, including the superoxide dismutase activity and the level of malonaldehyde in lung grafts were improved after hydrogen application. Furthermore, the lung injury score determined by histopathology, the cell apoptotic index, and the caspase-3 protein expression in lung grafts were decreased after hydrogen treatment, and the static pressure–volume curve of lung graft was improved by hydrogen inflation. In conclusion, lung inflation with 3% hydrogen during the cold ischemia phase alleviated lung graft injury and improved graft function. PMID:25662956

  18. Sex-specific Differences in Hyperoxic Lung Injury in Mice: Implications for Acute and Chronic Lung Disease in Humans

    PubMed Central

    Lingappan, Krithika; Jiang, Weiwu; Wang, Lihua; Couroucli, Xanthi I.; Barrios, Roberto; Moorthy, Bhagavatula

    2014-01-01

    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 (FiO2>0.95). After exposure to hyperoxia, lung injury, levels of 8-iso-prostaglandin F2 alpha (8-iso-PGF 2α) (LC-MS/MS), apoptosis (TUNEL) and inflammatory markers (suspension bead array) were determined. CytochromeP450 (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. PMID:23792423

  19. Role of Nrf2 and Autophagy in Acute Lung Injury

    PubMed Central

    de la Vega, Montserrat Rojo; Dodson, Matthew; Gross, Christine; Manzour, Heidi; Lantz, R. Clark; Chapman, Eli; Wang, Ting; Black, Stephen M.; Garcia, Joe G.N.; Zhang, Donna D.

    2016-01-01

    Acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) are the clinical manifestations of severe lung damage and respiratory failure. Characterized by severe inflammation and compromised lung function, ALI/ARDS result in very high mortality of affected individuals. Currently, there are no effective treatments for ALI/ARDS, and ironically, therapies intended to aid patients (specifically mechanical ventilation, MV) may aggravate the symptoms. Key events contributing to the development of ALI/ARDS are: increased oxidative and proteotoxic stresses, unresolved inflammation, and compromised alveolar-capillary barrier function. Since the airways and lung tissues are constantly exposed to gaseous oxygen and airborne toxicants, the bronchial and alveolar epithelial cells are under higher oxidative stress than other tissues. Cellular protection against oxidative stress and xenobiotics is mainly conferred by Nrf2, a transcription factor that promotes the expression of genes that regulate oxidative stress, xenobiotic metabolism and excretion, inflammation, apoptosis, autophagy, and cellular bioenergetics. Numerous studies have demonstrated the importance of Nrf2 activation in the protection against ALI/ARDS, as pharmacological activation of Nrf2 prevents the occurrence or mitigates the severity of ALI/ARDS. Another promising new therapeutic strategy in the prevention and treatment of ALI/ARDS is the activation of autophagy, a bulk protein and organelle degradation pathway. In this review, we will discuss the strategy of concerted activation of Nrf2 and autophagy as a preventive and therapeutic intervention to ameliorate ALI/ARDS. PMID:27313980

  20. The Lung Alveolar Lipofibroblast: An Evolutionary Strategy Against Neonatal Hyperoxic Lung Injury

    PubMed Central

    Torday, John S.

    2014-01-01

    Abstract Significance: Oxygen, the main mode of support for premature infants with immature lungs, can cause toxicity by producing reactive oxygen species (ROS) that disrupt homeostasis; yet, these same molecules were entrained to promote vertebrate lung phylogeny. By providing a deeper understanding of this paradox, we propose physiologically rational strategies to prevent chronic lung disease (CLD) of prematurity. Recent Advances: To prevent neonatal hyperoxic lung damage biologically, we have exploited the alveolar defense mechanism(s) that evolutionarily evolved to combat increased atmospheric oxygen during the vertebrate water to land transition. Critical Issues: Over the course of vertebrate lung evolution, ROS promoted the formation of lipofibroblasts, specialized adepithelial cells, which protect the alveoli against oxidant injury; peroxisome proliferator-activated receptor gamma (PPARγ), the master switch for lipofibroblast differentiation, prevents such oxidant lung injury, both by directly promoting mesodermal differentiation and its antioxidant defenses, and indirectly by stimulating the developmental epithelial–mesenchymal paracrine interactions that have physiologically determined lung surfactant production in accord with the lung's phylogenetic adaptation to atmospheric oxygen, preventing Respiratory Distress Syndrome at birth. Future Directions: The molecular strategy (PPARγ agonists) to prevent CLD of prematurity, proposed by us, although seems to be robust, effective, and safe under experimental conditions, it awaits detailed pharmacokinetic and pharmacodynamic studies for its safe and effective clinical translation to human infants. Antioxid. Redox Signal. 21, 1893–1904. “I have procured air [oxygen]…between five and six times as good as the best common air that I have ever met with.” —Joseph Priestley, 1775 PMID:24386954

  1. Deficiency in the divalent metal transporter 1 augments bleomycin-induced lung injury

    EPA Science Inventory

    Exposure to bleomycin can result in an inflammatory lung injury. The biological effect of this anti-neoplastic agent is dependent on its coordination of iron with subsequent oxidant generation. In lung cells, divalent metal transporter 1 (DMT1) can participate in metal transport ...

  2. Deficiency in the divalent metal transporter 1 augments bleomycin-induced lung injury

    EPA Science Inventory

    Exposure to bleomycin can result in an inflammatory lung injury. The biological effect of this anti-neoplastic agent is dependent on its coordination of iron with subsequent oxidant generation. In lung cells, divalent metal transporter 1 (DMT1) can participate in metal transport ...

  3. Ellagic acid ameliorates lung injury after intestinal ischemia-reperfusion

    PubMed Central

    Böyük, Abdullah; Önder, Akin; Kapan, Murat; Gümüş, Metehan; Fιrat, Uğur; Başaralι, Mustafa Kemal; Alp, Harun

    2011-01-01

    Background: The aim of this study was to investigate the possible protective role of antioxidant treatment with ellagic acid (EA) on lung injury after intestinal ischemia-reperfusion (I/R) injury using biochemical and histopatological approaches. Materials and Methods: Forty rats were divided into four groups as control, control + EA, I/R, and I/R + EA. The control and control + EA groups were also anesthetized and subjected to laparotomy, but without clamp application. The control + EA and I/R + EA groups were given EA (85 mg/kg) orally prior to experiment. The I/R and I/R + EA groups underwent 30 minutes of intestinal ischemia and 1 hour of reperfusion. In all groups, serum total antioxidant capacity (TAC) and malondialdehyde (MDA) levels were determined. TAC, total oxidative status (TOS), and oxidative stress index (OSI) in lung tissue were measured. Lung tissue histopathology was also evaluated by light microscopy. Results: TAC levels were higher in control, EA, and I/R + EA groups while TOS, OSI, and MDA levels were lower in these groups compared with I/R group. Serum MDA levels were significantly higher in I/R + EA group than that of control group. Lung tissue TAC levels were lower in I/R + EA group while OSI values were higher in that groups compared with EA group. Histological tissue damage was milder in the EA treatment group than in the I/R group. Conclusion: These results suggest that EA treatment protected the rats lung tissue against intestinal I/R injury. PMID:21969793

  4. Atelectasis causes alveolar injury in nonatelectatic lung regions.

    PubMed

    Tsuchida, Shinya; Engelberts, Doreen; Peltekova, Vanya; Hopkins, Natalie; Frndova, Helena; Babyn, Paul; McKerlie, Colin; Post, Martin; McLoughlin, Paul; Kavanagh, Brian P

    2006-08-01

    Many authors have suggested that the mechanism by which atelectasis contributes to injury is through the repetitive opening and closing of distal airways in lung regions that are atelectatic. However, neither the topographic nor mechanistic relationships between atelectasis and distribution of lung injury are known. To investigate how atelectasis contributes to ventilator-induced lung injury. Surfactant depletion was performed in anesthetized rats that were then allocated to noninjurious or injurious ventilation for 90 min. Lung injury was quantified by gas exchange, compliance, histology, wet-to-dry weight, and cytokine expression, and its distribution by histology, stereology, cytokine mRNA expression, in situ hybridization, and immunohistochemistry. Functional residual capacity, percent atelectasis, and injury-induced lung water accumulation were measured using gravimetric and volumetric techniques. Atelectasis occurred in the dependent lung regions. Injurious ventilation was associated with alveolar and distal airway injury, while noninjurious ventilation was not. With injurious ventilation, alveolar injury (i.e., histology, myeloperoxidase protein expression, quantification, and localization of cytokine mRNA expression) was maximal in nondependent regions, whereas distal airway injury was equivalent in atelectatic and nonatelectatic regions. These data support the notion that lung injury associated with atelectasis involves trauma to the distal airways. We provide topographic and biochemical evidence that such distal airway injury is not localized solely to atelectatic areas, but is instead generalized in both atelectatic and nonatelectatic lung regions. In contrast, alveolar injury associated with atelectasis does not occur in those areas that are atelectatic but occurs instead in remote nonatelectatic alveoli.

  5. Glutathione reductase targeted to type II cells does not protect mice from hyperoxic lung injury.

    PubMed

    Heyob, Kathryn M; Rogers, Lynette K; Welty, Stephen E

    2008-12-01

    Exposure of the lung epithelium to reactive oxygen species without adequate antioxidant defenses leads to airway inflammation, and may contribute to lung injury. Glutathione peroxidase catalyzes the reduction of peroxides by oxidation of glutathione (GSH) to glutathione disulfide (GSSG), which can in turn be reduced by glutathione reductase (GR). Increased levels of GSSG have been shown to correlate negatively with outcome after oxidant exposure, and increased GR activity has been protective against hyperoxia in lung epithelial cells in vitro. We tested the hypothesis that increased GR expression targeted to type II alveolar epithelial cells would improve outcome in hyperoxia-induced lung injury. Human GR with a mitochondrial targeting sequence was targeted to mouse type II cells using the SPC promoter. Two transgenic lines were identified, with Line 2 having higher lung GR activities than Line 1. Both transgenic lines had lower lung GSSG levels and higher GSH/GSSG ratios than wild-type. Six-week-old wild-type and transgenic mice were exposed to greater than 95% O2 or room air (RA) for 84 hours. After exposure, Line 2 mice had higher right lung/body weight ratios and lavage protein concentrations than wild-type mice, and both lines 1 and 2 had lower GSSG levels than wild-type mice. These findings suggest that GSSG accumulation in the lung may not play a significant role in the development of hyperoxic lung injury, or that compensatory responses to unregulated GR expression render animals more susceptible to hyperoxic lung injury.

  6. The serpentine path to a novel mechanism-based inhibitor of acute inflammatory lung injury

    PubMed Central

    2014-01-01

    The Comroe lecture on which this review is based described my research path during the past 45 years, beginning with studies of oxidant stress (hyperoxia) and eventuating in the discovery of a synthetic inhibitor of phospholipase A2 activity (called MJ33) that prevents acute lung injury in mice exposed to lipopolysaccharide. In between were studies of lung ischemia, lung surfactant metabolism, the protein peroxiredoxin 6 and its phospholipase A2 activity, and mechanisms for NADPH oxidase activation. These seemingly unrelated research activities provided the nexus for identification of a novel target and a potentially novel therapeutic agent for prevention or treatment of acute lung injury. PMID:24744383

  7. Space radiation-associated lung injury in a murine model

    PubMed Central

    Pietrofesa, Ralph A.; Arguiri, Evguenia; Schweitzer, Kelly S.; Berdyshev, Evgeny V.; McCarthy, Maureen; Corbitt, Astrid; Alwood, Joshua S.; Yu, Yongjia; Globus, Ruth K.; Solomides, Charalambos C.; Ullrich, Robert L.; Petrache, Irina

    2014-01-01

    Despite considerable progress in identifying health risks to crewmembers related to exposure to galactic/cosmic rays and solar particle events (SPE) during space travel, its long-term effects on the pulmonary system are unknown. We used a murine risk projection model to investigate the impact of exposure to space-relevant radiation (SR) on the lung. C3H mice were exposed to 137Cs gamma rays, protons (acute, low-dose exposure mimicking the 1972 SPE), 600 MeV/u 56Fe ions, or 350 MeV/u 28Si ions at the NASA Space Radiation Laboratory at Brookhaven National Laboratory. Animals were irradiated at the age of 2.5 mo and evaluated 23.5 mo postirradiation, at 26 mo of age. Compared with age-matched nonirradiated mice, SR exposures led to significant air space enlargement and dose-dependent decreased systemic oxygenation levels. These were associated with late mild lung inflammation and prominent cellular injury, with significant oxidative stress and apoptosis (caspase-3 activation) in the lung parenchyma. SR, especially high-energy 56Fe or 28Si ions markedly decreased sphingosine-1-phosphate levels and Akt- and p38 MAPK phosphorylation, depleted anti-senescence sirtuin-1 and increased biochemical markers of autophagy. Exposure to SR caused dose-dependent, pronounced late lung pathological sequelae consistent with alveolar simplification and cellular signaling of increased injury and decreased repair. The associated systemic hypoxemia suggested that this previously uncharacterized space radiation-associated lung injury was functionally significant, indicating that further studies are needed to define the risk and to develop appropriate lung-protective countermeasures for manned deep space missions. PMID:25526737

  8. Space radiation-associated lung injury in a murine model.

    PubMed

    Christofidou-Solomidou, Melpo; Pietrofesa, Ralph A; Arguiri, Evguenia; Schweitzer, Kelly S; Berdyshev, Evgeny V; McCarthy, Maureen; Corbitt, Astrid; Alwood, Joshua S; Yu, Yongjia; Globus, Ruth K; Solomides, Charalambos C; Ullrich, Robert L; Petrache, Irina

    2015-03-01

    Despite considerable progress in identifying health risks to crewmembers related to exposure to galactic/cosmic rays and solar particle events (SPE) during space travel, its long-term effects on the pulmonary system are unknown. We used a murine risk projection model to investigate the impact of exposure to space-relevant radiation (SR) on the lung. C3H mice were exposed to (137)Cs gamma rays, protons (acute, low-dose exposure mimicking the 1972 SPE), 600 MeV/u (56)Fe ions, or 350 MeV/u (28)Si ions at the NASA Space Radiation Laboratory at Brookhaven National Laboratory. Animals were irradiated at the age of 2.5 mo and evaluated 23.5 mo postirradiation, at 26 mo of age. Compared with age-matched nonirradiated mice, SR exposures led to significant air space enlargement and dose-dependent decreased systemic oxygenation levels. These were associated with late mild lung inflammation and prominent cellular injury, with significant oxidative stress and apoptosis (caspase-3 activation) in the lung parenchyma. SR, especially high-energy (56)Fe or (28)Si ions markedly decreased sphingosine-1-phosphate levels and Akt- and p38 MAPK phosphorylation, depleted anti-senescence sirtuin-1 and increased biochemical markers of autophagy. Exposure to SR caused dose-dependent, pronounced late lung pathological sequelae consistent with alveolar simplification and cellular signaling of increased injury and decreased repair. The associated systemic hypoxemia suggested that this previously uncharacterized space radiation-associated lung injury was functionally significant, indicating that further studies are needed to define the risk and to develop appropriate lung-protective countermeasures for manned deep space missions.

  9. Influenza lung injury: mechanisms and therapeutic opportunities.

    PubMed

    Gregory, David J; Kobzik, Lester

    2015-11-15

    In this Perspectives, we discuss some recent developments in the pathogenesis of acute lung injury following influenza infection, with an emphasis on promising therapeutic leads. Damage to the alveolar-capillary barrier has been quantified in mice, and agents have been identified that can help to preserve barrier integrity, such as vasculotide, angiopoietin-like 4 neutralization, and sphingosine 1-phosphate mimics. Results from studies using mesenchymal stem cells have been disappointing, despite promising data in other types of lung injury. The roles of fatty acid binding protein 5, prostaglandin E2, and the interplay between IFN-γ and STAT1 in epithelial signaling during infection have been addressed in vitro. Finally, we discuss the role of autophagy in inflammatory cytokine production and the viral life cycle and the opportunities this presents for intervention.

  10. Clarithromycin Attenuates Radiation-Induced Lung Injury in Mice.

    PubMed

    Lee, Seung Jun; Yi, Chin-ok; Heo, Rok Won; Song, Dae Hyun; Cho, Yu Ji; Jeong, Yi Yeong; Kang, Ki Mun; Roh, Gu Seob; Lee, Jong Deog

    2015-01-01

    Radiation-induced lung injury (RILI) is a common and unavoidable complication of thoracic radiotherapy. The current study was conducted to evaluate the ability of clarithromycin (CLA) to prevent radiation-induced pneumonitis, oxidative stress, and lung fibrosis in an animal model. C57BL/6J mice were assigned to control, irradiation only, irradiation plus CLA, and CLA only groups. Test mice received single thoracic exposures to radiation and/or oral CLA (100 mg/kg/day). Histopathologic findings and markers of inflammation, fibrosis, and oxidative stress were compared by group. On a microscopic level, CLA inhibited macrophage influx, alveolar fibrosis, parenchymal collapse, consolidation, and epithelial cell changes. The concentration of collagen in lung tissue was lower in irradiation plus CLA mice. Radiation-induced expression of tumor necrosis factor (TNF)-α, TNF receptor 1, acetylated nuclear factor kappa B, cyclooxygenase 2, vascular cell adhesion molecule 1, and matrix metallopeptidase 9 were also attenuated by CLA. Expression levels of nuclear factor erythroid 2-related factor 2 and heme oxygenase 1, transforming growth factor-β1, connective tissue growth factor, and type I collagen in radiation-treated lungs were also attenuated by CLA. These findings indicate that CLA ameliorates the deleterious effects of thoracic irradiation in mice by reducing pulmonary inflammation, oxidative damage, and fibrosis.

  11. Clarithromycin Attenuates Radiation-Induced Lung Injury in Mice

    PubMed Central

    Lee, Seung Jun; Yi, Chin-ok; Heo, Rok Won; Song, Dae Hyun; Cho, Yu Ji; Jeong, Yi Yeong; Kang, Ki Mun; Roh, Gu Seob; Lee, Jong Deog

    2015-01-01

    Radiation-induced lung injury (RILI) is a common and unavoidable complication of thoracic radiotherapy. The current study was conducted to evaluate the ability of clarithromycin (CLA) to prevent radiation-induced pneumonitis, oxidative stress, and lung fibrosis in an animal model. C57BL/6J mice were assigned to control, irradiation only, irradiation plus CLA, and CLA only groups. Test mice received single thoracic exposures to radiation and/or oral CLA (100 mg/kg/day). Histopathologic findings and markers of inflammation, fibrosis, and oxidative stress were compared by group. On a microscopic level, CLA inhibited macrophage influx, alveolar fibrosis, parenchymal collapse, consolidation, and epithelial cell changes. The concentration of collagen in lung tissue was lower in irradiation plus CLA mice. Radiation-induced expression of tumor necrosis factor (TNF)-α, TNF receptor 1, acetylated nuclear factor kappa B, cyclooxygenase 2, vascular cell adhesion molecule 1, and matrix metallopeptidase 9 were also attenuated by CLA. Expression levels of nuclear factor erythroid 2-related factor 2 and heme oxygenase 1, transforming growth factor-β1, connective tissue growth factor, and type I collagen in radiation-treated lungs were also attenuated by CLA. These findings indicate that CLA ameliorates the deleterious effects of thoracic irradiation in mice by reducing pulmonary inflammation, oxidative damage, and fibrosis. PMID:26114656

  12. Role of heme in bromine-induced lung injury.

    PubMed

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

    2016-06-01

    Bromine (Br2 ) gas inhalation poses an environmental and occupational hazard resulting in high morbidity and mortality. In this review, we underline the acute lung pathology (within 24 h of exposure) and potential therapeutic interventions that may be utilized to mitigate Br2 -induced human toxicity. We discuss our latest published data, which suggest that an increase in heme-dependent tissue injury underlies the pathogenesis of Br2 toxicity. Our study was based on previous findings that demonstrated that Br2 upregulates the heme-degrading enzyme heme oxygenase-1 (HO-1), which converts toxic heme into bilverdin. Interestingly, following Br2 inhalation, heme levels were indeed elevated in bronchoalveolar lavage fluid, plasma, and whole lung tissue in C57BL/6 mice. High heme levels correlated with increased lung oxidative stress, lung inflammation, respiratory acidosis, lung edema, higher airway resistance, and mortality. However, therapeutic reduction of heme levels, by either scavenging with hemopexin or degradation by HO-1, improved lung function and survival. Therefore, heme attenuation may prove a useful adjuvant therapy to treat patients after Br2 exposure. © 2016 New York Academy of Sciences.

  13. Xanthine oxidase inhibition attenuates ischemic-reperfusion lung injury

    SciTech Connect

    Lynch, M.J.; Grum, C.M.; Gallagher, K.P.; Bolling, S.F.; Deeb, G.M.; Morganroth, M.L.

    1988-05-01

    Ischemic-reperfusion lung injury is a factor potentially limiting the usefulness of distant organ procurement for heart-lung transplantation. Toxic oxygen metabolites are considered a major etiologic factor in reperfusion injury. Although oxygen-free radicals may be generated by many mechanisms, we investigated the role of xanthine oxidase in this injury process by using lodoxamide, a xanthine oxidase inhibitor, to inhibit ischemic-reperfusion injury in an isolated rat lung model. Isolated rat lungs were perfused with physiologic salt solution (PSS) osmotically stabilized with Ficoll until circulating blood elements were nondetectable in the pulmonary venous effluent. Lungs were rendered ischemic by interrupting ventilation and perfusion for 2 hr at 37/sup 0/C. After the ischemic interval, the lungs were reperfused with whole blood and lung injury was determined by measuring the accumulation of /sup 125/I-bovine serum albumin in lung parenchyma and alveolar lavage fluid as well as by gravimetric measurements. Lung effluent was collected immediately pre- and postischemia for analysis of uric acid by high-pressure liquid chromatography. Lodoxamide (1 mM) caused significant attenuation of postischemic lung injury. Uric acid levels in the lung effluent confirmed inhibition of xanthine oxidase. Protection from injury was not complete, however, implying that additional mechanisms may contribute to ischemic-reperfusion injury in the lung.

  14. Radiation-induced lung injury

    SciTech Connect

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

    1990-03-01

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

  15. Mechanisms of ventilator-induced lung injury in healthy lungs.

    PubMed

    Silva, Pedro Leme; Negrini, Daniela; Rocco, Patricia Rieken Macêdo

    2015-09-01

    Mechanical ventilation is an essential method of patient support, but it may induce lung damage, leading to ventilator-induced lung injury (VILI). VILI is the result of a complex interplay among various mechanical forces that act on lung structures, such as type I and II epithelial cells, endothelial cells, macrophages, peripheral airways, and the extracellular matrix (ECM), during mechanical ventilation. This article discusses ongoing research focusing on mechanisms of VILI in previously healthy lungs, such as in the perioperative period, and the development of new ventilator strategies for surgical patients. Several experimental and clinical studies have been conducted to evaluate the mechanisms of mechanotransduction in each cell type and in the ECM, as well as the role of different ventilator parameters in inducing or preventing VILI. VILI may be attenuated by reducing the tidal volume; however, the use of higher or lower levels of positive end-expiratory pressure (PEEP) and recruitment maneuvers during the perioperative period is a matter of debate. Many questions concerning the mechanisms of VILI in surgical patients remain unanswered. The optimal threshold value of each ventilator parameter to reduce VILI is also unclear. Further experimental and clinical studies are necessary to better evaluate ventilator settings during the perioperative period in different types of surgery. Copyright © 2015 Elsevier Ltd. All rights reserved.

  16. Paraquat lung injury in rabbits.

    PubMed Central

    Seidenfeld, J J; Wycoff, D; Zavala, D C; Richerson, H B

    1978-01-01

    An aerosol model for the study of paraquat (PQ) toxicity was developed using a 134 litre chamber and an ultrasonic nebuliser. Three groups of New Zealand white rabbits weighing 2-3 kg were studied. Group I (n = 6) was exposed to 10 g PQ/100 ml double-distilled water (DDW), Group II (n = 24) was exposed to 200 mg PQ/100 Ml DDW and a control group (n = 6) was exposed to 100 ml DDW. In a second experiment ten animals (Group III) were exposed to 10 mg PQ/100 ML DDW over a three-month period together with a control group (n = 5). Group I animals died with extensive haemorrhagic pneumonitis 38 hours after the last challenge. Most animals in Group II surviving more than three exposures had a significant reduction (P less than 0.001) in arterial oxygen tension (PaO2) and an increase (P less than 0.001) in the alveolar-arterial O2 gradient. Specific compliance decreased (P less than 0.005) and functional residual capacity and breathing frequency increased (P less than 0.05). Tissue PQ values showed even pulmonary distribution, with evidence of PQ accumulation after repeated inhalation. The lungs showed focal interstitial fibrosis, interstitial thickening, proliferation of macrophages in the alveoli, epithelioid changes in the interstitium, Type II cell hyperplasia, and foci of acute inflammation with consolidation. Controls and Group III animals were normal. This indicates that repeated inhalation of paraquat aerosol induces dose-related interstitial pneumonitis and fibrosis in rabbits. Images PMID:698141

  17. Treatment with either obestatin or ghrelin attenuates mesenteric ischemia-reperfusion-induced oxidative injury of the ileum and the remote organ lung.

    PubMed

    Şen, Leyla Semiha; Karakoyun, Berna; Yeğen, Cumhur; Akkiprik, Mustafa; Yüksel, Meral; Ercan, Feriha; Özer, Ayşe; Yeğen, Berrak Ç

    2015-09-01

    To evaluate the effects of exogenous ghrelin or obestatin on intestinal injury and accompanying pulmonary injury, intestinal ischemia-reperfusion (I/R) was induced in rats by obstructing the superior mesenteric artery for 60min, whereas laparotomy was performed in the sham group. At the beginning of the 90-min reperfusion period, the rats were injected with obestatin (100μg/kg), ghrelin (10ng/kg), or saline intravenously (iv). At the end of reperfusion, the blood, ileum, and lung samples were taken for the histological and biochemical assays. In the saline-treated I/R group, the increased serum interleukin (IL)-1β level, high damage scores, and elevated tissue malondialdehyde level and collagen content in both tissues were significantly reduced by obestatin or ghrelin. Increased ileal myeloperoxidase activity of the saline-treated I/R group was reduced by treatment with obestatin or ghrelin, whereas increased pulmonary myeloperoxidase activity was reduced with administration of obestatin. Increased DNA fragmentation in the ileum of the saline-treated I/R group was reduced by both peptides. Elevated luminol-lucigenin chemiluminescence levels and nuclear factor kappa B (NF-κB) messenger RNA (mRNA) expression in the ileum of the saline-treated-I/R group were significantly decreased by obestatin or ghrelin treatment. I/R-induced depletion of the antioxidant glutathione in both ileal and pulmonary tissues was prevented with either obestatin or ghrelin treatment. Administration of either obestatin or ghrelin exerts similar protective effects against I/R-induced ileal and pulmonary injury, thus warranting further investigation for their possible use against ischemic intestinal injury.

  18. Effect of Ergothioneine on Acute Lung Injury and Inflammation in Cytokine Insufflated Rats

    PubMed Central

    Repine, John E.; Elkins, Nancy D.

    2012-01-01

    Objective The Acute Respiratory Distress Syndrome (ARDS), the most severe form of Acute Lung Injury (ALI), is a highly-fatal, diffuse non-cardiogenic edematous lung disorder. The pathogenesis of ARDS is unknown but lung inflammation and lung oxidative stress are likely contributing factors. Since no specific pharmacologic intervention exists for ARDS, our objective was to determine the effect of treatment with ergothioneine---a safe agent with multiple anti-inflammatory and antioxidant properties on the development of lung injury and inflammation in rats insufflated with cytokines found in lung lavages of ARDS patients. Method Sprague-Dawley rats (3-10/group) were given 15 mg/kg or 150 mg/kg L-ergothioneine intravenously 1 hour before or 18 hours after cytokine (IL-1 and IFNγ) insufflation. Lung injury (lavage LDH levels) and lung inflammation (lavage neutrophil numbers) were measured 24 hours after cytokine insufflation. Results Ergothioneine pre- and post- treatment generally decreased lung injury and lung inflammation in cytokine insufflated rats. Conclusion Ergothioneine should be considered for additional testing as a potential therapy for treating and preventing ARDS. PMID:22197759

  19. Alveolar edema fluid clearance and acute lung injury.

    PubMed

    Berthiaume, Yves; Matthay, Michael A

    2007-12-15

    Although lung-protective ventilation strategies have substantially reduced mortality of acute lung injury patients there is still a need for new therapies that can further decrease mortality in patients with acute lung injury. Studies of epithelial ion and fluid transport across the distal pulmonary epithelia have provided important new concepts regarding potential new therapies for acute lung injury. Overall, there is convincing evidence that the alveolar epithelium is not only a tight epithelial barrier that resists the movement of edema fluid into the alveoli, but it is also actively involved in the transport of ions and solutes, a process that is essential for edema fluid clearance and the resolution of acute lung injury. The objective of this article is to consider some areas of recent progress in the field of alveolar fluid transport under normal and pathologic conditions. Vectorial ion transport across the alveolar and distal airway epithelia is the primary determinant of alveolar fluid clearance. The general paradigm is that active Na(+) and Cl(-) transport drives net alveolar fluid clearance, as demonstrated in several different species, including the human lung. Although these transport processes can be impaired in severe lung injury, multiple experimental studies suggest that upregulation of Na(+) and Cl(-) transport might be an effective therapy in acute lung injury. We will review mechanisms involved in pharmacological modulation of ion transport in lung injury with a special focus on the use of beta-adrenergic agonists which has generated considerable interest and is a promising therapy for clinical acute lung injury.

  20. Protective effect of sodium aescinate on lung injury induced by methyl parathion.

    PubMed

    Du, Yuan; Wang, Tian; Jiang, Na; Ren, Ru-Tong; Zhao, De-Lu; Li, Chong; Fu, Feng-Hua

    2011-10-01

    Methyl parathion (MP) is a high venenosus insecticide. It has been used in pest control of agriculture for several years. The present study is performed to investigate the protective effect of sodium aescinate (SA) on lung injury induced by MP. Forty male Sprague-Dawley rats are randomly divided into five groups, with 8 animals in each group: control group, MP administration group, MP plus SA at doses of 0.45 mg/kg, 0.9 mg/kg and 1.8 mg/kg groups. Acetylcholinesterase (AChE) activity and nitric oxide (NO) level in plasma, myeloperoxidase (MPO) activity, NO level, and antioxidative parameters in lung tissue are assayed. Histopathological examination of lung is also performed. The results show that SA has no effect on AChE. Treatment with SA decreases the activity of MPO in lung and the level of NO in plasma and lung. The level of malondialdehyde in lung is decreased after SA treatments. SA increases the activities of superoxide dismutase, glutathione peroxidase and the content of glutathione in lung. SA administration also ameliorates lung injury induced by MP. The findings indicate that SA could protect lung injury induced by MP and the mechanism of action is related to the anti-inflammatory and anti-oxidative effect of SA.

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

    PubMed

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

    2011-01-18

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

  2. Amelioration of superoxide dismutase on ventilator-induced lung injury by suppressing leukocyte in the lungs and systemic circulation.

    PubMed

    Su, Chien-Ling; Du, Wen-Yuan; Chiang, Ling-Ling; Lin, Yen-Kuang; Lee, Hui-Ling; Chen, Kuan-Hao; Wang, Jiun-; Wang, David

    2013-08-31

    Superoxide dismutase (SOD) is a free radical scavenger and a broad-spectrum antioxidant. Its anti-inflammatory and immunomodulatory effects have recently been noted. We studied the effects of this antioxidant on lung damage, oxidative stress, and inflammation in a model of ventilator-induced lung injury (VILI), using 8- to 12-wk-old Sprange-Dawley rats (n = 40). Animals were randomized and evenly divided into two experimental groups, low tidal volume (V(T)) ventilation (V(T) = 9 ml/kg) and high V(T) ventilation (V(T) = 28 ml/kg). Each group was evenly divided into two subgroups: ten animals were treated with superoxide dismutase (SOD; 10,000 U/kg i.v., 2 h prior to the ventilation) and the rests were treated with vehicle. Lung injury was evaluated by histological examination, and cells counts of red blood cells (RBC) and white blood cells (WBC) in the alveoli and the septal wall thickness in lung tissues and serum lactate dehydrogenase (LDH). The lung permeability was assessed by the wet-to-dry weight ratio (W/D), lung weight to body weight ratio (LW/BW) and protein concentration in broncholavage fluid (BALF). Levels of oxidative stress and lipid peroxidation in the lungs were evaluated by tissue malondialdehyde (MDA) and methylguanidine (MG) in BALF, respectively. SOD pretreatment significantly decreased WBC counts in systemic circulation and in alveoli, and effectively attenuated high V(T) ventilation induced lung injury by reducing hyaline membrane development, septal wall thickness, lung W/D and LW/BW and serum LDH in relation to those of the control. In addition, lung tissues MDA and MG in BALF were also notably reduced.

  3. Heliox attenuates lung inflammation and structural alterations in acute lung injury.

    PubMed

    Nawab, Ursula S; Touch, Suzanne M; Irwin-Sherman, Tami; Blackson, Thomas J; Greenspan, Jay S; Zhu, Guangfa; Shaffer, Thomas H; Wolfson, Marla R

    2005-12-01

    Low-density gas mixtures, such as heliox, were shown to reduce the work of breathing and facilitate the distribution of inspired gas. Since supplemental ventilatory and oxygen requirements may lead to pulmonary inflammation and structural alterations, we hypothesized that by reducing these requirements, heliox breathing may attenuate the acute inflammatory and structural changes associated with acute lung injury. Spontaneously breathing neonatal pigs were anesthetized, instrumented, supported with continuous positive airway pressure (CPAP), injured with oleic acid, and randomized to nitrox (n = 6) or heliox (n = 5).F(I)O(2) was titrated for pulse oximetry (SpO(2)) 95 +/- 2% for 4 hr. Gas exchange and pulmonary mechanics were measured. Lungs were analyzed for myeloperoxidase (MPO), interleukin-8 (IL-8), and histomorphometery. Relationships between physiologic indices and cumulative lung structure and inflammatory indices were evaluated. With heliox, compliance was significantly greater, while tidal volume, frequency, minute ventilation, F(I)O(2), arterial carbon dioxide tension (PaCO(2)), MPO, and IL-8 were significantly lower compared to nitrox. The expansion index and number of exchange units were significantly greater with heliox, while the exchange unit area (EUA) was smaller. MPO was significantly and positively correlated with F(I)O(2) (r = 0.76) and EUA (r = 0.63), and negatively correlated with number of open exchange units/field (r = -0.73). Compared to breathing nitrox, these data indicate that heliox improved the distribution of inspired gas, thereby recruiting more gas exchange units, improving gas exchange efficiency, reducing ventilatory and oxygen requirements, and attenuating lung inflammation. These data suggest that heliox breathing may have the combined therapeutic benefits of attenuating lung inflammation by reducing mechanical and oxidative stress in the clinical management of acute lung injury. (c) 2005 Wiley-Liss, Inc.

  4. Role of toxicological interactions in lung injury

    SciTech Connect

    Witschi, H.P.; Hakkinen, P.J.

    1984-04-01

    Interactions between two or more toxic agents can produce lung damage by chemical-chemical interactions, chemical-receptor interactions or by modification, by a first agent, of the cell and tissue response to a second agent. Interactions may occur by simultaneous exposure and if exposure to two agents is separated in time. Chemical-chemical interactions have been mostly studied in the toxicology of air pollutants, where it was shown that the untoward effect of certain oxidants may be enhanced in the presence of other aerosols. Interactions at the receptor site have been found in isolated perfused lung experiments. Oxygen tolerance may be an example, when pre-exposure to one concentration of oxygen mitigates later exposure to 100% oxygen by modifying cellular and enzymatic composition of the lung. Damage of the alveolar zone by the antioxidant butylated hydroxytoluene (BHT) can be greatly enhanced by subsequent exposure to oxygen concentration which, otherwise, would have little if any demonstrable effect. The synergistic interaction between BHT and oxygen results in a resulting interstitial pulmonary fibrosis. Acute or chronic lung disease may then be caused not only by one agent, but very likely in many instances by the interaction of several agents. 121 references.

  5. [Transfusion-related acute lung injury (TRALI)].

    PubMed

    Schweisfurth, H; Sopivnik, I; Moog, R

    2014-09-01

    Transfusion-related acute lung injury (TRALI) is primarily caused by transfusion of fresh frozen plasma or platelet concentrates and occurs by definition within 6 hours after transfusion with acute shortness of breath, hypoxemia and radiographically detectable bilateral infiltrates of the lung. Mostly leucocyte antibodies in the plasma of the blood donor (immunogenic TRALI) are responsible. Apart from antibodies, other substances such as biologically active lipids, mainly arising from the storage of platelet and red blood cell concentrates, can activate neutrophilic granulocytes and trigger a non-immunogenic TRALI. Pathophysiologically, granulocytes in the capillaries of the lung vessels release oxygen radicals and enzymes which damage the endothelial cells and cause pulmonary edema. Therapeutically, nasal oxygen administration may be sufficient. In severe cases, mechanical ventilation, invasive hemodynamic monitoring and fluid intake are required. Diuretics should be avoided. The administration of glucocorticoids is controversial. Antibody-related TRALI reactions occurred mainly after transfusion of fresh frozen plasma, which had been obtained from womenimmunized during pregnancy against leukocyte antigens. Therefore, in Germany, since 2009 only plasma from female donors without a history of prior or current pregnancy or negative testing for antibodies against HLA I, II or HNA has been used with the result that since then no TRALI-related death has been registered.

  6. Prevention of lung injury in cardiac surgery: a review.

    PubMed

    Young, Robert W

    2014-06-01

    Inflammatory lung injury is an inevitable consequence of cardiac surgery with cardiopulmonary bypass. The lungs are particularly susceptible to the effects of the systemic inflammatory response to cardiopulmonary bypass. This insult is further exacerbated by a pulmonary ischemia-reperfusion injury after termination of bypass. Older patients and those with pre-existing lung disease will clearly be less tolerant of any lung injury and more likely to develop respiratory failure in the postoperative period. A requirement for prolonged ventilation has implications for morbidity, mortality, and cost of treatment. This review contains a summary of recent interventions and changes of practice that may reduce inflammatory lung injury after cardiac surgery. The review also focuses on a number of general aspects of perioperative management, which may exacerbate such injury, if performed poorly.

  7. Acute Lung Injury: Making Injured Lungs Perform Better and Rebuilding Healthy Lungs

    DTIC Science & Technology

    2010-07-01

    systemic inflammatory response in patients with acute lung injury. Int Care Med 2002; 28: 834-841. 5. Grasso S, Stripoli T, De Michele M. ARDS Net...Chairs Jonathan Woodson, M.D. (Chair) (617) 638-8488 Louis Vachon , M.D. (Vice-Chair) (617) 638-8173 Sanford Auerbach, M.D. (Chair) (617) 638

  8. Hydrogen inhalation decreases lung graft injury in brain-dead donor rats.

    PubMed

    Zhou, Huacheng; Fu, Zhijie; Wei, Yuting; Liu, Jinfeng; Cui, Xiaoguang; Yang, Wanchao; Ding, Wengang; Pan, Peng; Li, Wenzhi

    2013-02-01

    The process of brain death induces acute lung injury in donors and aggravates ischemia-reperfusion injury (IRI) in grafts. Hydrogen, a new anti-oxidant, attenuates IRI in several organ transplant models. We examined whether 2% inhaled hydrogen would show favorable effects on lung grafts from brain-dead donor rats. Brain-dead donor rats inhaled mixed gases with either 50% oxygen and 50% nitrogen or mixed gases with 2% hydrogen, 50% oxygen and 48% nitrogen for 2 hours. The recipients inhaled the same gas as the donors and were euthanized 2 hours after lung transplantation. Hydrogen improved PaO(2)/FIO(2) and PVO(2)/FIO(2) from the arterial and pulmonary venous blood in recipients and decreased the lung injury score in grafts from brain-dead donors. Hydrogen decreased the amount of IL-8 and TNF-α in serum, inhibited the activity of malondialdehyde and myeloperoxidase, and increased the activity of superoxide dismutase in the lung grafts from brain-dead donors. Furthermore, hydrogen decreased the apoptotic index of the cells and inhibited the protein expression of intercellular adhesion molecule-1 and caspase-3 in lung grafts from brain-dead donors. Hydrogen can exert protective effects on lung grafts from brain-dead donors through anti-inflammatory, anti-oxidant and anti-apoptotic mechanisms. Copyright © 2013 International Society for Heart and Lung Transplantation. Published by Elsevier Inc. All rights reserved.

  9. Mitochondrial Biogenesis in the Pulmonary Vasculature During Inhalational Lung Injury and Fibrosis

    PubMed Central

    CARRAWAY, MARTHA S.; SULIMAN, HAGIR B.; KLIMENT, CORRINE; WELTY-WOLF, KAREN E.; OURY, TIM D.; PIANTADOSI, CLAUDE A.

    2008-01-01

    Cell survival and injury repair is facilitated by mitochondrial biogenesis; however, the role of this process in lung repair is unknown. We evaluated mitochondrial biogenesis in the mouse lung in two injuries that cause acute inflammation and in two that cause chronic inflammation and pulmonary fibrosis. By using reporter mice that express green fluorescent protein (GFP) exclusively in mitochondria, we tracked mitochondrial biogenesis and correlated it with histologic lung injury, proliferation, and fibrosis. At 72 hours after acute LPS or continuous exposure to hyperoxia (Fio2, 1.0), the lungs showed diffuse infiltration by inflammatory cells in the alveolar region. In reporter mice, patchy new mitochondrial fluorescence was found in the alveolar region but was most prominent and unexpected in perivascular regions. At 14 days after instillation of asbestos or bleomycin, diffuse chronic inflammation had developed, and green fluorescence appeared in inflammatory cells in the expanded interstitium and was most intense in smooth muscle cells of pulmonary vessels. In all four lung injuries, mitochondrial fluorescence colocalized with mitochondrial superoxide dismutase, but not with proliferating cell nuclear antigen. These data indicate that vascular mitochondrial biogenesis is activated in diverse inhalational lung injuries along with oxidative stress. This finding indicates a unique and unexpected mechanism of metabolic adaptation to pulmonary fibrotic injuries. PMID:17999632

  10. Development of Antisense Therapeutic and Imaging Agents to Detect and Suppress Inducible Nitric Oxide Synthase (iNOS) Expression in Acute Lung Injury (ALI)

    NASA Astrophysics Data System (ADS)

    Shen, Yuefei

    This dissertation focuses on the development and investigation of antisense imaging and therapeutic agents, combined with nanotechnology, to detect and suppress inducible nitric oxide synthase (iNOS) expression for the diagnosis and treatment of acute lung injury (ALI). To achieve this goal, several efforts were made. The first effort was the identification and characterization of high binding affinity antisense peptide nucleic acids (PNAs) and shell-crosslinked knedel-like nanoparticle (SCK)-PNA conjugates to the iNOS mRNA. Antisense binding sites on the iNOS mRNA were first mapped by a procedure for rapidly generating a library of antisense accessible sites on native mRNAs (MASL) which involves reverse transcription of whole cell mRNA extracts with a random oligodeoxynucleotide primer followed by mRNA-specific PCR. Antisense PNAs against the antisense accessible sites were accordingly synthesized and characterized. The second effort was the investigation of cationic shell crosslinked knedel-like nanoparticle (cSCK)-mediated siRNA delivery to suppress iNOS expression for the treatment of ALI. siRNA with its unique gene-specific properties could serve as a promising therapeutic agent, however success in this area has been challenged by a lack of efficient biocompatible transfection agents. cSCK with its nanometer size and positive charge previously showed efficient cellular delivery of phosphorothioate ODNs (oligodeoxynucleotides), plasmid DNA and PNA. Herein, cSCK showed good siRNA binding and facilitated efficient siRNA transfection in HeLa, a mouse macrophage cell line and other human cell lines. cSCK led to greater silencing efficiency than Lipofectamine 2000 in HeLa cells as determined by the viability following transfection with cytotoxic and non-cytotoxic siRNAs, as well in 293T and HEK cells, and was comparable in BEAS-2B and MCF10a cells. The third effort was the preparation of an iNOS imaging probe through electrostatic complexation between a radiolabeled

  11. Acute lung injury in fulminant hepatic failure following paracetamol poisoning.

    PubMed Central

    Baudouin, S. V.; Howdle, P.; O'Grady, J. G.; Webster, N. R.

    1995-01-01

    BACKGROUND--There is little information on the incidence of acute lung injury or changes in the pulmonary circulation in acute liver failure. The aim of this study was to record the incidence of acute lung injury in fulminant hepatic failure caused by paracetamol poisoning, to document the associated pulmonary circulatory changes, and to assess the impact of lung injury on patient outcome. METHODS--The degree of lung injury was retrospectively assessed by a standard scoring system (modified from Murray) in all patients with fulminant hepatic failure caused by paracetamol poisoning, admitted to the intensive care unit over a one year period. The severity of liver failure and illness, other organ system failure, and patient outcome were also analysed. RESULTS--Twenty four patients with paracetamol-induced liver failure were admitted and nine developed lung injury of whom eight (33%) had severe injury (Murray score > 2.5). In two patients hypoxaemia contributed to death. Patients with lung injury had higher median encephalopathy grades (4 v 2 in the non-injured group) and APACHE II scores (29 v 16). Circulatory failure, requiring vasoconstrictor support, occurred in all patients with lung injury but in only 40% of those without. Cerebral oedema, as detected by abnormal rises in intracranial pressure, also occurred in all patients with lung injury but in only 27% of the non-injured patients. The incidence of renal failure requiring renal replacement therapy was similar in both groups (67% and 47%). Pulmonary artery occlusion pressures were normal in the lung injury group. Cardiac output was high (median 11.2 1/min), systemic vascular resistance low (median 503 dynes/s/cm-5), and pulmonary vascular resistance low (median 70 dynes/s/cm-5), but not significantly different from the group without lung injury. Mortality was much higher in the lung injury group than in the non-injured group (89% v 13%). CONCLUSIONS--Acute lung injury was common in patients with paracetamol

  12. Induced hypernatraemia is protective in acute lung injury.

    PubMed

    Bihari, Shailesh; Dixon, Dani-Louise; Lawrence, Mark D; Bersten, Andrew D

    2016-06-15

    Sucrose induced hyperosmolarity is lung protective but the safety of administering hyperosmolar sucrose in patients is unknown. Hypertonic saline is commonly used to produce hyperosmolarity aimed at reducing intra cranial pressure in patients with intracranial pathology. Therefore we studied the protective effects of 20% saline in a lipopolysaccharide lung injury rat model. 20% saline was also compared with other commonly used fluids. Following lipopolysaccharide-induced acute lung injury, male Sprague Dawley rats received either 20% hypertonic saline, 0.9% saline, 4% albumin, 20% albumin, 5% glucose or 20% albumin with 5% glucose, i.v. During 2h of non-injurious mechanical ventilation parameters of acute lung injury were assessed. Hypertonic saline resulted in hypernatraemia (160 (1) mmol/l, mean (SD)) maintained through 2h of ventilation, and in amelioration of lung oedema, myeloperoxidase, bronchoalveolar cell infiltrate, total soluble protein and inflammatory cytokines, and lung histological injury score, compared with positive control and all other fluids (p ≤ 0.001). Lung physiology was maintained (conserved PaO2, elastance), associated with preservation of alveolar surfactant (p ≤ 0.0001). Independent of fluid or sodium load, induced hypernatraemia is lung protective in lipopolysaccharide-induced acute lung injury. Copyright © 2016 Elsevier B.V. All rights reserved.

  13. [Vasoconstriction is required for edema of contralateral lung after reperfusion injury of one lung].

    PubMed

    Pezzulo, Alejandro; Castro, Ignacio; Trejo, Humberto; Urich, Daniela; Caraballo, Juan; Gutiérrez, Jeydith; Cano, Camilo; Sánchez de León, Roberto

    2010-03-01

    Ischemia-reperfusion (IR) lung injury is a significant cause of morbidity and mortality in certain clinical scenarios that include transplantation, thromboendarterectomy and reexpansion injury of the lung. Edema of the contralateral lung after IR injury of one lung has been reported and this study was aimed to clarify the pathophysiology of this phenomenon. One-lung ischemia/hypoxia followed by reperfusion with either blood or an acellular plasma substitute was achieved in an isolated rabbit lung model by hilum clamping. After reperfusion, we studied the isolated effects of vasoconstriction and inflammation on contralateral lung injury by using papaverine or hydrocortisone as vasodilator and anti-inflammatory, respectively. We observed that IR of one lung induces edema of the contralateral lung. Absence of leukocytes and platelets in the perfusate or use of hydrocortisone completely inhibits IR injury. Moreover, papaverine suppresses edema of the contralateral, but not that of the reperfused lung. We concluded that IR of one lung produces edema in the contralateral lung that requires vasoconstriction of the latter.

  14. Smoked marijuana as a cause of lung injury.

    PubMed

    Tashkin, D P

    2005-06-01

    In many societies, marijuana is the second most commonly smoked substance after tobacco. While delta9-tetrahydrocannabinol (THC) is unique to marijuana and nicotine to tobacco, the smoke of marijuana, like that of tobacco, consists of a toxic mixture of gases and particulates, many of which are known to be harmful to the lung. Although far fewer marijuana than tobacco cigarettes are generally smoked on a daily basis, the pulmonary consequences of marijuana smoking may be magnified by the greater deposition of smoke particulates in the lung due to the differing manner in which marijuana is smoked. Whereas THC causes modest short-term bronchodilation, regular marijuana smoking produces a number of long-term pulmonary consequences, including chronic cough and sputum, histopathologic evidence of widespread airway inflammation and injury and immunohistochemical evidence of dysregulated growth of respiratory epithelial cells, that may be precursors to lung cancer. The THC in marijuana could contribute to some of these injurious changes through its ability to augment oxidative stress, cause mitochondrial dysfunction, and inhibit apoptosis. On the other hand, physiologic, clinical or epidemiologic evidence that marijuana smoking may lead to chronic obstructive pulmonary disease or respiratory cancer is limited and inconsistent. Habitual use of marijuana is also associated with abnormalities in the structure and function of alveolar macrophages, including impairment in microbial phagocytosis and killing that is associated with defective production of immunostimulatory cytokines and nitric oxide, thereby potentially predisposing to pulmonary infection. In view of the growing interest in medicinal marijuana, further epidemiologic studies are needed to clarify the true risks of regular marijuana smoking on respiratory health.

  15. Nilotinib ameliorates lipopolysaccharide-induced acute lung injury in rats

    SciTech Connect

    El-Agamy, Dina S.

    2011-06-01

    The present study aimed to investigate the effect of the new tyrosine kinase inhibitor, nilotinib on lipopolysaccharide (LPS)-induced acute lung injury (ALI) in rats and explore its possible mechanisms. Male Sprague-Dawley rats were given nilotinib (10 mg/kg) by oral gavage twice daily for 1 week prior to exposure to aerosolized LPS. At 24 h after LPS exposure, bronchoalveolar lavage fluid (BALF) samples and lung tissue were collected. The lung wet/dry weight (W/D) ratio, protein level and the number of inflammatory cells in the BALF were determined. Optical microscopy was performed to examine the pathological changes in lungs. Malondialdehyde (MDA) content, superoxidase dismutase (SOD) and reduced glutathione (GSH) activities as well as nitrite/nitrate (NO{sub 2}{sup -}/NO{sub 3}{sup -}) levels were measured in lung tissues. The expression of inflammatory cytokines, tumor necrosis factor-{alpha} (TNF-{alpha}), transforming growth factor-{beta}{sub 1} (TGF-{beta}{sub 1}) and inducible nitric oxide synthase (iNOS) were determined in lung tissues. Treatment with nilotinib prior to LPS exposure significantly attenuated the LPS-induced pulmonary edema, as it significantly decreased lung W/D ratio, protein concentration and the accumulation of the inflammatory cells in the BALF. This was supported by the histopathological examination which revealed marked attenuation of LPS-induced ALI in nilotinib treated rats. In addition, nilotinib significantly increased SOD and GSH activities with significant decrease in MDA content in the lung. Nilotinib also reduced LPS mediated overproduction of pulmonary NO{sub 2}{sup -}/NO{sub 3}{sup -} levels. Importantly, nilotinib caused down-regulation of the inflammatory cytokines TNF-{alpha}, TGF-{beta}{sub 1} and iNOS levels in the lung. Taken together, these results demonstrate the protective effects of nilotinib against the LPS-induced ALI. This effect can be attributed to nilotinib ability to counteract the inflammatory cells

  16. Pretreatment with perfluorohexane vapor attenuates fMLP-induced lung injury in isolated perfused rabbit lungs.

    PubMed

    Bleyl, Jörg U; Heller, Axel R; Fehrenbach, Antonia; Heintz, Manuel; Fehrenbach, Heinz; Klenz, Gesa; Gama de Abreu, Marcelo; Hübler, Matthias; Spieth, Peter M; Koch, Thea

    2010-08-01

    The authors investigated the protective effects and dose dependency of perfluorohexane (PFH) vapor on leukocyte-mediated lung injury in isolated, perfused, and ventilated rabbit lungs. Lungs received either 18 vol.% (n = 7), 9 vol.% (n = 7), or 4.5 vol.% (n = 7) PFH. Fifteen minutes after beginning of PFH application, lung injury was induced with formyl-Met-Leu-Phe (fMLP). Control lungs (n = 7) received fMLP only. In addition 5 lungs (PFH-sham) remained uninjured receiving 18 vol.% PFH only. Pulmonary artery pressure (mPAP), peak inspiratory pressure (P(max)), and lung weight were monitored for 90 minutes. Perfusate samples were taken at regular intervals for analysis and representative lungs were fixed for histological analysis. In the control, fMLP application led to a significant increase of mPAP, P(max), lung weight, and lipid mediators. Pretreatment with PFH attenuated the rise in these parameters. This was accompanied by preservation of the structural integrity of the alveolar architecture and air-blood barrier. In uninjured lungs, mPAP, P(max), lung weight, and lipid mediator formation remained uneffected in the presence of PFH. The authors concluded that pretreatment with PFH vapor leads to an attenuation of leukocyte-mediated lung injury. Vaporization of perfluorocarbons (PFCs) offers new therapeutic options, making use of their protective and anti-inflammatory properties in prophylaxis or in early treatment of acute lung injury.

  17. Transfusion-related acute lung injury (TRALI).

    PubMed

    Roberts, George H

    2004-01-01

    Transfusion is an inevitable event in the life of many individuals. Transfusion medicine personnel attempt to provide blood products that will result in a safe and harmless transfusion. However, this is not always possible since no laboratory test gives totally accurate and reliable results all the time and testing in routine transfusion services is devoted primarily to the identification of red blood cell problems. Thus, when patients are transfused, several possible adverse effects may occur in the transfused patient even though quality testing indicates no potential problem. These adverse events include infectious complications, hemolytic reactions, anaphylaxis, urticaria, circulatory overload, transfusion-associated graft-versus-host disease, chills and fever, immunomodulation, and transfusion-related acute lung injury (TRALI).

  18. Transfusion-related acute lung injury.

    PubMed

    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.

  19. Bronchoscopy-Derived Correlates of Lung Injury Following Inhalational Injuries: A Prospective Obervational Study

    EPA Science Inventory

    Acute lung injury (ALI) is a major factor determining morbidity following burns and inhalational injury. In experimental models, factors potentially contributing to ALI risk include inhalation of toxins directly causing cell damage; inflammation; and infection. However, few studi...

  20. Bronchoscopy-Derived Correlates of Lung Injury Following Inhalational Injuries: A Prospective Obervational Study

    EPA Science Inventory

    Acute lung injury (ALI) is a major factor determining morbidity following burns and inhalational injury. In experimental models, factors potentially contributing to ALI risk include inhalation of toxins directly causing cell damage; inflammation; and infection. However, few studi...

  1. Acute lung injury, overhydration or both?

    PubMed

    Groeneveld, A B Johan; Polderman, Kees H

    2005-04-01

    Acute lung injury or acute respiratory distress syndrome (ALI/ARDS) in the course of sepsis is thought to result from increased pulmonary capillary permeability and resultant edema. However, when the edema is assessed at the bedside by measuring the extravascular thermal volume by transpulmonary dilution, some ALI/ARDS patients with sepsis may have normal extravascular lung water (EVLW). Conversely, a raised EVLW may be present even when criteria for ALI/ARDS are not met, according to GS Martin and colleagues in this issue of Critical Care. This commentary puts the findings into a broader perspective and focuses on the difficulty, at the bedside, in recognizing and separating various types of pulmonary edema. Some of these forms of edema, classically differentiated on the basis of increased permeability and cardiogenic/hydrostatic factors, may overlap, whereas the criteria for ALI/ARDS may be loose, poorly reproducible, relatively insensitive and nonspecific, and highly therapy-dependent. Overhydration is particularly difficult to recognize. Additional diagnostics may be required to improve the delineation of pulmonary edema so as to redirect or redefine treatment and improve patient morbidity and, perhaps, mortality. Monitoring EVLW by single transpulmonary thermal dilution, for instance, might have a future role in this process.

  2. Platelets protect lung from injury induced by systemic inflammatory response

    PubMed Central

    Luo, Shuhua; Wang, Yabo; An, Qi; Chen, Hao; Zhao, Junfei; Zhang, Jie; Meng, Wentong; Du, Lei

    2017-01-01

    Systemic inflammatory responses can severely injure lungs, prompting efforts to explore how to attenuate such injury. Here we explored whether platelets can help attenuate lung injury in mice resulting from extracorporeal circulation (ECC)-induced systemic inflammatory responses. Mice were subjected to ECC for 30 min, then treated with phosphate-buffered saline, platelets, the GPIIb/IIIa inhibitor Tirofiban, or the combination of platelets and Tirofiban. Blood and lung tissues were harvested 60 min later, and lung injury and inflammatory status were assessed. As expected, ECC caused systemic inflammation and pulmonary dysfunction, and platelet transfusion resulted in significantly milder lung injury and higher lung function. It also led to greater numbers of circulating platelet-leukocyte aggregates and greater platelet accumulation in the lung. Platelet transfusion was associated with higher production of transforming growth factor-β and as well as lower levels of tumour necrosis factor-α and neutrophil elastase in plasma and lung. None of these platelet effects was observed in the presence of Tirofiban. Our results suggest that, at least under certain conditions, platelets can protect lung from injury induced by systemic inflammatory responses. PMID:28155889

  3. The relation between oxidative stress, inflammation, and neopterin in the paraquat-induced lung toxicity.

    PubMed

    Toygar, M; Aydin, I; Agilli, M; Aydin, F N; Oztosun, M; Gul, H; Macit, E; Karslioglu, Y; Topal, T; Uysal, B; Honca, M

    2015-02-01

    Paraquat (PQ) is a well-known quaternary nitrogen herbicide. The major target organ in PQ poisoning is the lung. Reactive oxygen species (ROS) and inflammation play a crucial role in the development of PQ-induced pulmonary injury. Neopterin is synthesized in macrophage by interferon γ and other cytokines. We aimed to evaluate the utility of neopterin as a diagnostic marker in PQ-induced lung toxicity. Sprague Dawley rats were randomly divided into two groups (sham and PQ), administered intraperitoneally 1 mL saline and PQ (15 mg/kg/mL) respectively. Blood samples and lungs were collected for analyses. Lung injury and fibrosis were seen in the PQ group. Serum total antioxidant capacity, lactate dehydrogenase (LDH), and lung transforming growth factor-1β (TGF-1β) levels were significantly higher than the sham group (in all, p < 0.001). In addition, in the PQ group, serum neopterin and lung malondialdehyde (MDA) levels were also significantly higher than the sham group (in all, p = 0.001). Serum neopterin levels were correlated with LDH activities, lung MDA, lung TGF-1β levels, and the degree of lung injury. These findings demonstrated that oxidative stress, reduction of antioxidant capacity, and inflammation play a crucial role in the PQ-induced lung injury. Elevated serum neopterin levels may be a prognostic parameter to determine extends of PQ-induced lung toxicity. Further studies may be performed to clarify the role of neopterin by different doses of PQ. © The Author(s) 2015.

  4. Enhanced fibrinolysis protects against lung ischemia-reperfusion injury.

    PubMed

    Lau, Christine L; Zhao, Yunge; Kim, Jiyoun; Kron, Irving L; Sharma, Ashish; Yang, Zequan; Laubach, Victor E; Linden, Joel; Ailawadi, Gorav; Pinsky, David J

    2009-05-01

    Ischemia-reperfusion injury continues to plague the field of lung transplantation, resulting in suboptimal outcomes. In acute lung injury, processes such as ventilator-induced injury, sepsis, or acute respiratory distress syndrome, extravascular fibrin has been shown to promote lung dysfunction and the acute inflammatory response. This study investigates the role of the fibrinolytic cascade in lung ischemia-reperfusion injury and investigates the interplay between the fibrinolytic system and the inflammatory response. Mice lacking the plasminogen activator inhibitor-1 gene (PAI-1 knock out, PAI-1 KO; and thus increased lysis of endogenous fibrin) and wild-type mice underwent in situ left lung ischemia and reperfusion. Fibrin content in the lung was evaluated by immunoblotting. Reperfusion injury was assessed by histologic and physiologic parameters. Proinflammatory mediators were measured in bronchoalveolar lavage fluid and plasma using enzyme-linked immunosorbent assays. Ischemia-reperfusion causes fibrin deposition in murine lungs. Less fibrin was seen in PAI-1 KO mice than in wild-type mice subjected to the same ischemia-reperfusion conditions. By histologic criteria, more evidence of ischemia-reperfusion injury was noted (thickening of the interstium, cellular infiltration in the alveoli) in the wild-type than in PAI-1 KO mice. Physiologic parameters also revealed more ischemia-reperfusion injury in the wild-type than in PAI-1 KO mice. Cytokine and chemokines were elevated more in the wild-type group than the PAI-1 KO group. Lung ischemia-reperfusion injury triggers fibrin deposition in the murine lungs and fibrin creates a proinflammatory environment. Preventing fibrin deposition may reduce ischemia-reperfusion injury and inflammation. This finding may lead to novel treatment strategies for ischemia-reperfusion.

  5. OXIDANTS AND THE PATHOGENESIS OF LUNG DISEASES

    PubMed Central

    Ciencewicki, Jonathan; Trivedi, Shweta; Kleeberger, Steven R.

    2009-01-01

    The increasing number of population-based and epidemiological associations between oxidant pollutant exposures and cardiopulmonary disease exacerbation, decrements in pulmonary function, and mortality underscores the important detrimental effects of oxidants on public health. Because inhaled oxidants initiate a number of pathologic processes, including inflammation of the airways which may contribute to the pathogenesis and/or exacerbation of airways disease, it is critical to understand the mechanisms through which exogenous and endogenous oxidants interact with molecules in the cells, tissues, and epithelial lining fluid (ELF) of the lung. Furthermore, it is clear that inter-individual variation in response to a given exposure also exists across an individual lifetime. Because of the potential impact that oxidant exposures may have on reproductive outcomes and infant, child, and adult health, identification of the intrinsic and extrinsic factors that may influence susceptibility to oxidants remains an important issue. In this review, we discuss mechanisms of oxidant stress in the lung, the role of oxidants in lung disease pathogenesis and exacerbation (e.g. asthma, COPD, and ARDS), and the potential risk factors (e.g. age, genetics) for enhanced susceptibility to oxidant-induced disease. PMID:18774381

  6. Atelectasis Induced by Thoracotomy Causes Lung Injury during Mechanical Ventilation in Endotoxemic Rats

    PubMed Central

    Kwon, Kun Young; Kim, Jin Mo; Quinn, Deborah A.; Hales, Charles A.; Seo, Jeong Wook

    2008-01-01

    Atelectasis can impair arterial oxygenation and decrease lung compliance. However, the effects of atelectasis on endotoxemic lungs during ventilation have not been well studied. We hypothesized that ventilation at low volumes below functional residual capacity (FRC) would accentuate lung injury in lipopolysaccharide (LPS)-pretreated rats. LPS-pretreated rats were ventilated with room air at 85 breaths/min for 2 hr at a tidal volume of 10 mL/kg with or without thoracotomy. Positive end-expiratory pressure (PEEP) was applied to restore FRC in the thoracotomy group. While LPS or thoracotomy alone did not cause significant injury, the combination of endotoxemia and thoracotomy caused significant hypoxemia and hypercapnia. The injury was observed along with a marked accumulation of inflammatory cells in the interstitium of the lungs, predominantly comprising neutrophils and mononuclear cells. Immunohistochemistry showed increased inducible nitric oxide synthase (iNOS) expression in mononuclear cells accumulated in the interstitium in the injury group. Pretreatment with PEEP or an iNOS inhibitor (1400 W) attenuated hypoxemia, hypercapnia, and the accumulation of inflammatory cells in the lung. In conclusion, the data suggest that atelectasis induced by thoracotomy causes lung injury during mechanical ventilation in endotoxemic rats through iNOS expression. PMID:18583875

  7. Atelectasis induced by thoracotomy causes lung injury during mechanical ventilation in endotoxemic rats.

    PubMed

    Choi, Won-Il; Kwon, Kun Young; Kim, Jin Mo; Quinn, Deborah A; Hales, Charles A; Seo, Jeong Wook

    2008-06-01

    Atelectasis can impair arterial oxygenation and decrease lung compliance. However, the effects of atelectasis on endotoxemic lungs during ventilation have not been well studied. We hypothesized that ventilation at low volumes below functional residual capacity (FRC) would accentuate lung injury in lipopolysaccharide (LPS)-pretreated rats. LPS-pretreated rats were ventilated with room air at 85 breaths/min for 2 hr at a tidal volume of 10 mL/kg with or without thoracotomy. Positive end-expiratory pressure (PEEP) was applied to restore FRC in the thoracotomy group. While LPS or thoracotomy alone did not cause significant injury, the combination of endotoxemia and thoracotomy caused significant hypoxemia and hypercapnia. The injury was observed along with a marked accumulation of inflammatory cells in the interstitium of the lungs, predominantly comprising neutrophils and mononuclear cells. Immunohistochemistry showed increased inducible nitric oxide synthase (iNOS) expression in mononuclear cells accumulated in the interstitium in the injury group. Pretreatment with PEEP or an iNOS inhibitor (1400 W) attenuated hypoxemia, hypercapnia, and the accumulation of inflammatory cells in the lung. In conclusion, the data suggest that atelectasis induced by thoracotomy causes lung injury during mechanical ventilation in endotoxemic rats through iNOS expression.

  8. Endothelial dysfunction and lung capillary injury in cardiovascular diseases.

    PubMed

    Guazzi, Marco; Phillips, Shane A; Arena, Ross; Lavie, Carl J

    2015-01-01

    Cardiac dysfunction of both systolic and diastolic origins leads to increased left atrial pressure, lung capillary injury and increased resistance to gas transfer. Acutely, pressure-induced trauma disrupts the endothelial and alveolar anatomical configuration and definitively causes an impairment of cellular pathways involved in fluid-flux regulation and gas exchange efficiency, a process well identified as stress failure of the alveolar-capillary membrane. In chronic heart failure (HF), additional stimuli other than pressure may trigger the true remodeling process of capillaries and small arteries characterized by endothelial dysfunction, proliferation of myofibroblasts, fibrosis and extracellular matrix deposition. In parallel there is a loss of alveolar gas diffusion properties due to the increased path from air to blood (thickening of extracellular matrix) and loss of fine molecular mechanism involved in fluid reabsorption and clearance. Deleterious changes in gas transfer not only reflect the underlying lung tissue damage but also portend independent prognostic information and may play a role in the pathogenesis of exercise limitation and ventilatory abnormalities observed in these patients. Few currently approved treatments for chronic HF have the potential to positively affect structural remodeling of the lung capillary network; angiotensin-converting enzyme inhibitors are one of the few currently established options. Recently, more attention has been paid to novel therapies specifically targeting the nitric oxide pathway as a suitable target to improve endothelial function and permeability as well as alveolar gas exchange properties.

  9. TYLOXAPOL CONFERS DURABLE PROTECTION AGAINST HYPEROXIC LUNG INJURY IN THE RAT

    EPA Science Inventory

    We tested the hypothesis that the non-lipid components of ExosurfR, tyloxapol (TY) and cetyl alcohol (CA), protect against hyperoxic lung injury by either 1) direct radical scavenging activity or 2) induction of the animals? endogenous anti-oxidant defenses. Adult rats were in...

  10. TYLOXAPOL CONFERS DURABLE PROTECTION AGAINST HYPEROXIC LUNG INJURY IN THE RAT

    EPA Science Inventory

    We tested the hypothesis that the non-lipid components of ExosurfR, tyloxapol (TY) and cetyl alcohol (CA), protect against hyperoxic lung injury by either 1) direct radical scavenging activity or 2) induction of the animals? endogenous anti-oxidant defenses. Adult rats were in...

  11. Body temperature control in sepsis-induced acute lung injury.

    PubMed

    Wang, Giueng-Chueng; Chi, Wei-Ming; Perng, Wan-Cherng; Huang, Kun-Lun

    2003-12-31

    Body temperature is precisely regulated to maintain homeostasis in homeothermic animals. Although it remains unproved whether change of body temperature constitutes a beneficial or a detrimental component of the septic response, temperature control should be an important entity in septic experiments. We investigated the effect of body temperature control on the lipopolysaccharide (LPS)-induced lung injury. Acute lung injury in rats was induced by intratracheal spray of LPS and body temperature was either clamped at 37 degrees C for 5 hours or not controlled. The severity of lung injury was evaluated at the end of the experiment. Intratracheal administration of aerosolized LPS caused a persistent decline in body temperature and a significant lung injury as indicated by an elevation of protein-concentration and LDH activity in the bronchoalveolar lavage (BAL) fluid and wet/dry weight (W/D) ratio of lungs. Administration of LPS also caused neutrophil sequestration and lipid peroxidation in the lung tissue as indicated by increase in myeloperoxidase (MPO) activity and malondialdehyde (MDA) production, respectively. Control of body temperature at 37 degrees C after LPS (LPS/BT37, n = 11) significantly reduced acute lung injury as evidenced by decreases in BAL fluid protein concentration (983 +/- 189 vs. 1403 +/- 155 mg/L) and LDH activity (56 +/- 10 vs. 123 +/- 17 deltamAbs/min) compared with the LPS group (n = 11). Although the W/D ratio of lung and MDA level were lower in the rats received temperature control compared with those received LPS only, the differences were not statistically significant. Our results demonstrated that intratracheal administration of aerosolized LPS induced a hypothermic response and acute lung injury in rats and controlling body temperature at a normal range may alleviate the LPS-induced lung injury.

  12. Adenosine promotes vascular barrier function in hyperoxic lung injury

    PubMed Central

    Davies, Jonathan; Karmouty‐Quintana, Harry; Le, Thuy T.; Chen, Ning‐Yuan; Weng, Tingting; Luo, Fayong; Molina, Jose; Moorthy, Bhagavatula; Blackburn, Michael R.

    2014-01-01

    Abstract Hyperoxic lung injury is characterized by cellular damage from high oxygen concentrations that lead to an inflammatory response in the lung with cellular infiltration and pulmonary edema. Adenosine is a signaling molecule that is generated extracellularly by CD73 in response to injury. Extracellular adenosine signals through cell surface receptors and has been found to be elevated and plays a protective role in acute injury situations. In particular, ADORA2B activation is protective in acute lung injury. However, little is known about the role of adenosine signaling in hyperoxic lung injury. We hypothesized that hyperoxia‐induced lung injury leads to CD73‐mediated increases in extracellular adenosine, which is protective through ADORA2B signaling pathways. To test this hypothesis, we exposed C57BL6, CD73−/−, and Adora2B−/− mice to 95% oxygen or room air and examined markers of pulmonary inflammation, edema, and monitored lung histology. Hyperoxic exposure caused pulmonary inflammation and edema in association with elevations in lung adenosine levels. Loss of CD73‐mediated extracellular adenosine production exacerbated pulmonary edema without affecting inflammatory cell counts. Furthermore, loss of the ADORA2B had similar results with worsening of pulmonary edema following hyperoxia exposure without affecting inflammatory cell infiltration. This loss of barrier function correlated with a decrease in occludin in pulmonary vasculature in CD73−/− and Adora2B−/− mice following hyperoxia exposure. These results demonstrate that exposure to a hyperoxic environment causes lung injury associated with an increase in adenosine concentration, and elevated adenosine levels protect vascular barrier function in hyperoxic lung injury through the ADORA2B‐dependent regulation of occludin. PMID:25263205

  13. Reversal of dependent lung collapse predicts response to lung recruitment in children with early acute lung injury.

    PubMed

    Wolf, Gerhard K; Gómez-Laberge, Camille; Kheir, John N; Zurakowski, David; Walsh, Brian K; Adler, Andy; Arnold, John H

    2012-09-01

    To describe the resolution of regional atelectasis and the development of regional lung overdistension during a lung-recruitment protocol in children with acute lung injury. Prospective interventional trial. Pediatric intensive care unit. Ten children with early (<72 hrs) acute lung injury. Sustained inflation maneuver (positive airway pressure of 40 cm H2O for 40 secs), followed by a stepwise recruitment maneuver (escalating plateau pressures by 5 cm H2O every 15 mins) until physiologic lung recruitment, defined by PaO2 + PaCO2 ≥400 mm Hg, was achieved. Regional lung volumes and mechanics were measured using electrical impedance tomography. Patients that responded to the stepwise lung-recruitment maneuver had atelectasis in 54% of the dependent lung regions, while nonresponders had atelectasis in 10% of the dependent lung regions (p = .032). In the pressure step preceding physiologic lung recruitment, a significant reversal of atelectasis occurred in 17% of the dependent lung regions (p = .016). Stepwise recruitment overdistended 8% of the dependent lung regions in responders, but 58% of the same regions in nonresponders (p < .001). Lung compliance in dependent lung regions increased in responders, while compliance in nonresponders did not improve. In contrast to the stepwise recruitment maneuver, the sustained inflation did not produce significant changes in atelectasis or oxygenation: atelectasis was only reversed in 12% of the lung (p = .122), and there was only a modest improvement in oxygenation (27 ± 14 mm Hg, p = .088). Reversal of atelectasis in the most dependent lung region preceded improvements in gas exchange during a stepwise lung-recruitment strategy. Lung recruitment of dependent lung areas was accompanied by considerable overdistension of nondependent lung regions. Larger amounts of atelectasis in dependent lung areas were associated with a positive response to a stepwise lung-recruitment maneuver.

  14. Methylene blue attenuates ischemia--reperfusion injury in lung transplantation.

    PubMed

    Abreu, Marcus da Matta; Pazetti, Rogerio; Almeida, Francine Maria de; Correia, Aristides Tadeu; Parra, Edwin Roger; Silva, Laís Pereira da; Vieira, Rodolfo de Paula; Pêgo-Fernandes, Paulo Manuel; Jatene, Fabio Biscegli

    2014-12-01

    Ischemia-reperfusion injury (IRI) is one of the principal obstacles for the lung transplantation (LTx) success. Several strategies have been adopted to minimize the effects of IRI in lungs, including ex vivo conditioning of the grafts and the use of antioxidant drugs, such as methylene blue (MB). We hypothesized that MB could minimize the effects of IRI in a LTx rodent model. Forty rats were divided into four groups (n = 10) according to treatment (saline solution or MB) and graft cold ischemic time (3 or 6 h). All animals underwent unilateral LTx. Recipients received 2 mL of saline or MB intraperitoneally before transplantation. After 2 h of reperfusion, arterial blood and exhaled nitric oxide samples were collected and bronchoalveolar lavage performed. Then animals were euthanized, and histopathology analysis as well as cell counts and cytokine levels measurements in bronchoalveolar lavage fluid were performed. There was a significant decrease in exhaled nitric oxide, neutrophils, interleukin-6, and tumor necrosis factor-α in MB-treated animals. PaO2 and uric acid levels were higher in MB group. MB was able in attenuating IRI in this LTx model. Copyright © 2014 Elsevier Inc. All rights reserved.

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

    PubMed Central

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

    2013-01-01

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

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

    PubMed

    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.

  17. Effect of hypertonic saline treatment on the inflammatory response after hydrochloric acid-induced lung injury in pigs

    PubMed Central

    Holms, Carla Augusto; Otsuki, Denise Aya; Kahvegian, Marcia; Massoco, Cristina Oliveira; Fantoni, Denise Tabacchi; Gutierrez, Paulo Sampaio; Junior, Jose Otavio Costa Auler

    2015-01-01

    OBJECTIVES: Hypertonic saline has been proposed to modulate the inflammatory cascade in certain experimental conditions, including pulmonary inflammation caused by inhaled gastric contents. The present study aimed to assess the potential anti-inflammatory effects of administering a single intravenous dose of 7.5% hypertonic saline in an experimental model of acute lung injury induced by hydrochloric acid. METHODS: Thirty-two pigs were anesthetized and randomly allocated into the following four groups: Sham, which received anesthesia and were observed; HS, which received intravenous 7.5% hypertonic saline solution (4 ml/kg); acute lung injury, which were subjected to acute lung injury with intratracheal hydrochloric acid; and acute lung injury + hypertonic saline, which were subjected to acute lung injury with hydrochloric acid and treated with hypertonic saline. Hemodynamic and ventilatory parameters were recorded over four hours. Subsequently, bronchoalveolar lavage samples were collected at the end of the observation period to measure cytokine levels using an oxidative burst analysis, and lung tissue was collected for a histological analysis. RESULTS: Hydrochloric acid instillation caused marked changes in respiratory mechanics as well as blood gas and lung parenchyma parameters. Despite the absence of a significant difference between the acute lung injury and acute lung injury + hypertonic saline groups, the acute lung injury animals presented higher neutrophil and tumor necrosis factor alpha (TNF-α), interleukin (IL)-6 and IL-8 levels in the bronchoalveolar lavage analysis. The histopathological analysis revealed pulmonary edema, congestion and alveolar collapse in both groups; however, the differences between groups were not significant. Despite the lower cytokine and neutrophil levels observed in the acute lung injury + hypertonic saline group, significant differences were not observed among the treated and non-treated groups. CONCLUSIONS: Hypertonic saline

  18. Effect of hypertonic saline treatment on the inflammatory response after hydrochloric acid-induced lung injury in pigs.

    PubMed

    Holms, Carla Augusto; Otsuki, Denise Aya; Kahvegian, Marcia; Massoco, Cristina Oliveira; Fantoni, Denise Tabacchi; Gutierrez, Paulo Sampaio; Auler Junior, Jose Otavio Costa

    2015-08-01

    Hypertonic saline has been proposed to modulate the inflammatory cascade in certain experimental conditions, including pulmonary inflammation caused by inhaled gastric contents. The present study aimed to assess the potential anti-inflammatory effects of administering a single intravenous dose of 7.5% hypertonic saline in an experimental model of acute lung injury induced by hydrochloric acid. Thirty-two pigs were anesthetized and randomly allocated into the following four groups: Sham, which received anesthesia and were observed; HS, which received intravenous 7.5% hypertonic saline solution (4 ml/kg); acute lung injury, which were subjected to acute lung injury with intratracheal hydrochloric acid; and acute lung injury + hypertonic saline, which were subjected to acute lung injury with hydrochloric acid and treated with hypertonic saline. Hemodynamic and ventilatory parameters were recorded over four hours. Subsequently, bronchoalveolar lavage samples were collected at the end of the observation period to measure cytokine levels using an oxidative burst analysis, and lung tissue was collected for a histological analysis. Hydrochloric acid instillation caused marked changes in respiratory mechanics as well as blood gas and lung parenchyma parameters. Despite the absence of a significant difference between the acute lung injury and acute lung injury + hypertonic saline groups, the acute lung injury animals presented higher neutrophil and tumor necrosis factor alpha (TNF-α), interleukin (IL)-6 and IL-8 levels in the bronchoalveolar lavage analysis. The histopathological analysis revealed pulmonary edema, congestion and alveolar collapse in both groups; however, the differences between groups were not significant. Despite the lower cytokine and neutrophil levels observed in the acute lung injury + hypertonic saline group, significant differences were not observed among the treated and non-treated groups. Hypertonic saline infusion after intratracheal hydrochloric

  19. Experimental chronic kidney disease attenuates ischemia-reperfusion injury in an ex vivo rat lung model

    PubMed Central

    Huang, Kun-Lun; Lan, Chou-Chin; Hsu, Yu-Juei; Wu, Geng-Chin; Peng, Chia-Hui

    2017-01-01

    Lung ischemia reperfusion injury (LIRI) is one of important complications following lung transplant and cardiopulmonary bypass. Although patients on hemodialysis are still excluded as lung transplant donors because of the possible effects of renal failure on the lungs, increased organ demand has led us to evaluate the influence of chronic kidney disease (CKD) on LIRI. A CKD model was induced by feeding Sprague-Dawley rats an adenine-rich (0.75%) diet for 2, 4 and 6 weeks, and an isolated rat lung in situ model was used to evaluate ischemia reperfusion (IR)-induced acute lung injury. The clinicopathological parameters of LIRI, including pulmonary edema, lipid peroxidation, histopathological changes, immunohistochemistry changes, chemokine CXCL1, inducible nitric oxide synthase (iNOS), proinflammatory and anti-inflammatory cytokines, heat shock protein expression, and nuclear factor-κB (NF-κB) activation were determined. Our results indicated that adenine-fed rats developed CKD as characterized by increased blood urea nitrogen and creatinine levels and the deposition of crystals in the renal tubules and interstitium. IR induced a significant increase in the pulmonary arterial pressure, lung edema, lung injury scores, the expression of CXCL1 mRNA, iNOS level, and protein concentration of the bronchial alveolar lavage fluid (BALF). The tumor necrosis factor-α levels in the BALF and perfusate; the interleukin-10 level in the perfusate; and the malondialdehyde levels in the lung tissue and perfusate were also significantly increased by LIRI. Counterintuitively, adenine-induced CKD significantly attenuated the severity of lung injury induced by IR. CKD rats exhibited increased heat shock protein 70 expression and decreased activation of NF-κB signaling. In conclusion, adenine-induced CKD attenuated LIRI by inhibiting the NF-κB pathway. PMID:28291795

  20. RAGE inhibition reduces acute lung injury in mice.

    PubMed

    Blondonnet, Raiko; Audard, Jules; Belville, Corinne; Clairefond, Gael; Lutz, Jean; Bouvier, Damien; Roszyk, Laurence; Gross, Christelle; Lavergne, Marilyne; Fournet, Marianne; Blanchon, Loic; Vachias, Caroline; Damon-Soubeyrand, Christelle; Sapin, Vincent; Constantin, Jean-Michel; Jabaudon, Matthieu

    2017-08-03

    The receptor for advanced glycation end-products (RAGE) is involved in inflammatory response during acute respiratory distress syndrome (ARDS). Growing body of evidence support strategies of RAGE inhibition in experimental lung injury, but its modalities and effects remain underinvestigated. Anesthetised C57BL/6JRj mice were divided in four groups; three of them underwent orotracheal instillation of acid and were treated with anti-RAGE monoclonal antibody (mAb) or recombinant soluble RAGE (sRAGE), acting as a decoy receptor. The fourth group served as a control. Lung injury was assessed by the analysis of blood gases, alveolar permeability, histology, AFC, and cytokines. Lung expression and distribution epithelial channels ENaC, Na,K-ATPase, and aquaporin (AQP)-5 were assessed. Treatment with either anti-RAGE mAb or sRAGE improved lung injury, arterial oxygenation and decreased alveolar inflammation in acid-injured animals. Anti-RAGE therapies were associated with restored AFC and increased lung expression of AQP-5 in alveolar cell. Blocking RAGE had potential therapeutic effects in a translational mouse model of ARDS, possibly through a decrease in alveolar type 1 epithelial cell injury as shown by restored AFC and lung AQP-5 expression. Further mechanistic studies are warranted to describe intracellular pathways that may control such effects of RAGE on lung epithelial injury and repair.

  1. Nicotinamide Phosphoribosyltransferase Inhibitor Is a Novel Therapeutic Candidate in Murine Models of Inflammatory Lung Injury

    PubMed Central

    Moreno-Vinasco, Liliana; Quijada, Hector; Sammani, Saad; Siegler, Jessica; Letsiou, Eleftheria; Deaton, Ryan; Saadat, Laleh; Zaidi, Rafe S.; Messana, Joe; Gann, Peter H.; Machado, Roberto F.; Camp, Sara M.; Wang, Ting

    2014-01-01

    We previously identified the intracellular nicotinamide phosphoribosyltransferase (iNAMPT, aka pre–B-cell colony enhancing factor) as a candidate gene promoting acute respiratory distress syndrome (ARDS) and ventilator-induced lung injury (VILI) with circulating nicotinamide phosphoribosyltransferase potently inducing NF-κB signaling in lung endothelium. iNAMPT also synthesizes intracellular nicotinamide adenine dinucleotide (iNAD) in response to extracellular oxidative stress, contributing to the inhibition of apoptosis via ill-defined mechanisms. We now further define the role of iNAMPT activity in the pathogenesis of ARDS/VILI using the selective iNAMPT inhibitor FK-866. C57/B6 mice were exposed to VILI (40 ml/kg, 4 h) or LPS (1.5 mg/kg, 18 h) after osmotic pump delivery of FK-866 (100 mg/kg/d, intraperitoneally). Assessment of total bronchoalveolar lavage (BAL) protein, polymorphonuclear neutrophil (PMN) levels, cytokine levels (TNF-α, IL-6, IL-1α), lung iNAD levels, and injury scores revealed that FK-866–mediated iNAMPT inhibition successfully reduced lung tissue iNAD levels, BAL injury indices, inflammatory cell infiltration, and lung injury scores in LPS- and VILI-exposed mice. FK-866 further increased lung PMN apoptosis, as reflected by caspase-3 activation in BAL PMNs. These findings support iNAMPT inhibition via FK-866 as a novel therapeutic agent for ARDS via enhanced apoptosis in inflammatory PMNs. PMID:24588101

  2. Phosphotyrosine phosphatase and tyrosine kinase inhibition modulate airway pressure-induced lung injury.

    PubMed

    Parker, J C; Ivey, C L; Tucker, A

    1998-11-01

    We determined whether drugs which modulate the state of protein tyrosine phosphorylation could alter the threshold for high airway pressure-induced microvascular injury in isolated perfused rat lungs. Lungs were ventilated for successive 30-min periods with peak inflation pressures (PIP) of 7, 20, 30, and 35 cmH2O followed by measurement of the capillary filtration coefficient (Kfc), a sensitive index of hydraulic conductance. In untreated control lungs, Kfc increased by 1.3- and 3.3-fold relative to baseline (7 cmH2O PIP) after ventilation with 30 and 35 cmH2O PIP. However, in lungs treated with 100 microM phenylarsine oxide (a phosphotyrosine phosphatase inhibitor), Kfc increased by 4.7- and 16.4-fold relative to baseline at these PIP values. In lungs treated with 50 microM genistein (a tyrosine kinase inhibitor), Kfc increased significantly only at 35 cmH2O PIP, and the three groups were significantly different from each other. Thus phosphotyrosine phosphatase inhibition increased the susceptibility of rat lungs to high-PIP injury, and tyrosine kinase inhibition attenuated the injury relative to the high-PIP control lungs.

  3. Adrenomedullin ameliorates lipopolysaccharide-induced acute lung injury in rats.

    PubMed

    Itoh, Takefumi; Obata, Hiroaki; Murakami, Shinsuke; Hamada, Kaoru; Kangawa, Kenji; Kimura, Hiroshi; Nagaya, Noritoshi

    2007-08-01

    Adrenomedullin (AM), an endogenous peptide, has been shown to have a variety of protective effects on the cardiovascular system. However, the effect of AM on acute lung injury remains unknown. Accordingly, we investigated whether AM infusion ameliorates lipopolysaccharide (LPS)-induced acute lung injury in rats. Rats were randomized to receive continuous intravenous infusion of AM (0.1 microg x kg(-1) x min(-1)) or vehicle through a microosmotic pump. The animals were intratracheally injected with either LPS (1 mg/kg) or saline. At 6 and 18 h after intratracheal instillation, we performed histological examination and bronchoalveolar lavage and assessed the lung wet/dry weight ratio as an index of acute lung injury. Then we measured the numbers of total cells and neutrophils and the levels of tumor necrosis factor (TNF)-alpha and cytokine-induced neutrophil chemoattractant (CINC) in bronchoalveolar lavage fluid (BALF). In addition, we evaluated BALF total protein and albumin levels as indexes of lung permeability. LPS instillation caused severe acute lung injury, as indicated by the histological findings and the lung wet/dry weight ratio. However, AM infusion attenuated these LPS-induced abnormalities. AM decreased the numbers of total cells and neutrophils and the levels of TNF-alpha and CINC in BALF. AM also reduced BALF total protein and albumin levels. In addition, AM significantly suppressed apoptosis of alveolar wall cells as indicated by cleaved caspase-3 staining. In conclusion, continuous infusion of AM ameliorated LPS-induced acute lung injury in rats. This beneficial effect of AM on acute lung injury may be mediated by inhibition of inflammation, hyperpermeability, and alveolar wall cell apoptosis.

  4. Linking lung function and inflammatory responses in ventilator-induced lung injury.

    PubMed

    Cannizzaro, Vincenzo; Hantos, Zoltan; Sly, Peter D; Zosky, Graeme R

    2011-01-01

    Despite decades of research, the mechanisms of ventilator-induced lung injury are poorly understood. We used strain-dependent responses to mechanical ventilation in mice to identify associations between mechanical and inflammatory responses in the lung. BALB/c, C57BL/6, and 129/Sv mice were ventilated using a protective [low tidal volume and moderate positive end-expiratory pressure (PEEP) and recruitment maneuvers] or injurious (high tidal volume and zero PEEP) ventilation strategy. Lung mechanics and lung volume were monitored using the forced oscillation technique and plethysmography, respectively. Inflammation was assessed by measuring numbers of inflammatory cells, cytokine (IL-6, IL-1β, and TNF-α) levels, and protein content of the BAL. Principal components factor analysis was used to identify independent associations between lung function and inflammation. Mechanical and inflammatory responses in the lung were dependent on ventilation strategy and mouse strain. Three factors were identified linking 1) pulmonary edema, protein leak, and macrophages, 2) atelectasis, IL-6, and TNF-α, and 3) IL-1β and neutrophils, which were independent of responses in lung mechanics. This approach has allowed us to identify specific inflammatory responses that are independently associated with overstretch of the lung parenchyma and loss of lung volume. These data provide critical insight into the mechanical responses in the lung that drive local inflammation in ventilator-induced lung injury and the basis for future mechanistic studies in this field.

  5. Coagulation, fibrinolysis, and fibrin deposition in acute lung injury.

    PubMed

    Idell, Steven

    2003-04-01

    To review: a) the role of extravascular fibrin deposition in the pathogenesis of acute lung injury; b) the abnormalities in the coagulation and fibrinolysis pathways that promote fibrin deposition in the acutely injured lung; and c) the pathways that contribute to the regulation of the fibrinolytic system via the lung epithelium, including newly recognized posttranscriptional and urokinase-dependent pathways. Another objective was to determine how novel anticoagulant or fibrinolytic strategies may be used to protect against acute inflammation or accelerated fibrosis in acute lung injury. Published medical literature. Alveolar fibrin deposition is characteristic of diverse forms of acute lung injury. Intravascular thrombosis or disseminated intravascular coagulation can also occur in the acutely injured lung. Extravascular fibrin deposition promotes lung dysfunction and the acute inflammatory response. In addition, transitional fibrin in the alveolar compartment undergoes remodeling leading to accelerated pulmonary fibrosis similar to the events associated with wound healing, or desmoplasia associated with solid neoplasms. In acute lung injury, alveolar fibrin deposition is potentiated by consistent changes in endogenous coagulation and fibrinolytic pathways. Procoagulant activity is increased in conjunction with depression of fibrinolytic activity in the alveolar compartment. Initiation of the procoagulant response occurs as a result of local overexpression of tissue factor associated with factor VII. Depression of fibrinolytic activity occurs as a result of inhibition of urokinase plasminogen activator (uPA) by plasminogen activators, or series inhibition of plasmin by antiplasmins. Locally increased amplification of plasminogen activator inhibitor-1 (PAI-1) is largely responsible for this fibrinolytic defect. Newly described pathways by which lung epithelial cells regulate expression of uPA, its receptor uPAR, and PAI-1 at the posttranscriptional level have been

  6. High flow nasal heliox improves work of breathing and attenuates lung injury in a newborn porcine lung injury model.

    PubMed

    Jassar, R K; Vellanki, H; Zhu, Yan; Hesek, A M; Wang, J; Rodriguez, E; Wolfson, M R; Shaffer, T H

    2015-01-01

    High flow nasal cannula (HFNC) has been shown to improve ventilation and oxygenation and reduce work of breathing in newborns with respiratory distress. Heliox, decreases resistance to airflow, reduces the work of breathing, facilitates the distribution of inspired gas, and has been shown to attenuate lung inflammation during the treatment of acute lung injury. Heliox delivered by HFNC will decrease resistive load, decrease work of breathing, improve ventilation and attenuate lung inflammation during spontaneous breathing following acute lung injury in the newborn pig. Spontaneously breathing neonatal pigs received Nitrox or Heliox by HFNC and studied over 4 hrs following oleic acid injury. Gas exchange, pulmonary mechanics and systemic inflammation were measured serially. Lung inflammation biomarkers were assessed at termination. Heliox breathing animals demonstrated lower work of breathing reflected by lower tracheal pressure, phase angle and phase relationship. Ventilation efficiency index was greater compared to Nitrox. Heliox group showed less lung inflammation reflected by lower tissue interleukin-6 and 8. High flow nasal Heliox decreased respiratory load, reduced resistive work of breathing indices and attenuated lung inflammatory profile while ventilation was supported at less pressure effort in the presence of acute lung injury.

  7. Stem cell conditioned medium improves acute lung injury in mice: in vivo evidence for stem cell paracrine action

    PubMed Central

    Ionescu, Lavinia; Byrne, Roisin N.; van Haaften, Tim; Vadivel, Arul; Alphonse, Rajesh S.; Rey-Parra, Gloria J.; Weissmann, Gaia; Hall, Adam; Eaton, Farah

    2012-01-01

    Mortality and morbidity of acute lung injury and acute respiratory distress syndrome remain high because of the lack of pharmacological therapies to prevent injury or promote repair. Mesenchymal stem cells (MSCs) prevent lung injury in various experimental models, despite a low proportion of donor-derived cell engraftment, suggesting that MSCs exert their beneficial effects via paracrine mechanisms. We hypothesized that soluble factors secreted by MSCs promote the resolution of lung injury in part by modulating alveolar macrophage (AM) function. We tested the therapeutic effect of MSC-derived conditioned medium (CdM) compared with whole MSCs, lung fibroblasts, and fibroblast-CdM. Intratracheal MSCs and MSC-CdM significantly attenuated lipopolysaccharide (LPS)-induced lung neutrophil influx, lung edema, and lung injury as assessed by an established lung injury score. MSC-CdM increased arginase-1 activity and Ym1 expression in LPS-exposed AMs. In vivo, AMs from LPS-MSC and LPS-MSC CdM lungs had enhanced expression of Ym1 and decreased expression of inducible nitric oxide synthase compared with untreated LPS mice. This suggests that MSC-CdM promotes alternative macrophage activation to an M2 “healer” phenotype. Comparative multiplex analysis of MSC- and fibroblast-CdM demonstrated that MSC-CdM contained several factors that may confer therapeutic benefit, including insulin-like growth factor I (IGF-I). Recombinant IGF-I partially reproduced the lung protective effect of MSC-CdM. In summary, MSCs act through a paracrine activity. MSC-CdM promotes the resolution of LPS-induced lung injury by attenuating lung inflammation and promoting a wound healing/anti-inflammatory M2 macrophage phenotype in part via IGF-I. PMID:23023971

  8. High-frequency oscillation combined with arteriovenous extracorporeal lung assist reduces lung injury.

    PubMed

    Muellenbach, Ralf M; Kredel, Markus; Wilhelm, Jochen; Küstermann, Julian; Fink, Ludger; Siebenlist, Gregor; Siebenliest, Gregor; Klosterhalfen, Bernd; Foerster, Carola Y; Kranke, Peter; Wunder, Christian; Roewer, Norbert; Brederlau, Jörg

    2010-04-01

    In order to optimize the lung-protective potential of high-frequency oscillatory ventilation (HFOV), it is currently recommended to maximize oscillatory frequencies. However, very high frequencies may lead to insufficient CO(2) elimination with severe respiratory acidosis. Arteriovenous extracorporeal lung assist (av-ECLA) allows near total CO(2) removal, thereby allowing for maximization of the lung-protective potential of HFOV. The aim of this study was to determine the impact of HFOV and av-ECLA on lung inflammation and function compared to conventional lung-protective ventilation. In a porcine surfactant depletion model of lung injury, the authors randomly assigned 16 female pigs to conventional lung-protective ventilation and HFOV/ECLA. Both strategies were combined with an "open-lung" approach. Gas exchange and hemodynamic parameters were measured at intervals during the 24-hour study period. Postmortem, lung tissue was analyzed to determine histological damage and lung inflammation. The authors found that the combination of HFOV and av-ECLA (1) allows significant reductions in mean and peak airway pressures; and (2) reduces histological signs of lung inflammation in the basal regions of the lung. HFOV/av-ECLA reduces histological signs of lung inflammation compared to conventional lung-protective ventilation strategies. Thus, combination of HFOV and av-ECLA might be a further lung-protective tool if conventional ventilation strategies are failing.

  9. Subcutaneous administration of bovine superoxide dismutase protects lungs from radiation-induced lung injury.

    PubMed

    Antonic, Vlado; Rabbani, Zahid N; Jackson, Isabel L; Vujaskovic, Zeljko

    2015-10-01

    The objective of the present study was to determine whether single administration of the antioxidant enzyme bovine superoxide dismutase (bSOD) after radiation therapy (RT) mitigates development of pulmonary toxicity in rats. Female F344 rats (n = 60) were divided among six experimental groups: (1) RT, single dose of 21 Gy to the right hemithorax; (2) RT + 5 mg/kg bSOD; (3) RT + 15 mg/kg bSOD; (4) No RT; (5) sham RT + 5 mg/kg bSOD; and (6) sham RT + 15 mg/kg bSOD. A single subcutaneous injection of bSOD (5 or 15 mg/kg) was administered 24 h post-radiation. The effects of bSOD on radiation-induced lung injury were assessed by measurement of body weight, breathing frequency, and histopathological changes. Immunohistochemistry was used to evaluate oxidative stress (8-OHdG(+), NOX4(+), nitrotyrosine(+), and 4HNE(+) cells), macrophage activation (ED1(+)), and expression of profibrotic transforming growth factor-β or TGF-β in irradiated tissue. Radiation led to an increase in all the evaluated parameters. Treatment with 15 mg/kg bSOD significantly decreased levels of all the evaluated parameters including tissue damage and breathing frequency starting 6 weeks post-radiation. Animals treated with 5 mg/kg bSOD trended toward a suppression of radiation-induced lung damage but did not reach statistical significance. The single application of bSOD (15 mg/kg) ameliorates radiation-induced lung injury through suppression of reactive oxygen species/reactive nitrogen species or ROS/RNS-dependent tissue damage.

  10. Role of mesenchymal cell death in lung remodeling after injury.

    PubMed Central

    Polunovsky, V A; Chen, B; Henke, C; Snover, D; Wendt, C; Ingbar, D H; Bitterman, P B

    1993-01-01

    Repair after acute lung injury requires elimination of granulation tissue from the alveolar airspace. We hypothesized that during lung repair, signals capable of inducing the death of the two principal cellular elements of granulation tissue, fibroblasts and endothelial cells, would be present at the air-lung interface. Bronchoalveolar lavage fluid obtained from patients during lung repair induced both fibroblast and endothelial cell death, while fluid obtained at the time of injury or from patient controls did not. The mode of cell death for endothelial cells was apoptosis. Fibroblast death, while morphologically distinct from necrosis, also differed from typical apoptosis. Only proliferating cells were susceptible to the bioactivities in lavage fluid, which were trypsin sensitive and lipid insoluble. Histological examination of lung tissue from patients after lung injury revealed evidence of apoptotic cells within airspace granulation tissue. Our results suggest that cell death induced by peptide(s) present at the air-lung interface may participate in the remodeling process that accompanies tissue repair after injury. Images PMID:8326006

  11. The Field of Tissue Injury in the Lung and Airway

    PubMed Central

    Steiling, Katrina; Ryan, John; Brody, Jerome S.; Spira, Avrum

    2009-01-01

    The concept of field cancerization was first introduced over six decades ago in the setting of oral cancer. Later, field cancerization involving histologic and molecular changes of neoplasms and adjacent tissue began to be characterized in smokers with or without lung cancer. Investigators also described a diffuse, non-neoplastic field of molecular injury throughout the respiratory tract that is attributable to cigarette smoking and susceptibility to smoking-induced lung disease. The potential molecular origins of field cancerization and the field of injury following cigarette smoke exposure in lung and airway epithelia are critical to understanding the impact of the field of injury on clinical diagnostics and therapeutics for smoking-induced lung disease. PMID:19138985

  12. Ventilator-induced lung injury in preterm infants

    PubMed Central

    Carvalho, Clarissa Gutierrez; Silveira, Rita C; Procianoy, Renato Soibelmann

    2013-01-01

    In preterm infants, the need for intubation and mechanical ventilation is associated with ventilator-induced lung injuries and subsequent bronchopulmonary dysplasia. The aim of the present review was to improve the understanding of the mechanisms of injury that involve cytokine-mediated inflammation to contribute to the development of new preventive strategies. Relevant articles were retrieved from the PubMed database using the search terms "ventilator-induced lung injury preterm", "continuous positive airway pressure", "preterm", and "bronchopulmonary dysplasia". The resulting data and other relevant information were divided into several topics to ensure a thorough, critical view of ventilation-induced lung injury and its consequences in preterm infants. The role of pro-inflammatory cytokines (particularly interleukins 6 and 8 and tumor necrosis factor alpha) as mediators of lung injury was assessed. Evidence from studies conducted with animals and human newborns is described. This evidence shows that brief periods of mechanical ventilation is sufficient to induce the release of pro-inflammatory cytokines. Other forms of mechanical and non-invasive ventilation were also analyzed as protective alternatives to conventional mechanical ventilation. It was concluded that non-invasive ventilation, intubation followed by early surfactant administration and quick extubation for nasal continuous positive airway pressure, and strategies that regulate tidal volume and avoid volutrauma (such as volume guarantee ventilation) protect against ventilator-induced lung injury in preterm infants. PMID:24553514

  13. Lung computed tomography during a lung recruitment maneuver in patients with acute lung injury.

    PubMed

    Bugedo, Guillermo; Bruhn, Alejandro; Hernández, Glenn; Rojas, Gonzalo; Varela, Cristián; Tapia, Juan Carlos; Castillo, Luis

    2003-02-01

    To assess the acute effect of a lung recruitment maneuver (LRM) on lung morphology in patients with acute lung injury (ALI) or acute respiratory distress syndrome (ARDS). Ten patients with ALI/ARDS on mechanical ventilation. Prospective clinical study. Computed tomography (CT) scan facility in a teaching hospital. An LRM performed by stepwise increases in positive end-expiratory pressure (PEEP) of up to 30-40 cm H(2)O. Lung basal CT sections were taken at end-expiration (patients 1 to 5), and at end-expiration and end-inspiration (patients 6 to 10). Arterial blood gases and static compliance (C(st)) were measured before, during and after the LRM. Poorly aerated and non-aerated tissue at PEEP 10 cm H(2)O accounted for 60.0+/-29.1% of lung parenchyma, while only 1.1+/-1.8% was hyperinflated. Increasing PEEP to 20 and 30 cm H(2)O, compared to PEEP 10 cm H(2)O, decreased poorly aerated and non-aerated tissue by 16.2+/-28.0% and 33.4+/-13.8%, respectively ( p<0.05). This was associated with an increase in PaO(2) and a decrease in total static compliance. Inspiration increased alveolar recruitment at all PEEP levels. Hyperinflated tissue increased up to 2.9+/-4.0% with PEEP 30 cm H(2)O, and to a lesser degree with inspiration. No barotrauma or severe hypotension occurred. Lung recruitment maneuvers improve oxygenation by expanding collapsed alveoli without inducing too much hyperinflation in ALI/ARDS patients. An LRM during the CT scan gives morphologic and functional information that could be useful in setting ventilatory parameters.

  14. Optical imaging of tissue mitochondrial redox state in intact rat lungs in two models of pulmonary oxidative stress

    PubMed Central

    Sepehr, Reyhaneh; Staniszewski, Kevin; Maleki, Sepideh; Jacobs, Elizabeth R.; Audi, Said

    2012-01-01

    Abstract. Ventilation with enhanced fractions of O2 (hyperoxia) is a common and necessary treatment for hypoxemia in patients with lung failure, but prolonged exposure to hyperoxia causes lung injury. Ischemia-reperfusion (IR) injury of lung tissue is common in lung transplant or crush injury to the chest. These conditions are associated with apoptosis and decreased survival of lung tissue. The objective of this work is to use cryoimaging to evaluate the effect of exposure to hyperoxia and IR injury on lung tissue mitochondrial redox state in rats. The autofluorescent mitochondrial metabolic coenzymes nicotinamide adenine dinucleotide (NADH) and flavin adenine dinucleotide (FAD) are electron carriers in ATP generation. These intrinsic fluorophores were imaged for rat lungs using low-temperature fluorescence imaging (cryoimaging). Perfused lungs from four groups of rats were studied: normoxia (control), control perfused with an mitochondrial complex IV inhibitor (potassium cyanide, KCN), rats exposed to hyperoxia (85% O2) for seven days, and from rats subjected to lung IR in vivo 24 hours prior to study. Each lung was sectioned sequentially in the transverse direction, and the images were used to reconstruct a three-dimensional (3-D) rendering. In KCN perfused lungs the respiratory chain was more reduced, whereas hyperoxic and IR lung tissue have a more oxidized respiratory chain than control lung tissue, consistent with previously measured mitochondrial dysfunction in both hyperoxic and IR lungs. PMID:22559688

  15. Optical imaging of tissue mitochondrial redox state in intact rat lungs in two models of pulmonary oxidative stress

    NASA Astrophysics Data System (ADS)

    Sepehr, Reyhaneh; Staniszewski, Kevin; Maleki, Sepideh; Jacobs, Elizabeth R.; Audi, Said; Ranji, Mahsa

    2012-04-01

    Ventilation with enhanced fractions of O2 (hyperoxia) is a common and necessary treatment for hypoxemia in patients with lung failure, but prolonged exposure to hyperoxia causes lung injury. Ischemia-reperfusion (IR) injury of lung tissue is common in lung transplant or crush injury to the chest. These conditions are associated with apoptosis and decreased survival of lung tissue. The objective of this work is to use cryoimaging to evaluate the effect of exposure to hyperoxia and IR injury on lung tissue mitochondrial redox state in rats. The autofluorescent mitochondrial metabolic coenzymes nicotinamide adenine dinucleotide (NADH) and flavin adenine dinucleotide (FAD) are electron carriers in ATP generation. These intrinsic fluorophores were imaged for rat lungs using low-temperature fluorescence imaging (cryoimaging). Perfused lungs from four groups of rats were studied: normoxia (control), control perfused with an mitochondrial complex IV inhibitor (potassium cyanide, KCN), rats exposed to hyperoxia (85% O2) for seven days, and from rats subjected to lung IR in vivo 24 hours prior to study. Each lung was sectioned sequentially in the transverse direction, and the images were used to reconstruct a three-dimensional (3-D) rendering. In KCN perfused lungs the respiratory chain was more reduced, whereas hyperoxic and IR lung tissue have a more oxidized respiratory chain than control lung tissue, consistent with previously measured mitochondrial dysfunction in both hyperoxic and IR lungs.

  16. Serum copper concentration as an index of experimental lung injury

    SciTech Connect

    Ward, W.F.; Molteni, A.; Ts'ao, C.; Ischiropoulos, H. )

    1989-01-01

    Serum copper (Cu) concentration was evaluated as an index of lung injury in two rat models of pneumotoxicity: hemithoracic irradiation and monocrotaline ingestion. In both models there was a dose- and time-dependent increase in serum Cu concentration. This hypercupremia paralleled the development of pulmonary endothelial dysfunction (decreased lung plasminogen activator activity and increased prostacyclin production) and pulmonary fibrosis (hydroxyproline accumulation). In the radiation model, lung injury and hypercupremia persisted for at least 6 months, and were spared similarly when the total dose was delivered in multiple daily fractions as compared to single doses. In irradiated rats, the elevated serum Cu concentration was accompanied by increases in plasma ceruloplasmin, lung Cu concentration, and lung Cu/Zn superoxide dismutase (SOD) activity. In monocrotaline-treated rats, lung damage and hypercupremia also were accompanied by a reduction in liver Cu concentration, and by a direct correlation between the concentrations of Cu and SGOT in the serum. In both models, some but not all modifiers of lung damage (penicillamine, angiotensin converting enzyme inhibitors, pentoxifylline) also partially prevented the insult-induced hypercupremia. In contrast, serum iron concentration was largely independent of treatment in all experiments. These data suggest that elevated serum copper concentration is an accurate and minimally invasive index of lung injury in irradiated and monocrotaline-treated rats.

  17. Aerosolized alpha-tocopherol ameliorates acute lung injury following combined burn and smoke inhalation injury in sheep.

    PubMed

    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, <40 degrees C). All groups were resuscitated with 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.

  18. Mustard Vesicant-induced Lung Injury: Advances in Therapy

    PubMed Central

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

    2016-01-01

    Most mortality and morbidity following exposure to vesicants such as sulfur mustard is due to pulmonary toxicity. Acute injury is characterized by epithelial detachment and necrosis in the pharynx, trachea and bronchioles, while long-term consequences include fibrosis and in some instances, cancer. Current therapies to treat mustard poisoning are primarily palliative and do not target underlying pathophysiologic mechanisms. New knowledge about vesicant-induced pulmonary disease pathogenesis has led to the identification of potentially efficacious strategies to reduce injury by targeting inflammatory cells and mediators including reactive oxygen and nitrogen species, proteases and proinflammatory/cytotoxic cytokines. Therapeutics under investigation include corticosteroids, N-acetyl cysteine, which has both mucolytic and antioxidant properties, inducible nitric oxide synthase inhibitors, liposomes containing superoxide dismutase, catalase, and/or tocopherols, protease inhibitors, and cytokine antagonists such as anti-tumor necrosis factor (TNF)-α antibody and pentoxifylline. Antifibrotic and fibrinolytic treatments may also prove beneficial in ameliorating airway obstruction and lung remodeling. More speculative approaches include inhibitors of transient receptor potential channels, which regulate pulmonary epithelial cell membrane permeability, non-coding RNAs and mesenchymal stem cells. As mustards represent high priority chemical threat agents, identification of effective therapeutics for mitigating toxicity is highly significant. PMID:27212445

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

    PubMed

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

    2016-08-15

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

  20. Lung injury after cigarette smoking is particle related.

    PubMed

    Sangani, Rahul G; Ghio, Andrew J

    2011-01-01

    The specific component responsible and the mechanistic pathway for increased human morbidity and mortality after cigarette smoking are yet to be delineated. We propose that 1) injury and disease following cigarette smoking are associated with exposure to and retention of particles produced during smoking and 2) the biological effects of particles associated with cigarette smoking share a single mechanism of injury with all particles. Smoking one cigarette exposes the human respiratory tract to between 15,000 and 40,000 μg particulate matter; this is a carbonaceous product of an incomplete combustion. There are numerous human exposures to other particles, and these vary widely in composition, absolute magnitude, and size of the particle. Individuals exposed to all these particles share a common clinical presentation with a loss of pulmonary function, increased bronchial hyperresponsiveness, pathologic changes of emphysema and fibrosis, and comorbidities, including cardiovascular disease, cerebrovascular disease, peripheral vascular disease, and cancers. Mechanistically, all particle exposures produce an oxidative stress, which is associated with a series of reactions, including an activation of kinase cascades and transcription factors, release of inflammatory mediators, and apoptosis. If disease associated with cigarette smoking is recognized to be particle related, then certain aspects of the clinical presentation can be predicted; this would include worsening of pulmonary function and progression of pathological changes and comorbidity (eg, emphysema and carcinogenesis) after smoking cessation since the particle is retained in the lung and the exposure continues.

  1. Metallothionein-induced zinc partitioning exacerbates hyperoxic acute lung injury

    PubMed Central

    Lee, Sang-Min; McLaughlin, Joseph N.; Frederick, Daniel R.; Zhu, Lin; Thambiayya, Kalidasan; Wasserloos, Karla J.; Kaminski, Iris; Pearce, Linda L.; Peterson, Jim; Li, Jin; Latoche, Joseph D.; Peck Palmer, Octavia M.; Stolz, Donna Beer; Fattman, Cheryl L.; Alcorn, John F.; Oury, Tim D.; Angus, Derek C.; Pitt, Bruce R.

    2013-01-01

    Hypozincemia, with hepatic zinc accumulation at the expense of other organs, occurs in infection, inflammation, and aseptic lung injury. Mechanisms underlying zinc partitioning or its impact on extrahepatic organs are unclear. Here we show that the major zinc-binding protein, metallothionein (MT), is critical for zinc transmigration from lung to liver during hyperoxia and preservation of intrapulmonary zinc during hyperoxia is associated with an injury-resistant phenotype in MT-null mice. Particularly, lung-to-liver zinc ratios decreased in wild-type (WT) and increased significantly in MT-null mice breathing 95% oxygen for 72 h. Compared with female adult WT mice, MT-null mice were significantly protected against hyperoxic lung injury indicated by reduced inflammation and interstitial edema, fewer necrotic changes to distal airway epithelium, and sustained lung function at 72 h hyperoxia. Lungs of MT-null mice showed decreased levels of immunoreactive LC3, an autophagy marker, compared with WT mice. Analysis of superoxide dismutase (SOD) activity in the lungs revealed similar levels of manganese-SOD activity between strains under normoxia and hyperoxia. Lung extracellular SOD activity decreased significantly in both strains at 72 h of hyperoxia, although there was no difference between strains. Copper-zinc-SOD activity was ∼4× higher under normoxic conditions in MT-null compared with WT mice but was not affected in either group by hyperoxia. Collectively the data suggest that genetic deletion of MT-I/II in mice is associated with compensatory increase in copper-zinc-SOD activity, prevention of hyperoxia-induced zinc transmigration from lung to liver, and hyperoxia-resistant phenotype strongly associated with differences in zinc homeostasis during hyperoxic acute lung injury. PMID:23275622

  2. Supplementary catechins attenuate cooking-oil-fumes-induced oxidative stress in rat lung.

    PubMed

    Yang, Chao-Huei; Lin, Chun-Yao; Yang, Joan-Hwa; Liou, Shaw-Yih; Li, Ping-Chia; Chien, Chiang-Ting

    2009-06-30

    Cooking-oil-fumes containing toxic components may induce reactive oxygen species (ROS) to oxidize macromolecules and lead to acute lung injury. Our previous study showed that a decaffineated green tea extract containing (+)-catechin, (-)-epicatechin, (+)-gallocatechin, (-)-epigallocatechin, (-)-epicatechin gallate, and (-)-epigallocatechin gallate can inhibit oxidation, inflammation, and apoptosis. We determined whether the catechins supplement may reduce cooking-oil-fumes-induced acute lung injury in rat. In the urethane-anesthetized Wistar rat subjected to 30-120 min of cooking-oil-fumes exposure, blood ROS significantly increased in the recovery stage. After 30-min cooking-oil-fumes exposure, the enhanced blood ROS level further increased in a time-dependent manner during the recovery stage (321 +/- 69 counts/10 s after 1 h, 540 +/- 89 counts/10 s after 2 h, and 873 +/- 112 counts/10 s after 4 h). Four hours after 30-min cooking-oil-fumes exposure, lung lavage neutrophils and ROS as well as lung tissue dityrosine and 4-hydroxy-2-nonenal increased significantly. Two weeks of catechins supplememnt significantly reduced the enhanced lavage ROS, lung dityrosine and 4-hydroxy-2-nonenal level. Cooking-oil-fumes-induced oxidative stress decreased lung Bcl-2/Bax ratio and HSP70 expression, but catechins treatment preserved the downregulation of Bcl-2/Bax ratio and HSP70 expression. We conclude that catechins supplement attenuates cooking-oil-fumes-induced acute lung injury via the preservation of oil-smoke induced downregulation of antioxidant, antiapoptosis, and chaperone protein expression.

  3. Diallyl Trisulfide Inhibits Growth of NCI-H460 in Vitro and in Vivo, and Ameliorates Cisplatin-Induced Oxidative Injury in the Treatment of Lung Carcinoma in Xenograft Mice

    PubMed Central

    Jiang, Xiaoyan; Zhu, Xiaosong; Liu, Na; Xu, Hongya; Zhao, Zhongxi; Li, Siying; Li, Shanzhong; Cai, Jianhua; Cao, Jimin

    2017-01-01

    Diallyl trisulfide (DATS), an organosulfuric component of garlic oil, exhibits potential anticancer and chemopreventive effects. Cisplatin (DDP), a common chemotherapeutic agent, has provided great therapeutic contributions to treating solid tumors, but with serious side effects. Here, we verified the anti-tumor properties of DATS on lung cancer in vitro and in vivo, and evaluated synergistic effects of DATS combined with DDP on the NCI-H460 xenograft model. Significantly decreased cell viabilities, cell cycle G1 arrest, and apoptosis induction were observed in DATS treated NCI-H460 cells (p<0.05). And injection of DATS (30 or 40 mg/kg) to female Balb/c mice significantly inhibited the growth of human NCI-H460 cell tumor xenograft (p<0.001). Moreover, DATS in combination with DDP exhibited enhanced anti-tumor activity via induction of apoptosis. Apoptosis pathways were confirmed by modulation of p53, Bcl-2 family members; induction of active caspase-3/8/9 and activation of JNK- and p38-MAPK pathways. Interestedly, DATS+DDP administration exerted fewer side effects, such as suppressing the weight loss and ameliorating DDP-induced oxidative injury, especially in renal parenchyma. In addition, increased E-cadherin and decreased MMP-9 expression levels were observed in DATS-treated tumor tissues. These studies provide supports that DATS might be a potential candidate for combination with DDP in cancer treatment. PMID:28255269

  4. Diallyl Trisulfide Inhibits Growth of NCI-H460 in Vitro and in Vivo, and Ameliorates Cisplatin-Induced Oxidative Injury in the Treatment of Lung Carcinoma in Xenograft Mice.

    PubMed

    Jiang, Xiaoyan; Zhu, Xiaosong; Liu, Na; Xu, Hongya; Zhao, Zhongxi; Li, Siying; Li, Shanzhong; Cai, Jianhua; Cao, Jimin

    2017-01-01

    Diallyl trisulfide (DATS), an organosulfuric component of garlic oil, exhibits potential anticancer and chemopreventive effects. Cisplatin (DDP), a common chemotherapeutic agent, has provided great therapeutic contributions to treating solid tumors, but with serious side effects. Here, we verified the anti-tumor properties of DATS on lung cancer in vitro and in vivo, and evaluated synergistic effects of DATS combined with DDP on the NCI-H460 xenograft model. Significantly decreased cell viabilities, cell cycle G1 arrest, and apoptosis induction were observed in DATS treated NCI-H460 cells (p<0.05). And injection of DATS (30 or 40 mg/kg) to female Balb/c mice significantly inhibited the growth of human NCI-H460 cell tumor xenograft (p<0.001). Moreover, DATS in combination with DDP exhibited enhanced anti-tumor activity via induction of apoptosis. Apoptosis pathways were confirmed by modulation of p53, Bcl-2 family members; induction of active caspase-3/8/9 and activation of JNK- and p38-MAPK pathways. Interestedly, DATS+DDP administration exerted fewer side effects, such as suppressing the weight loss and ameliorating DDP-induced oxidative injury, especially in renal parenchyma. In addition, increased E-cadherin and decreased MMP-9 expression levels were observed in DATS-treated tumor tissues. These studies provide supports that DATS might be a potential candidate for combination with DDP in cancer treatment.

  5. Acute Respiratory Distress Syndrome: Role of Oleic Acid-Triggered Lung Injury and Inflammation

    PubMed Central

    Gonçalves-de-Albuquerque, Cassiano Felippe; Silva, Adriana Ribeiro; Burth, Patrícia; Castro-Faria, Mauro Velho; Castro-Faria-Neto, Hugo Caire

    2015-01-01

    Lung injury especially acute respiratory distress syndrome (ARDS) can be triggered by diverse stimuli, including fatty acids and microbes. ARDS affects thousands of people worldwide each year, presenting high mortality rate and having an economic impact. One of the hallmarks of lung injury is edema formation with alveoli flooding. Animal models are used to study lung injury. Oleic acid-induced lung injury is a widely used model resembling the human disease. The oleic acid has been linked to metabolic and inflammatory diseases; here we focus on lung injury. Firstly, we briefly discuss ARDS and secondly we address the mechanisms by which oleic acid triggers lung injury and inflammation. PMID:26640323

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

    PubMed Central

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

    2016-01-01

    Mechanical ventilation (MV) is a therapeutic intervention widely used in the clinic to assist patients that have difficulty breathing due to lung edema, trauma, or general anesthesia. However, MV causes ventilator-induced lung injury (VILI), a condition characterized by increased permeability of the alveolar-capillary barrier that results in edema, hemorrhage, and neutrophil infiltration, leading to exacerbated lung inflammation and oxidative stress. This study explored the feasibility of using bixin, a canonical NRF2 inducer identified during the current study, to ameliorate lung damage in a murine VILI model. In vitro, bixin was found to activate the NRF2 signaling pathway through blockage of ubiquitylation and degradation of NRF2 in a KEAP1-C151 dependent manner; intraperitoneal (IP) injection of bixin led to pulmonary upregulation of the NRF2 response in vivo. Remarkably, IP administration of bixin restored normal lung morphology and attenuated inflammatory response and oxidative DNA damage following MV. This observed beneficial effect of bixin derived from induction of the NRF2 cytoprotective response since it was only observed in Nrf2+/+ but not in Nrf2−/− mice. This is the first study providing proof-of-concept that NRF2 activators can be developed into pharmacological agents for clinical use to prevent patients from lung injury during MV treatment. PMID:26729554

  7. Corticosteroids found ineffective for phosgene-induced acute lung injury in rats.

    PubMed

    Luo, Sa; Pauluhn, Jürgen; Trübel, Hubert; Wang, Chen

    2014-08-17

    Various therapeutic regimes have been proposed with limited success for treatment of phosgene-induced acute lung injury (P-ALI). Corticoids were shown to be efficacious against chlorine-induced lung injury but there is still controversy whether this applies also to P-ALI. This study investigates whether different regimen of curatively administered budesonide (BUD, 10 mg/kg bw, i.p. bid; 100 mg/m(3)×30 min, nose-only inhalation), mometasone (MOM, 3 mg/kg bw, i.p. bid) and dexamethasone (DEX, 10, 30 mg/kg bw, i.p. bid), show efficacy to alleviate P-ALI. Efficacy of drugs was judged by nitric oxide (eNO) and carbon dioxide (eCO2) in exhaled air and whether these non-invasive biomarkers are suitable to assess the degree of airway injury (chlorine) relative to alveolar injury (phosgene). P-ALI related analyses included lung function (enhanced pause, Penh), morbidity, increased lung weights, and protein in bronchial alveolar lavage fluid (BALF) one day postexposure. One of the pathophysiological hallmarks of P-ALI was indicated by increased Penh lasting for approximately 20 h postexposure. Following the administration of BUD, this increase could be suppressed; however, without significant improvement in survival and lung edema (increased lung weights and BALF-protein). Collectively, protocols shown to be efficacious for chlorine (Chen et al., 2013) were ineffective and even increased adversity in the P-ALI model. This outcome warrants further study to seek for early biomarkers suitable to differentiate chlorine- and phosgene-induced acute lung injury at yet asymptomatic stage. The patterns of eNO and eCO2 observed following exposure to chlorine and phosgene may be suitable to guide the specialized clinical interventions required for each type of ALI. Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.

  8. Effects of sphingosylphosphorylcholine against oxidative stress and acute lung ınjury ınduced by pulmonary contusion in rats.

    PubMed

    Aksu, Burhan; Ayvaz, Süleyman; Aksu, Feyza; Karaca, Turan; Cemek, Mustafa; Ayaz, Ahmet; Demirtaş, Selim

    2015-04-01

    The goal of this study was to evaluate effects of exogenous sphingosylphosphorylcholine (SPC) administration on acute lung injury induced by pulmonary contusion in rats. Eight animals were included in each of the following five groups: control, contusion, contusion phosphate-buffered solution (PBS), contusion SPC 2, contusion SPC 10. SPC was administered 3 days at a daily two different doses of 2 μm/ml and 10 μm/ml intraperitoneally. The severity of lung injury was determined by the neutrophil activation and histological and immunohistochemical changes in the lung. Malondialdehyde (MDA), nitric oxide (NO), superoxide dismutase (SOD), glutathione peroxidase (GPx) and glutathione (GSH) were determined to evaluate the oxidative status in the lung tissue. Treatment with 2 μM SPC inhibited the increase in lung MDA and NO levels significantly and also attenuated the depletion of SOD, GPx, and GSH in the lung injury induced by pulmonary contusion. These data were supported by histopathological findings. The inducible nitric oxide synthase (iNOS) positive cells and apoptotic cells in the lung tissue were observed to be reduced with the 2 μM SPC treatment. But, the 10 μM SPC treatment did not provide similar effects. In conclusion, these findings suggested that 2 μM SPC can attenuate lung damage in pulmonary contusion by prevention of oxidative stress, inflammatory process and apoptosis. All these findings suggest that low dose SPC may be a promising new therapeutic agent for acute lung injury. Copyright © 2015. Published by Elsevier Inc.

  9. Extravascular lung water index improves the diagnostic accuracy of lung injury in patients with shock.

    PubMed

    Chew, Michelle S; Ihrman, Lilian; During, Joachim; Bergenzaun, Lill; Ersson, Anders; Undén, Johan; Ryden, Jörgen; Åkerman, Eva; Larsson, Marina

    2012-01-03

    The diagnosis of acute lung injury (ALI) may be more robust if more accurate physiological markers can be identified. Extravascular lung water (EVLW) is one possible marker, and it has been shown to correlate with respiratory function and mortality in patients with sepsis. Whether EVLW confers diagnostic value in a general population with shock, as well as which index performs best, is unclear. We investigated the diagnostic accuracy of various EVLW indices in patients with shock. We studied a prospective, observational cohort of 51 patients with shock admitted to a tertiary ICU. EVLW was measured within 6 hours of ICU admission and indexed to actual body weight (EVLW/ABW), predicted body weight (EVLW/PBW) and pulmonary blood volume (EVLW/PBV). The relationship of these indices to the diagnosis and severity of lung injury and ICU mortality were studied. Positive and negative likelihood ratios, pre- and posttest odds for diagnosis of lung injury and mortality were calculated. All EVLW indices were higher among patients with lung injury and significantly correlated with respiratory parameters. Furthermore, all EVLW indices were significantly higher in nonsurvivors. The use of EVLW improves the posttest OR for the diagnosis of ALI, acute respiratory distress syndrome (ARDS) and severe lung injury (sLI) by up to eightfold. Combining increased EVLW and a diagnosis of ALI, ARDS or sLI increases the posttest odds of ICU mortality. EVLW/ABW and EVLW/PBV demonstrated the best diagnostic performance in this population. EVLW was associated with degree of lung injury and mortality, regardless of the index used, confirming that it may be used as a bedside indicator of disease severity. The use of EVLW as a bedside test conferred added diagnostic value for the identification of patients with lung injury.

  10. Extravascular lung water index improves the diagnostic accuracy of lung injury in patients with shock

    PubMed Central

    2012-01-01

    Introduction The diagnosis of acute lung injury (ALI) may be more robust if more accurate physiological markers can be identified. Extravascular lung water (EVLW) is one possible marker, and it has been shown to correlate with respiratory function and mortality in patients with sepsis. Whether EVLW confers diagnostic value in a general population with shock, as well as which index performs best, is unclear. We investigated the diagnostic accuracy of various EVLW indices in patients with shock. Methods We studied a prospective, observational cohort of 51 patients with shock admitted to a tertiary ICU. EVLW was measured within 6 hours of ICU admission and indexed to actual body weight (EVLW/ABW), predicted body weight (EVLW/PBW) and pulmonary blood volume (EVLW/PBV). The relationship of these indices to the diagnosis and severity of lung injury and ICU mortality were studied. Positive and negative likelihood ratios, pre- and posttest odds for diagnosis of lung injury and mortality were calculated. Results All EVLW indices were higher among patients with lung injury and significantly correlated with respiratory parameters. Furthermore, all EVLW indices were significantly higher in nonsurvivors. The use of EVLW improves the posttest OR for the diagnosis of ALI, acute respiratory distress syndrome (ARDS) and severe lung injury (sLI) by up to eightfold. Combining increased EVLW and a diagnosis of ALI, ARDS or sLI increases the posttest odds of ICU mortality. EVLW/ABW and EVLW/PBV demonstrated the best diagnostic performance in this population. Conclusions EVLW was associated with degree of lung injury and mortality, regardless of the index used, confirming that it may be used as a bedside indicator of disease severity. The use of EVLW as a bedside test conferred added diagnostic value for the identification of patients with lung injury. PMID:22214612

  11. Angiotensin converting enzyme 2 abrogates bleomycin-induced lung injury.

    PubMed

    Rey-Parra, G J; Vadivel, A; Coltan, L; Hall, A; Eaton, F; Schuster, M; Loibner, H; Penninger, J M; Kassiri, Z; Oudit, G Y; Thébaud, B

    2012-06-01

    Despite substantial progress, mortality and morbidity of the acute respiratory distress syndrome (ARDS), a severe form of acute lung injury (ALI), remain unacceptably high. There is no effective treatment for ARDS/ALI. The renin-angiotensin system (RAS) through Angiotensin-converting enzyme (ACE)-generated Angiotensin II contributes to lung injury. ACE2, a recently discovered ACE homologue, acts as a negative regulator of the RAS and counterbalances the function of ACE. We hypothesized that ACE2 prevents Bleomycin (BLM)-induced lung injury. Fourteen to 16-week-old ACE2 knockout mice-male (ACE2(-/y)) and female (ACE2(-/-))-and age-matched wild-type (WT) male mice received intratracheal BLM (1.5U/kg). Male ACE2(-/y) BLM injured mice exhibited poorer exercise capacity, worse lung function and exacerbated lung fibrosis and collagen deposition compared with WT. These changes were associated with increased expression of the profibrotic genes α-smooth muscle actin (α-SMA) and Transforming Growth Factor ß1. Compared with ACE2(-/y) exposed to BLM, ACE2(-/-) exhibited better lung function and architecture and decreased collagen deposition. Treatment with intraperitoneal recombinant human (rh) ACE2 (2 mg/kg) for 21 days improved survival, exercise capacity, and lung function and decreased lung inflammation and fibrosis in male BLM-WT mice. Female BLM WT mice had mild fibrosis and displayed a possible compensatory upregulation of the AT2 receptor. We conclude that ACE2 gene deletion worsens BLM-induced lung injury and more so in males than females. Conversely, ACE2 protects against BLM-induced fibrosis. rhACE2 may have therapeutic potential to attenuate respiratory morbidity in ALI/ARDS.

  12. Disruption of Cytochrome P4501A2 in mice leads to increased susceptibility to hyperoxic lung injury

    PubMed Central

    Wang, Lihua; Lingappan, Krithika; Jiang, Weiwu; Couroucli, Xanthi I.; Welty, Stephen E.; Shivanna, Binoy; Barrios, Roberto; Wang, Gangduo; Khan, M. Firoze; Gonzalez, Frank J.; Roberts, L Jackson; Moorthy, Bhagavatula

    2015-01-01

    Hyperoxia contributes to acute lung injury (ALI) in diseases such as acute respiratory distress syndrome (ARDS). Cytochrome P450 (CYP)1A enzymes have been implicated in hyperoxic lung injury, but the mechanistic role(s) of CYP1A2 in pulmonary injury is not known. We hypothesized that mice lacking the gene for Cyp1a2 (which is predominantly expressed in the liver) will be more sensitive to lung injury and inflammation mediated by hyperoxia, and that CYP1A2 will play a protective role by attenuating lipid peroxidation and oxidative stress in the lung. Eight to ten week old WT (C57BL/6) or Cyp1a2(−/−) mice were exposed to hyperoxia (>95% O2) or maintained in room air for 24–72 h. Lung injury was assessed by determining the ratios of lung weight/body weight (LW/BW), and by histology. Extent of inflammation was determined by measuring the number of neutrophils in the lung as well as cytokine expression. The Cyp1a2(−/−) mice under hyperoxic conditions showed increased LW/BW ratios, lung injury, neutrophil infiltration, IL-6 and TNF-α levels, and augmented lipid peroxidation, as evidenced by increased formation of malondialdehyde (MDA)- and 4-hydroxynonenal (4-HNE)-protein adducts, and pulmonary isofurans compared to those of WT mice. In vitro experiments showed that the F2-isoprostane PGF2-α is metabolized by CYP1A2 to a dinor metabolite, providing evidence for a catalytic role for CYP1A2 in the metabolism of F2-isoprostanes. In summary, our results support the hypothesis that hepatic CYP1A2 plays a critical role in the attenuation against hyperoxic lung injury by decreasing lipid peroxidation and oxidative stress in vivo. PMID:25680282

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

    SciTech Connect

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

    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

  14. Obesity-induced Endoplasmic Reticulum Stress Causes Lung Endothelial Dysfunction and Promotes Acute Lung Injury.

    PubMed

    Shah, Dilip; Romero, Freddy; Guo, Zhi; Sun, Jianxin; Li, Jonathan; Kallen, Caleb B; Naik, Ulhas P; Summer, Ross

    2017-03-09

    Obesity is a significant risk factor for the acute respiratory distress syndrome (ARDS). The mechanisms underlying this association are unknown. We recently showed that diet-induced obese (DIO) mice exhibit pulmonary vascular endothelial dysfunction which is associated with enhanced susceptibility to lipopolysaccharide (LPS)-induced lung injury. Here, we demonstrate that lung endothelial dysfunction in DIO mice coincides with increased endoplasmic reticulum (ER) stress. Specifically, we observed enhanced expression of the major sensors of misfolded proteins including PERK, IREα and ATF6, in whole lung and in lung endothelial cells isolated from DIO mice. Further, we found that lung endothelial cells exposed to serum from obese mice, or to saturated fatty acids that mimic obese serum, resulted in enhanced expression of markers of ER stress and the induction of other biological responses that typify the lung endothelium of DIO mice. Similar changes were observed in lung endothelial cells and in whole lung tissue after exposure to tunicamycin, a compound that causes ER stress by blocking N-linked glycosylation; indicating that ER stress causes endothelial dysfunction in the lung. Treatment with 4-PBA, a chemical protein chaperone that reduces ER stress, restored vascular endothelial cell expression of adhesion molecules and protected against LPS-induced acute lung injury in DIO mice. Our work indicates that fatty acids in obese serum induce ER stress in the pulmonary endothelium leading to pulmonary endothelial cell dysfunction. Our work suggests that reducing protein load in the endoplasmic reticulum of pulmonary endothelial cells might protect against ARDS in obese individuals.

  15. Therapeutic treatments of phosgene-induced lung injury.

    PubMed

    Sciuto, Alfred M; Hurt, Holcombe H

    2004-07-01

    A series of studies was performed to address treatment against the former chemical warfare edemagenic gas phosgene. Both in situ and in vivo models were used to assess the efficacy of postexposure treatment of phosgene-induced lung injury using clinically existing drugs. The degree of efficacy was judged by examining treatment effects on pulmonary edema formation (PEF) as measured by wet/dry weight (WW/DW) ratios, real-time (in situ) lung weight gain (LWG), survival rates (SR), odds ratios, and glutathione (GSH) redox states. Drugs included N-acetylcysteine (NAC), ibuprofen (IBU), aminophylline (AMIN), and isoproterenol (ISO). Using the in situ isolated perfused rabbit lung model (IPRLM), intratracheal (IT) NAC (40 mg/kg bolus) delivered 45-60 min after phosgene exposure (650 mg/m(3)) for10 min lowered pulmonary artery pressure, LWG, leukotrienes (LT) C(4)/D(4)/E(4), lipid peroxidation, and oxidized GSH. We concluded that NAC protected against phosgene-induced lung injury by acting as an antioxidant by maintaining protective levels of GSH, reducing both lipid peroxidation and production of arachidonic acid metabolites. Also in IPRLM, administration of AMIN (30 mg/kg) 80-90 min after phosgene exposure significantly reduced lipid peroxidation and perfusate LTC(4)/D(4)/E(4), reduced LWG, and prevented phosgene-induced decreases in lung tissue cAMP. These data suggest that protective mechanisms observed with AMIN involve decreased LTC(4)/D(4)/E(4) mediated pulmonary capillary permeability and attenuated lipid peroxidation. Direct antipermeability effects of AMIN-induced upregulation of cAMP on cellular contraction may also be important in protection against phosgene-induced lung injury. Posttreatment with ISO in the IPRLM by either combined intravascular (iv; infused into pulmonary artery at 24 microg/min infused) + IT (24 microg bolus) or IT route alone 50-60 min after phosgene exposure significantly lowered pulmonary artery pressure, tracheal pressure, and LWG. ISO

  16. IL-6 ameliorates acute lung injury in influenza virus infection

    PubMed Central

    Yang, Mei-Lin; Wang, Chung-Teng; Yang, Shiu-Ju; Leu, Chia-Hsing; Chen, Shun-Hua; Wu, Chao-Liang; Shiau, Ai-Li

    2017-01-01

    Interleukin 6 (IL-6) is involved in innate and adaptive immune responses to defend against pathogens. It also participates in the process of influenza infection by affecting viral clearance and immune cell responses. However, whether IL-6 impacts lung repair in influenza pathogenesis remains unclear. Here, we studied the role of IL-6 in acute influenza infection in mice. IL-6-deficient mice infected with influenza virus exhibited higher lethality, lost more body weight and had higher fibroblast accumulation and lower extracellular matrix (ECM) turnover in the lung than their wild-type counterparts. Deficiency in IL-6 enhanced proliferation, migration and survival of lung fibroblasts, as well as increased virus-induced apoptosis of lung epithelial cells. IL-6-deficient lung fibroblasts produced elevated levels of TGF-β, which may contribute to their survival. Furthermore, macrophage recruitment to the lung and phagocytic activities of macrophages during influenza infection were reduced in IL-6-deficient mice. Collectively, our results indicate that IL-6 is crucial for lung repair after influenza-induced lung injury through reducing fibroblast accumulation, promoting epithelial cell survival, increasing macrophage recruitment to the lung and enhancing phagocytosis of viruses by macrophages. This study suggests that IL-6 may be exploited for lung repair during influenza infection. PMID:28262742

  17. Low Tidal Volume Ventilation in Patients Without Acute Lung Injury.

    PubMed

    Tang, Weibing; Wang, Zhi; Liu, Ye; Zhu, Jing

    2015-05-01

    Acute respiratory distress syndrome is a life threatening respiratory condition characterized by breakdown of the alveolar-capillary barrier, leading to flooding of the alveolar space producing the classical chest radiograph of bilateral pulmonary infiltrates. In this study, we employed lung protective ventilation strategies in patients without acute lung injury (ALI) to determine whether mechanical ventilation with lower tidal volume would provide more clinical benefits to patients without ALI.

  18. Cardiotrophin-1 attenuates endotoxin-induced acute lung injury.

    PubMed

    Pulido, E J; Shames, B D; Pennica, D; O'leary, R M; Bensard, D D; Cain, B S; McIntyre, R C

    1999-06-15

    Cardiotrophin-1 (CT-1) is a recently discovered member of the gp130 cytokine family, which includes IL-6, IL-11, leukemia inhibitory factor, ciliary neurotrophic factor, and oncostatin M. Recent evidence suggests that, like other members of this family, CT-1 may possess anti-inflammatory properties. We hypothesized that in vivo CT-1 administration would attenuate endotoxin (ETX)-induced acute lung injury. We studied the effects of CT-1 (100 microgram/kg ip, 10 min prior to ETX) in a rat model of ETX-induced acute lung injury (Salmonella typhimurium lipopolysaccharide, 20 mg/kg ip). Six hours after ETX, lungs were harvested for determination of neutrophil accumulation (myeloperoxidase, MPO, assay) and lung edema (wet-to-dry weight ratio). Mechanisms of pulmonary vasorelaxation were examined in isolated pulmonary artery rings at 6 h by interrogating endothelium-dependent (response to acetylcholine) and endothelium-independent (response to sodium nitroprusside) relaxation following alpha-adrenergic (phenylephrine)-stimulated preconstriction. CT-1 abrogated the endotoxin-induced lung neutrophil accumulation: 2.3 +/- 0.2 units MPO/g wet lung (gwl) vs 6. 3 +/- 0.3 units MPO/gwl in the ETX group (P < 0.05 vs ETX, P > 0.05 vs control). Similarly, CT-1 prevented ETX-induced lung edema: wet-to-dry-weight ratio, 4.473 +/- 0.039 vs 4.747 +/- 0.039 in the ETX group (P < 0.05 vs ETX, P > 0.05 vs control). Endotoxin caused significant impairment of both endothelium-dependent and -independent pulmonary vasorelaxation, and CT-1 attenuated this injury. Thus, cardiotrophin-1 possesses significant anti-inflammatory properties in a model of endotoxin-induced acute lung injury. Copyright 1999 Academic Press.

  19. Effect of dexmedetomidine on lung ischemia-reperfusion injury

    PubMed Central

    JIANG, LILI; LI, LI; SHEN, JINMEI; QI, ZEYOU; GUO, LIANG

    2014-01-01

    Dexmedetomidine, a specific selective α2-adrenergic agonist, does not only have the characteristics of being a sedative and analgesic, but also exhibits a protective role in brain ischemia-reperfusion injury and inhibits the inflammation in animals with sepsis. The objective of the present study was to investigate whether dexmedetomidine is capable of attenuating rat pulmonary damage induced by ischemia-reperfusion injury, which is a type of acute sterile lung injury. Sprague-Dawley rats were randomly assigned into six groups: The sham-operated (sham) group, the lung ischemia-reperfusion (I/R) group, intravenous injection of dexmedetomidine 2.5 μg/kg/h (Dex2.5) or 5 μg/kg/h (Dex5) for 1 h prior to ischemia, combination of α2-adrenergic antagonist yohimbine prior to dexmedetomidine pre-treatment (Dex+Yoh) and pre-administration of yohimbine alone (Yoh) prior to ischemia. Lung injury was assessed by the histopathological changes, arterial blood gas, wet/dry (w/d) weight ratio and myeloperoxidase (MPO) activity of the lung. The concentration of tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6) and monocyte chemoattractant protein-1 (MCP-1) in bronchoalveolar lavage fluid (BALF) was measured by an enzyme-linked immunosorbent assay. The expression of toll-like receptor-4 (TLR4) and myeloid differentiation factor 88 (MyD88) mRNA in the lung were determined by quantitative PCR, and phosphorylated levels of c-Jun N-terminal kinase (JNK) and extracellular signal-regulated kinase (ERK)1/2 were determined by western blotting. Pre-treatment with dexmedetomidine significantly reduced the lung injury, w/d weight ratio and MPO activity, and decreased the concentration of TNF-α, IL-6 and MCP-1 in BALF compared with the I/R group. The expression of TLR4 and MyD88 mRNA and the levels of phosphorylated JNK and ERK1/2 in the lung tissue were markedly downregulated by intravenous injection of dexmedetomidne for 1 h prior to lung I/R. The protective effects of dexmedetomidine

  20. Sports-related lung injury during breath-hold diving.

    PubMed

    Mijacika, Tanja; Dujic, Zeljko

    2016-12-01

    The number of people practising recreational breath-hold diving is constantly growing, thereby increasing the need for knowledge of the acute and chronic effects such a sport could have on the health of participants. Breath-hold diving is potentially dangerous, mainly because of associated extreme environmental factors such as increased hydrostatic pressure, hypoxia, hypercapnia, hypothermia and strenuous exercise.In this article we focus on the effects of breath-hold diving on pulmonary function. Respiratory symptoms have been reported in almost 25% of breath-hold divers after repetitive diving sessions. Acutely, repetitive breath-hold diving may result in increased transpulmonary capillary pressure, leading to noncardiogenic oedema and/or alveolar haemorrhage. Furthermore, during a breath-hold dive, the chest and lungs are compressed by the increasing pressure of water. Rapid changes in lung air volume during descent or ascent can result in a lung injury known as pulmonary barotrauma. Factors that may influence individual susceptibility to breath-hold diving-induced lung injury range from underlying pulmonary or cardiac dysfunction to genetic predisposition.According to the available data, breath-holding does not result in chronic lung injury. However, studies of large populations of breath-hold divers are necessary to firmly exclude long-term lung damage. Copyright ©ERS 2016.

  1. Role of kinase suppressor of ras-1 in lipopolysaccharide-induced acute lung injury.

    PubMed

    Li, Xiang; Gulbins, Erich; Zhang, Yang

    2012-01-01

    Kinase suppressor of ras-1 (Ksr1) has been recently shown to be a central signaling molecule in the host response to Pseudomonas aeruginosa infections in the lung. Ksr1 functions to regulate the release of nitric oxide (NO)-radicals upon P. aeruginosa infections. Ksr1 also enhances Raf-1/MEK/ERK signaling and is involved in a variety of cellular responses, including cell differentiation, proliferation, and apoptosis. Here, we investigated whether Ksr1 is involved in the host immune response to lipopolysaccharide (LPS), one of the major components of gram-negative bacteria, in the lung. To this end, we induced an acute lung injury in wild type and Ksr1-deficient mice by intratracheal instillation of LPS. We found that LPS-induces acute lung injury, as characterized by cytokine expression, neutrophil infiltration and protein extrusion in wildtype mice. Ksr1-deficient mice showed a very similar reaction to LPS as the wildtype mice. In freshly isolated alveolar macrophages from wild type and Ksr1-deficient mice, LPS increased ERK activation, nuclear translocation of NFĸB and expression of inflammatory cytokines and chemokines in a similar pattern. Inhibition of Src or Raf-1 blocked LPS-induced ERK activation. Taken together, these findings indicate that Ksr1 plays a dispensable role in LPS-induced ERK activation in alveolar macrophages and does not contribute to the development of acute lung injury in the LPS model.

  2. Postexposure aerosolized heparin reduces lung injury in chlorine-exposed mice

    PubMed Central

    Zarogiannis, Sotirios G.; Wagener, Brant M.; Basappa, Susanna; Doran, Stephen; Rodriguez, Cilina A.; Jurkuvenaite, Asta; Pittet, Jean Francois

    2014-01-01

    Chlorine (Cl2) is a highly reactive oxidant gas that, when inhaled, may cause acute lung injury culminating in death from respiratory failure. In this study, we tested the hypothesis that exposure of mice to Cl2 causes intra-alveolar and systemic activation of the coagulation cascade that plays an important role in development of lung injury. C57Bl/6 mice were exposed to Cl2 (400 for 30 min or 600 ppm for 45 min) in environmental chambers and then returned to room air for 1 or 6 h. Native coagulation (NATEM) parameters such as blood clotting time and clot formation time were measured in whole blood by the viscoelastic technique. D-dimers and thrombin-anti-thrombin complexes were measured in both plasma and bronchoalveolar lavage fluid (BALF) by ELISA. Our results indicate that mice exposed to Cl2 gas had significantly increased clotting time, clot formation time, and D-dimers compared with controls. The thrombin-anti-thrombin complexes were also increased in the BALF of Cl2 exposed animals. To test whether increased coagulation contributed to the development of acute lung injury, mice exposed to Cl2 and returned to room air were treated with aerosolized heparin or vehicle for 20 min. Aerosolized heparin significantly reduced protein levels and the number of inflammatory cells in the BALF at 6 h postexposure. These findings highlight the importance of coagulation abnormities in the development of Cl2-induced lung injury. PMID:25038191

  3. Aminophylline treatment in meconium-induced acute lung injury in a rabbit model.

    PubMed

    Mokra, D; Mokry, J; Tatarkova, Z; Redfors, B; Petraskova, M; Calkovska, A

    2007-11-01

    Administration of methylxanthines may diminish meconium-induced acute lung injury. Meconium-instilled rabbits intravenously received aminophylline (2.0 mg/kg) at two doses 0.5 h and 2.5 h after meconium instillation or were left without treatment, and were oxygen-ventilated for additional 5 h. At the end of experiment, lungs and trachea were excised. Within 5 h after the first dose of treatment, aminophylline significantly improved gas exchange and decreased right-to-left pulmonary shunts, central venous pressure, and ventilatory pressures. Moreover, aminophylline reduced meconium-induced lung edema formation, airway hyperreactivity to histamine, count of neutrophils in bronchoalveolar lavage fluid associated with higher total white blood cells and neutrophils in the blood, and diminished oxidative modifications of proteins and lipids in lung tissue compared with the non-treated meconium-instilled group. In a rabbit model of the meconium aspiration syndrome, aminophylline treatment enhanced pulmonary functions and alleviated oxidative injury and changes in airway reactivity related to lung inflammation.

  4. First-pass studies of acute lung injury.

    PubMed

    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.

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

    PubMed

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

    2015-01-01

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

  6. Grape seed and skin extract protects against bleomycin-induced oxidative stress in rat lung.

    PubMed

    Khazri, Olfa; Charradi, Kamel; Limam, Ferid; El May, Michelle Veronique; Aouani, Ezzedine

    2016-07-01

    Lung fibrosis is a common side effect of the chemotherapeutic agent bleomycin and current evidence suggests that reactive oxygen species play a key role in the development of lung injury. We examined whether grape seed and skin extract (GSSE), a polyphenolic mixture exhibiting antioxidant properties, is able to protect against bleomycin-induced lung oxidative stress and injury. Rats were pre-treated during three weeks either with vehicle (ethanol 10% control) or GSSE (4g/kg), then administered with a single high dose bleomycin (15mg/kg) at the 7th day. Bleomycin increased lung lipoperoxidation, carbonylation and decreased antioxidant enzyme activities as catalase (CAT), superoxide dismutase (SOD) and glutathione peroxidase (GPx). Bleomycin also induced copper depletion from the lung and iron accumulation within the lung, but had no effect on either zinc nor manganese. Correlatively bleomycin decreased the copper associated enzyme tyrosinase, increased the zinc dependent lactate dehydrogenase (LDH) and did not affect the manganese dependent glutamine synthetase. GSSE efficiently counteracted almost all bleomycin-induced oxidative stress, biochemical and morphological changes of lung tissue. Data suggest that GSSE exerts potent antioxidant properties that could find potential application in the protection against bleomycin-induced lung fibrosis. Copyright © 2016. Published by Elsevier Masson SAS.

  7. Dose impact in radiographic lung injury following lung SBRT: Statistical analysis and geometric interpretation

    SciTech Connect

    Yu, Victoria; Kishan, Amar U.; Cao, Minsong; Low, Daniel; Lee, Percy; Ruan, Dan

    2014-03-15

    Purpose: To demonstrate a new method of evaluating dose response of treatment-induced lung radiographic injury post-SBRT (stereotactic body radiotherapy) treatment and the discovery of bimodal dose behavior within clinically identified injury volumes. Methods: Follow-up CT scans at 3, 6, and 12 months were acquired from 24 patients treated with SBRT for stage-1 primary lung cancers or oligometastic lesions. Injury regions in these scans were propagated to the planning CT coordinates by performing deformable registration of the follow-ups to the planning CTs. A bimodal behavior was repeatedly observed from the probability distribution for dose values within the deformed injury regions. Based on a mixture-Gaussian assumption, an Expectation-Maximization (EM) algorithm was used to obtain characteristic parameters for such distribution. Geometric analysis was performed to interpret such parameters and infer the critical dose level that is potentially inductive of post-SBRT lung injury. Results: The Gaussian mixture obtained from the EM algorithm closely approximates the empirical dose histogram within the injury volume with good consistency. The average Kullback-Leibler divergence values between the empirical differential dose volume histogram and the EM-obtained Gaussian mixture distribution were calculated to be 0.069, 0.063, and 0.092 for the 3, 6, and 12 month follow-up groups, respectively. The lower Gaussian component was located at approximately 70% prescription dose (35 Gy) for all three follow-up time points. The higher Gaussian component, contributed by the dose received by planning target volume, was located at around 107% of the prescription dose. Geometrical analysis suggests the mean of the lower Gaussian component, located at 35 Gy, as a possible indicator for a critical dose that induces lung injury after SBRT. Conclusions: An innovative and improved method for analyzing the correspondence between lung radiographic injury and SBRT treatment dose has

  8. Glycyrrhetinic acid alleviates radiation-induced lung injury in mice

    PubMed Central

    Chen, Jinmei; Zhang, Weijian; Zhang, Lurong; Zhang, Jiemin; Chen, Xiuying; Yang, Meichun; Chen, Ting; Hong, Jinsheng

    2017-01-01

    Radiation-induced lung injury (RILI) is a common complication of thoracic radiotherapy, but efficacious therapy for RILI is lacking. This study ascertained whether glycyrrhetinic acid (GA; a functional hydrolyzed product of glycyrrhizic acid, which is extracted from herb licorice) can protect against RILI and investigated its relationship to the transforming growth factor (TGF)-β1/Smads signaling pathway. C57BL/6 mice were divided into four groups: a control group, a GA group and two irradiation (IR) groups. IR groups were exposed to a single fraction of X-rays (12 Gy) to the thorax and administered normal saline (IR + NS group) or GA (IR + GA group). Two days and 17 days after irradiation, histologic analyses were performed to assess the degree of lung injury, and the expression of TGF-β1, Smad2, Smad3 and Smad7 was recorded. GA administration mitigated the histologic changes of lung injury 2 days and 17 days after irradiation. Protein and mRNA expression of TGF-β1, Smad2 and Smad3, and the mRNA level of Smad7, in lung tissue were significantly elevated after irradiation. GA decreased expression of TGF-β1, Smad2 and Smad3 in lung tissue, but did not increase Smad7 expression. GA can protect against early-stage RILI. This protective effect may be associated with inhibition of the TGF-β1/Smads signaling pathway. PMID:27672101

  9. [Transfusion-associated lung injury (TRALI): obvious and incomprehensible].

    PubMed

    Bulanov, A Iu

    2009-01-01

    Acute transfusion-associated lung injury (TRALI) is an acute lung injury associated with and develops within 6 hours after the transfusion of components and blood preparations. Today there are no uniform views on the pathogenesis of TRALI. The discussion of immune and non-immune mechanisms is relevant. The key link of the former is that the presence of anti-leukocytic antibodies in a donor or a recipient and their interaction during transfusion with the leukocytes of the recipient or the donor, respectively; that of the latter link is the accumulation of biologically active substances in the transfusion media during storage and their passive administration to the recipient during transfusion. In both cases, the total link is drastic increased pulmonary capillary permeability. The clinical presentation of TRALI is nonspecific and generally similar to that of the adult respiratory distress syndrome and lung injuries of another genesis. It is necessary to make its differential diagnosis with allergic reactions, the transfusion of bacterially contaminated media and mainly with circulatory overload. Specific treatments for transfusion-associated lung injury are unavailable. Diferent variants of respiratory therapy are effective. Prevention of TRALI is mainly based on its immune mechanism. The leading direction of its prevention is to select donors.

  10. Betulin attenuates lung and liver injuries in sepsis.

    PubMed

    Zhao, Hongyu; Liu, Zhenning; Liu, Wei; Han, Xinfei; Zhao, Min

    2016-01-01

    Sepsis is a complex condition with unacceptable mortality. Betulin is a natural extract with multiple bioactivities. This study aims to evaluate the potential effects of betulin on lung and liver injury in sepsis. Cecal ligation and puncture was used to establish the rat model of sepsis. A single dose of 4mg/kg or 8mg/kg betulin was injected intraperitoneally immediately after the model establishment. The survival rate was recorded every 12h for 96h. The organ injury was examined using hematoxylin and eosin staining and serum biochemical test. The levels of proinflammatory cytokines and high mobility group box 1 in the serum were measured using ELISA. Western blotting was used to detect the expression of proteins in NF-κB and MAPK signaling pathways. Betulin treatment significantly improved the survival rate of septic rats, and attenuated lung and liver injury in sepsis, including the reduction of lung wet/dry weight ratio and activities of alanine aminotransferase and aspartate aminotransferase in the serum. In addition, levels of tumor necrosis factor-α, interleukin-1β, interleukin-6 and high mobility group box 1 in the serum were also lowered by betulin treatment. Moreover, sepsis-induced activation of the NF-κB and MAPK signaling pathway was inhibited by betulin as well. Our findings demonstrate the protective effect of betulin in lung and liver injury in sepsis. This protection may be mediated by its anti-inflammatory and NF-κB and MAPK inhibitory effects.

  11. Efficacy of Methylprednisolone in Preventing Lung Injury Following Pulmonary Thromboendarterectomy

    PubMed Central

    Auger, William R.; Marsh, James J.; Devendra, Gehan; Spragg, Roger G.; Kim, Nick H.; Channick, Richard N.; Jamieson, Stuart W.; Madani, Michael M.; Manecke, Gerard R.; Roth, David M.; Shragg, Gordon P.; Fedullo, Peter F.

    2012-01-01

    Background: We sought to determine the efficacy and safety of perioperative treatment with methylprednisolone on the development of lung injury after pulmonary thromboendarterectomy. Methods: This was a randomized, prospective, double-blind, placebo-controlled study of 98 adult patients with chronic thromboembolic pulmonary hypertension who were undergoing pulmonary thromboendarterectomy at a single institution. The patients received either placebo (n = 47) or methylprednisolone (n = 51) (30 mg/kg in the cardiopulmonary bypass prime, 500 mg IV bolus following the final circulatory arrest, and 250 mg IV bolus 36 h after surgery). The primary end point was the presence of lung injury as determined by two independent, blinded physicians using prospectively defined criteria. The secondary end points included ventilator-free, ICU-free, and hospital-free days and selected levels of cytokines in the blood and in BAL fluid. Results: The incidence of lung injury was similar in both treatment groups (45% placebo, 41% steroid; P = .72). There were no statistical differences in the secondary clinical end points between treatment groups. Treatment with methylprednisolone, compared with placebo, was associated with a statistically significant reduction in plasma IL-6 and IL-8, a significant increase in plasma IL-10, and a significant reduction in postoperative IL-1ra and IL-6, but not IL-8 in BAL fluid obtained 1 day after surgery. Conclusions: Perioperative methylprednisolone does not reduce the incidence of lung injury following pulmonary thromboendarterectomy surgery despite having an antiinflammatory effect on plasma and lavage cytokine levels. PMID:21835900

  12. Preventive Effects of Carnosine on Lipopolysaccharide-induced Lung Injury

    PubMed Central

    Tanaka, Ken-Ichiro; Sugizaki, Toshifumi; Kanda, Yuki; Tamura, Fumiya; Niino, Tomomi; Kawahara, Masahiro

    2017-01-01

    Acute respiratory distress syndrome (ARDS) is a potentially devastating form of acute lung injury, which involves neutrophilic inflammation and pulmonary cell death. Reactive oxygen species (ROS) play important roles in ARDS development. New compounds for inhibiting the onset and progression of ARDS are required. Carnosine (β-alanyl-L-histidine) is a small di-peptide with numerous activities, including antioxidant effects, metal chelation, proton buffering capacity and the inhibition of protein carbonylation and glycoxidation. We have examined the preventive effects of carnosine on tissue injury, oedema and inflammation in a murine model for ARDS. Oral administration of carnosine suppressed lipopolysaccharide (LPS)-induced vascular permeability, tissue injury and inflammation in the lung. In vivo imaging analysis revealed that LPS administration increased the level of ROS and that this increase was inhibited by carnosine administration. Carnosine also suppressed LPS-induced neutrophilic inflammation (evaluated by activation of myeloperoxidase in the lung and increased extracellular DNA in bronchoalveolar lavage fluid). Furthermore, carnosine administration suppressed the LPS-induced endoplasmic reticulum stress response in vivo. These results suggest that the oral administration of carnosine suppresses LPS-induced lung injury via carnosine’s ROS-reducing activity. Therefore, carnosine may be beneficial for suppressing the onset and progression of ARDS. PMID:28205623

  13. Susceptibility of the Aging Lung to Environmental Injury

    PubMed Central

    Wang, Lei; Green, Francis H.Y.; Smiley-Jewell, Suzette M.

    2015-01-01

    With an ever increasing number of elderly individuals in the world, a better understanding of the issues associated with aging and the environment is needed. The respiratory system is one of the primary interfaces between the body and the external environment. An expanding number of studies suggest that the aging pulmonary system (>65 years) is at increased risk for adverse health effects from environmental insult, such as by air pollutants, infection, and climate change. However, the mechanism(s) for increased susceptibility in this subpopulation is not well understood. In this review, we provide a limited, but comprehensive overview of how the lung ages, examples of environmental exposures associated with injury to the aging lung and potential mechanisms underlining the increased vulnerability of the aging lung to injury from environmental factors. PMID:20941655

  14. Phosphatidic acid signaling mediates lung cytokine expression and lung inflammatory injury after hemorrhage in mice.

    PubMed

    Abraham, E; Bursten, S; Shenkar, R; Allbee, J; Tuder, R; Woodson, P; Guidot, D M; Rice, G; Singer, J W; Repine, J E

    1995-02-01

    Because phosphatidic acid (PA) pathway signaling may mediate many basic reactions involving cytokine-dependent responses, we investigated the effects of CT1501R, a functional inhibitor of the enzyme lysophosphatidic acid acyltransferase (LPAAT) which converts lysophosphatidic acid (Lyso-PA) to PA. We found that CT1501R treatment not only prevented hypoxia-induced PA increases and lyso-PA consumption in human neutrophils, but also prevented neutrophil chemotaxis and adherence in vitro, and lung injury and lung neutrophil accumulation in mice subjected to hemorrhage and resuscitation. In addition, CT1501R treatment prevented increases in mRNA levels and protein production of a variety of proinflammatory cytokines in multiple lung cell populations after blood loss and resuscitation. Our results indicate the fundamental role of PA metabolism in the development of acute inflammatory lung injury after blood loss.

  15. A biomechanical model of pendelluft induced lung injury.

    PubMed

    Alzahrany, Mohammed; Banerjee, Arindam

    2015-07-16

    Lung ventilation using high frequency oscillatory techniques have been documented to attain adequate gas exchange through various gas transport mechanisms. Among them, the pendelluft flow is considered one of the most crucial mechanisms. In this work, we computationally investigate the induction of abnormal mechanical stresses and a regionally trapped volume of gas due to pendelluft flow. Large eddy simulation was used to model the turbulence in an upper tracheobronchial lung geometry that was derived from CT scans. The pendelluft flow was captured by modeling physiological boundary conditions at the truncated level of the lung model that is sensitive to the coupled resistance and compliance of individual patients. The flow-volume and volume-pressure loops are characterized by irregular shapes and suggest abnormal regional lung ventilation. Incomplete loops were observed indicating gas trapping in these regions signifying a potential for local injury due to incomplete ventilation from a residual volume build-up at the end of the expiration phase. In addition, the gas exchange between units was observed to create a velocity gradient causing a region of high wall shear stress surrounding the carina ridges. The recurrence of the pendelluft flow could cause a rupture to the lung epithelium layer. The trapped gas and wall shear stress were observed to amplify with increasing compliance asymmetry and ventilator operating frequency. In general, despite the significant contribution of the pendelluft flow to the gas exchange augmentation there exists significant risks of localized lung injury, phenomena we describe as pendelluft induced lung injury or PILI. Copyright © 2015 Elsevier Ltd. All rights reserved.

  16. Pulmonary expression of nitric oxide synthase isoforms in sheep with smoke inhalation and burn injury.

    PubMed

    Cox, Robert A; Jacob, Sam; Oliveras, Gloria; Murakami, Kazunori; Enkhbaatar, Perenlei; Traber, Lillian; Schmalstieg, Frank C; Herndon, David N; Traber, Daniel L; Hawkins, Hal K

    2009-03-01

    Previous studies have indicated increased plasma levels of inducible nitric oxide synthase in lung. This study further examines the pulmonary expression of nitric oxide synthase (NOS) isoforms in an ovine model of acute lung injury induced by smoke inhalation and burn injury (S+B injury). Female range bred sheep (4 per group) were sacrificed at 4, 8, 12, 24, and 48 hours after injury and immunohistochemistry was performed in tissues for various NOS isoforms. The study indicates that in uninjured sheep lung, endothelial (eNOS) is constitutively expressed in the endothelial cells associated with the airways and parenchyma, and in macrophages. Similarly, neuronal (nNOS) is constitutively present in the mucous cells of the epithelium and in neurons of airway ganglia. In uninjured lung, inducible (iNOS) was present in bronchial secretory cells and macrophages. In tissue after S+B injury, new expression of iNOS was evident in bronchial ciliated cells, basal cells, and mucus gland cells. In the parenchyma, a slight increase in iNOS immunostaining was seen in type I cells at 12 and 24 hours after injury only. Virtually no change in eNOS or nNOS was seen after injury.

  17. Oxidant Mechanisms in Renal Injury and Disease.

    PubMed

    Ratliff, Brian B; Abdulmahdi, Wasan; Pawar, Rahul; Wolin, Michael S

    2016-07-20

    A common link between all forms of acute and chronic kidney injuries, regardless of species, is enhanced generation of reactive oxygen species (ROS) and reactive nitrogen species (RNS) during injury/disease progression. While low levels of ROS and RNS are required for prosurvival signaling, cell proliferation and growth, and vasoreactivity regulation, an imbalance of ROS and RNS generation and elimination leads to inflammation, cell death, tissue damage, and disease/injury progression. Many aspects of renal oxidative stress still require investigation, including clarification of the mechanisms which prompt ROS/RNS generation and subsequent renal damage. However, we currently have a basic understanding of the major features of oxidative stress pathology and its link to kidney injury/disease, which this review summarizes. The review summarizes the critical sources of oxidative stress in the kidney during injury/disease, including generation of ROS and RNS from mitochondria, NADPH oxidase, and inducible nitric oxide synthase. The review next summarizes the renal antioxidant systems that protect against oxidative stress, including superoxide dismutase and catalase, the glutathione and thioredoxin systems, and others. Next, we describe how oxidative stress affects kidney function and promotes damage in every nephron segment, including the renal vessels, glomeruli, and tubules. Despite the limited success associated with the application of antioxidants for treatment of kidney injury/disease thus far, preventing the generation and accumulation of ROS and RNS provides an ideal target for potential therapeutic treatments. The review discusses the shortcomings of antioxidant treatments previously used and the potential promise of new ones. Antioxid. Redox Signal. 25, 119-146.

  18. Oxidant Mechanisms in Renal Injury and Disease

    PubMed Central

    Ratliff, Brian B.; Abdulmahdi, Wasan; Pawar, Rahul

    2016-01-01

    Abstract Significance: A common link between all forms of acute and chronic kidney injuries, regardless of species, is enhanced generation of reactive oxygen species (ROS) and reactive nitrogen species (RNS) during injury/disease progression. While low levels of ROS and RNS are required for prosurvival signaling, cell proliferation and growth, and vasoreactivity regulation, an imbalance of ROS and RNS generation and elimination leads to inflammation, cell death, tissue damage, and disease/injury progression. Recent Advances: Many aspects of renal oxidative stress still require investigation, including clarification of the mechanisms which prompt ROS/RNS generation and subsequent renal damage. However, we currently have a basic understanding of the major features of oxidative stress pathology and its link to kidney injury/disease, which this review summarizes. Critical Issues: The review summarizes the critical sources of oxidative stress in the kidney during injury/disease, including generation of ROS and RNS from mitochondria, NADPH oxidase, and inducible nitric oxide synthase. The review next summarizes the renal antioxidant systems that protect against oxidative stress, including superoxide dismutase and catalase, the glutathione and thioredoxin systems, and others. Next, we describe how oxidative stress affects kidney function and promotes damage in every nephron segment, including the renal vessels, glomeruli, and tubules. Future Directions: Despite the limited success associated with the application of antioxidants for treatment of kidney injury/disease thus far, preventing the generation and accumulation of ROS and RNS provides an ideal target for potential therapeutic treatments. The review discusses the shortcomings of antioxidant treatments previously used and the potential promise of new ones. Antioxid. Redox Signal. 25, 119–146. PMID:26906267

  19. New insights into experimental evidence on atelectasis and causes of lung injury.

    PubMed

    Muders, Thomas; Wrigge, Hermann

    2010-06-01

    Development of atelectasis is common in both patients with and without lung injury during mechanical ventilation. Atelectasis might contribute to or attenuate lung injury by different possible mechanisms. Possible direct effects of atelectasis include inflammatory activation or infection of the affected regional lung tissues. In addition, the loss of aerated lung volume due to atelectasis in mechanically ventilated patients indirectly results in increased mechanical strain of the reduced number of ventilated lung regions, if ventilation is not adequately decreased. This study discusses possible mechanisms and interactions between atelectasis formation in the lungs and the development or aggravation of acute lung injury.

  20. Malondialdehyde-acetaldehyde-adducted protein inhalation causes lung injury.

    PubMed

    Wyatt, Todd A; Kharbanda, Kusum K; McCaskill, Michael L; Tuma, Dean J; Yanov, Daniel; DeVasure, Jane; Sisson, Joseph H

    2012-02-01

    that the lung surfactant protein is a biologically relevant target for malondialdehyde and acetaldehyde adduction. These data further implicate MAA-adduct formation as a potential mechanism for smoke- and alcohol-induced lung injury.

  1. Antioxidant effects of selenium on lung injury in paraquat intoxicated rats

    USGS Publications Warehouse

    Kim, K.S.; Suh, G.J.; Kwon, W.Y.; Kwak, Y.H.; Lee, Kenneth; Lee, H.J.; Jeong, K.Y.; Lee, M.W.

    2012-01-01

    CONTEXT: Paraquat (PQ) causes lethal intoxication by inducing oxidant injury to the lung. Selenium is a cofactor for glutathione peroxidase (GPx), which is one of the major endogenous antioxidant enzymes. OBJECTIVE: To determine whether selenium post-treatment activates GPx, decreases lung injury, and improves survival in PQ intoxicated rats. MATERIALS AND METHODS: Male Spraque-Dawley rats were categorized into three groups: sham (n = 6), PQ (n = 12), and PQ + Se (n = 12). In the PQ and PQ + Se groups, 50 mg/kg of PQ was administered intraperitoneally. After 10 minutes, 60 μg/kg of Se (PQ + Se) or saline (PQ) was administered via the tail vein. Six rats per group were euthanized 6 hours or 24 hours later. Lung tissues were harvested for the measurement of GPx activity, reduced glutathione (GSH), glutathione disulfide (GSSG) and malondialdehyde (MDA) and for histological analysis. Using separated set of rats, survival of PQ (n = 10) and PQ + Se (n = 10) were observed for 72 hours. RESULTS: GPx activity in the PQ group at the 6-hour and 24-hour time points was lower than in the sham group (p CONCLUSION: Single dose of selenium post-treatment activates GPx and attenuates lipid peroxidation and lung injury early after paraquat intoxication, but does not improve 72 hours of survival.

  2. Xanthine oxidase is increased and contributes to paraquat-induced acute lung injury.

    PubMed

    Waintrub, M L; Terada, L S; Beehler, C J; Anderson, B O; Leff, J A; Repine, J E

    1990-04-01

    Two lines of investigation suggested that xanthine oxidase- (XO) derived O2 metabolites contribute to paraquat- (PQ) induced acute lung injury. First, PQ treatment increased lung XO activity and decreased lung xanthine dehydrogenase activity. Second, lung albumin uptake increased compared with control values in untreated XO-replete but not tungsten-treated XO-depleted lungs in rats treated with PQ.

  3. Lung injury in dimethyl sulfate poisoning

    SciTech Connect

    Ip, M.; Wong, K.L.; Wong, K.F.; So, S.Y.

    1989-02-01

    Two manual laborers were exposed to dimethyl sulfate during work and sustained mucosal injury to the eyes and respiratory tract. In one of them, noncardiogenic pulmonary edema occurred and improved with high-dose methylprednisolone. On follow-up for 10 months, this patient developed persistent productive cough with no evidence of bronchiectasis or bronchial hyperreactivity.

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

    SciTech Connect

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

    2011-02-01

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

  5. N-acetylcysteine abrogates acute lung injury induced by endotoxin.

    PubMed

    Kao, Shang Jyh; Wang, David; Lin, Hen I; Chen, Hsing I

    2006-01-01

    1. Acute lung injury (ALI) or acute respiratory distress syndrome is a serious clinical problem with high mortality. N-Acetylcysteine (NAC) is an anti-oxidant and a free radical scavenger. It has been reported recently that NAC ameliorates organ damage induced by endotoxin (lipopolysaccharide; LPS) in conscious rats. The present study was designed to evaluate the effects of NAC on LPS-induced ALI and other changes in anaesthetized rats. 2. Sprague-Dawley rats were anaesthetized with pentobarbital (40 mg/kg, i.p.). Endotracheal intubation was performed to provide artificial ventilation. Arterial pressure and heart rate were monitored. The extent of ALI was evaluated with the lung weight (LW)/bodyweight ratio, LW gain, exhaled nitric oxide (NO) and protein concentration in bronchoalveolar lavage (PCBAL). Haematocrit, white blood cells, plasma nitrate/nitrite, methyl guanidine (MG), tumour necrosis factor (TNF)-alpha and interleukin (IL)-1b were measured. Pathological changes in the lung were examined and evaluated. 3. Endotoxaemia was produced by injection of 10 mg/kg, i.v., LPS (Escherichia coli). Animals were randomly divided into three groups. In the vehicle group, rats received an i.v. drip of physiological saline solution (PSS) at a rate of 0.3 mL/h. The LPS group received an i.v. drip of PSS for 1 h, followed by LPS (10 mg/kg by slow blous injection, i.v., over 1-2 min). Rats in the LPS + NAC group received NAC by i.v. drip at a rate of 150 mg/kg per h (0.3 mL/h) for 60 min starting 10 min before LPS administration (10 mg/kg by slow blous injection, i.v., over 1-2 min). Each group was observed for a period of 6 h. 4. N-Acetylcysteine treatment improved the LPS-induced hypotension and leukocytopenia. It also reduced the extent of ALI, as evidenced by reductions in LW changes, exhaled NO, PCBAL and lung pathology. In addition, NAC diminished the LPS-induced increases in nitrate/nitrite, MG, TNF-a and IL-1b. 5. In another series of experiments, LPS increased the

  6. Acute lung injury after inhalation of nitric acid.

    PubMed

    Kao, Shih Ling; Yap, Eng Soo; Khoo, See Meng; Lim, Tow Keang; Mukhopadhyay, Amartya; Teo, Sylvia Tzu Li

    2008-12-01

    We report two cases of acute lung injury after the inhalation of nitric acid fumes in an industrial accident. The first patient, who was not using a respirator and standing in close proximity to the site of spillage of concentrated nitric acid, presented within 12 h with worsening dyspnea and required noninvasive ventilation for type 1 respiratory failure. The second case presented 1 day later with similar symptoms, but only required supportive treatment with high-flow oxygen. Both patients' chest radiographs showed widespread bilateral airspace shadows consistent with acute lung injury. Both received treatment with systemic steroids. They were discharged from hospital 5 days postexposure. Initial lung function test showed a restrictive pattern that normalized by 3 weeks postexposure. This case series describes the natural history after acute inhalation of nitric acid fumes, and demonstrates that the severity of lung injury is directly dependent on the exposure level. It also highlights the use of noninvasive ventilatory support in the management of such patients.

  7. A micro-CT analysis of murine lung recruitment in bleomycin-induced lung injury

    PubMed Central

    Shofer, Scott; Badea, Cristian; Qi, Yi; Potts, Erin; Foster, W. Michael; Johnson, G. Allan

    2008-01-01

    The effects of lung injury on pulmonary recruitment are incompletely understood. X-ray computed tomography (CT) has been a valuable tool in assessing changes in recruitment during lung injury. With the development of preclinical CT scanners designed for thoracic imaging in rodents, it is possible to acquire high-resolution images during the evolution of a pulmonary injury in living mice. We quantitatively assessed changes in recruitment caused by intratracheal bleomycin at 1 and 3 wk after administration using micro-CT in 129S6/SvEvTac mice. Twenty female mice were administered 2.5 U of bleomycin or saline and imaged with micro-CT at end inspiration and end expiration. Mice were extubated and allowed to recover from anesthesia and then reevaluated in vivo for quasi-static compliance measurements, followed by harvesting of the lungs for collagen analysis and histology. CT images were converted to histograms and analyzed for mean lung attenuation (MLA). MLA was significantly greater for bleomycin-exposed mice at week 1 for both inspiration (P < 0.0047) and exhalation (P < 0.0377) but was not significantly different for week 3 bleomycin-exposed mice. However, week 3 bleomycin-exposed mice did display significant increases in MLA shift from expiration to inspiration compared with either group of control mice (P < 0.005), suggesting increased lung recruitment at this time point. Week 1 bleomycin-exposed mice displayed normal shifts in MLA with inspiration, suggesting normal lung recruitment despite significant radiographic and histological changes. Lung alveolar recruitment is preserved in a mouse model of bleomycin-induced parenchymal injury despite significant changes in radiographic and physiological parameters. PMID:18566189

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

    PubMed

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

    2012-03-01

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

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

    PubMed Central

    2012-01-01

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

  10. [Protective effect of melatonin in rats with phosgene-induced lung injury].

    PubMed

    Zhang, Lin; Shen, Jie; Gan, Zheng-yi; He, Dai-kun; Zhong, Zhi-yue

    2012-11-01

    To investigate the antioxidant effect of melatonin (MT) in the rats with phosgene-induced lung injury and its possible mechanism. Fifty male SD rats were equally randomized into phosgene exposure group, air control group, MT treatment group, dexamethasone (DX) treatment group, and negative control group. All groups except the air control group were exposed to 8.33 mg/L phosgene for 5 min, and the MT treatment group, DX treatment group, and negative control group were injected with MT (10 mg/kg), DX (2.5 mg/kg), and 1% ethanol saline (1 ml/kg), respectively, via the caudal vein 1 hour after exposure. The rats were sacrificed 6h later. Then, the wet/dry ratio of the lung, the total protein content and neutrophil count in bronchoalveolar lavage fluid (BALF), and the malonaldehyde (MDA) content and superoxide dismutase (SOD) and myeloperoxidase (MPO) activities in lung homogenate were measured; pathological observation was made on the lung tissue under an optical microscope; the protein expression of inducible nitric oxide synthase (iNOS) and NF-κB in the lung tissue was measured by Western blot. Compared with the air control group, the phosgene exposure group showed significantly increased wet/dry ratio of the lung and total protein content and neutrophil count in BALF (P < 0.01) as well as significantly increased MDA content and MPO activity in the lung tissue (P < 0.05). Compared with the phosgene exposure group, the MT treatment group showed significantly decreased MDA content and MPO activity and significantly increased SOD activity (P < 0.01), and the MT treatment group and DX treatment group showed significantly decreased protein expression of iNOS and NF-κB (P < 0.01). MT has protective effect in phosgene-induced lung injury, and its protective mechanism may be associated with scavenging free radicals and inhibiting expression of iNOS and NF-κB.

  11. Genetic Targets of Hydrogen Sulfide in Ventilator-Induced Lung Injury – A Microarray Study

    PubMed Central

    Spassov, Sashko; Pfeifer, Dietmar; Strosing, Karl; Ryter, Stefan; Hummel, Matthias; Faller, Simone; Hoetzel, Alexander

    2014-01-01

    Recently, we have shown that inhalation of hydrogen sulfide (H2S) protects against ventilator-induced lung injury (VILI). In the present study, we aimed to determine the underlying molecular mechanisms of H2S-dependent lung protection by analyzing gene expression profiles in mice. C57BL/6 mice were subjected to spontaneous breathing or mechanical ventilation in the absence or presence of H2S (80 parts per million). Gene expression profiles were determined by microarray, sqRT-PCR and Western Blot analyses. The association of Atf3 in protection against VILI was confirmed with a Vivo-Morpholino knockout model. Mechanical ventilation caused a significant lung inflammation and damage that was prevented in the presence of H2S. Mechanical ventilation favoured the expression of genes involved in inflammation, leukocyte activation and chemotaxis. In contrast, ventilation with H2S activated genes involved in extracellular matrix remodelling, angiogenesis, inhibition of apoptosis, and inflammation. Amongst others, H2S administration induced Atf3, an anti-inflammatory and anti-apoptotic regulator. Morpholino mediated reduction of Atf3 resulted in elevated lung injury despite the presence of H2S. In conclusion, lung protection by H2S during mechanical ventilation is associated with down-regulation of genes related to oxidative stress and inflammation and up-regulation of anti-apoptotic and anti-inflammatory genes. Here we show that Atf3 is clearly involved in H2S mediated protection. PMID:25025333

  12. Attenuation of endoplasmic reticulum stress by caffeine ameliorates hyperoxia-induced lung injury.

    PubMed

    Teng, Ru-Jeng; Jing, Xigang; Michalkiewicz, Teresa; Afolayan, Adeleye J; Wu, Tzong-Jin; Konduri, Girija G

    2017-05-01

    Rodent pups exposed to hyperoxia develop lung changes similar to bronchopulmonary dysplasia (BPD) in extremely premature infants. Oxidative stress from hyperoxia can injure developing lungs through endoplasmic reticulum (ER) stress. Early caffeine treatment decreases the rate of BPD, but the mechanisms remain unclear. We hypothesized that caffeine attenuates hyperoxia-induced lung injury through its chemical chaperone property. Sprague-Dawley rat pups were raised either in 90 (hyperoxia) or 21% (normoxia) oxygen from postnatal day 1 (P1) to postnatal day 10 (P10) and then recovered in 21% oxygen until P21. Caffeine (20 mg/kg) or normal saline (control) was administered intraperitoneally daily starting from P2. Lungs were inflation-fixed for histology or snap-frozen for immunoblots. Blood caffeine levels were measured in treated pups at euthanasia and were found to be 18.4 ± 4.9 μg/ml. Hyperoxia impaired alveolar formation and increased ER stress markers and downstream effectors; caffeine treatment attenuated these changes at P10. Caffeine also attenuated the hyperoxia-induced activation of cyclooxygenase-2 and markers of apoptosis. In conclusion, hyperoxia-induced alveolar growth impairment is mediated, in part, by ER stress. Early caffeine treatment protects developing lungs from hyperoxia-induced injury by attenuating ER stress. Copyright © 2017 the American Physiological Society.

  13. Circulating Histones Are Mediators of Trauma-associated Lung Injury

    PubMed Central

    Abrams, Simon T.; Zhang, Nan; Manson, Joanna; Liu, Tingting; Dart, Caroline; Baluwa, Florence; Wang, Susan Siyu; Brohi, Karim; Kipar, Anja; Yu, Weiping

    2013-01-01

    Rationale: Acute lung injury is a common complication after severe trauma, which predisposes patients to multiple organ failure. This syndrome largely accounts for the late mortality that arises and despite many theories, the pathological mechanism is not fully understood. Discovery of histone-induced toxicity in mice presents a new dimension for elucidating the underlying pathophysiology. Objectives: To investigate the pathological roles of circulating histones in trauma-induced lung injury. Methods: Circulating histone levels in patients with severe trauma were determined and correlated with respiratory failure and Sequential Organ Failure Assessment (SOFA) scores. Their cause–effect relationship was studied using cells and mouse models. Measurements and Main Results: In a cohort of 52 patients with severe nonthoracic blunt trauma, circulating histones surged immediately after trauma to levels that were toxic to cultured endothelial cells. The high levels were significantly associated with the incidence of acute lung injury and SOFA scores, as well as markers of endothelial damage and coagulation activation. In in vitro systems, histones damaged endothelial cells, stimulated cytokine release, and induced neutrophil extracellular trap formation and myeloperoxidase release. Cellular toxicity resulted from their direct membrane interaction and resultant calcium influx. In mouse models, cytokines and markers for endothelial damage and coagulation activation significantly increased immediately after trauma or histone infusion. Pathological examinations showed that lungs were the predominantly affected organ with edema, hemorrhage, microvascular thrombosis, and neutrophil congestion. An anti-histone antibody could reduce these changes and protect mice from histone-induced lethality. Conclusions: This study elucidates a new mechanism for acute lung injury after severe trauma and proposes that circulating histones are viable therapeutic targets for improving survival

  14. Superoxide dismutase 3 dysregulation in a murine model of neonatal lung injury.

    PubMed

    Poonyagariyagorn, Hataya K; Metzger, Shana; Dikeman, Dustin; Mercado, Armando Lopez; Malinina, Alla; Calvi, Carla; McGrath-Morrow, Sharon; Neptune, Enid R

    2014-09-01

    Bronchopulmonary dysplasia (BPD), a common chronic respiratory disease that occurs after premature birth, is believed to be secondary to oxidative damage from hyperoxia and inflammation, which leads to impaired alveolar formation and chronic lung dysfunction. We hypothesized that extracellular superoxide dismutase (SOD)3, an antioxidant uniquely targeted to the extracellular matrix (ECM) and alveolar fluid, might have a different response (down-regulation) to hyperoxic injury and recovery in room air (RA), thereby contributing to the persistent airspace injury and inflammation. We used a murine BPD model using postnatal hyperoxia (O2) (4 or 5 d) followed by short-term recovery (14 d) in RA, which mimics the durable effects after injury during alveolar development. This was associated with significantly increased mRNA expression for antioxidant genes mediated by nuclear factor erythroid 2-related factor (Nrf2) in the O2 (n = 4) versus RA group (n = 5). SOD3, an Nrf2-independent antioxidant, was significantly reduced in the O2-exposed mice compared with RA. Immunohistochemistry revealed decreased and disrupted SOD3 deposition in the alveolar ECM of O2-exposed mice. Furthermore, this distinct hyperoxic antioxidant and injury profile was reproducible in murine lung epithelial 12 cells exposed to O2. Overexpression of SOD3 rescued the injury measures in the O2-exposed cells. We establish that reduced SOD3 expression correlates with alveolar injury measures in the recovered neonatal hyperoxic lung, and SOD3 overexpression attenuates hyperoxic injury in an alveolar epithelial cell line. Such findings suggest a candidate mechanism for the pathogenesis of BPD that may lead to targeted interventions.

  15. Superoxide Dismutase 3 Dysregulation in a Murine Model of Neonatal Lung Injury

    PubMed Central

    Poonyagariyagorn, Hataya K.; Metzger, Shana; Dikeman, Dustin; Mercado, Armando Lopez; Malinina, Alla; Calvi, Carla; McGrath-Morrow, Sharon

    2014-01-01

    Bronchopulmonary dysplasia (BPD), a common chronic respiratory disease that occurs after premature birth, is believed to be secondary to oxidative damage from hyperoxia and inflammation, which leads to impaired alveolar formation and chronic lung dysfunction. We hypothesized that extracellular superoxide dismutase (SOD)3, an antioxidant uniquely targeted to the extracellular matrix (ECM) and alveolar fluid, might have a different response (down-regulation) to hyperoxic injury and recovery in room air (RA), thereby contributing to the persistent airspace injury and inflammation. We used a murine BPD model using postnatal hyperoxia (O2) (4 or 5 d) followed by short-term recovery (14 d) in RA, which mimics the durable effects after injury during alveolar development. This was associated with significantly increased mRNA expression for antioxidant genes mediated by nuclear factor erythroid 2–related factor (Nrf2) in the O2 (n = 4) versus RA group (n = 5). SOD3, an Nrf2-independent antioxidant, was significantly reduced in the O2-exposed mice compared with RA. Immunohistochemistry revealed decreased and disrupted SOD3 deposition in the alveolar ECM of O2-exposed mice. Furthermore, this distinct hyperoxic antioxidant and injury profile was reproducible in murine lung epithelial 12 cells exposed to O2. Overexpression of SOD3 rescued the injury measures in the O2-exposed cells. We establish that reduced SOD3 expression correlates with alveolar injury measures in the recovered neonatal hyperoxic lung, and SOD3 overexpression attenuates hyperoxic injury in an alveolar epithelial cell line. Such findings suggest a candidate mechanism for the pathogenesis of BPD that may lead to targeted interventions. PMID:24673633

  16. Stevioside protects LPS-induced acute lung injury in mice.

    PubMed

    Yingkun, Nie; Zhenyu, Wang; Jing, Lin; Xiuyun, Lu; Huimin, Yu

    2013-02-01

    Stevioside, a diterpene glycoside component of Stevia rebaudiana, has been known to exhibit anti-inflammatory properties. To evaluate the effect and the possible mechanism of stevioside in lipopolysaccharide (LPS)-induced acute lung injury, male BALB/c mice were pretreated with stevioside or dexamethasone 1 h before intranasal instillation of LPS. Seven hours later, tumor necrosis factor-α, interleukin-1β, and interleukin-6 in bronchoalveolar lavage fluid (BALF) were measured by using enzyme-linked immunosorbent assay. The number of total cells, neutrophils, and macrophages in the BALF were also determined. The right lung was excised for histological examination and analysis of myeloperoxidase activity and nitrate/nitrite content. Cyclooxygenase 2 (COX-2), inducible NO synthase (iNOS), nuclear factor-kappa B (NF-κB), inhibitory kappa B protein were detected by western blot. The results showed that stevioside markedly attenuated the LPS-induced histological alterations in the lung. Stevioside inhibited the production of pro-inflammatory cytokines and the expression of COX-2 and iNOS induced by LPS. In addition, not only was the wet-to-dry weight ratio of lung tissue significantly decreased, the number of total cells, neutrophils, and macrophages in the BALF were also significantly reduced after treatment with stevioside. Moreover, western blotting showed that stevioside inhibited the phosphorylation of IκB-α and NF-κB caused by LPS. Taken together, our results suggest that anti-inflammatory effect of stevioside against the LPS-induced acute lung injury may be due to its ability of inhibition of the NF-κB signaling pathway. Stevioside may be a promising potential therapeutic reagent for acute lung injury treatment.

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

    PubMed

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

    2016-06-01

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

  18. TRPV4 channels augment macrophage activation and ventilator-induced lung injury

    PubMed Central

    Hamanaka, Kazutoshi; Jian, Ming-Yuan; Townsley, Mary I.; King, Judy A.; Liedtke, Wolfgang; Weber, David S.; Eyal, Fabien G.; Clapp, Mary M.

    2010-01-01

    We have previously implicated transient receptor potential vanilloid 4 (TRPV4) channels and alveolar macrophages in initiating the permeability increase in response to high peak inflation pressure (PIP) ventilation. Alveolar macrophages were harvested from TRPV4−/− and TRPV4+/+ mice and instilled in the lungs of mice of the opposite genotype. Filtration coefficients (Kf) measured in isolated perfused lungs after ventilation with successive 30-min periods of 9, 25, and 35 cmH2O PIP did not significantly increase in lungs from TRPV4−/− mice but increased >2.2-fold in TRPV4+/+ lungs, TRPV4+/+ lungs instilled with TRPV4−/− macrophages, and TRPV4−/− lungs instilled with TRPV4+/+ macrophages after ventilation with 35 cmH2O PIP. Activation of TRPV4 with 4-α-phorbol didecanoate (4αPDD) significantly increased intracellular calcium, superoxide, and nitric oxide production in TRPV4+/+ macrophages but not TRPV4−/− macrophages. Cross-sectional areas increased nearly 3-fold in TRPV4+/+ macrophages compared with TRPV4−/− macrophages after 4αPDD. Immunohistochemistry staining of lung tissue for nitrotyrosine revealed increased amounts in high PIP ventilated TRPV4+/+ lungs compared with low PIP ventilated TRPV4+/+ or high PIP ventilated TRPV4−/− lungs. Thus TRPV4+/+ macrophages restored susceptibility of TRPV4−/− lungs to mechanical injury. A TRPV4 agonist increased intracellular calcium and reactive oxygen and nitrogen species in harvested TRPV4+/+ macrophages but not TRPV4−/− macrophages. Kf increases correlated with tissue nitrotyrosine, a marker of peroxynitrite production. PMID:20562229

  19. Hepatic cryoablation-induced acute lung injury: histopathologic findings.

    PubMed

    Washington, K; Debelak, J P; Gobbell, C; Sztipanovits, D R; Shyr, Y; Olson, S; Chapman, W C

    2001-01-01

    We have previously shown that hepatic cryoablation (cryo), but not partial hepatectomy, induces a systemic inflammatory response, with distant organ injury and overproduction of NF-kappaB-dependent cytokines. Serum tumor necrosis factor-alpha (TNF-alpha) and macrophage inflammatory protein-2 (MIP-2) levels are markedly increased 1 h and beyond after cryo compared with partial hepatectomy where no elevation occurs. NF-kappaB activation (by electrophoretic mobility shift assay) is strikingly increased in the noncryo liver (but not in the lung) at 30 min and in both the liver and lung tissue 1 h after cryo, returning to the baseline by 2 h and beyond. The current study investigated the histopathologic changes associated with cryoablation-induced acute lung injury. Animals underwent 35% hepatic resection or a similar volume hepatic cryo and were sacrificed at 1, 2, 6, and 24 h. Pulmonary histologic features were assessed using hematoxylin and eosin and immunoperoxidase staining with a macrophage-specific antibody (anti-lysozyme, 1:200 dilution, Dako, Carpinteria, CA). The following features were graded semiquantitatively (0-3): perivascular lymphoid cuffs, airspace edema and hemorrhage, margination of neutrophils within pulmonary vasculature, and the presence of macrophages with foamy cytoplasm in the pulmonary interstitium. Hepatic resection (n = 21) resulted in slight perivascular edema at 1, 2, 6, and 24 h post-resection, but there were no other significant changes. Pulmonary findings after hepatic cryo (n = 22) included prominent perivascular lymphoid cuffs 1 and 2 h following hepatic injury that were not present at any other time point (P 0.01). Marginating PMNs and foamy macrophages were more common after cryo at all time points (P<0.05, cryo vs resection). Severe lung injury, as evidenced by airspace edema and parenchymal hemorrhage, was present in four of six (67%) animals at 24 h (P 0.03). In follow-up studies immediate resection (n = 15) of the cryo

  20. Anti-Inflammatory Effects of Adrenomedullin on Acute Lung Injury Induced by Carrageenan in Mice

    PubMed Central

    Elena, Talero; Rosanna, Di Paola; Emanuela, Mazzon; Esposito, Emanuela; Virginia, Motilva; Salvatore, Cuzzocrea

    2012-01-01

    Adrenomedullin (AM) is a 52 amino acid peptide that has shown predominant anti-inflammatory activities. In the present study, we evaluated the possible therapeutic effect of this peptide in an experimental model of acute inflammation, the carrageenan- (CAR-) induced pleurisy. Pleurisy was induced by injection of CAR into the pleural cavity of mice. AM (200 ng/kg) was administered by intraperitoneal route 1 h after CAR, and the animals were sacrificed 4 h after that. AM treatment attenuated the recruitment of leucocytes in the lung tissue and the generation and/or the expression of the proinflammatory cytokines as well as the expression of the intercellular cell adhesion molecules. Moreover, AM inhibited the induction of inducible nitric oxide synthase (iNOS), thereby abating the generation of nitric oxide (NO) and prevented the oxidative and nitroxidative lung tissue injury, as shown by the reduction of nitrotyrosine, malondialdehyde (MDA), and poly (ADP-ribose) polymerase (PARP) levels. Finally, we demonstrated that these anti-inflammatory effects of AM were associated with the inhibition of nuclear factor-κB (NF-κB) activation. All these parameters were markedly increased by intrapleural CAR in the absence of any treatment. We report that treatment with AM significantly reduces the development of acute lung injury by downregulating a broad spectrum of inflammatory factors. PMID:22685374

  1. PEEP decreases atelectasis and extravascular lung water but not lung tissue volume in surfactant-washout lung injury.

    PubMed

    Luecke, Thomas; Roth, Harry; Herrmann, Peter; Joachim, Alf; Weisser, Gerald; Pelosi, Paolo; Quintel, Michael

    2003-11-01

    To examine the effects of positive end-expiratory pressure (PEEP) on extravascular lung water (EVLW), lung tissue, and lung volume. Experimental animal study at a university research facility. Fifteen adult sheep. All animals were studied before and after saline washout-induced lung injury while ventilated with sequentially increasing PEEP (0, 7, 14, or 21 cmH(2)O). Lung volume was determined by computed tomography and EVLW by the thermal dye dilution technique. Saline washout significantly increased lung tissue volume (21+/-3 to 37+/-5 ml/kg) and EVLW (9+/-2 to 36+/-9 ml/kg). While increasing levels of PEEP reduced EVLW (30+/-7, 24+/-8, and 18+/-4 ml/kg), lung tissue volume remained constant. Total lung volume significantly increased (50+/-8 ml/kg at PEEP 0 to 77+/-12 ml/kg at PEEP 21). Nonaerated lung volume significantly decreased and was closely correlated with the changes in EVLW ( r=0.67). In addition, a highly significant correlation was found between PEEP-induced decrease in nonaerated lung volume and decrease in transpulmonary shunt ( r=0.83). The main findings are as follows: (a) PEEP effectively decreases EVLW. (b) The decrease in EVLW is closely correlated with the PEEP-induced decrease in nonaerated lung volume, making EVLW a valuable bedside parameter indicating alveolar recruitment, similar to measurements of transpulmonary shunt. (c) As excess tissue volume remained constant, however, EVLW may not be suitable to reflect overall severity of lung disease

  2. Nrf2 protects against diquat-induced liver and lung injury.

    PubMed

    Wu, Kai Connie; Zhang, Youcai; Klaassen, Curtis D

    2012-10-01

    Diquat is an herbicide that generates superoxide anions through redox cycling. Nuclear factor erythroid-derived 2- like 2 (Nrf2) is a transcription factor that up-regulates cytoprotective genes in response to oxidative stress. To investigate the protective effect of Nrf2 against diquat-induced toxicity, wild-type, Nrf2-null and Kelch-like ECH-associated protein 1-knockdown (Keap1-KD) mice with enhanced Nrf2 activity were treated with diquat dibromide (125 mg/kg, i.p.). Blood and tissues were collected at 1, 2, 4 and 6 hours after treatment. Administration of diquat resulted in lipid peroxidation and lethality in wild-type mice, which were more in Nrf2-null mice and less in Keap1-KD mice. Diquat produced liver injury in Nrf2-null mice, as evidenced by increased serum ALT activity and extensive hepatic necrosis, but not in wild-type and Keap1-KD mice. Diquat produced more severe lung injury in Nrf2-null than in wild-type mice, as evidenced by increased lung weight and alveolar collapse. In contrast, Keap1-KD mice had attenuated lung edema and no histopathological alterations. To further investigate the mechanism of the protective effects of Nrf2, lung and liver glutathione (GSH) concentrations were quantified. Diquat decreased GSH in lung and liver in wild-type mice, and the decrease was more in Nrf2-null mice, and less in Keap1-KD mice. After diquat treatment, the mRNA of the GSH synthesis enzyme Gclc was increased in Keap1-KD, but not in Nrf2-null mice. Collectively, Nrf2 plays an important role in preventing diquat-induced liver and lung injury, and this protective effect results from Nrf2-regulated elevation of cellular GSH and expression of GSH synthetic genes.

  3. Hydrogen Gas Inhalation Attenuates Seawater Instillation-Induced Acute Lung Injury via the Nrf2 Pathway in Rabbits.

    PubMed

    Diao, Mengyuan; Zhang, Sheng; Wu, Lifeng; Huan, Le; Huang, Fenglou; Cui, Yunliang; Lin, Zhaofen

    2016-12-01

    Seawater instillation-induced acute lung injury involves oxidative stress and apoptosis. Although hydrogen gas inhalation is reportedly protective in multiple types of lung injury, the effect of hydrogen gas inhalation on seawater instillation-induced acute lung injury remains unknown. This study investigated the effect of hydrogen gas on seawater instillation-induced acute lung injury and explored the mechanisms involved. Rabbits were randomly assigned to control, hydrogen (2 % hydrogen gas inhalation), seawater (3 mL/kg seawater instillation), and seawater + hydrogen (3 mL/kg seawater instillation + 2 % hydrogen gas inhalation) groups. Arterial partial oxygen pressure and lung wet/dry weight ratio were detected. Protein content in bronchoalveolar lavage fluid (BALF) and serum as well as tumor necrosis factor (TNF)-α, interleukin (IL)-1β, and IL-6 levels were determined. Hematoxylin-eosin staining was used to monitor changes in lung specimens, and malondialdehyde (MDA) content and myeloperoxidase (MPO) activity were assayed. In addition, NF-E2-related factor (Nrf) 2 and heme oxygenase (HO)-1 mRNA and protein expression were measured, and apoptosis was assessed by measuring caspase-3 expression and using terminal deoxy-nucleotidyl transferase dUTP nick end-labeling (TUNEL) staining. Hydrogen gas inhalation markedly improved lung endothelial permeability and decreased both MDA content and MPO activity in lung tissue; these changes were associated with decreases in TNF-α, IL-1β, and IL-6 in BALF. Hydrogen gas also alleviated histopathological changes and cell apoptosis. Moreover, Nrf2 and HO-1 expressions were significantly activated and caspase-3 expression was inhibited. These results demonstrate that hydrogen gas inhalation attenuates seawater instillation-induced acute lung injury in rabbits and that the protective effects observed may be related to the activation of the Nrf2 pathway.

  4. [Current concept of TRALI (transfusion-related acute lung injury)].

    PubMed

    Iijima, Takehiko; Okazai, Hitoshi

    2007-11-01

    It is only 20 years since TRALI was clinically recognized. As it is gradually recognized among Japanese medical community, the number of cases reported is increasing gradually. In the past nine years (1997-2005), Japanese Red Cross confirmed 118 TRALI cases and 38 possible TRALI cases in Japan. Twelve TRALI cases among them occurred during or after anesthesia on the day of operation. Since acute lung injury is caused by multiple pathological factors, it is difficult to identify its main cause as transfusion. Therefore, TRALI has been underdiagnosed and underreported. Several mechanisms have been proposed. Although anti-HLA antibody, anti-HNA antibody, or other immunoreactive substances appear to be involved in developing TRALI, underlying conditions like systemic inflammation may be required for igniting TRALI Although TRALI developed in the operating theater seems to be a small fraction of whole TRALI cases, anesthesiologists should be aware of TRALI, and remember it as one of the causes of acute lung injury.

  5. Experimental Models of Transfusion-Related Acute Lung Injury (TRALI)

    PubMed Central

    Gilliss, Brian M.; Looney, Mark R.

    2010-01-01

    Transfusion-related acute lung injury (TRALI) is defined clinically as acute lung injury occurring within six hours of the transfusion of any blood product. It is the leading cause of transfusion-related death in the United States, but under-recognition and diagnostic uncertainty have limited clinical research to smaller case control studies. In this review we will discuss the contribution of experimental models to the understanding of TRALI pathophysiology and potential therapeutic approaches. Experimental models suggest that TRALI occurs when a host, with a primed immune system, is exposed to an activating agent such as anti-leukocyte antibody or a biologic response modifier such as lysophosphatidylcholines. Recent work has suggested a critical role for platelets in antibody-based experimental models and identified potential therapeutic strategies for TRALI. PMID:21134622

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

    PubMed

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

    2013-06-01

    To determine biventricular cardiac function in pneumovirus-induced acute lung injury in spontaneously breathing mice. Experimental animal study. Animal laboratory. C57Bl/6 mice. Mice were inoculated with the rodent pneumovirus, pneumonia virus of mice. Pneumonia virus of mice-infected mice were studied for right and left ventricular function variables by high-field strength (7 Tesla) cardiac MRI at specific time points during the course of disease compared with baseline. One day before and at peak disease severity, pneumonia virus of mice-infected mice showed significant right and left ventricular systolic and diastolic volume changes, with a progressive decrease in stroke volume and ejection fraction. No evidence for viral myocarditis or viral presence in heart tissue was found. These findings show adverse pulmonary-cardiac interaction in pneumovirus-induced acute lung injury, unrelated to direct virus-mediated effects on the heart.

  7. Ameliorative effect of Leflunomide on lung injury following an aspiration.

    PubMed

    Yilmaz, M Z; Torun, A C; Guzel, A; Murat, N; Okuyucu, A; Yilmaz, N; Gacar, A; Guvenc, T; Guzel, A

    2015-01-01

    We aimed to investigate the therapeutic effectiveness of leflunomide (LEF) in lung injury after an aspiration of unknown pathophysiology. Forty-two healthy Sprague Dawley rats were anesthetized and allocated to six experimental groups: saline (S) aspirated, S+LEF, hydrochloric acid (HCl) aspirated, HCl+LEF, formula aspirated (FOR), and FOR+LEF. The treatment groups (S+LEF, HCl+LEF, and FOR+LEF) received 20 mg/kg/day intraperitoneal (i.p.) injection of LEF for seven days. At the end of the seven days, blood and tissue samples were taken from the rats for histopathological, biochemical, and immunohistochemical examination. There was a significant increase in serum levels of YKL-40, a chitinase-like protein, in the HCl group after the aspiration (p<0.01). The increase in serum YKL-40 levels decreased significantly with LEF treatment (p<0.01). There was no significant difference in serum YKL-40 levels in the FOR group compared to the control group at pretreatment and in the FOR+LEF group at post-treatment. There was a significant increase in serum thiobarbituric acid-reactive species (TBARS) values in the HCl and FOR groups compared to the control group (p=0.001 and p<0.01, respectively). In both treatment groups, the serum TBARS values significantly decreased after treatment with LEF (p=0.001 and p<0.05, respectively). There was a significant improvement in the histopathological scores, which deteriorated after the aspiration, and in the number of inducible nitric oxide synthase (iNOS)-positive cells after treatment with LEF.

  8. Lung epithelial cell focal adhesion kinase signaling inhibits lung injury and fibrosis.

    PubMed

    Wheaton, Amanda K; Agarwal, Manisha; Jia, Shijing; Kim, Kevin K

    2017-05-01

    Progressive pulmonary fibrosis is a devastating consequence of many acute and chronic insults to the lung. Lung injury leads to alveolar epithelial cell (AEC) death, destruction of the basement membrane, and activation of transforming growth factor-β (TGF-β). There is subsequent resolution of the injury and a coordinated and concurrent initiation of fibrosis. Both of these processes may involve activation of similar intracellular signaling pathways regulated in part by dynamic changes to the extracellular matrix. Matrix signaling can augment the profibrotic fibroblast response to TGF-β. However, similar matrix/integrin signaling pathways may also be involved in the inhibition of ongoing TGF-β-induced AEC apoptosis. Focal adhesion kinase (FAK) is an integrin-associated signaling molecule expressed by many cell types. We used mice with AEC-specific FAK deletion to isolate the epithelial aspect of integrin signaling in the bleomycin model of lung injury and fibrosis. Mice with AEC-specific deletion of FAK did not exhibit spontaneous lung injury but did have significantly greater terminal deoxynucleotidyl transferase dUTP-mediated nick-end labeling-positive cells (18.6 vs. 7.1) per ×200 field, greater bronchoalveolar lavage protein (3.2 vs. 1.8 mg/ml), and significantly greater death (77 vs. 19%) after bleomycin injury compared with littermate control mice. Within primary AECs, activated FAK directly associates with caspase-8 and inhibits activation of the caspase cascade resulting in less apoptosis in response to TGF-β. Our studies support a model in which dynamic changes to the extracellular matrix after injury promote fibroblast activation and inhibition of epithelial cell apoptosis in response to TGF-β through FAK activation potentially complicating attempts to nonspecifically target this pathway for antifibrotic therapy. Copyright © 2017 the American Physiological Society.

  9. Mitigation of Lung Injury after Accidental Exposure to Radiation

    PubMed Central

    Mahmood, J.; Jelveh, S.; Calveley, V.; Zaidi, A.; Doctrow, S. R.; Hill, R. P.

    2011-01-01

    There is a serious need to develop effective mitigators against accidental radiation exposures. In radiation accidents, many people may receive nonuniform whole-body or partial-body irradiation. The lung is one of the more radiosensitive organs, demonstrating pneumonitis and fibrosis that are believed to develop at least partially because of radiation-induced chronic inflammation. Here we addressed the crucial questions of how damage to the lung can be mitigated and whether the response is affected by irradiation to the rest of the body. We examined the widely used dietary supplement genistein given at two dietary levels (750 or 3750 mg/kg) to Fischer rats irradiated with 12 Gy to the lung or 8 Gy to the lung + 4 Gy to the whole body excluding the head and tail (whole torso). We found that genistein had promising mitigating effects on oxidative damage, pneumonitis and fibrosis even at late times (36 weeks) when drug treatment was initiated 1 week after irradiation and stopped at 28 weeks postirradiation. The higher dose of genistein showed no greater beneficial effect. Combined lung and whole-torso irradiation caused more lung-related severe morbidity resulting in euthanasia of the animals than lung irradiation alone. PMID:22013884

  10. Transfusion related acute lung injury (TRALI): a review.

    PubMed

    Menitove, Jay E

    2007-01-01

    Transfusion Related Acute Lung Injury, or TRALI, denotes the most frequently reported fatal complication of blood transfusion. TRALI accounted for 34% of transfusion associated mortalities reported to the Food and Drug Administration (FDA) in 2005. TRALI caused more deaths than those attributed to hemolytic reactions following incorrect blood administration or sepsis resulting from bacterial contamination of platelet and red cell components. (Holness, Leslie. Food and Drug Administration. Personal Communication, 2006) This paper reviews TRALI for the clinical physician.

  11. Peroxisome proliferator-activated receptors and acute lung injury.

    PubMed

    Cuzzocrea, Salvatore

    2006-06-01

    Peroxisome proliferator-activated receptors (PPARs) are members of the nuclear hormone receptor superfamily of ligand-activated transcription factors that are related to retinoid, steroid and thyroid hormone receptors. The PPAR subfamily comprises three members: PPAR-alpha, PPAR-beta and PPAR-gamma. PPARs have recently been implicated as regulators of cellular proliferation and inflammatory responses. Furthermore, it has been demonstrated that PPAR-gamma and PPAR-alpha reduce lung injury associated with inflammation and shock.

  12. Budesonide inhalation ameliorates endotoxin-induced lung injury in rabbits

    PubMed Central

    Gao, Wei

    2015-01-01

    Acute respiratory distress syndrome (ARDS) is a serious clinical problem that has a 30–50% mortality rate. Budesonide has been used to reduce lung injury. This study aims to investigate the effects of nebulized budesonide on endotoxin-induced ARDS in a rabbit model. Twenty-four rabbits were randomized into three groups. Rabbits in the control and budesonide groups were injected with endotoxin. Thereafter, budesonide or saline was instilled, ventilated for four hours, and recovered spontaneous respiratory. Peak pressure, compliance, and PaO2/FiO2 were monitored for 4 h. After seven days, PaO2/FiO2 ratios were measured. Wet-to-dry weight ratios, total protein, neutrophil elastase, white blood cells, and percentage of neutrophils in BALF were evaluated. TNF-α, IL-1β, IL-8, and IL-10 in BALF were detected. Lung histopathologic injury and seven-day survival rate of the three groups were recorded. Peak pressure was downregulated, but compliance and PaO2/FiO2 were upregulated by budesonide. PaO2/FiO2 ratios significantly increased due to budesonide. Wet-to-dry weight ratios, total protein, neutrophil elastase, white blood cells and percentage of neutrophils in BALF decreased in the budesonide group. TNF-α, IL-1β, and IL-8 levels decreased in BALF, while IL-10 levels increased in the budesonide group. Lung injuries were reduced and survival rate was upregulated by budesonide. Budesonide effectively ameliorated respiratory function, attenuated endotoxin-induced lung injury, and improved the seven-day survival rate. PMID:25956681

  13. Presumptive acute lung injury following multiple surgeries in a cat.

    PubMed

    Katayama, Masaaki; Okamura, Yasuhiko; Katayama, Rieko; Sasaki, Jun; Shimamura, Shunsuke; Uzuka, Yuji; Kamishina, Hiroaki; Nezu, Yoshinori

    2013-04-01

    A 12-year-old, 3.5-kg spayed female domestic shorthair cat had a tracheal mass identified as malignant B-cell lymphoma. The cat had tracheal resection and subsequently developed laryngeal paralysis. Due to multiple episodes of respiratory distress the cat subsequently had tracheal surgeries. Finally, the cat had a sudden onset of severe respiratory distress and collapsed. Computed tomography imaging and arterial blood gas analysis supported a diagnosis of acute lung injury.

  14. Eriodictyol, a plant flavonoid, attenuates LPS-induced acute lung injury through its antioxidative and anti-inflammatory activity

    PubMed Central

    ZHU, GUANG-FA; GUO, HONG-JUAN; HUANG, YAN; WU, CHUN-TING; ZHANG, XIANG-FENG

    2015-01-01

    Acute lung injury (ALI) is characterized by excessive inflammatory responses and oxidative injury in the lung tissue. It has been suggested that anti-inflammatory or antioxidative agents could have therapeutic effects in ALI, and eriodictyol has been reported to exhibit antioxidative and anti-inflammatory activity in vitro. The aim of the present study was to investigate the effect of eriodictyol on lipopolysaccharide (LPS)-induced ALI in a mouse model. The mice were divided into four groups: Phosphate-buffered saline-treated healthy control, LPS-induced ALI, vehicle-treated ALI (LPS + vehicle) and eriodictyol-treated ALI (LPS + eriodictyol). Eriodictyol (30 mg/kg) was administered orally once, 2 days before the induction of ALI. The data showed that eriodictyol pretreatment attenuated LPS-induced ALI through its antioxidative and anti-inflammatory activity. Furthermore, the eriodictyol pretreatment activated the nuclear factor erythroid-2-related factor 2 (Nrf2) pathway in the ALI mouse model, which attenuated the oxidative injury and inhibited the inflammatory cytokine expression in macrophages. In combination, the results of the present study demonstrated that eriodictyol could alleviate the LPS-induced lung injury in mice by regulating the Nrf2 pathway and inhibiting the expression of inflammatory cytokines in macrophages, suggesting that eriodictyol could be used as a potential drug for the treatment of LPS-induced lung injury. PMID:26668626

  15. Normal versus sickle red blood cells: hemodynamic and permeability characteristics in reperfusion lung injury.

    PubMed

    Haynes, J; Seibert, A; Shah, A; Taylor, A

    1990-01-01

    Decreased deformability and increased internal viscosity of the sickle red blood cell (SRBC) contribute to abnormal flow in the microcirculation. Since the lungs are commonly affected in sickle cell disease, we compared the hemodynamics of the normal human red blood cell (NRBC) with the SRBC in the pulmonary circulation. The SRBC has decreased antioxidant enzyme activities compared with the NRBC. Thus, using the capillary filtration coefficient (Kfc), we determined the ability of the NRBC and the SRBC to attenuate the increased permeability and resulting edema seen in the oxidant stress of reperfusion lung injury (RLI). We found that lungs perfused with a 5% SRBC perfusate had higher pulmonary arterial pressures (Ppa) and resistances than lungs perfused with a 5% NRBC perfusate. Lungs made ischemic and reperfused with a physiologic cell-free perfusate resulted in a significant increase (P less than .05) in Kfc compared with the preischemic Kfc (.45 +/- .06 to 1.4 +/- 22 mL.min-1.cm H2O.100 g-1). In lungs reperfused with 5% RBC-containing perfusates, the Kfc did not change from preischemic Kfc with NRBCs and decreased from the preischemic Kfc with SRBCs. These findings suggest that the SRBC causes physiologically significant increases in Ppa and resistances and the SRBC, like the NRBC, offers apparent protection in RLI.

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

    PubMed

    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.

  17. Pathophysiology of pulmonary hypertension in acute lung injury

    PubMed Central

    Price, Laura C.; McAuley, Danny F.; Marino, Philip S.; Finney, Simon J.; Griffiths, Mark J.

    2012-01-01

    Acute lung injury (ALI) and acute respiratory distress syndrome are characterized by protein rich alveolar edema, reduced lung compliance, and acute severe hypoxemia. A degree of pulmonary hypertension (PH) is also characteristic, higher levels of which are associated with increased morbidity and mortality. The increase in right ventricular (RV) afterload causes RV dysfunction and failure in some patients, with associated adverse effects on oxygen delivery. Although the introduction of lung protective ventilation strategies has probably reduced the severity of PH in ALI, a recent invasive hemodynamic analysis suggests that even in the modern era, its presence remains clinically important. We therefore sought to summarize current knowledge of the pathophysiology of PH in ALI. PMID:22246001

  18. Adult Lysophosphatidic Acid Receptor 1-Deficient Rats with Hyperoxia-Induced Neonatal Chronic Lung Disease Are Protected against Lipopolysaccharide-Induced Acute Lung Injury

    PubMed Central

    Chen, Xueyu; Walther, Frans J.; Laghmani, El H.; Hoogeboom, Annemarie M.; Hogen-Esch, Anne C. B.; van Ark, Ingrid; Folkerts, Gert; Wagenaar, Gerry T. M.

    2017-01-01

    Aim: Survivors of neonatal chronic lung disease or bronchopulmonary dysplasia (BPD) suffer from compromised lung function and are at high risk for developing lung injury by multiple insults later in life. Because neonatal lysophosphatidic acid receptor-1 (LPAR1)-deficient rats are protected against hyperoxia-induced lung injury, we hypothesize that LPAR1-deficiency may protect adult survivors of BPD from a second hit response against lipopolysaccharides (LPS)-induced lung injury. Methods: Directly after birth, Wistar control and LPAR1-deficient rat pups were exposed to hyperoxia (90%) for 8 days followed by recovery in room air. After 7 weeks, male rats received either LPS (2 mg kg−1) or 0.9% NaCl by intraperitoneal injection. Alveolar development and lung inflammation were investigated by morphometric analysis, IL-6 production, and mRNA expression of cytokines, chemokines, coagulation factors, and an indicator of oxidative stress. Results: LPAR1-deficient and control rats developed hyperoxia-induced neonatal emphysema, which persisted into adulthood, as demonstrated by alveolar enlargement and decreased vessel density. LPAR1-deficiency protected against LPS-induced lung injury. Adult controls with BPD exhibited an exacerbated response toward LPS with an increased expression of pro-inflammatory mRNAs, whereas LPAR1-deficient rats with BPD were less sensitive to this “second hit” with a decreased pulmonary influx of macrophages and neutrophils, interleukin-6 (IL-6) production, and mRNA expression of IL-6, monocyte chemoattractant protein-1, cytokine-induced neutrophil chemoattractant 1, plasminogen activator inhibitor-1, and tissue factor. Conclusion: LPAR1-deficient rats have increased hyperoxia-induced BPD survival rates and, despite the presence of neonatal emphysema, are less sensitive to an aggravated “second hit” than Wistar controls with BPD. Intervening in LPA-LPAR1-dependent signaling may not only have therapeutic potential for neonatal chronic

  19. Diabetes, insulin, and development of acute lung injury

    PubMed Central

    Honiden, Shyoko; Gong, Michelle N.

    2009-01-01

    Objectives Recently, many studies have investigated the immunomodulatory effects of insulin and glucose control in critical illness. This review examines evidence regarding the relationship between diabetes and the development of acute lung injury/acute respiratory distress syndrome (ALI/ARDS), reviews studies of lung injury related to glycemic and nonglycemic metabolic features of diabetes, and examines the effect of diabetic therapies. Data Sources and Study Selection A MEDLINE/PubMed search from inception to August 1, 2008, was conducted using the search terms acute lung injury, acute respiratory distress syndrome, hyperglycemia, diabetes mellitus, insulin, hydroxymethylglutaryl-CoA reductase inhibitors (statins), angiotensin-converting enzyme inhibitor, and peroxisome proliferator-activated receptors, including combinations of these terms. Bibliographies of retrieved articles were manually reviewed. Data Extraction and Synthesis Available studies were critically reviewed, and data were extracted with special attention to the human and animal studies that explored a) diabetes and ALI; b) hyperglycemia and ALI; c) metabolic nonhyperglycemic features of diabetes and ALI; and d) diabetic therapies and ALI. Conclusions Clinical and experimental data indicate that diabetes is protective against the development of ALI/ARDS. The pathways involved are complex and likely include effects of hyperglycemia on the inflammatory response, metabolic abnormalities in diabetes, and the interactions of therapeutic agents given to diabetic patients. Multidisciplinary, multifaceted studies, involving both animal models and clinical and molecular epidemiology techniques, are essential. PMID:19531947

  20. IL-13 is a therapeutic target in radiation lung injury.

    PubMed

    Chung, Su I; Horton, Jason A; Ramalingam, Thirumalai R; White, Ayla O; Chung, Eun Joo; Hudak, Kathryn E; Scroggins, Bradley T; Arron, Joseph R; Wynn, Thomas A; Citrin, Deborah E

    2016-12-22

    Pulmonary fibrosis is a potentially lethal late adverse event of thoracic irradiation. Prior research indicates that unrestrained TGF-β1 and/or type 2 cytokine-driven immune responses promote fibrosis following radiation injury, but the full spectrum of factors governing this pathology remains unclear. Interleukin 13 (IL-13) is a key factor in fibrotic disease associated with helminth infection, but it is unclear whether it plays a similar role in radiation-induced lung fibrosis. Using a mouse model, we tested the hypothesis that IL-13 drives the progression of radiation-induced pulmonary fibrosis. Irradiated lungs from wild-type c57BL/6NcR mice accumulated alternatively-activated macrophages, displayed elevated levels of IL-13, and extensive fibrosis, whereas IL-13 deficient mice were resistant to these changes. Furthermore, plasma from irradiated wild-type mice showed a transient increase in the IL-13 saturated fraction of the circulating decoy receptor IL-13Rα2. Finally, we determined that therapeutic neutralization of IL-13, during the period of IL-13Rα2 saturation was sufficient to protect mice from lung fibrosis. Taken together, our results demonstrate that IL-13 is a major regulator of radiation-induced lung injury and demonstrates that strategies focusing on IL-13 may be useful in screening for timely delivery of anti-IL-13 therapeutics.

  1. Effects of body temperature on ventilator-induced lung injury.

    PubMed

    Akinci, Ozkan I; Celik, Mehmet; Mutlu, Gökhan M; Martino, Janice M; Tugrul, Simru; Ozcan, Perihan E; Yilmazbayhan, Dilek; Yeldandi, Anjana V; Turkoz, Kemal H; Kiran, Bayram; Telci, Lütfi; Cakar, Nahit

    2005-03-01

    To evaluate the effects of body temperature on ventilator-induced lung injury. Thirty-four male Sprague-Dawley rats were randomized into 6 groups based on their body temperature (normothermia, 37 +/- 1 degrees C; hypothermia, 31 +/- 1 degrees C; hyperthermia, 41 +/- 1 degrees C). Ventilator-induced lung injury was achieved by ventilating for 1 hour with pressure-controlled ventilation mode set at peak inspiratory pressure (PIP) of 30 cmH2O (high pressure, or HP) and positive end-expiratory pressure (PEEP) of 0 cmH2O. In control subjects, PIP was set at 14 cmH2O (low pressure, or LP) and PEEP set at 0 cmH2O. Systemic chemokine and cytokine (tumor necrosis factor alpha , interleukin 1 beta , interleukin 6, and monocyte chemoattractant protein 1) levels were measured. The lungs were assessed for histological changes. Serum chemokines and cytokines were significantly elevated in the hyperthermia HP group compared with all 3 groups, LP (control), normothermia HP, and hypothermia HP. Oxygenation was better but not statistically significant in hypothermia HP compared with other HP groups. Cumulative mean histology scores were higher in hyperthermia HP and normothermia HP groups compared with control and normothermia HP groups. Concomitant hyperthermia increased systemic inflammatory response during HP ventilation. Although hypothermia decreased local inflammation in the lung, it did not completely attenuate systemic inflammatory response associated with HP ventilation.

  2. IL-13 is a therapeutic target in radiation lung injury

    PubMed Central

    Chung, Su I.; Horton, Jason A.; Ramalingam, Thirumalai R.; White, Ayla O.; Chung, Eun Joo; Hudak, Kathryn E.; Scroggins, Bradley T.; Arron, Joseph R.; Wynn, Thomas A.; Citrin, Deborah E.

    2016-01-01

    Pulmonary fibrosis is a potentially lethal late adverse event of thoracic irradiation. Prior research indicates that unrestrained TGF-β1 and/or type 2 cytokine-driven immune responses promote fibrosis following radiation injury, but the full spectrum of factors governing this pathology remains unclear. Interleukin 13 (IL-13) is a key factor in fibrotic disease associated with helminth infection, but it is unclear whether it plays a similar role in radiation-induced lung fibrosis. Using a mouse model, we tested the hypothesis that IL-13 drives the progression of radiation-induced pulmonary fibrosis. Irradiated lungs from wild-type c57BL/6NcR mice accumulated alternatively-activated macrophages, displayed elevated levels of IL-13, and extensive fibrosis, whereas IL-13 deficient mice were resistant to these changes. Furthermore, plasma from irradiated wild-type mice showed a transient increase in the IL-13 saturated fraction of the circulating decoy receptor IL-13Rα2. Finally, we determined that therapeutic neutralization of IL-13, during the period of IL-13Rα2 saturation was sufficient to protect mice from lung fibrosis. Taken together, our results demonstrate that IL-13 is a major regulator of radiation-induced lung injury and demonstrates that strategies focusing on IL-13 may be useful in screening for timely delivery of anti-IL-13 therapeutics. PMID:28004808

  3. The Effects of Dexamethasone and L-NAME on Acute Lung Injury in Rats with Lung Contusion.

    PubMed

    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.

  4. Acute lung injury following refrigeration coil deicing.

    PubMed

    McKeown, Nathanael J; Burton, Brent T

    2012-03-01

    We report a case of a worker who developed ALI requiring mechanical ventilatory support after attempting to melt ice condensate by applying the flame of an oxy-acetylene torch to refrigeration coils charged with a halocarbon refrigerant in a closed environment. A discussion of possible etiologies are discussed, including phosgene, carbonyl fluoride, and nitrogen oxides. Primary prevention with adequate respiratory protection is recommended whenever deicing is performed in a closed space environment.

  5. Acute lung injury after instillation of human breast milk or infant formula into rabbits' lungs.

    PubMed

    O'Hare, B; Lerman, J; Endo, J; Cutz, E

    1996-06-01

    Recent interest in shortening the fasting interval after ingestion of milk products demonstrated large volumes of breast milk in the stomach 2 h after breastfeeding. Although aspiration is a rare event, if it were to occur with human breast milk, it is important to understand the extent of the lung injury that might occur. Therefore, the response to instillation of acidified breast milk and infant formula in the lungs of adult rabbits was studied. In 18 anesthetized adult rabbits, 1 of 3 fluids (in a volume of 0.8 ml.kg-1 and pH level of 1.8, acidified with hydrochloric acid); saline, breast milk, or infant formula (SMA, Wyeth, Windsor, Ontario), was instilled into the lungs via a tracheotomy. The lungs were ventilated for 4 h after instillation. Alveolar-to-arterial oxygen gradient and dynamic compliance were measured before and at hourly intervals after instillation. After 4 h, the rabbits were killed and the lungs were excised. Neutrophil infiltration was quantitated by a pathologist blinded to the instilled fluid. A histologic control group of four rabbits was ventilated under study conditions without any intratracheal fluid instillation. Alveolar-to-arterial oxygen gradient increased and dynamic compliance decreased significantly during the 4 h after instillation of both breast milk and infant formula compared with baseline measurements and with saline controls (P < 0.05). The neutrophil counts in the lungs from the saline, breast milk, and formula rabbits were significantly greater than those in the control group. Instillation of acidified breast milk or infant formula (in a volume of 0.8 ml.kg-1 and pH level of 1.8) into rabbits' lungs induces acute lung injury of similar intensity that lasts at least 4 h.

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

    PubMed

    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.

  7. Peripheral 5-HT7 receptors as a new target for prevention of lung injury and mortality in septic rats.

    PubMed

    Cadirci, Elif; Halici, Zekai; Bayir, Yasin; Albayrak, Abdulmecit; Karakus, Emre; Polat, Beyzagul; Unal, Deniz; Atamanalp, Sabri S; Aksak, Selina; Gundogdu, Cemal

    2013-10-01

    Sepsis is a complex pathophysiological event involving metabolic acidosis, systemic inflammatory response syndrome, tissue damage and multiple organ dysfunction syndrome. Although many new mechanisms are being investigated to enlighten the pathophysiology of sepsis, there is no effective treatment protocol yet. Presence of 5-HT7 receptors in immune tissues prompted us to hypothesize that these receptors have roles in inflammation and sepsis. We investigated the effects of 5-HT7 receptor agonists and antagonists on serum cytokine levels, lung oxidative stress, lung histopathology, nuclear factor κB (NF-κB) positivity and lung 5-HT7 receptor density in cecal ligation and puncture (CLP) induced sepsis model of rats. Agonist administration to septic rats increased survival time; decreased serum cytokine response against CLP; decreased oxidative stress and increased antioxidant system in lungs; decreased the tissue NF-κB immunopositivity, which is high in septic rats; and decreased the sepsis-induced lung injury. In septic rats, as a result of high inflammatory response, 5-HT7 receptor expression in lungs increased significantly and agonist administration, which decreased inflammatory response and related mortality, decreased the 5-HT7 receptor expression. In conclusion, all these data suggest that stimulation of 5-HT7 receptors may be a new therapeutic target for prevention of impaired inflammatory response related lung injury and mortality.

  8. Lung injury and respiratory mechanics in rugby union.

    PubMed

    Lindsay, Angus; Bernard, Angelique; Davidson, Shaun M; Redmond, Daniel P; Chiew, Yeong S; Pretty, Christopher; Chase, J Geoffrey; Shaw, Geoffrey M; Gieseg, Steven P; Draper, Nick

    2016-04-01

    Rugby is a highly popular team contact sport associated with high injury rates. Specifically, there is a chance of inducing internal lung injuries as a result of the physical nature of the game. Such injuries are only identified with the use of specific invasive protocols or equipment. This study presents a model-based method to assess respiratory mechanics of N=11 rugby players that underwent a low intensity experimental Mechanical Ventilation (MV) Test before and after a rugby game. Participants were connected to a ventilator via a facemask and their respiratory mechanics estimated using a time-varying elastance model. All participants had a respiratory elastance <10 cmH2O/L with no significant difference observed between pre and postgame respiratory mechanics (P>0.05). Model-based respiratory mechanics estimation has been used widely in the treatment of the critically ill in intensive care. However, the application of a ventilator to assess the respiratory mechanics of healthy human beings is limited. This method adapted from ICU mechanical ventilation can be used to provide insight to respiratory mechanics of healthy participants that can be used as a more precise measure of lung inflammation/injury that avoids invasive procedures. This is the first study to conceptualize the assessment of respiratory mechanics in healthy athletes as a means to monitor postexercise stress and therefore manage recovery.

  9. Lung contusion: inflammatory mechanisms and interaction with other injuries.

    PubMed

    Raghavendran, Krishnan; Notter, Robert H; Davidson, Bruce A; Helinski, Jadwiga D; Kunkel, Steven L; Knight, Paul R

    2009-08-01

    This article reviews current animal models and laboratory studies investigating the pathophysiology of lung contusion (LC), a common and severe condition in patients with blunt thoracic trauma. Emphasis is on studies elucidating cells, mediators, receptors, and processes important in the innate pulmonary inflammatory response that contribute to LC injury. Surfactant dysfunction in the pathogenesis of LC is also discussed, as is the potential role of epithelial cell or neutrophil apoptosis. Studies examining combination injuries where LC is exacerbated by secondary insults such as gastric aspiration in trauma patients are also noted. The need for continuing mechanism-based research to further clarify the pathophysiology of LC injury, and to define and test potential therapeutic interventions targeting specific aspects of inflammation or surfactant dysfunction to improve clinical outcomes in patients with LC, is also emphasized.

  10. Lung Contusion: Inflammatory Mechanisms and Interaction with Other Injuries

    PubMed Central

    Raghavendran, Krishnan; Notter, Robert H.; Davidson, Bruce A.; Helinski, Jadwiga D.; Kunkel, Steven L.; Knight, Paul R.

    2009-01-01

    This article reviews current animal models and laboratory studies investigating the pathophysiology of lung contusion (LC), a common and severe condition in patients with blunt thoracic trauma. Emphasis is on studies elucidating cells, mediators, receptors and processes important in the innate pulmonary inflammatory response that contribute to LC injury. Surfactant dysfunction in the pathogenesis of LC is also discussed, as is the potential role of epithelial cell or neutrophil apoptosis. Studies examining combination injuries where LC is exacerbated by secondary insults like gastric aspiration in trauma patients are also noted. The need for continuing mechanism-based research to further clarify the pathophysiology of LC injury, and to define and test potential therapeutic interventions targeting specific aspects of inflammation or surfactant dysfunction to improve clinical outcomes in patients with LC, is also emphasized. PMID:19174738

  11. Vascular pharmacology of acute lung injury and acute respiratory distress syndrome.

    PubMed

    Groeneveld, A B Johan

    2002-11-01

    Acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) following sepsis, major trauma and surgery are leading causes of respiratory insufficiency, warranting artificial ventilation in the intensive care unit. It is caused by an inflammatory reaction in the lung upon exogenous or endogenous etiologies eliciting proinflammatory factors, and results in increased alveolocapillary permeability and protein-rich alveolar edema. The interstitial and alveolar inflammation and edema alter ventilation perfusion matching, gas exchange and mechanical properties of the lung. The current therapy of the condition is supportive, paying careful attention to fluid balance, relieving the increased work of breathing and improving gas exchange by mechanical ventilation, but in vitro, animal and some clinical research is done to evaluate the value of anti-inflammatory therapies on morbidity and outcome, including inflammatory cell-stabilizing corticosteroids, xanthine derivates, prostanoids and inhibitors, O(2) radical scavenging factors such as N-acetylcysteine, surfactant replacement, vasodilators including inhaled nitric oxide, vasoconstrictors such as almitrine, and others. None of these compounds has been proven to benefit survival in patients, however, even though carrying a physiologic benefit, except perhaps for steroids that may improve outcome in the later stage of ARDS. This partly relates to the difficulty to assess the lung injury at the bedside, to the multifactorial pathogenesis and the severity of comorbidity, adversely affecting survival.

  12. Effects of methylene blue in acute lung injury induced by oleic acid in rats

    PubMed Central

    Cassiano Silveira, Ana Paula; Vento, Daniella Alves; Albuquerque, Agnes Afrodite Sumarelli; Celotto, Andrea Carla; Tefé-Silva, Cristiane; Ramos, Simone Gusmão; Rubens de Nadai, Tales; Rodrigues, Alfredo José; Poli-Neto, Omero Benedicto

    2016-01-01

    Background In acute lung injury (ALI), rupture of the alveolar-capillary barrier determines the protein-rich fluid influx into alveolar spaces. Previous studies have reported that methylene blue (MB) attenuates such injuries. This investigation was carried out to study the MB effects in pulmonary capillary permeability. Methods Wistar rats were divided into five groups: (I) Sham: saline bolus; (II) MB, MB infusion for 2 h; (III) oleic acid (OA), OA bolus; (IV) MB/OA, MB infusion for 2 h, and at 5 min after from the beginning, concurrently with an OA bolus; and (V) OA/MB, OA bolus, and after 2 h, MB infusion for 2 h. After 4 h, blood, bronchoalveolar lavage (BAL), and lung tissue were collected from all groups for analysis of plasma and tissue nitric oxide, calculation of the wet weight to dry weight ratio (WW/DW), and histological examination of lung tissue. Statistical analysis was performed using nonparametric test. Results Although favourable trends have been observed for permeability improvement parameters (WW/WD and protein), the results were not statistically significant. However, histological analysis of lung tissue showed reduced lesion areas in both pre- and post-treatment groups. Conclusions The data collected using this experimental model was favourable only through macroscopic and histological analysis. These observations are valid for both MB infusions before or after induction of ALI. PMID:26855944

  13. Computerized tomography versus perfusion lung scanning in canine radiation lung injury

    SciTech Connect

    Ahmed, I.H.; Logus, J.W.; El-Khatib, E.; Battista, J.J.; Ferri, H.; Lentle, B.C.; Man, G.C.; Man, S.F. )

    1990-03-01

    Computerized tomographic (CT) measurements of lung density were obtained before and serially after thoracic irradiation in dogs to detect the alterations caused by radiation therapy. Fourteen mongrel dogs were given either 2000 cGy (Group A, 10 dogs, right lower zone irradiation), 1000 cGy (Group B, 2 dogs, right lower zone irradiation), or 500 cGy (Group C, 2 dogs, right lung irradiation) in one fraction. Once before and bi-weekly after irradiation, the anesthetized dogs had thoracic CT scans. CT numbers for the irradiated area were compared to their preirradiation control values. Macro-aggregated albumin (MAA) perfusion lung scans were also obtained before and at weekly intervals after irradiation and were evaluated visually and quantitatively for abnormalities. When both these tests were abnormal, or at the end of the scheduled study, the dogs were sacrificed to confirm radiation lung injury histologically. Our results showed that CT numbers (as a measure of tissue density) were higher with higher doses of radiation. Among all the techniques used, only the quantitative assessment of macro-aggregated albumin perfusion scan detected abnormalities in all the dogs given 2000 cGy. Their abnormalities correlated well with the presence of radiation lung damage histologically, however, the applicability of these methods in the detection of early injury has to be further evaluated.

  14. Open Tracheostomy Gastric Acid Aspiration Murine Model of Acute Lung Injury Results in Maximal Acute Nonlethal Lung Injury.

    PubMed

    Alluri, Ravi; Kutscher, Hilliard L; Mullan, Barbara A; Davidson, Bruce A; Knight, Paul R

    2017-02-26

    Acid pneumonitis is a major cause of sterile acute lung injury (ALI) in humans. Acid pneumonitis spans the clinical spectrum from asymptomatic to acute respiratory distress syndrome (ARDS), characterized by neutrophilic alveolitis, and injury to both alveolar epithelium and vascular endothelium. Clinically, ARDS is defined by acute onset of hypoxemia, bilateral patchy pulmonary infiltrates and non-cardiogenic pulmonary edema. Human studies have provided us with valuable information about the physiological and inflammatory changes in the lung caused by ARDS, which has led to various hypotheses about the underling mechanisms. Unfortunately, difficulties determining the etiology of ARDS, as well as a wide range of pathophysiology have resulted in a lack of critical information that could be useful in developing therapeutic strategies. Translational animal models are valuable when their pathogenesis and pathophysiology accurately reproduce a concept proven in both in vitro and clinical settings. Although large animal models (e.g., sheep) share characteristics of the anatomy of human trachea-bronchial tree, murine models provide a host of other advantages including: low cost; short reproductive cycle lending itself to greater data acquisition; a well understood immunologic system; and a well characterized genome leading to the availability of a variety of gene deletion and transgenic strains. A robust model of low pH induced ARDS requires a murine ALI that targets mainly the alveolar epithelium, secondarily the vascular endothelium, as well as the small airways leading to the alveoli. Furthermore, a reproducible injury with wide differences between different injurious and non-injurious insults is important. The murine gastric acid aspiration model presented here using hydrochloric acid employs an open tracheostomy and recreates a pathogenic scenario that reproduces the low pH pneumonitis injury in humans. Additionally, this model can be used to examine interaction of a

  15. Prospective study on the clinical course and outcomes in transfusion-related acute lung injury*.

    PubMed

    Looney, Mark R; Roubinian, Nareg; Gajic, Ognjen; Gropper, Michael A; Hubmayr, Rolf D; Lowell, Clifford A; Bacchetti, Peter; Wilson, Gregory; Koenigsberg, Monique; Lee, Deanna C; Wu, Ping; Grimes, Barbara; Norris, Philip J; Murphy, Edward L; Gandhi, Manish J; Winters, Jeffrey L; Mair, David C; Schuller, Randy M; Hirschler, Nora V; Rosen, Rosa Sanchez; Matthay, Michael A; Toy, Pearl

    2014-07-01

    Transfusion-related acute lung injury is the leading cause of transfusion-related mortality. A prospective study using electronic surveillance was conducted at two academic medical centers in the United States with the objective to define the clinical course and outcomes in transfusion-related acute lung injury cases. Prospective case study with controls. University of California, San Francisco and Mayo Clinic, Rochester. We prospectively enrolled 89 patients with transfusion-related acute lung injury, 164 transfused controls, and 145 patients with possible transfusion-related acute lung injury. None. Patients with transfusion-related acute lung injury had fever, tachycardia, tachypnea, hypotension, and prolonged hypoxemia compared with controls. Of the patients with transfusion-related acute lung injury, 29 of 37 patients (78%) required initiation of mechanical ventilation and 13 of 53 (25%) required initiation of vasopressors. Patients with transfusion-related acute lung injury and possible transfusion-related acute lung injury had an increased duration of mechanical ventilation and increased days in the ICU and hospital compared with controls. There were 15 of 89 patients with transfusion-related acute lung injury (17%) who died, whereas 61 of 145 patients with possible transfusion-related acute lung injury (42%) died and 7 of 164 of controls (4%) died. Patients with transfusion-related acute lung injury had evidence of more systemic inflammation with increases in circulating neutrophils and a decrease in platelets compared with controls. Patients with transfusion-related acute lung injury and possible transfusion-related acute lung injury also had a statistically significant increase in plasma interleukin-8, interleukin-10, and interleukin-1 receptor antagonist posttransfusion compared with controls. In conclusion, transfusion-related acute lung injury produced a condition resembling the systemic inflammatory response syndrome and was associated with

  16. Betulin protects mice from bacterial pneumonia and acute lung injury.

    PubMed

    Wu, Qianchao; Li, Hongyu; Qiu, Jiaming; Feng, Haihua

    2014-10-01

    Betulin, a naturally occurring triterpene, has shown anti-HIV activity, but details on the anti-inflammatory activity are scanty. In this study, we sought to investigate the effect of Betulin on LPS-induced activation of cell lines with relevance for lung inflammation in vitro and on lung inflammation elicited by either LPS or viable Escherichia coli (E. coli) in vivo. In vitro, Betulin inhibited LPS-induced tumor necrosis factor α (TNF-α) and (interleukin) IL-6 levels and up-regulated the level of IL-10. Also Betulin suppressed the phosphorylation of nuclear factor-κB (NF-κB) p65 protein in LPS-stimulated RAW 264.7 cells. In vivo, Betulin alleviated LPS-induced acute lung injury. Treatment with Betulin diminished pro-inflammatory cytokines, myeloperoxidase activity and bacterial loads in lung tissue during gram-negative pneumonia. Our findings demonstrated that Betulin inhibits pro-inflammatory responses induced by the gram-negative stimuli LPS and E. coli, suggesting that Betulin may represent a novel strategy for the treatment of lung inflammation.

  17. Mechanism underlying acute lung injury due to sulfur mustard exposure in rats.

    PubMed

    Xiaoji, Zhu; Xiao, Meng; Rui, Xu; Haibo, Chu; Chao, Zhao; Chengjin, Lian; Tao, Wang; Wenjun, Guo; Shengming, Zhang

    2016-08-01

    Sulfur mustard (SM), a bifunctional alkylating agent that causes severe lung damage, is a significant threat to both military and civilian populations. The mechanisms mediating the cytotoxic effects of SM are unknown and were investigated in this study. The purpose of this study was to establish a rat model of SM-induced lung injury to observe the resulting changes in the lungs. Male rats (Sprague Dawley) were anesthetized, intratracheally intubated, and exposed to 2 mg/kg of SM by intratracheal instillation. Animals were euthanized 6, 24, 48, and 72 h post-exposure, and bronchoalveolar lavage fluid (BALF) and lung tissues were collected. Exposure of rats to SM resulted in rapid pulmonary toxicity, including partial bronchiolar epithelium cell shedding, focal ulceration, and an increased amount of inflammatory exudate and number of cells in the alveoli. There was also evidence that the protein content and cell count of BALF peaked at 48 h, and the alveolar septum was widened and filled with lymphocytes. SM exposure also resulted in partial loss of type I alveolar epithelial cell membranes, fuzzy mitochondrial cristae, detachment and dissociation of ribosomes attached to the surface of rough endoplasmic reticulum, cracked, missing, and disorganized microvilli of type II alveolar epithelial cells, and increased apoptotic cells in the alveolar septum. The propylene glycol control group, however, was the same as the normal group. These data demonstrate that the mechanism of a high concentration of SM (2 mg/kg) induced acute lung injury include histologic changes, inflammatory reactions, apoptosis, oxidative stress, and nuclear DNA damage; the degree of injury is time dependent. © The Author(s) 2014.

  18. Mechanical Power and Development of Ventilator-induced Lung Injury.

    PubMed

    Cressoni, Massimo; Gotti, Miriam; Chiurazzi, Chiara; Massari, Dario; Algieri, Ilaria; Amini, Martina; Cammaroto, Antonio; Brioni, Matteo; Montaruli, Claudia; Nikolla, Klodiana; Guanziroli, Mariateresa; Dondossola, Daniele; Gatti, Stefano; Valerio, Vincenza; Vergani, Giordano Luca; Pugni, Paola; Cadringher, Paolo; Gagliano, Nicoletta; Gattinoni, Luciano

    2016-05-01

    The ventilator works mechanically on the lung parenchyma. The authors set out to obtain the proof of concept that ventilator-induced lung injury (VILI) depends on the mechanical power applied to the lung. Mechanical power was defined as the function of transpulmonary pressure, tidal volume (TV), and respiratory rate. Three piglets were ventilated with a mechanical power known to be lethal (TV, 38 ml/kg; plateau pressure, 27 cm H2O; and respiratory rate, 15 breaths/min). Other groups (three piglets each) were ventilated with the same TV per kilogram and transpulmonary pressure but at the respiratory rates of 12, 9, 6, and 3 breaths/min. The authors identified a mechanical power threshold for VILI and did nine additional experiments at the respiratory rate of 35 breaths/min and mechanical power below (TV 11 ml/kg) and above (TV 22 ml/kg) the threshold. In the 15 experiments to detect the threshold for VILI, up to a mechanical power of approximately 12 J/min (respiratory rate, 9 breaths/min), the computed tomography scans showed mostly isolated densities, whereas at the mechanical power above approximately 12 J/min, all piglets developed whole-lung edema. In the nine confirmatory experiments, the five piglets ventilated above the power threshold developed VILI, but the four piglets ventilated below did not. By grouping all 24 piglets, the authors found a significant relationship between the mechanical power applied to the lung and the increase in lung weight (r = 0.41, P = 0.001) and lung elastance (r = 0.33, P < 0.01) and decrease in PaO2/FIO2 (r = 0.40, P < 0.001) at the end of the study. In piglets, VILI develops if a mechanical power threshold is exceeded.

  19. Acute kidney injury after ex vivo lung perfusion (EVLP).

    PubMed

    Hauck, J; Osho, A; Castleberry, A; Hartwig, M; Reddy, L; Phillips-Bute, B; Swaminathan, M; Mathew, J; Stafford-Smith, M

    2014-12-01

    Ex vivo lung perfusion (EVLP) identifies viability for marginal organs but complicates and lengthens lung transplantation surgery. Preliminary evidence supports equivalency for EVLP-assisted versus traditional (non-EVLP) procedures regarding graft function, postoperative course, mortality, and survival. However, acute kidney injury (AKI), a common serious complication of lung transplantation, has not been assessed. We tested the hypothesis that EVLP-assisted and non-EVLP lung transplantations are associated with different AKI rates. Demographic, procedural, and renal data were gathered for 13 EVLP-viable lung transplantations and a non-EVLP group matched 4:1 for single versus double, pulmonary disease, and age. AKI was defined by AKI Network (AKIN) criteria and peak creatinine rise relative to baseline (Δ%Cr) during the 1st 10 postoperative days. Chi-square was performed for AKIN and 2-tailed t test for %ΔCr. Patient and procedural characteristics were similar between the groups. One non-EVLP patient required postoperative dialysis. AKI rates were also similar, as assessed by both AKIN (EVLP 7/13 (54%) vs non-EVLP 32/52 (62%); P = .61) and %ΔCr (EVLP 91 ± 81% vs non-EVLP 72 ± 62%; P = .63). We did not observe different AKI rates between EVLP-assisted and traditional lung transplant procedures. Although 1 non-EVLP patient required dialysis, AKI rates were otherwise similar. These findings further support EVLP as a strategy to expand the organ pool and reduce concerns for high-renal risk recipients. The small sample size and retrospective design are limitations. However, our sample size is similar to other reports, and it is the first to analyze AKI after EVLP-assisted lung transplantation. Larger multicenter prospective studies are needed. Copyright © 2014 Elsevier Inc. All rights reserved.

  20. Manipulations of core temperatures in ischemia-reperfusion lung injury in rabbits.

    PubMed

    Chang, Hung; Huang, Kun-Lun; Li, Min-Hui; Hsu, Ching-Wang; Tsai, Shih-Hung; Chu, Shi-Jye

    2008-01-01

    The present study was designed to determine the effect of various core temperatures on acute lung injury induced by ischemia-reperfusion (I/R) in our isolated rabbit lung model. Typical acute lung injury was successfully induced by 30 min of ischemia followed by 90 min of reperfusion observation. The I/R elicited a significant increase in pulmonary arterial pressure, microvascular permeability (measured by using the capillary filtration coefficient, Kfc), Delta Kfc ratio, lung weight gain and the protein concentration of the bronchoalveolar lavage fluid. Mild hypothermia significantly attenuated acute lung injury induced by I/R, all parameters having decreased significantly (p<0.05); conversely, mild hyperthermia did not further exacerbate acute lung injury. These experimental data suggest that mild hypothermia significantly ameliorated acute lung injury induced by ischemia-reperfusion in rabbits.

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

    PubMed

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

    2006-08-01

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

  2. Static inflation attenuates ischemia/reperfusion injury in an isolated rat lung in situ.

    PubMed

    Kao, Shang Jyh; Wang, David; Yeh, Diana Yu-Wung; Hsu, Kang; Hsu, Yung Hsiang; Chen, Hsing I

    2004-08-01

    Ischemia (I)/reperfusion (R) lung injury is an important clinical issue in lung transplantation. In the present study, we observed the effects of lung static inflation, different perfusates, and ventilatory gas with nitrogen or oxygen on the I/R-induced pulmonary damage. A total of 96 male Sprague-Dawley rats were used. The lung was isolated in situ. In an isolated lung, the capillary filtration coefficient (Kfc), lung weight gain (LWG), lung weight (LW)/body weight (BW) ratio, and protein concentration in BAL fluid (PCBAL) were measured or calculated to evaluate the degree of lung injury. Histologic examinations with hematoxylin-eosin staining were performed. I/R caused lung injury, as reflected by increases in Kfc, LWG, LW/BW, and PCBAL. The histopathologic picture revealed the presence of hyaline membrane formation and the infiltration of inflammatory cells. These values were significantly attenuated by static lung inflation. The I/R lung damage appeared to be less in the lung perfused with whole blood than in the lung perfused with an isotonic solution. Therapy with ventilatory air (ie, nitrogen or oxygen) did not alter the I/R lung damage. The data suggest that lung inflation is protective to I/R injury, irrespective of the type of ventilatory air used for treatment. The preservation of the lung for transplantation is better kept at a static inflation state and perfused with whole blood instead of an isotonic physiologic solution.

  3. Interleukin-33 potentiates bleomycin-induced lung injury.

    PubMed

    Luzina, Irina G; Kopach, Pavel; Lockatell, Virginia; Kang, Phillip H; Nagarsekar, Ashish; Burke, Allen P; Hasday, Jeffrey D; Todd, Nevins W; Atamas, Sergei P

    2013-12-01

    The mechanisms of interstitial lung disease (ILD) remain incompletely understood, although recent observations have suggested an important contribution by IL-33. Substantial elevations in IL-33 expression were found in the lungs of patients with idiopathic pulmonary fibrosis and scleroderma lung disease, as well as in the bleomycin injury mouse model. Most of the observed IL-33 expression was intracellular and intranuclear, suggesting involvement of the full-length (fl) protein, but not of the proteolytically processed mature IL-33 cytokine. The effects of flIL-33 on mouse lungs were assessed independently and in combination with bleomycin injury, using recombinant adenovirus-mediated gene delivery. Bleomycin-induced changes were not affected by gene deficiency of the IL-33 receptor T1/ST2. Combined flIL-33 expression and bleomycin injury exerted a synergistic effect on pulmonary lymphocyte and collagen accumulation, which could be explained by synergistic regulation of the cytokines transforming growth factor-β, IL-6, monocyte chemotactic protein-1, macrophage inflammatory protein\\x{2013}1α, and tumor necrosis factor-α. By contrast, no increase in the levels of the Th2 cytokines IL-4, IL-5, or IL-13 was evident. Moreover, flIL-33 was found to increase the expression of several heat shock proteins (HSPs) significantly, and in particular HSP70, which is known to be associated with ILD. Thus, flIL-33 is a synergistic proinflammatory and profibrotic regulator that acts by stimulating the expression of several non-Th2 cytokines, and activates the expression of HSP70.

  4. The protective effect of infliximab against carbon tetrachloride-induced acute lung injury

    PubMed Central

    Kurt, Aysel; Tumkaya, Levent; Yuce, Suleyman; Turut, Hasan; Cure, Medine Cumhur; Sehitoglu, Ibrahim; Kalkan, Yildiray; Pusuroglu, Gokhan; Cure, Erkan

    2016-01-01

    Objective(s): Carbon tetrachloride (CCl4) causes pulmonary toxicity. Infliximab (Ib) is a potent inhibitor of tumor necrosis factor-alpha (TNF-α). We aimed to investigate whether Ib has a protective effect on CCl4 induced lung injury. Materials and Methods: Rats were divided into control, CCl4, and CCl4+Ib groups. A single dose of 2 ml/kg CCI4 was administered to CCI4 group and a single dose of 7 mg/kg Ib was given to CCl4+Ib group 24 hr before applying CCI4. Results: TNF-α, malondialdehyde (MDA), nitric oxide (NO) and caspase-3 levels of the CCl4 group were markedly higher than both the control and CCl4+Ib groups. The CCI4+Ib group had lower histopathological injury than the CCl4 group. Conclusion: Ib as a strong TNF-α blocker decreases the production of proinflammatory cytokines, MDA, and oxidative stress leading to a protective effect against CCl4 induced lung tissue injury. PMID:27482351

  5. Creatine supplementation attenuates pulmonary and systemic effects of lung ischemia and reperfusion injury.

    PubMed

    Almeida, Francine Maria; Oliveira-Junior, Manoel Carneiro; Souza, Renato Aparecido; Petroni, Ricardo Costa; Soto, Sonia Fatima; Soriano, Francisco Garcia; Carvalho, Paulo Tarso Camillo de; Albertini, Regiane; Damaceno-Rodrigues, Nilsa Regina; Lopes, Fernanda Degobbi Tenorio Quirino Santos; Castro-Faria-Neto, Hugo Caire; Martins, Milton Arruda; Dolhnikoff, Marisa; Pazetti, Rogerio; Vieira, Rodolfo Paula

    2016-02-01

    Creatine (Cr) is a dietary supplement that presents beneficial effects in experimental models of heart and brain ischemia and reperfusion (I/R) injury. It can improve adenosine 5'-triphosphate generation and reduce cell damage. This study evaluated the effects of Cr supplementation in a model of lung I/R. Forty male Wistar rats were divided into 4 groups: sham operated, Cr+sham, I/R, and Cr+I/R. We investigated the effects of 5 days of Cr supplementation (0.5 g/kg/day by gavage) before left pulmonary artery ischemia (90 minutes) and reperfusion (120 minutes) on pulmonary and systemic response. Cr inhibited the I/R-induced increase in exhaled nitric oxide (p < 0.05), total cells (p < 0.01), and neutrophils (p < 0.001) in bronchoalveolar lavage fluid and in the systemic circulation (p < 0.001). The levels of interleukin-1β (p < 0.05), tissue damping, and tissue elastance (p < 0.05) were also minimized. Cr also inhibited pulmonary edema formation (total proteins in bronchoalveolar lavage fluid, p < 0.001; histologic edema index, p < 0.001) and neutrophils accumulation in lung tissue (p < 0.001). As possible mechanisms underlying Cr effects, we observed a reduced expression of caspase 3 (p < 0.05), reduced expression of Toll-like receptor (TLR) 4, and increased expression of TLR7 in lung tissue (p < 0.001). Cr supplementation presents pulmonary and systemic protective effects in acute lung injury induced by I/R in rats. These beneficial effects seem to be related to the anti-inflammatory and anti-oxidant properties of Cr and modulation of TLRs. Copyright © 2016 International Society for Heart and Lung Transplantation. Published by Elsevier Inc. All rights reserved.

  6. Soyasaponin Ab inhibits lipopolysaccharide-induced acute lung injury in mice.

    PubMed

    Lin, Jing; Cheng, Yanwen; Wang, Tao; Tang, Lihua; Sun, Yan; Lu, Xiuyun; Yu, Huimin

    2016-01-01

    Soyasaponin Ab (SA) has been reported to have anti-inflammatory effect. However, the effects of SA on lipopolysaccharide (LPS)-induced acute lung injury (ALI) have not been reported. The aim of this study was to investigate the anti-inflammatory effects of SA on LPS-induced ALI and clarify the possible mechanism. The mice were stimulated with LPS to induce ALI. SA was given 1h after LPS treatment. 12h later, lung tissues were collected to assess pathological changes and edema. Bronchoalveolar lavage fluid (BALF) was collected to assess inflammatory cytokines and nitric oxide (NO) production. In vitro, mice alveolar macrophages were used to investigate the anti-inflammatory mechanism of SA. Our results showed that SA attenuated LPS-induced lung pathological changes, edema, the expression of cycloxygenase-2 (COX-2) and inducible nitric oxide synthase (iNOS) in lung tissues, as well as TNF-α, IL-6, IL-1β, and NO production in mice. Meanwhile, SA up-regulated the activities of superoxide dismutase (SOD) and catalase decreased by LPS in mice. SA also inhibited LPS-induced TNF-α, IL-6 and IL-1β production as well as NF-κB activation in alveolar macrophages. Furthermore, SA could activate Liver X Receptor Alpha (LXRα) and knockdown of LXRα by RNAi abrogated the anti-inflammatory effects of SA. In conclusion, the current study demonstrated that SA exhibited protective effects against LPS-induced acute lung injury and the possible mechanism was involved in activating LXRα, thereby inhibiting LPS-induced inflammatory response. Copyright © 2015 Elsevier B.V. All rights reserved.

  7. Single high-dose dexamethasone and sodium salicylate failed to attenuate phosgene-induced acute lung injury in rats.

    PubMed

    Liu, Fangfang; Pauluhn, Jürgen; Trübel, Hubert; Wang, Chen

    2014-01-06

    Life-threatening acute lung injury potentially occurs following high-level accidental exposures to phosgene gas. This situation was mirrored in rats exposed nose-only at 900-1000 mg phosgene/m(3)min. At this exposure level, previous studies on rats demonstrated sustained reflexively induced cardiopulmonary dysfunction and evidence of vascular fluid redistribution. These findings challenge the currently applied treatment strategies to mitigate the presumed non-cardiogenic lung edema by steroidal or non-steroidal anti-inflammatory drugs. This study investigates whether high doses of curatively administered dexamethasone (DX; 100 mg/kg bw, ip) and sodium salicylate (SS; 200 mg/kg bw, ip), alone or in combination, show efficacy to mitigate the phosgene-induced lung edema. Exhaled nitric oxide (eNO), animal morbidity and mortality, and increased lung weights one day postexposure served as endpoints of lung injury and drug efficacy. When applying this dosing regimen, SS showed minimal (if any) efficacy while DX, alone or in combination with SS, substantially aggravated the emerging lung edema (lung weights) with 40% mortality. The degree of acute lung injury (ALI) was mirrored by increased eNO. Its direct relationship to ALI-severity was evidenced by decreased eNO following NO-synthetase inhibitor administration (aminoguanidine-aerosol) and associated mitigation of ALI. All non-treated phosgene-exposed as well as treated but non-phosgene-exposed rats survived. This experimental evidence suggests that high-dose corticoid treatments may aggravate the pulmonary toxicity of phosgene. Similarly, this outcome supports the supposition that non-inflammatory, cardiogenic and/or neurogenic factors play a role in this type of acute lung injury. Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.

  8. Pleiotropic Effects of Levofloxacin, Fluoroquinolone Antibiotics, against Influenza Virus-Induced Lung Injury.

    PubMed

    Enoki, Yuki; Ishima, Yu; Tanaka, Ryota; Sato, Keizo; Kimachi, Kazuhiko; Shirai, Tatsuya; Watanabe, Hiroshi; Chuang, Victor T G; Fujiwara, Yukio; Takeya, Motohiro; Otagiri, Masaki; Maruyama, Toru

    2015-01-01

    Reactive oxygen species (ROS) and nitric oxide (NO) are major pathogenic molecules produced during viral lung infections, including influenza. While fluoroquinolones are widely used as antimicrobial agents for treating a variety of bacterial infections, including secondary infections associated with the influenza virus, it has been reported that they also function as anti-oxidants against ROS and as a NO regulator. Therefore, we hypothesized that levofloxacin (LVFX), one of the most frequently used fluoroquinolone derivatives, may attenuate pulmonary injuries associated with influenza virus infections by inhibiting the production of ROS species such as hydroxyl radicals and neutrophil-derived NO that is produced during an influenza viral infection. The therapeutic impact of LVFX was examined in a PR8 (H1N1) influenza virus-induced lung injury mouse model. ESR spin-trapping experiments indicated that LVFX showed scavenging activity against neutrophil-derived hydroxyl radicals. LVFX markedly improved the survival rate of mice that were infected with the influenza virus in a dose-dependent manner. In addition, the LVFX treatment resulted in a dose-dependent decrease in the level of 8-hydroxy-2'-deoxyguanosine (a marker of oxidative stress) and nitrotyrosine (a nitrative marker) in the lungs of virus-infected mice, and the nitrite/nitrate ratio (NO metabolites) and IFN-γ in BALF. These results indicate that LVFX may be of substantial benefit in the treatment of various acute inflammatory disorders such as influenza virus-induced pneumonia, by inhibiting inflammatory cell responses and suppressing the overproduction of NO in the lungs.

  9. Preventive effects of curcumin on different aspiration material-induced lung injury in rats.

    PubMed

    Guzel, Ahmet; Kanter, Mehmet; Aksu, Burhan; Basaran, Umit Nusret; Yalçin, Omer; Guzel, Aygul; Uzun, Hafise; Konukoğlu, Dildar; Karasalihoglu, Serap

    2009-01-01

    We have studied whether curcumin protects different pulmonary aspiration material-induced lung injury in rats. The experiments were designed in 60 Sprague-Dawley rats, randomly allotted into one of six groups (n=10): normal saline (NS, control), enteral formula (Biosorb Energy Plus, BIO), hydrochloric acid (HCl), NS+curcumin-treated, BIO+curcumin-treated, and HCl+curcumin-treated. NS, BIO, HCl were injected in to the lungs. The rats received curcumin twice daily only for 7 days. Seven days later, both lungs in all groups were examined histopathologically, immunohistochemically, and biochemically. Histopathologic examination was performed according to the presence of peribronchial inflammatory cell infiltration, alveolar septal infiltration, alveolar edema, alveolar exudate, alveolar histiocytes, interstitial fibrosis, granuloma, and necrosis formation. Immunohistochemical assessments were examined for the activity of inducible nitric oxide synthase (iNOS) and the expression of surfactant protein D (SP-D). Malondialdehyde (MDA), hydroxyproline (HP), superoxide dismutase (SOD), and glutathione peroxidase (GSH-Px) activity were measured in the lung tissue. Our findings show that curcumin inhibits the inflammatory response reducing significantly (P<0.05) all histopathological parameters in different pulmonary aspiration models. Pulmonary aspiration significantly increased the tissue HP content, MDA levels and decreased the antioxidant enzyme (SOD, GSH-Px) activities. Curcumin treatment significantly decreased the elevated tissue HP content, and MDA levels and prevented inhibition of SOD, and GSH-Px enzymes in the tissues. Furthermore, our data suggest that there is a significant reduction in the activity of iNOS and a rise in the expression of SP-D in lung tissue of different pulmonary aspiration models with curcumin therapy. Our findings support the use of curcumin as a potential therapeutic agent in acute lung injury.

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

    PubMed

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

    2015-10-01

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

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

    PubMed Central

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

    2015-01-01

    Oxidative stress injury is an important pathogenesis of influenza virus in critically ill patients. The present study investigated the efficacy of carnosine, an antioxidant and free radical scavenger, on a model of acute lung injury (ALI) induced by H9N2 swine influenza virus. Female specific-pathogen-free BALB/c mice were randomized into four groups and treated as follows: (1) H9N2 group, (2) mock control group, (3) H9N2+carnosine group and (4) carnosine control group. The H9N2 group mice were inoculated intranasally with A/Swine/Hebei/012/2008/ (H9N2) virus (100 μl) in allantoic fluid (AF), whilst mock-infected animals were intranasally inoculated with non-infectious AF. Carnosine [10 mg (kg body mass)− 1] was administered orally (100 μl) for 7 days consecutively. The survival rate, lung water content, TNF-α and IL-1β levels, lung histopathology, myeloperoxidase (MPO) activity, and Toll-like receptor (TLR)-4 levels were determined at 2, 4, 6, 8 and 14 days after inoculation. Carnosine treatment effectively decreased the mortality (43 versus 75 %, P < 0.05), significantly ameliorated pathological lesions in lungs and decreased the lung wet/dry mass ratio (P < 0.05). It also inhibited MPO activity, suppressed TNF-α and IL-1β release, decreased the H9N2 viral titre, and markedly inhibited levels of TLR-4 mRNA and protein in the lungs of infected mice (P < 0.05), which supported the use of carnosine for managing severe influenza cases. PMID:26233716

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

    PubMed

    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.

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

    PubMed

    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.

  14. Assessment of Oxidative Stress in Lungs from Sheep After Inhalation of Wood Smoke

    DTIC Science & Technology

    2004-01-01

    hypoxia. Plasma and expired breath samples were collected pre-smoke, and 6, 12, 18, 24, 36 and 48 h after smoke exposure. Sheep were euthanatized 48... h after smoke exposure and lung and airway sections were evaluated histologically for injury and biochemically for indices of oxidative stress. Plasma...thiobarbituric acid reactive substances (TBARS) were 66 and 69% higher than controls after moderate and severe smoke exposure at 48 h , whereas total

  15. [Acute lung injury as a consequence of blood transfusion].

    PubMed

    Rodríguez-Moyado, Héctor

    2011-01-01

    Acute lung injury (ALI) has been recognized as a consequence of blood transfusion (BT) since 1978; the Food and Drug Administration, has classified it as the third BT mortality issue, in 2004, and in first place related with ALI. It can be mainly detected as: Acute respiratory distress syndrome (ARDS), transfusion associated circulatory overload (TACO) and transfusion related acute lung injury (TRALI). The clinical onset is: severe dyspnea, bilateral lung infiltration and low oxygen saturation. In USA, ARDS has an incidence of three to 22.4 cases/100 000 inhabitants, with 58.3 % mortality. TACO and TRALI are less frequent; they have been reported according to the number of transfusions: one in 1275 to 6000 for TRALI and one in 356 transfusions for TACO. Mortality is reported from two to 20 % in TRALI and 20 % in TACO. Antileukocyte antibodies in blood donors plasma, caused TRALI in 89 % of cases; also it has been found antigen specificity against leukocyte blood receptor in 59 %. The UCI patients who received a BT have ALI as a complication in 40 % of cases. The capillary pulmonary endothelia is the target of leukocyte antibodies and also plasma biologic modifiers of the stored plasma, most probable like a Sanarelli-Shwar-tzman phenomenon.

  16. Experimental lung injury promotes alterations in energy metabolism and respiratory mechanics in the lungs of rats: prevention by exercise.

    PubMed

    da Cunha, Maira J; da Cunha, Aline A; Scherer, Emilene B S; Machado, Fernanda Rossato; Loureiro, Samanta O; Jaenisch, Rodrigo B; Guma, Fátima; Lago, Pedro Dal; Wyse, Angela T S

    2014-04-01

    In the present study we investigated the effects of lung injury on energy metabolism (succinate dehydrogenase, complex II, cytochrome c oxidase, and ATP levels), respiratory mechanics (dynamic and static compliance, elastance and respiratory system resistance) in the lungs of rats, as well as on phospholipids in bronchoalveolar lavage fluid. The protective effect of physical exercise on the alterations caused by lung injury, including lung edema was also evaluated. Wistar rats were submitted to 2 months of physical exercise. After this period the lung injury was induced by intratracheal instillation of lipopolysaccharide. Adult Wistar rats were submitted to 2 months of physical exercise and after this period the lung injury was induced by intratracheal instillation of lipopolysaccharide in dose 100 μg/100 g body weight. The sham group received isotonic saline instillation. Twelve hours after the injury was performed the respiratory mechanical and after the rats were decapitated and samples were collected. The rats subjected to lung injury presented a decrease in activities of the enzymes of the electron transport chain and ATP levels in lung, as well as the formation of pulmonary edema. A decreased lung dynamic and static compliance, as well as an increase in respiratory system resistance, and a decrease in phospholipids content were observed. Physical exercise was able to totally prevent the decrease in succinate dehydrogenase and complex II activities and the formation of pulmonary edema. It also partially prevented the increase in respiratory system resistance, but did not prevent the decrease in dynamic and static compliance, as well as in phospholipids content. These findings suggest that the mitochondrial dysfunction may be one of the important contributors to lung damage and that physical exercise may be beneficial in this pathology, although it did not prevent all changes present in lung injury.

  17. Minimizing Oxidation and Stable Nanoscale Dispersion Improves the Biocompatibility of Graphene in the Lung

    PubMed Central

    Duch, Matthew C.; Scott Budinger, G. R.; Liang, Yu Teng; Soberanes, Saul; Urich, Daniela; Chiarella, Sergio E.; Campochiaro, Laura A; Gonzalez, Angel; Chandel, Navdeep S.; Hersam, Mark C.; Mutlu, Gökhan M.

    2011-01-01

    To facilitate the proposed use of graphene and its derivative graphene oxide (GO) in widespread applications, we explored strategies that improve the biocompatibility of graphene nanomaterials in the lung. In particular, solutions of aggregated graphene, Pluronic dispersed graphene, and GO were administered directly into the lungs of mice. The introduction of GO resulted in severe and persistent lung injury. Furthermore, in cells, GO increased the rate of mitochondrial respiration and the generation of reactive oxygen species, activating inflammatory and apoptotic pathways. In contrast, this toxicity was significantly reduced in the case of pristine graphene after liquid phase exfoliation, and was further minimized when the unoxidized graphene was well-dispersed with the block copolymer Pluronic. Our results demonstrate that the covalent oxidation of graphene is a major contributor to its pulmonary toxicity and suggest that dispersion of pristine graphene in Pluronic provides a pathway for the safe handling and potential biomedical application of two-dimensional carbon nanomaterials. PMID:22023654

  18. Gene Expression Analysis to Assess the Relevance of Rodent Models to Human Lung Injury.

    PubMed

    Sweeney, Timothy E; Lofgren, Shane; Khatri, Purvesh; Rogers, Angela J

    2017-08-01

    The relevance of animal models to human diseases is an area of intense scientific debate. The degree to which mouse models of lung injury recapitulate human lung injury has never been assessed. Integrating data from both human and animal expression studies allows for increased statistical power and identification of conserved differential gene expression across organisms and conditions. We sought comprehensive integration of gene expression data in experimental acute lung injury (ALI) in rodents compared with humans. We performed two separate gene expression multicohort analyses to determine differential gene expression in experimental animal and human lung injury. We used correlational and pathway analyses combined with external in vitro gene expression data to identify both potential drivers of underlying inflammation and therapeutic drug candidates. We identified 21 animal lung tissue datasets and three human lung injury bronchoalveolar lavage datasets. We show that the metasignatures of animal and human experimental ALI are significantly correlated despite these widely varying experimental conditions. The gene expression changes among mice and rats across diverse injury models (ozone, ventilator-induced lung injury, LPS) are significantly correlated with human models of lung injury (Pearson r = 0.33-0.45, P < 1E(-16)). Neutrophil signatures are enriched in both animal and human lung injury. Predicted therapeutic targets, peptide ligand signatures, and pathway analyses are also all highly overlapping. Gene expression changes are similar in animal and human experimental ALI, and provide several physiologic and therapeutic insights to the disease.

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

    PubMed

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

    2016-01-01

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

  20. Lung inflation with hydrogen sulfide during the warm ischemia phase ameliorates injury in rat donor lungs via metabolic inhibition after cardiac death.

    PubMed

    Meng, Chao; Cui, Xiaoguang; Qi, Sihua; Zhang, Jiahang; Kang, Jiyu; Zhou, Huacheng

    2017-05-01

    Hydrogen sulfide attenuates lung ischemia-reperfusion injury when inhaled or administered intraperitoneally. This study investigated the effects of lung inflation with H2S during the warm ischemia phase on lung grafts from rat donors after cardiac death. One hour after cardiac death, donor lungs were inflated in situ for 2 h with either O2 or H2S (O2 or H2S group) during the warm ischemia phase or were deflated as a control procedure (n = 8). After 3 h of cold preservation, lung transplantation was performed. During the warm ischemia phase, the metabolism and mitochondrial structures of donor lungs were analyzed. Arterial blood gas analysis was performed on the recipients. Protein expression in the graft of nuclear factor E2-related factor (Nrf)2 and nuclear factor kappa B (NF-κB) was analyzed by Western blotting, and static compliance, inflammation, oxidative stress, and cell apoptosis were assessed after 3 h of reperfusion. When the O2 and H2S groups were compared with the control group, the mitochondrial structures were improved, and lactic acid levels, inflammation, oxidative stress, and cell apoptosis were significantly decreased; and glucose levels, as well as graft oxygenation and static compliance were increased. Simultaneously, the above indices showed further improvements, and the Nrf2 protein expression was significantly greater, and NF-κB protein expression was less in the H2S group than the O2 group. Lung inflation with H2S during the warm ischemia phase inhibited metabolism in donor lungs via mitochondrial protection, attenuated graft ischemic-reperfusion injury, and improved graft function through NF-κB-dependent anti-inflammatory and Nrf2-dependent antioxidative and antiapoptotic effects. Copyright © 2016 Elsevier Inc. All rights reserved.

  1. Mesenchymal stem cells improves survival in LPS-induced acute lung injury acting through inhibition of NETs formation.

    PubMed

    Pedrazza, Leonardo; Cunha, Aline Andrea; Luft, Carolina; Nunes, Nailê Karine; Schimitz, Felipe; Gassen, Rodrigo Benedetti; Breda, Ricardo Vaz; Donadio, Marcio Vinícius Fagundes; de Souza Wyse, Angela Terezinha; Pitrez, Paulo Marcio Condessa; Rosa, Jose Luis; de Oliveira, Jarbas Rodrigues

    2017-01-23

    Acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) are syndromes of acute hypoxemic respiratory failure resulting from a variety of direct and indirect injuries to the gas exchange parenchyma of the lungs. During the ALI, we have an increase release of proinflammatory cytokines and high reactive oxygen species (ROS) formation. These factors are responsible for the release and activation of neutrophil-derived proteases and the formation of neutrophil extracellular traps (NETs). The excessive increase in the release of NETs cause damage to lung tissue. Recent studies have studies involving the administration of mesenchymal stem cells (MSCs) for the treatment of experimental ALI has shown promising results. In this way, the objective of our study is to evaluate the ability of MSCs, in a lipopolysaccharide (LPS)-induced ALI model, to reduce inflammation, oxidative damage, and consequently decrease the release of NETs. Mice were submitted lung injury induced by intratracheal instillation of LPS and subsequently treated or not with MSCs. Treatment with MSCs was able to modulate pulmonary inflammation, decrease oxidative damage, and reduce the release of NETs. These benefits from treatment are evident when we observe a significant increase in the survival curve in the treated animals. Our results demonstrate that MSCs treatment is effective for the treatment of ALI. For the first time, it is described that MSCs can reduce the formation of NETs and an experimental model of ALI. This finding is directly related to these cells modulate the inflammatory response and oxidative damage in the course of the pathology.

  2. Therapeutic Whole-body Hypothermia Protects Remote Lung, Liver, and Kidney Injuries after Blast Limb Trauma in Rats.

    PubMed

    Ning, Jiaolin; Mo, Liwen; Yi, Bin; Gu, Jianteng; Lu, Kaizhi; Zhou, Yaying; Lai, Xinan; Zhao, Hailin; Ma, Daqing

    2016-06-01

    Severe blast limb trauma (BLT) induces distant multiple-organ injuries. In the current study, the authors determined whether whole-body hypothermia (WH) and its optimal duration (if any) afford protection to the local limb damage and distant lung, liver, and kidney injuries after BLT in rats. Rats with BLT, created by using chartaceous electricity detonators, were randomly treated with WH for 30 min, 60 min, 3 h, and 6 h (n = 12/group). Rectal temperature and arterial blood pressure were monitored throughout. Blood and lung, liver, and kidney tissue samples were harvested for measuring tumor necrosis factor-α, interleukin-6 and interleukin-10, myeloperoxidase activity, hydrogen sulfide, and biomarkers of oxidative stress at 6 h after BLT. The pathologic lung injury and the water content of the lungs, liver, and kidneys and blast limb tissue were assessed. Unlike WH for 30 min, WH for 60 min reduced lung water content, lung myeloperoxidase activity, and kidney myeloperoxidase activity by 10, 39, and 28% (all P < 0.05), respectively. WH for 3 h attenuated distant vital organs and local traumatic limb damage and reduced myeloperoxidase activity, hydrogen peroxide and malondialdehyde concentration, and tumor necrosis factor-α and interleukin-6 levels by up to 49% (all P < 0.01). Likewise, WH for 6 h also provided protection to such injured organs but increased blood loss from traumatic limb. Results of this study indicated that WH may provide protection for distant organs and local traumatic limb after blast trauma, which warrants further study.

  3. NOX2 protects against progressive lung injury and multiple organ dysfunction syndrome

    PubMed Central

    Whitmore, Laura C.; Goss, Kelli L.; Newell, Elizabeth A.; Hilkin, Brieanna M.; Hook, Jessica S.

    2014-01-01

    Systemic inflammatory response syndrome (SIRS) is a common clinical condition in patients in intensive care units that can lead to complications, including multiple organ dysfunction syndrome (MODS). MODS carries a high mortality rate, and it is unclear why some patients resolve SIRS, whereas others develop MODS. Although oxidant stress has been implicated in the development of MODS, several recent studies have demonstrated a requirement for NADPH oxidase 2 (NOX2)-derived oxidants in limiting inflammation. We recently demonstrated that NOX2 protects against lung injury and mortality in a murine model of SIRS. In the present study, we investigated the role of NOX2-derived oxidants in the progression from SIRS to MODS. Using a murine model of sterile systemic inflammation, we observed significantly greater illness and subacute mortality in gp91phox−/y (NOX2-deficient) mice compared with wild-type mice. Cellular analysis revealed continued neutrophil recruitment to the peritoneum and lungs of the NOX2-deficient mice and altered activation states of both neutrophils and macrophages. Histological examination showed multiple organ pathology indicative of MODS in the NOX2-deficient mice, and several inflammatory cytokines were elevated in lungs of the NOX2-deficient mice. Overall, these data suggest that NOX2 function protects against the development of MODS and is required for normal resolution of systemic inflammation. PMID:24793165

  4. NOX2 protects against progressive lung injury and multiple organ dysfunction syndrome.

    PubMed

    Whitmore, Laura C; Goss, Kelli L; Newell, Elizabeth A; Hilkin, Brieanna M; Hook, Jessica S; Moreland, Jessica G

    2014-07-01

    Systemic inflammatory response syndrome (SIRS) is a common clinical condition in patients in intensive care units that can lead to complications, including multiple organ dysfunction syndrome (MODS). MODS carries a high mortality rate, and it is unclear why some patients resolve SIRS, whereas others develop MODS. Although oxidant stress has been implicated in the development of MODS, several recent studies have demonstrated a requirement for NADPH oxidase 2 (NOX2)-derived oxidants in limiting inflammation. We recently demonstrated that NOX2 protects against lung injury and mortality in a murine model of SIRS. In the present study, we investigated the role of NOX2-derived oxidants in the progression from SIRS to MODS. Using a murine model of sterile systemic inflammation, we observed significantly greater illness and subacute mortality in gp91(phox-/y) (NOX2-deficient) mice compared with wild-type mice. Cellular analysis revealed continued neutrophil recruitment to the peritoneum and lungs of the NOX2-deficient mice and altered activation states of both neutrophils and macrophages. Histological examination showed multiple organ pathology indicative of MODS in the NOX2-deficient mice, and several inflammatory cytokines were elevated in lungs of the NOX2-deficient mice. Overall, these data suggest that NOX2 function protects against the development of MODS and is required for normal resolution of systemic inflammation. Copyright © 2014 the American Physiological Society.

  5. Peptide nanomedicines for treatment of acute lung injury.

    PubMed

    Sadikot, Ruxana T

    2012-01-01

    Acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) represent a heterogenous group of lung disease in critically ill patients. Despite the increased understanding of the molecular pathogenesis of ARDS, the mortality remains unacceptably high, ranging from 34% to 64%. Hence, ARDS represents an unmet medical need with an urgency to develop effective pharmacotherapies. Several promising targets that have been identified as potential therapies for ARDS have been limited because of difficulty with delivery. In particular, delivery of peptides and proteins to the lung is an ongoing challenge. Nanobiotechnology and nanoscience are the basis of innovative techniques to deliver drugs targeted to the site of inflamed organs, such as the lungs. Nanoscale drug delivery systems have the ability to improve the pharmacokinetics and pharmakodynamics of agents allowing an increase in the biodistribution of therapeutic agents to target organs, resulting in improved efficacy with reduction in drug toxicity. These systems are exploited for therapeutic purpose to carry the drug in the body in a controlled manner from the site of administration to the therapeutic target. Hence, it is an attractive strategy to test potential targets for ALI/ARDS using nanotechnology. To this end, we have identified several potential targets and proposed the delivery of these agents using nanomicelles to improve the drug delivery. Copyright © 2012 Elsevier Inc. All rights reserved.

  6. Plasminogen activator inhibitor-1 in acute hyperoxic mouse lung injury.

    PubMed Central

    Barazzone, C; Belin, D; Piguet, P F; Vassalli, J D; Sappino, A P

    1996-01-01

    Hyperoxia-induced lung disease is associated with prominent intraalveolar fibrin deposition. Fibrin turnover is tightly regulated by the concerted action of proteases and antiproteases, and inhibition of plasmin-mediated proteolysis could account for fibrin accumulation in lung alveoli. We show here that lungs of mice exposed to hyperoxia overproduce plasminogen activator inhibitor-1 (PAI-1), and that PAI-1 upregulation impairs fibrinolytic activity in the alveolar compartment. To explore whether increased PAI-1 production is a causal or only a correlative event for impaired intraalveolar fibrinolysis and the development of hyaline membrane disease, we studied mice genetically deficient in PAI-1. We found that these mice fail to develop intraalveolar fibrin deposits in response to hyperoxia and that they are more resistant to the lethal effects of hyperoxic stress. These observations provide clear and novel evidence for the pathogenic contribution of PAI-1 in the development of hyaline membrane disease. They identify PAI-1 as a major deleterious mediator of hyperoxic lung injury. PMID:8981909

  7. Suppression of nuclear factor erythroid‑2‑related factor 2‑mediated antioxidative defense in the lung injury induced by chronic exposure to methamphetamine in rats.

    PubMed

    Bai, Yang; Wang, Yun; Liu, Ming; Gu, Yu-Han; Jiang, Bin; Wu, Xu; Wang, Huai-Liang

    2017-05-01

    The imbalance between oxidative stress and antioxidant defense is important in the pathogenesis of lung diseases. Nuclear factor erythroid‑2‑related factor 2 (Nrf2) is a key transcriptional factor that regulates the antioxidant response. The purpose of the present study was to investigate whether Nrf2‑mediated antioxidative defense is involved in methamphetamine (MA)‑induced lung injury in rats. Following establishment of chronic MA toxicity in rats, Doppler ultrasonic detection was used to measure the changes of physiological indexes, followed by hematoxylin and eosin staining, ELISA and western blot analysis. MA was demonstrated to increase the heart rate and peak blood flow velocity of pulmonary arterial valves and to decrease the survival rate of rats, and resulted in lung injury characterized by perivascular exudates, airspace edema, slight hemorrhage and inflammatory cell infiltration. MA significantly inhibited the expression of nuclear Nrf2 protein and its target genes (glutamate‑cysteine ligase catalytic subunit C and heme oxygenase‑1), and dose‑dependently reduced glutathione (GSH) levels and the ratio of GSH/oxidized glutathione, accompanied by increases in reactive oxygen species (ROS) levels in rat lungs. Linear regression analysis revealed that there was a positive correlation between lung ROS level and lung injury indexes. These findings suggested that chronic exposure to MA led to lung injury by suppression of Nrf2‑mediated antioxidative defense, suggesting that Nrf2 may be an important therapeutic target for MA‑induced chronic lung toxicity.

  8. Enhancement of ozone-induced lung injury by exercise

    SciTech Connect

    Mautz, W.J.; McClure, T.R.; Reischl, P.; Phalen, R.F.; Crocker, T.T.

    1985-01-01

    Rats were exposed for up to 3.75 h to 0.20-0.80 ppm O/sub 3/ under conditions of rest and treadmill exercise up to 30 m/min, 20% grade, to assess the importance of exposure duration, O/sub 3/ concentration, and exercise on lung tissue injury. Focal lung parenchymal lesions increased in abundance and severity in response to the three variables; however, exercise was the most important. Lesion response to exercise was greater than that predicted by a simple proportion to estimated effective dose of O/sub 3/. The results emphasize the importance of including exercise in assessment of possible adverse health effects of exposure to airborne pollutants.

  9. Determinants of Lung Volumes in Chronic Spinal Cord Injury

    PubMed Central

    Stepp, Evan L.; Brown, Robert; Tun, Carlos G.; Gagnon, David R.; Jain, Nitin B.; Garshick, Eric

    2008-01-01

    Objective To characterize determinants of lung volumes in chronic spinal cord injury (SCI). Design Cross-sectional. Setting VA Boston Healthcare System. Participants White men (N=330) with chronic SCI. Interventions Not applicable. Main Outcome Measures Questionnaire responses and measurements of lung volumes. Results Adjusted for SCI severity and stature, greater body mass index (BMI) was associated (all P<.05) with lower total lung capacity (TLC) (−38.7mL·kg−1·m2), functional residual capacity (FRC) (−73.9mL·kg−1·m2), residual volume (RV) (−40.4mL·kg−1·m2), and expiratory reserve volume (ERV) (−32.2mL·kg−1·m2). The effect of BMI on RV was most pronounced in quadriplegia (−72mL·kg−1·m2). Lifetime smoking was associated with a greater FRC (5.3mL/pack a year) and RV (3.1mL/pack a year). The effects of lifetime smoking were also greatest in quadriplegia (11mL/pack a year for FRC; 7.8mL/pack a year for RV). Time since injury, independent of age, was associated with a decrease in TLC, FRC, ERV, and RV (P<.05). Age was not a predictor of TLC once time since injury was considered. Conclusions Determinants of FRC, TLC, ERV, and RV in chronic SCI include factors related and unrelated to SCI. The mechanisms remain to be determined but likely involve the elastic properties and muscle function of the respiratory system and perhaps the effects of systemic inflammation related to adiposity. Addressing modifiable factors such as obesity, muscle stiffness, and smoking may improve respiratory morbidity and mortality in SCI by improving pulmonary function. PMID:18674986

  10. Efferent vagal nerve stimulation attenuates acute lung injury following burn: The importance of the gut-lung axis

    PubMed Central

    Krzyzaniak, Michael J.; Peterson, Carrie Y.; Cheadle, Gerald; Loomis, William; Wolf, Paul; Kennedy, Vince; Putnam, James G.; Bansal, Vishal; Eliceiri, Brian; Baird, Andrew; Coimbra, Raul

    2014-01-01

    Background The purpose of this study was to assess acute lung injury when protection to the gut mucosal barrier offered by vagus nerve stimulation is eliminated by an abdominal vagotomy. Methods Male balb/c mice were subjected to 30% total body surface area steam burn with and without electrical stimulation to the right cervical vagus nerve. A cohort of animals were subjected to abdominal vagotomy. Lung histology, myeloperoxidase and ICAM-1 immune staining, myeloperoxidase enzymatic assay, and tissue KC levels were analyzed 24 hours after burn. Additionally, lung IkB-α, NF-kB immunoblots, and NF-kB-DNA binding measured by photon emission analysis using NF-kB-luc transgenic mice were performed. Results Six hours post burn, phosphorylation of both NF-kB p65 and IkB-α were observed. Increased photon emission signal was seen in the lungs of NF-kB-luc transgenic animals. Vagal nerve stimulation blunted NF-kB activation similar to sham animals whereas abdominal vagotomy eliminated the anti-inflammatory effect. After burn, MPO positive cells and ICAM-1 expression in the lung endothelium was increased, and lung histology demonstrated significant injury at 24 hours. Vagal nerve stimulation markedly decreased neutrophil infiltration as demonstrated by MPO immune staining and enzyme activity. Vagal stimulation also markedly attenuated acute lung injury at 24 hours. The protective effects of vagal nerve stimulation were reversed by performing an abdominal vagotomy. Conclusion Vagal nerve stimulation is an effective strategy to protect against acute lung injury following burn. Moreover, the protective effects of vagal nerve stimulation in the prevention of acute lung injury are eliminated by performing an abdominal vagotomy. These results establish the importance of the gut-lung axis after burn in the genesis of acute lung injury. PMID:21783215

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

    PubMed

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

    2015-05-01

    The present study aimed to investigate the combined effects of puerarin with edaravone on inhalation lung injury induced by black gunpowder smog. Male Wistar rats were divided into five groups (control group, edaravone group, puerarin group, edaravone combined with puerarin group and inhalation group). The severity of pulmonary injuries was evaluated after inducing acute lung injury. Arterial blood gas, inflammatory cytokines, biochemical, parameters, cell counting, W/D weight ratio and histopathology were analyzed. Results in lung tissues, either edaravone or puerarin treatment alone showed significant protective effects against neutrophil infiltration and tissue injury, as demonstrated by myeloperoxidase activity and histopathological analysis (all p<0.05). In addition, combined treatment with both edaravone and puerarin demonstrated additive protective effects on smog-induced lung injury, compared with single treatment. Combination of edaravone and puerarin shows promise as a new treatment option for acute lung injury/acute respiratory distress syndrome patients. Copyright © 2015 Elsevier B.V. All rights reserved.

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

    PubMed

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

    2016-12-01

    Induction of oxidative stress and inflammation are considered the primary mechanism of cadmium (Cd) toxicity. Nigella sativa (NS) seeds and their oil (NSO) have been reported to possess antioxidant and anti-inflammatory potential. This study was conducted to assess the protective effect of NSO on Cd-induced lung damage in rat. Forty adult male Wistar rats were divided equally into 4 groups. Animals in groups I, II, and III received 1 ml of isotonic saline intraperitoneally (IP), 2 mg/kg of cadmium chloride (CdCl2) dissolved in isotonic saline IP, and 1 ml/kg of NSO by gastric gavage, respectively. Group IV rats received NSO an hour prior to CdCl2 administration via the same routes and doses as previously described. All animals were treated for 28 days. At the end of the study, animals were sacrificed; lungs were harvested for histopathological studies using light and electron microscopy. Saline-treated and NSO-treated rats showed normal lung parenchyma. However, CdCl2-treated rats showed massive degenerative changes in alveolar epithelial lining, disrupted interalveolar septa, and hemolytic debris in alveoli. Rats treated with both NSO and CdCl2 (group IV) showed amelioration of most Cd-induced lung damage with minimal histopathological changes in lung architecture. This study elucidates the protective effects of NSO on Cd-induced lung injury in rats and highlights the possibility of using NSO as a protective agent in individuals at high risk of Cd-induced lung toxicity.

  13. Characterization of Distinct Macrophage Subpopulations during Nitrogen Mustard-Induced Lung Injury and Fibrosis.

    PubMed

    Venosa, Alessandro; Malaviya, Rama; Choi, Hyejeong; Gow, Andrew J; Laskin, Jeffrey D; Laskin, Debra L

    2016-03-01

    Nitrogen mustard (NM) is an alkylating agent known to cause extensive pulmonary injury progressing to fibrosis. This is accompanied by a persistent macrophage inflammatory response. In these studies, we characterized the phenotype of macrophages accumulating in the lung over time following NM exposure. Treatment of rats with NM (0.125 mg/kg, intratracheally) resulted in an increase in CD11b(+) macrophages in histologic sections. These cells consisted of inducible nitric oxide synthase(+) (iNOS) proinflammatory M1 macrophages, and CD68(+), CD163(+), CD206(+), YM-1(+), and arginase-II(+)antiinflammatory M2 macrophages. Although M1 macrophages were prominent 1-3 days after NM, M2 macrophages were most notable at 28 days. At this time, they were enlarged and vacuolated, consistent with a profibrotic phenotype. Flow cytometric analysis of isolated lung macrophages identified three phenotypically distinct subpopulations: mature CD11b(-), CD43(-), and CD68(+) resident macrophages, which decreased in numbers after NM; and two infiltrating (CD11b(+)) macrophage subsets: immature CD43(+) M1 macrophages and mature CD43(-) M2 macrophages, which increased sequentially. Time-related increases in M1 (iNOS, IL-12α, COX-2, TNF-α, matrix metalloproteinase-9, matrix metalloproteinase-10) and M2 (IL-10, pentraxin-2, connective tissue growth factor, ApoE) genes, as well as chemokines/chemokine receptors associated with trafficking of M1 (CCR2, CCR5, CCL2, CCL5) and M2 (CX3CR1, fractalkine) macrophages to sites of injury, were also noted in macrophages isolated from the lung after NM. The appearance of M1 and M2 macrophages in the lung correlated with NM-induced acute injury and the development of fibrosis, suggesting a potential role of these macrophage subpopulations in the pathogenic response to NM.

  14. Heme Attenuation Ameliorates Irritant Gas Inhalation-Induced Acute Lung Injury

    PubMed Central

    Aggarwal, Saurabh; Lam, Adam; Bolisetty, Subhashini; Carlisle, Matthew A.; Traylor, Amie; Agarwal, Anupam

    2016-01-01

    Abstract Aims: Exposure to irritant gases, such as bromine (Br2), poses an environmental and occupational hazard that results in severe lung and systemic injury. However, the mechanism(s) of Br2 toxicity and the therapeutic responses required to mitigate lung damage are not known. Previously, it was demonstrated that Br2 upregulates the heme degrading enzyme, heme oxygenase-1 (HO-1). Since heme is a major inducer of HO-1, we determined whether an increase in heme and heme-dependent oxidative injury underlies the pathogenesis of Br2 toxicity. Results: C57BL/6 mice were exposed to Br2 gas (600 ppm, 30 min) and returned to room air. Thirty minutes postexposure, mice were injected intraperitoneally with a single dose of the heme scavenging protein, hemopexin (Hx) (3 μg/gm body weight), or saline. Twenty-four hours postexposure, saline-treated mice had elevated total heme in bronchoalveolar lavage fluid (BALF) and plasma and acute lung injury (ALI) culminating in 80% mortality after 10 days. Hx treatment significantly lowered heme, decreased evidence of ALI (lower protein and inflammatory cells in BALF, lower lung wet-to-dry weight ratios, and decreased airway hyperreactivity to methacholine), and reduced mortality. In addition, Br2 caused more severe ALI and mortality in mice with HO-1 gene deletion (HO-1−/−) compared to wild-type controls, while transgenic mice overexpressing the human HO-1 gene (hHO-1) showed significant protection. Innovation: This is the first study delineating the role of heme in ALI caused by Br2. Conclusion: The data suggest that attenuating heme may prove to be a useful adjuvant therapy to treat patients with ALI. Antioxid. Redox Signal. 24, 99–112. PMID:26376667

  15. Characterization of Distinct Macrophage Subpopulations during Nitrogen Mustard–Induced Lung Injury and Fibrosis

    PubMed Central

    Venosa, Alessandro; Malaviya, Rama; Choi, Hyejeong; Gow, Andrew J.; Laskin, Jeffrey D.

    2016-01-01

    Nitrogen mustard (NM) is an alkylating agent known to cause extensive pulmonary injury progressing to fibrosis. This is accompanied by a persistent macrophage inflammatory response. In these studies, we characterized the phenotype of macrophages accumulating in the lung over time following NM exposure. Treatment of rats with NM (0.125 mg/kg, intratracheally) resulted in an increase in CD11b+ macrophages in histologic sections. These cells consisted of inducible nitric oxide synthase+ (iNOS) proinflammatory M1 macrophages, and CD68+, CD163+, CD206+, YM-1+, and arginase-II+antiinflammatory M2 macrophages. Although M1 macrophages were prominent 1–3 days after NM, M2 macrophages were most notable at 28 days. At this time, they were enlarged and vacuolated, consistent with a profibrotic phenotype. Flow cytometric analysis of isolated lung macrophages identified three phenotypically distinct subpopulations: mature CD11b−, CD43−, and CD68+ resident macrophages, which decreased in numbers after NM; and two infiltrating (CD11b+) macrophage subsets: immature CD43+ M1 macrophages and mature CD43− M2 macrophages, which increased sequentially. Time-related increases in M1 (iNOS, IL-12α, COX-2, TNF-α, matrix metalloproteinase-9, matrix metalloproteinase-10) and M2 (IL-10, pentraxin-2, connective tissue growth factor, ApoE) genes, as well as chemokines/chemokine receptors associated with trafficking of M1 (CCR2, CCR5, CCL2, CCL5) and M2 (CX3CR1, fractalkine) macrophages to sites of injury, were also noted in macrophages isolated from the lung after NM. The appearance of M1 and M2 macrophages in the lung correlated with NM-induced acute injury and the development of fibrosis, suggesting a potential role of these macrophage subpopulations in the pathogenic response to NM. PMID:26273949

  16. Beneficial Effects of Concomitant Neuronal and Inducible Nitric Oxide Synthase Inhibition in Ovine Burn and Inhalation Injury

    PubMed Central

    Lange, Matthias; Hamahata, Atsumori; Enkhbaatar, Perenlei; Cox, Robert A.; Nakano, Yoshimitsu; Westphal, Martin; Traber, Lillian D.; Herndon, David N.; Traber, Daniel L.

    2013-01-01

    Different isoforms of nitric oxide synthase are critically involved in the development of pulmonary failure secondary to acute lung injury. Here we tested the hypothesis that simultaneous blockade of inducible and neuronal nitric oxide synthase effectively prevents the pulmonary lesions in an ovine model of acute respiratory distress syndrome (ARDS) induced by combined burn and smoke inhalation injury. Chronically instrumented sheep were allocated to a sham-injured group (n = 6), an injured and untreated group (n = 6), or an injured group treated with simultaneous infusion of selective inducible and neuronal nitric oxide synthase inhibitors (n = 5). The injury was induced by 48 breath of cotton smoke and a 3rd degree burn of 40% total body surface area. All sheep were mechanically ventilated and fluid resuscitated. The injury induced severe pulmonary dysfunction as indicated by decreases in PaO2/FiO2 ratio and increases in pulmonary shunt fraction, ventilatory pressures, lung lymph flow, and lung wet/dry weight ratio. The treatment fully prevented the elevations in lymph and plasma nitrate/nitrite levels, pulmonary shunting, ventilatory pressures, lung lymph flow, and wet/dry weight ratio and significantly attenuated the decline in PaO2/FiO2 ratio. In conclusion, simultaneous blockade of inducible and neuronal nitric oxide synthase exerts beneficial pulmonary effects in an ovine model of ARDS secondary to combined burn and smoke inhalation injury. This novel treatment strategy may represent a useful therapeutic adjunct for patients with these injuries. PMID:21263377

  17. S100A8 induces IL-10 and protects against acute lung injury.

    PubMed

    Hiroshima, Yuka; Hsu, Kenneth; Tedla, Nicodemus; Chung, Yuen Ming; Chow, Sharron; Herbert, Cristan; Geczy, Carolyn L

    2014-03-15

    S100A8 is considered proinflammatory by activating TLR4 and/or the receptor for advanced glycation end products. The aim was to investigate inflammatory effects of S100A8 in murine lung. S100A8 was administered to BALB/c mice by nasal inhalation and genes induced over a time-course assessed. LPS was introduced intranasally either alone or 2 h after pretreatment of mice with intranasal application of S100A8 or dexamethasone. A Cys(42)-Ala(42) mutant S100A8 mutant was used to assess whether S100A8's effects were via pathways that were dependent on reactive oxygen species. S100A8 induced IL-10 mRNA, and expression was apparent only in airway epithelial cells. Importantly, it suppressed acute lung injury provoked by LPS inhalation by suppressing mast-cell activation and induction of mediators orchestrating leukocyte recruitment, possibly by reducing NF-κB activation via an IκBα/Akt pathway and by downmodulating pathways generating oxidative stress. The Cys(42)-Ala(42) S100A8 mutant did not induce IL-10 and was less immunosuppressive, indicating modulation by scavenging oxidants. S100A8 inhibition of LPS-mediated injury was as potent, and outcomes were remarkably similar to immunosuppression by dexamethasone. We challenge the notion that S100A8 is an agonist for TLR4 or the receptor for advanced glycation end products. S100A8 induced IL-10 in vivo and initiates a feedback loop that attenuates acute lung injury.

  18. Effects of budesonide on the lung functions, inflammation and apoptosis in a saline-lavage model of acute lung injury.

    PubMed

    Mokra, D; Kosutova, P; Balentova, S; Adamkov, M; Mikolka, P; Mokry, J; Antosova, M; Calkovska, A

    2016-12-01

    Diffuse alveolar injury, edema, and inflammation are fundamental signs of acute lung injury (ALI) and acute respiratory distress syndrome (ARDS). Whereas the systemic administration of corticosteroids previously led to controversial results, this study evaluated if corticosteroids given intratracheally may improve lung functions and reduce edema formation, migration of cells into the lung and their activation in experimentally-induced ALI. In oxygen-ventilated rabbits, ALI was induced by repetitive saline lung lavage, until PaO2 decreased to < 26.7 kPa in FiO2 1.0. Then, one group of animals was treated with corticosteroid budesonide (Pulmicort susp inh, AstraZeneca; 0.25 mg/kg) given intratracheally by means of inpulsion regime of high-frequency jet ventilation, while another group was non-treated, and both groups were oxygen-ventilated for following 5 hours. Another group of animals served as healthy controls. After sacrifice of animals, left lung was saline-lavaged and protein content was measured and cells in the lavage fluid were determined microscopically. Right lung tissue was used for estimation of edema formation (expressed as wet/dry weight ratio), for histomorphological investigation, immunohistochemical determination of apoptosis of lung cells, and for determination of markers of inflammation and lung injury (IL-1β, IL-6, IL-8, TNF-α, IFNγ, esRAGE, caspase-3) by ELISA methods. Levels of several cytokines were estimated also in plasma. Repetitive lung lavage worsened gas exchange, induced lung injury, inflammation and lung edema and increased apoptosis of lung epithelial cells. Budesonide reduced lung edema, cell infiltration into the lung and apoptosis of epithelial cells and decreased concentrations of proinflammatory markers in the lung and blood. These changes resulted in improved ventilation. Concluding, curative intratracheal treatment with budesonide alleviated lung injury, inflammation, apoptosis of lung epithelial cells and lung edema and

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

    PubMed Central

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

    2015-01-01

    Chronic obstructive pulmonary disease (COPD) is characterized by lung destruction and inflammation. As a major compound of cigarette smoke, acrolein plays a critical role in the induction of respiratory diseases. GADD34 is known as a growth arrest and DNA damage-related gene, which can be overexpressed in adverse environmental conditions. Here we investigated the effects of GADD34 on acrolein-induced lung injury. The intranasal exposure of acrolein induced the expression of GADD34, developing the pulmonary damage with inflammation and increase of reactive oxygen species (ROS). Conversely, the integrality of pulmonary structure was preserved and the generation of ROS was reduced in GADD34-knockout mice. Acrolein-induced phosphorylation of eIF2α in GADD34-knockout epithelial cells by shRNA protected cell death by reducing misfolded protein-caused oxidative stress. These data indicate that GADD34 participates in the development of acrolein-induced lung injury. PMID:25821552

  20. Effect of tramadol on lung injury induced by skeletal muscle ischemia-reperfusion: an experimental study*

    PubMed Central

    Takhtfooladi, Mohammad Ashrafzadeh; Jahanshahi, Amirali; Sotoudeh, Amir; Jahanshahi, Gholamreza; Takhtfooladi, Hamed Ashrafzadeh; Aslani, Kimia

    2013-01-01

    OBJECTIVE: To determine whether tramadol has a protective effect against lung injury induced by skeletal muscle ischemia-reperfusion. METHODS: Twenty Wistar male rats were allocated to one of two groups: ischemia-reperfusion (IR) and ischemia-reperfusion + tramadol (IR+T). The animals were anesthetized with intramuscular injections of ketamine and xylazine (50 mg/kg and 10 mg/kg, respectively). All of the animals underwent 2-h ischemia by occlusion of the femoral artery and 24-h reperfusion. Prior to the occlusion of the femoral artery, 250 IU heparin were administered via the jugular vein in order to prevent clotting. The rats in the IR+T group were treated with tramadol (20 mg/kg i.v.) immediately before reperfusion. After the reperfusion period, the animals were euthanized with pentobarbital (300 mg/kg i.p.), the lungs were carefully removed, and specimens were properly prepared for histopathological and biochemical studies. RESULTS: Myeloperoxidase activity and nitric oxide levels were significantly higher in the IR group than in the IR+T group (p = 0.001 for both). Histological abnormalities, such as intra-alveolar edema, intra-alveolar hemorrhage, and neutrophil infiltration, were significantly more common in the IR group than in the IR+T group. CONCLUSIONS: On the basis of our histological and biochemical findings, we conclude that tramadol prevents lung tissue injury after skeletal muscle ischemia-reperfusion. PMID:24068264

  1. Stressed lungs: unveiling the role of circulating stress hormones in ozone-induced lung injury and inflammation.

    EPA Science Inventory

    Ozone, a major component of smog generated through the interaction of light and anthropogenic emissions, induces adverse pulmonary, cardiovascular, and systemic health effects upon inhalation. It is generally accepted that ozone-induced lung injury is mediated by its interaction ...

  2. Stressed lungs: unveiling the role of circulating stress hormones in ozone-induced lung injury and inflammation.

    EPA Science Inventory

    Ozone, a major component of smog generated through the interaction of light and anthropogenic emissions, induces adverse pulmonary, cardiovascular, and systemic health effects upon inhalation. It is generally accepted that ozone-induced lung injury is mediated by its interaction ...

  3. Seawater-drowning-induced acute lung injury: From molecular mechanisms to potential treatments

    PubMed Central

    Jin, Faguang; Li, Congcong

    2017-01-01

    Drowning is a crucial public safety problem and is the third leading cause of accidental fatality, claiming ~372,000 lives annually, worldwide. In near-drowning patients, acute lung injury (ALI) or acute respiratory distress syndrome (ARDS) is one of the most common complications. Approximately 1/3 of near-drowning patients fulfill the criteria for ALI or ARDS. In the present article, the current literature of near-drowning, pathophysiologic changes and the molecular mechanisms of seawater-drowning-induced ALI and ARDS was reviewed. Seawater is three times more hyperosmolar than plasma, and following inhalation of seawater the hyperosmotic seawater may cause serious injury in the lung and alveoli. The perturbing effects of seawater may be primarily categorized into insufficiency of pulmonary surfactant, blood-air barrier disruption, formation of pulmonary edema, inflammation, oxidative stress, autophagy, apoptosis and various other hypertonic stimulation. Potential treatments for seawater-induced ALI/ARDS were also presented, in addition to suggestions for further studies. A total of nine therapeutic strategies had been tested and all had focused on modulating the over-activated immunoreactions. In conclusion, seawater drowning is a complex injury process and the exact mechanisms and potential treatments require further exploration. PMID:28587319

  4. Oxidative Lung Damage Resulting from Repeated Exposure to Radiation and Hyperoxia Associated with Space Exploration

    PubMed Central

    Pietrofesa, Ralph A; Turowski, Jason B; Arguiri, Evguenia; Milovanova, Tatyana N; Solomides, Charalambos C; Thom, Stephen R; Christofidou-Solomidou, Melpo

    2013-01-01

    Background Spaceflight missions may require crewmembers to conduct Extravehicular Activities (EVA) for repair, maintenance or scientific purposes. Pre-breathe protocols in preparation for an EVA entail 100% hyperoxia exposure that may last for a few hours (5-8 hours), and may be repeated 2-3 times weekly. Each EVA is associated with additional challenges such as low levels of total body cosmic/galactic radiation exposure that may present a threat to crewmember health and therefore, pose a threat to the success of the mission. We have developed a murine model of combined, hyperoxia and radiation exposure (double-hit) in the context of evaluating countermeasures to oxidative lung damage associated with space flight. In the current study, our objective was to characterize the early and chronic effects of repeated single and double-hit challenge on lung tissue using a novel murine model of repeated exposure to low-level total body radiation and hyperoxia. This is the first study of its kind evaluating lung damage relevant to space exploration in a rodent model. Methods Mouse cohorts (n=5-15/group) were exposed to repeated: a) normoxia; b) >95% O2 (O2); c) 0.25Gy single fraction gamma radiation (IR); or d) a combination of O2 and IR (O2+IR) given 3 times per week for 4 weeks. Lungs were evaluated for oxidative damage, active TGFβ1 levels, cell apoptosis, inflammation, injury, and fibrosis at 1, 2, 4, 8, 12, 16, and 20 weeks post-initiation of exposure. Results Mouse cohorts exposed to all challenge conditions displayed decreased bodyweight compared to untreated controls at 4 and 8 weeks post-challenge initiation. Chronic oxidative lung damage to lipids (malondialdehyde levels), DNA (TUNEL, cleaved Caspase 3, cleaved PARP positivity) leading to apoptotic cell death and to proteins (nitrotyrosine levels) was elevated all treatment groups. Importantly, significant systemic oxidative stress was also noted at the late phase in mouse plasma, BAL fluid, and urine. Importantly

  5. Oxidative Lung Damage Resulting from Repeated Exposure to Radiation and Hyperoxia Associated with Space Exploration.

    PubMed

    Pietrofesa, Ralph A; Turowski, Jason B; Arguiri, Evguenia; Milovanova, Tatyana N; Solomides, Charalambos C; Thom, Stephen R; Christofidou-Solomidou, Melpo

    2013-09-30

    Spaceflight missions may require crewmembers to conduct Extravehicular Activities (EVA) for repair, maintenance or scientific purposes. Pre-breathe protocols in preparation for an EVA entail 100% hyperoxia exposure that may last for a few hours (5-8 hours), and may be repeated 2-3 times weekly. Each EVA is associated with additional challenges such as low levels of total body cosmic/galactic radiation exposure that may present a threat to crewmember health and therefore, pose a threat to the success of the mission. We have developed a murine model of combined, hyperoxia and radiation exposure (double-hit) in the context of evaluating countermeasures to oxidative lung damage associated with space flight. In the current study, our objective was to characterize the early and chronic effects of repeated single and double-hit challenge on lung tissue using a novel murine model of repeated exposure to low-level total body radiation and hyperoxia. This is the first study of its kind evaluating lung damage relevant to space exploration in a rodent model. Mouse cohorts (n=5-15/group) were exposed to repeated: a) normoxia; b) >95% O2 (O2); c) 0.25Gy single fraction gamma radiation (IR); or d) a combination of O2 and IR (O2+IR) given 3 times per week for 4 weeks. Lungs were evaluated for oxidative damage, active TGFβ1 levels, cell apoptosis, inflammation, injury, and fibrosis at 1, 2, 4, 8, 12, 16, and 20 weeks post-initiation of exposure. Mouse cohorts exposed to all challenge conditions displayed decreased bodyweight compared to untreated controls at 4 and 8 weeks post-challenge initiation. Chronic oxidative lung damage to lipids (malondialdehyde levels), DNA (TUNEL, cleaved Caspase 3, cleaved PARP positivity) leading to apoptotic cell death and to proteins (nitrotyrosine levels) was elevated all treatment groups. Importantly, significant systemic oxidative stress was also noted at the late phase in mouse plasma, BAL fluid, and urine. Importantly, however, late oxidative

  6. Transfusion-related acute lung injury: a review.

    PubMed

    Looney, Mark R; Gropper, Michael A; Matthay, Michael A

    2004-07-01

    Transfusion-related acute lung injury (TRALI) is an underreported complication of transfusion therapy, and it is the third most common cause of transfusion-associated death. TRALI is defined as noncardiogenic pulmonary edema temporally related to transfusion therapy. The diagnosis of TRALI relies on excluding other diagnoses such as sepsis, volume overload, and cardiogenic pulmonary edema. Supportive diagnostic evidence includes identifying neutrophil or human leukocyte antigen (HLA) antibodies in the donor or recipient plasma. All plasma-containing blood products have been implicated in TRALI, with the majority of cases linked to whole blood, packed RBCs, platelets, and fresh-frozen plasma. The pathogenesis of TRALI may be explained by a "two-hit" hypothesis, with the first "hit" being a predisposing inflammatory condition commonly present in the operating room or ICU. The second hit may involve the passive transfer of neutrophil or HLA antibodies from the donor or the transfusion of biologically active lipids from older, cellular blood products. Treatment is supportive, with a prognosis substantially better than most causes of clinical acute lung injury.

  7. Lung protective mechanical ventilation and two year survival in patients with acute lung injury: prospective cohort study

    PubMed Central

    Colantuoni, Elizabeth; Mendez-Tellez, Pedro A; Dinglas, Victor D; Sevransky, Jonathan E; Dennison Himmelfarb, Cheryl R; Desai, Sanjay V; Shanholtz, Carl; Brower, Roy G; Pronovost, Peter J

    2012-01-01

    Objective To evaluate the association of volume limited and pressure limited (lung protective) mechanical ventilation with two year survival in patients with acute lung injury. Design Prospective cohort study. Setting 13 intensive care units at four hospitals in Baltimore, Maryland, USA. Participants 485 consecutive mechanically ventilated patients with acute lung injury. Main outcome measure Two year survival after onset of acute lung injury. Results 485 patients contributed data for 6240 eligible ventilator settings, as measured twice daily (median of eight eligible ventilator settings per patient; 41% of which adhered to lung protective ventilation). Of these patients, 311 (64%) died within two years. After adjusting for the total duration of ventilation and other relevant covariates, each additional ventilator setting adherent to lung protective ventilation was associated with a 3% decrease in the risk of mortality over two years (hazard ratio 0.97, 95% confidence interval 0.95 to 0.99, P=0.002). Compared with no adherence, the estimated absolute risk reduction in two year mortality for a prototypical patient with 50% adherence to lung protective ventilation was 4.0% (0.8% to 7.2%, P=0.012) and with 100% adherence was 7.8% (1.6% to 14.0%, P=0.011). Conclusions Lung protective mechanical ventilation was associated with a substantial long term survival benefit for patients with acute lung injury. Greater use of lung protective ventilation in routine clinical practice could reduce long term mortality in patients with acute lung injury. Trial registration Clinicaltrials.gov NCT00300248. PMID:22491953

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

    PubMed

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

    2012-12-01

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

  9. The role of toxicological interactions in lung injury.

    PubMed Central

    Witschi, H P; Hakkinen, P J

    1984-01-01

    Interactions between two or more toxic agents can produce lung damage by chemical-chemical interactions, chemical-receptor interactions or by modification, by a first agent, of the cell and tissue response to a second agent. Interactions may occur by simultaneous exposure and if exposure to the two agents is separated in time. Chemical-chemical interactions have been mostly studied in the toxicology of air pollutants, where it was shown that the untoward effect of certain oxidants may be enhanced in the presence of other aerosols. Interactions at the receptor site have been found in isolated perfused lung experiments. Oxygen tolerance may be an example, when pre-exposure to one concentration of oxygen mitigates later exposure to 100% oxygen by modifying cellular and enzymatic composition of the lung. Damage of the alveolar zone by the antioxidant butylated hydroxytoluene (BHT) can be greatly enhanced by subsequent exposure to oxygen concentration which, otherwise, would have little if any demonstrable effect. The synergistic interaction between BHT and oxygen results in a resulting interstitial pulmonary fibrosis. Acute or chronic lung disease may then be caused not only by one agent, but very likely in many instances by the interaction of several agents. PMID:6376096

  10. Sclareol ameliorate lipopolysaccharide-induced acute lung injury through inhibition of MAPK and induction of HO-1 signaling.

    PubMed

    Hsieh, Yung-Hung; Deng, Jeng-Shyan; Pan, Hsin-Pao; Liao, Jung-Chun; Huang, Shyh-Shyun; Huang, Guan-Jhong

    2017-03-01

    Sclareol is a natural fragrance compound that is used widely in the cosmetic and food industries. This study examined the effect of sclareol on lipopolysaccharide (LPS)-induced acute lung injury (ALI) in mice. Mice were treated with sclareol 1h before an intratracheal (I.T.) LPS challenge to induce an ALI model. The effects on lung tissue and lung injury were evaluated 6h after LPS induction. Pretreatment with sclareol noticeably improved the LPS-induced histological alterations and edema in lung tissue. Sclareol also inhibited the release of pro-inflammatory mediators. Differences in nitric oxide (NO), tumor necrosis factor alpha (TNF-α), interleukin-1 beta (IL-1β), IL-6, and IL-10 were found in the bronchoalveolar lavage fluid (BALF) 6h after LPS-induced lung injury. This study also found a reduced number of total cells and reduced protein concentrations in the BALF. There were also changes in the pulmonary wet/dry (W/D) weight ratio, antioxidant enzyme activity, and myeloperoxidase activity in lung tissues. Sclareol effectively blocked the phosphorylation of mitogen-activated protein kinases (MAPKs) and impeded the protein expression of inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2). The compound boosted the expression of heme oxygenase-1 (HO-1) and inhibited the breakdown of nuclear factor-kappa B (NF-κB) and inhibitor of kappa B (IκBα). To the best of the authors' knowledge, this study is the first to demonstrate that sclareol effectively inhibits acute lung edema, and the results suggest that sclareol may be a potential agent for the treatment of ALI. The potential therapeutic benefits may include the attenuation of LPS-induced pulmonary inflammation due to sclareol's effects on several pathways, including NF-κB, MAPKs and HO-1, as well as the regulation of antioxidant enzyme activity. Copyright © 2016. Published by Elsevier B.V.

  11. Riboflavin supplementation does not attenuate hyperoxic lung injury in transgenic spc–mthGR mice

    PubMed Central

    Heyob, Kathryn M.; Rogers, Lynette K.; Tipple, Trent E.; Welty, Stephen E.

    2017-01-01

    The aims of this study were to test the hypothesis that mice expressing mitochondrially targeted human glutathione reductase (GR) driven by a surfactant protein C promoter (spc–mthGR) are functionally riboflavin deficient and that this deficiency exacerbates hyperoxic lung injury. The authors further hypothesized that dietary supplementation with riboflavin (FADH) will improve the bioactivity of GR, thus enhancing resistance to hyperoxic lung injury. Transgenic mt–spchGR mice and their nontransgenic littermates were fed control or riboflavin-supplemented diets upon weaning. At 6 weeks of age the mice were exposed to either room air (RA) or >95% O2 for up to 84 hours. GR activities (with and without exogenous FADH) and GR protein levels were measured in lung tissue homogenates. Glutathione (GSH) and glutathione disulfide (GSSG) concentrations were assayed to identify changes in GR activity in vivo. Lung injury was assessed by right lung to body weight ratios and bronchoalveolar lavage protein concentrations. The data showed that enhanced GR activity in the mitochondria of lung type II cells does not protect adult mice from hyperoxic lung injury. Furthermore, the addition of riboflavin to the diets of spc–mthGR mice neither enhances GR activities nor offers protection from hyperoxic lung injury. The results indicated that modulation of mitochondrial GR activity in lung type II cells is not an effective therapy to minimize hyperoxic lung injury. PMID:21128861

  12. Riboflavin supplementation does not attenuate hyperoxic lung injury in transgenic (spc-mt)hGR mice.

    PubMed

    Heyob, Kathryn M; Rogers, Lynette K; Tipple, Trent E; Welty, Stephen E

    2011-04-01

    The aims of this study were to test the hypothesis that mice expressing mitochondrially targeted human glutathione reductase (GR) driven by a surfactant protein C promoter ((spc-mt)hGR) are functionally riboflavin deficient and that this deficiency exacerbates hyperoxic lung injury. The authors further hypothesized that dietary supplementation with riboflavin (FADH) will improve the bioactivity of GR, thus enhancing resistance to hyperoxic lung injury. Transgenic (mt-spc)hGR mice and their nontransgenic littermates were fed control or riboflavin-supplemented diets upon weaning. At 6 weeks of age the mice were exposed to either room air (RA) or >95% O(2) for up to 84 hours. GR activities (with and without exogenous FADH) and GR protein levels were measured in lung tissue homogenates. Glutathione (GSH) and glutathione disulfide (GSSG) concentrations were assayed to identify changes in GR activity in vivo. Lung injury was assessed by right lung to body weight ratios and bronchoalveolar lavage protein concentrations. The data showed that enhanced GR activity in the mitochondria of lung type II cells does not protect adult mice from hyperoxic lung injury. Furthermore, the addition of riboflavin to the diets of (spc-mt)hGR mice neither enhances GR activities nor offers protection from hyperoxic lung injury. The results indicated that modulation of mitochondrial GR activity in lung type II cells is not an effective therapy to minimize hyperoxic lung injury.

  13. Treatment of acute lung injury by targeting MG53-mediated cell membrane repair

    PubMed Central

    Lieber, Gissela; Nishi, Miyuki; Yan, Rosalie; Wang, Zhen; Yao, Yonggang; Li, Yu; Whitson, Bryan A.; Duann, Pu; Li, Haichang; Zhou, Xinyu; Zhu, Hua; Takeshima, Hiroshi; Hunter, John C.; McLeod, Robbie L.; Weisleder, Noah; Zeng, Chunyu; Ma, Jianjie

    2014-01-01

    Injury to lung epithelial cells has a role in multiple lung diseases. We previously identified mitsugumin 53 (MG53) as a component of the cell membrane repair machinery in striated muscle cells. Here we show that MG53 also has a physiological role in the lung and may be used as a treatment in animal models of acute lung injury. Mice lacking MG53 show increased susceptibility to ischemia-reperfusion and over-ventilation induced injury to the lung when compared with wild type mice. Extracellular application of recombinant human MG53 (rhMG53) protein protects cultured lung epithelial cells against anoxia/reoxygenation-induced injuries. Intravenous delivery or inhalation of rhMG53 reduces symptoms in rodent models of acute lung injury and emphysema. Repetitive administration of rhMG53 improves pulmonary structure associated with chronic lung injury in mice. Our data indicate a physiological function for MG53 in the lung and suggest that targeting membrane repair may be an effective means for treatment or prevention of lung diseases. PMID:25034454

  14. Death receptors mediate the adverse effects of febrile-range hyperthermia on the outcome of lipopolysaccharide-induced lung injury

    PubMed Central

    Matute-Bello, Gustavo; Herrero, Raquel; Wong, Venus A.; Mongovin, Stephen M.; Martin, Thomas R.

    2011-01-01

    We have shown that febrile-range hyperthermia enhances lung injury and mortality in mice exposed to inhaled LPS and is associated with increased TNF-α receptor activity, suppression of NF-κB activity in vitro, and increased apoptosis of alveolar epithelial cells in vivo. We hypothesized that hyperthermia enhances lung injury and mortality in vivo by a mechanism dependent on TNF receptor signaling. To test this, we exposed mice lacking the TNF-receptor family members TNFR1/R2 or Fas (TNFR1/R2−/− and lpr) to inhaled LPS with or without febrile-range hyperthermia. For comparison, we studied mice lacking IL-1 receptor activity (IL-1R−/−) to determine the role of inflammation on the effect of hyperthermia in vivo. TNFR1/R2−/− and lpr mice were protected from augmented alveolar permeability and mortality associated with hyperthermia, whereas IL-1R−/− mice were susceptible to augmented alveolar permeability but protected from mortality associated with hyperthermia. Hyperthermia decreased pulmonary concentrations of TNF-α and keratinocyte-derived chemokine after LPS in C57BL/6 mice and did not affect pulmonary inflammation but enhanced circulating markers of oxidative injury and nitric oxide metabolites. The data suggest that hyperthermia enhances lung injury by a mechanism that requires death receptor activity and is not directly associated with changes in inflammation mediated by hyperthermia. In addition, hyperthermia appears to enhance mortality by generating a systemic inflammatory response and not by a mechanism directly associated with respiratory failure. Finally, we observed that exposure to febrile-range hyperthermia converts a modest, survivable model of lung injury into a fatal syndrome associated with oxidative and nitrosative stress, similar to the systemic inflammatory response syndrome. PMID:21515659

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

    EPA Science Inventory

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

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

    EPA Science Inventory

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

  17. Traumatic forequarter amputation associated acute lung injury (ALI): report of one case.

    PubMed

    Liang, K; Gan, X; Deng, Z

    2012-07-01

    One case of traumatic forequarter amputation associated acute lung injury (ALI) was presented. A discussion reviewing the treatment guidelines for this devastating injury, and pointing out the importance of supporting the lung and preventing the development of acute respiratory distress syndrome (ARDS) was included.

  18. Mifepristone-inducible recombinant adenovirus attenuates paraquat-induced lung injury in rats.

    PubMed

    Hong, G-L; Cai, Q-Q; Tan, J-P; Jiang, X-Z; Zhao, G-J; Wu, B; Li, M-F; Qiu, Q-M; Lu, Z-Q

    2015-01-01

    To investigate the effects of overexpression of nuclear factor E2-related factor-2 (NRF2) on lung injury in rats exposed to paraquat (PQ) poisoning. A mifepristone (RU486)-inducible recombinant adenoviral vector carrying the human NRF2 gene (Ad-RUNRF2) was constructed and transfected via airway into the rats 7 days before the administration of RU486. Rats were orally challenged with PQ at 20 mg/kg 24 h after the injection of RU486. On days 0.5, 3 and 21 after PQ poisoning, the expressions of NRF2 and cytokines related to inflammation and oxidation in lung tissue were examined. RU486 remarkably enhanced NRF2 mRNA and NRF2 protein levels in Ad-RUNRF2-transfected rats in a dose-dependent manner (p < 0.01). PQ stimulated compensatory overexpression of NRF2, heme oxygenase 1 (HO-1) and NAD(P)H quinone oxidoreductase 1 (NQO-1) in lungs on days 0.5 and 3 after exposure (p < 0.05), but depleted the expression of catalase (CAT), glutathione peroxidase (GSH-Px) and glutathione (GSH), with an increased malondialdehyde (MDA) (p < 0.05). However, pretreatment with Ad-RUNRF2 and RU486 strongly enhanced the expression levels of NRF2, HO-1, NQO-1, CAT and GSH-Px in the lungs of PQ intoxicated rats, with increased GSH and decreased MDA (p < 0.05). Pretreatment with Ad-RUNRF2 and RU486 also strongly suppressed the PQ-induced activation of nuclear factor κB (NF-κB) and decreased the levels of tumour necrosis factor-α (TNF-α), interleukin-1β (IL-1β) and interleukin-6 (IL-6). In addition, Ad-RUNRF2 and RU486 induction significantly reduced PQ-induced pathological changes in lungs and attenuated lung oedema and protein leakage caused by PQ (p < 0.05). RU486-induced overexpression of NRF2 in lungs transfected with Ad-RUNRF2 can ameliorate PQ-induced lung injury by the activation of the NRF2-antioxidant response element (ARE) pathway. © The Author(s) 2014.

  19. Creation of Lung-Targeted Dexamethasone Immunoliposome and Its Therapeutic Effect on Bleomycin-Induced Lung Injury in Rats

    PubMed Central

    Li, Nan; Hu, Yang; Zhang, Yuan; Xu, Jin-Fu; Li, Xia; Ren, Jie; Su, Bo; Yuan, Wei-Zhong; Teng, Xin-Rong; Zhang, Rong-Xuan; Jiang, Dian-hua; Mulet, Xavier; Li, Hui-Ping

    2013-01-01

    Objective Acute lung injury (ALI), is a major cause of morbidity and mortality, which is routinely treated with the administration of systemic glucocorticoids. The current study investigated the distribution and therapeutic effect of a dexamethasone(DXM)-loaded immunoliposome (NLP) functionalized with pulmonary surfactant protein A (SP-A) antibody (SPA-DXM-NLP) in an animal model. Methods DXM-NLP was prepared using film dispersion combined with extrusion techniques. SP-A antibody was used as the lung targeting agent. Tissue distribution of SPA-DXM-NLP was investigated in liver, spleen, kidney and lung tissue. The efficacy of SPA-DXM-NLP against lung injury was assessed in a rat model of bleomycin-induced acute lung injury. Results The SPA-DXM-NLP complex was successfully synthesized and the particles were stable at 4°C. Pulmonary dexamethasone levels were 40 times higher with SPA-DXM-NLP than conventional dexamethasone injection. Administration of SPA-DXM-NLP significantly attenuated lung injury and inflammation, decreased incidence of infection, and increased survival in animal models. Conclusions The administration of SPA-DXM-NLP to animal models resulted in increased levels of DXM in the lungs, indicating active targeting. The efficacy against ALI of the immunoliposomes was shown to be superior to conventional dexamethasone administration. These results demonstrate the potential of actively targeted glucocorticoid therapy in the treatment of lung disease in clinical practice. PMID:23516459

  20. Caveolin-1: a critical regulator of lung injury

    PubMed Central

    Lee, Seon-Jin; Minshall, Richard D.; Choi, Augustine M. K.

    2011-01-01

    Caveolin-1 (cav-1), a 22-kDa transmembrane scaffolding protein, is the principal structural component of caveolae. Cav-1 regulates critical cell functions including proliferation, apoptosis, cell differentiation, and transcytosis via diverse signaling pathways. Abundant in almost every cell type in the lung, including type I epithelial cells, endothelial cells, smooth muscle cells, fibroblasts, macrophages, and neutrophils, cav-1 plays a crucial role in the pathogenesis of acute lung injury (ALI). ALI and its severe form, acute respiratory distress syndrome (ARDS), are responsible for significant morbidity and mortality in intensive care units, despite improvement in ventilation strategies. The pathogenesis of ARDS is still poorly understood, and therapeutic options remain limited. In this article, we summarize recent data regarding the regulation and function of cav-1 in lung biology and pathology, in particular as it relates to ALI. We further discuss the potential molecular and cellular mechanisms by which cav-1 expression contributes to ALI. Investigating the cellular functions of cav-1 may provide new insights for understanding the pathogenesis of ALI and provide novel targets for therapeutic interventions in the future. PMID:21097526

  1. The pathogenesis of transfusion-related acute lung injury (TRALI).

    PubMed

    Bux, Jürgen; Sachs, Ulrich J H

    2007-03-01

    In recent years, transfusion-related acute lung injury (TRALI) has developed from an almost unknown transfusion reaction to the most common cause of transfusion-related major morbidities and fatalities. A clinical definition of TRALI was established in 2004, based on acute respiratory distress, non-cardiogenic lung oedema temporal association with transfusion and hypoxaemia. Histological findings reveal lung oedema, capillary leucostasis and neutrophil extravasation. However, the pathogenesis of TRALI remains controversial. Leucocyte antibodies, present in fresh frozen plasma and platelet concentrates from multiparous donors, and neutrophil priming agents released in stored cellular blood components have been considered to be causative. As neutrophils and endothelial cells are pivotal in the pathogenesis of TRALI, a threshold model was established to try to unify the various reported findings on pathogenesis. This model comprises the priming of neutrophils and/or endothelium by the patient's co-morbidity, neutrophil and/or endothelial cell activation by the transfused blood component, and the severity of the TRALI reaction.

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

    PubMed

    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.

  3. Toxic Inhalational Injury-Associated Interstitial Lung Disease in Children

    PubMed Central

    Lee, Eun; Seo, Ju-Hee; Kim, Hyung Young; Yu, Jinho; Jhang, Won-Kyoung; Park, Seong-Jong; Kwon, Ji-Won; Kim, Byoung-Ju; Do, Kyung-Hyun; Cho, Young Ah; Kim, Sun-A; Jang, Se Jin

    2013-01-01

    Interstitial lung disease in children (chILD) is a group of disorders characterized by lung inflammation and interstitial fibrosis. In the past recent years, we noted an outbreak of child in Korea, which is possibly associated with inhalation toxicity. Here, we report a series of cases involving toxic inhalational injury-associated chILD with bronchiolitis obliterans pattern in Korean children. This study included 16 pediatric patients confirmed by lung biopsy and chest computed tomography, between February 2006 and May 2011 at Asan Medical Center Children's Hospital. The most common presenting symptoms were cough and dyspnea. The median age at presentation was 26 months (range: 12-47 months), with high mortality (44%). Histopathological analysis showed bronchiolar destruction and centrilobular distribution of alveolar destruction by inflammatory and fibroproliferative process with subpleural sparing. Chest computed tomography showed ground-glass opacities and consolidation in the early phase and diffuse centrilobular nodular opacity in the late phase. Air leak with severe respiratory difficulty was associated with poor prognosis. Although respiratory chemicals such as humidifier disinfectants were strongly considered as a cause of this disease, further studies are needed to understand the etiology and pathophysiology of the disease to improve the prognosis and allow early diagnosis and treatment. PMID:23772158

  4. Ventilator-related causes of lung injury: the mechanical power.

    PubMed

    Gattinoni, L; Tonetti, T; Cressoni, M; Cadringher, P; Herrmann, P; Moerer, O; Protti, A; Gotti, M; Chiurazzi, C; Carlesso, E; Chiumello, D; Quintel, M

    2016-10-01

    We hypothesized that the ventilator-related causes of lung injury may be unified in a single variable: the mechanical power. We assessed whether the mechanical power measured by the pressure-volume loops can be computed from its components: tidal volume (TV)/driving pressure (∆P aw), flow, positive end-expiratory pressure (PEEP), and respiratory rate (RR). If so, the relative contributions of each variable to the mechanical power can be estimated. We computed the mechanical power by multiplying each component of the equation of motion by the variation of volume and RR: [Formula: see text]where ∆V is the tidal volume, ELrs is the elastance of the respiratory system, I:E is the inspiratory-to-expiratory time ratio, and R aw is the airway resistance. In 30 patients with normal lungs and in 50 ARDS patients, mechanical power was computed via the power equation and measured from the dynamic pressure-volume curve at 5 and 15 cmH2O PEEP and 6, 8, 10, and 12 ml/kg TV. We then computed the effects of the individual component variables on the mechanical power. Computed and measured mechanical powers were similar at 5 and 15 cmH2O PEEP both in normal subjects and in ARDS patients (slopes = 0.96, 1.06, 1.01, 1.12 respectively, R (2) > 0.96 and p < 0.0001 for all). The mechanical power increases exponentially with TV, ∆P aw, and flow (exponent = 2) as well as with RR (exponent = 1.4) and linearly with PEEP. The mechanical power equation may help estimate the contribution of the different ventilator-related causes of lung injury and of their variations. The equation can be easily implemented in every ventilator's software.

  5. Kallistatin protects against sepsis-related acute lung injury via inhibiting inflammation and apoptosis.

    PubMed

    Lin, Wei-Chieh; Chen, Chang-Wen; Huang, Yu-Wen; Chao, Lee; Chao, Julie; Lin, Yee-Shin; Lin, Chiou-Feng

    2015-07-22

    Kallistatin, an endogenous plasma protein, exhibits pleiotropic properties in inhibiting inflammation, oxidative stress and apoptosis, as evidenced in various animal models and cultured cells. Here, we demonstrate that kallistatin levels were positively correlated with the concentration of total protein in bronchoalveolar lavage fluids (BALF) from patients with sepsis-related acute respiratory distress syndrome (ARDS), indicating a compensatory mechanism. Lower ratio of kallistatin to total protein in BALF showed a significant trend toward elevated neutrophil counts (P = 0.002) in BALF and increased mortality (P = 0.046). In lipopolysaccharide (LPS)-treated mice, expression of human kallistatin in lung by gene transfer with human kallistatin-encoding plasmid ameliorated acute lung injury (ALI) and reduced cytokine/chemokine levels in BALF. These mice exhibited attenuated lung epithelial apoptosis and decreased Fas/FasL expression compared to the control mice. Mouse survival was improved by kallistatin gene transfer or recombinant human kallistatin treatment after LPS challenge. In LPS-stimulated A549 human lung epithelial cells, kallistatin attenuated apoptosis, down-regulated Fas/FasL signaling, suppressed intracellular reactive oxygen species (ROS) and inhibited ROS-mediated NF-κB activation and inflammation. Furthermore, LPS-induced apoptosis was blocked by antioxidant N-acetylcysteine or NF-κB inhibitor via down-regulating Fas expression. These findings suggest the therapeutic potential of kallistatin for sepsis-related ALI/ARDS.

  6. Leptin treatment ameliorates acute lung injury in rats with cerulein-induced acute pancreatitis

    PubMed Central

    Gultekin, Fatma Ayca; Kerem, Mustafa; Tatlicioglu, Ertan; Aricioglu, Aysel; Unsal, Cigdem; Bukan, Neslihan

    2007-01-01

    AIM: To determine the effect of exogenous leptin on acute lung injury (ALI) in cerulein-induced acute pancreatitis (AP). METHODS: Forty-eight rats were randomly divided into 3 groups. AP was induced by intraperitoneal (i.p.) injection of cerulein (50 μg/kg) four times, at 1 h intervals. The rats received a single i.p. injection of 10 μg/kg leptin (leptin group) or 2 mL saline (AP group) after cerulein injections. In the sham group, animals were given a single i.p. injection of 2 mL saline. Experimental samples were collected for biochemical and histological evaluations at 24 h and 48 h after the induction of AP or saline administration. Blood samples were obtained for the determination of amylase, lipase, tumor necrosis factor (TNF)-α, interleukin (IL)-1β, macrophage inflammatory peptide (MIP)-2 and soluble intercellular adhesion molecule (sICAM)-1 levels, while pancreatic and lung tissues were removed for myeloperoxidase (MPO) activity, nitric oxide (NOx) level, CD40 expression and histological evaluation. RESULTS: Cerulein injection caused severe AP, confirmed by an increase in serum amylase and lipase levels, histopathological findings of severe AP, and pancreatic MPO activity, compared to the values obtained in the sham group. In the leptin group, serum levels of MIP-2, sICMA-1, TNF-α, and IL-1β, pancreatic MPO activity, CD40 expression in pancreas and lung tissues, and NOx level in the lung tissue were lower compared to those in the AP group. Histologically, pancreatic and lung damage was less severe following leptin administration. CONCLUSION: Exogenous leptin attenuates inflamma-tory changes, and reduces pro-inflammatory cytokines, nitric oxide levels, and CD40 expression in cerulein-induced AP and may be protective in AP associated ALI. PMID:17589942

  7. Alveolar recruitment prevents rapid-reperfusion-induced injury of lung transplants.

    PubMed

    DeCampos, K N; Keshavjee, S; Slutsky, A S; Liu, M

    1999-11-01

    Physical factors play an important role in ischemia-reperfusion-induced injury of lung transplants. For example, rapid restoration of reperfusion resulted in severe pulmonary edema and deterioration of pulmonary function of lung explants in an ex vivo reperfusion system. This type of injury can be prevented by a stepwise increase in the perfusion flow rate, or by adding prostaglandin E1 (PGE1) to the blood perfusate during the first 10 minutes. However, the mechanisms of these protective effects are unknown. We noted a dramatic decrease in airway pressure rather than pulmonary arterial pressure in these studies, suggesting that lung recruitment may be an important factor in minimizing injury. In the present study, we examined the importance of alveolar recruitment in preventing rapid-reperfusion-induced lung injury. Rat lungs were flushed preserved with low potassium dextran solution for 12 hours at 4 degrees C. Lung explants were randomly divided into three groups: 1) untreated control; 2) lungs inflated to total lung capacity for 2 minutes; and 3) lungs ventilated for 10 minutes prior to reperfusion. Postpreservation lung function was assessed in an isolated rat lung reperfusion model. Rapid initiation of reperfusion led to severe pulmonary edema and significant pulmonary dysfunction. In inflation or ventilation groups, the injury was significantly attenuated. The PaO2 and shunt fractions in these lungs were comparable to normal lungs. A significant drop in airway pressure was observed in these two groups and the lung compliance in the inflation group was significantly better than other two groups. These results suggest that overcoming alveolar collapse with inflation or ventilation, may protect the lung from mechanical-stress-induced injury during reperfusion.

  8. Glycyrrhizic Acid Prevents Sepsis-Induced Acute Lung Injury and Mortality in Rats

    PubMed Central

    Zhao, Hongyu; Zhao, Min; Wang, Yu; Li, Fengchun; Zhang, Zhigang

    2015-01-01

    Glycyrrhizic acid (GA), an active ingredient in licorice, has multiple pharmacological activities. However, the effects of GA on sepsis-induced acute lung injury (ALI) have not been determined. Tthe aim of this study was to investigate the molecular mechanism involved in the effects of GA against sepsis-induced ALI in rats. We found that GA alleviated sepsis-induced ALI through improvements in various pathological changes, as well as decreases in the lung wet/dry weight ratio and total protein content in bronchoalveolar lavage fluid, and a significant increase in the survival rate of treated rats. Additionally, GA markedly inhibited sepsis-induced pulmonary inflammatory responses. Moreover, we found that treatment with GA inhibited oxidative stress damage and apoptosis in lung tissue induced by ALI. Finally, GA treatment significantly inhibited NF-κ B, JNK and P38 MAPK activation. Our data indicate that GA has a protective effect against sepsis-induced ALI by inhibiting the inflammatory response, damage from oxidative stress, and apoptosis via inactivation of NF-κB and MAPK signaling pathways, providing a molecular basis for a new medical treatment for sepsis-induced ALI. PMID:26385569

  9. Glycyrrhizic Acid Prevents Sepsis-Induced Acute Lung Injury and Mortality in Rats.

    PubMed

    Zhao, Hongyu; Zhao, Min; Wang, Yu; Li, Fengchun; Zhang, Zhigang

    2016-02-01

    Glycyrrhizic acid (GA), an active ingredient in licorice, has multiple pharmacological activities. However, the effects of GA on sepsis-induced acute lung injury (ALI) have not been determined. Tthe aim of this study was to investigate the molecular mechanism involved in the effects of GA against sepsis-induced ALI in rats. We found that GA alleviated sepsis-induced ALI through improvements in various pathological changes, as well as decreases in the lung wet/dry weight ratio and total protein content in bronchoalveolar lavage fluid, and a significant increase in the survival rate of treated rats. Additionally, GA markedly inhibited sepsis-induced pulmonary inflammatory responses. Moreover, we found that treatment with GA inhibited oxidative stress damage and apoptosis in lung tissue induced by ALI. Finally, GA treatment significantly inhibited NF-κ B, JNK and P38 MAPK activation. Our data indicate that GA has a protective effect against sepsis-induced ALI by inhibiting the inflammatory response, damage from oxidative stress, and apoptosis via inactivation of NF-κB and MAPK signaling pathways, providing a molecular basis for a new medical treatment for sepsis-induced ALI.

  10. Increased susceptibility to hyperoxic lung injury and alveolar simplification in newborn rats by prenatal administration of benzo[a]pyrene

    PubMed Central

    Thakur, Vijay S.; Liang, Yanhong W.; Lingappan, Krithika; Jiang, Weiwu; Wang, Lihua; Barrios, Roberto; Zhou, Guodong; Guntupalli, Bharath; Shivanna, Binoy; Maturu, Paramahamsa; Welty, Stephen E.; Moorthy, Bhagavatula; Couroucli, Xanthi I.

    2014-01-01

    Maternal smoking is one of the risk factors for preterm birth and for the development of bronchopulmonary dysplasia (BPD). In this study, we tested the hypothesis that prenatal exposure of rats to benzo[a]pyrene (BP), a component of cigarette smoke, will result in increased susceptibility of newborns to oxygen-mediated lung injury and alveolar simplification, and that cytochrome P450 (CYP)1A and 1B1 enzymes and oxidative stress mechanistically contribute to this phenomenon. Timed pregnant Fisher 344 rats were administered BP (25 mg/Kg) or the vehicle corn oil (CO) on gestational days 18, 19 and 20, and newborn were either maintained in room air or exposed to hyperoxia (85% O2) for 7 or 14 days. Hyperoxic newborn rats prenatally exposed to the vehicle CO showed lung injury and alveolar simplification, and inflammation, and these effects were potentiated in rats that were prenatally exposed to BP. Prenatal exposure to BP, followed by hyperoxia, also resulted in significant modulation of hepatic and pulmonary cytochrome P450 (CYP)1A and 1B1 enzymes at PND 7-14. These rats displayed significant oxidative stress in lungs at postnatal day (PND) 14, as evidenced by increased levels of the F2-isoprostane 8-iso-PGF2α. Furthermore, these animals showed BP-derived DNA adducts and oxidative DNA adducts in the lung. In conclusion, our results show increased susceptibility of newborns to oxygen-mediated lung injury and alveolar simplification following maternal exposure to BP, and our results suggest that modulation of CYP1A/1B1 enzymes, increases in oxidative stress, and BP-DNA adducts contributed to this phenomenon. PMID:24657529

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

    PubMed

    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. Endothelial-to-mesenchymal transition in lipopolysaccharide-induced acute lung injury drives a progenitor cell-like phenotype.

    PubMed

    Suzuki, Toshio; Tada, Yuji; Nishimura, Rintaro; Kawasaki, Takeshi; Sekine, Ayumi; Urushibara, Takashi; Kato, Fumiaki; Kinoshita, Taku; Ikari, Jun; West, James; Tatsumi, Koichiro

    2016-06-01

    Pulmonary vascular endothelial function may be impaired by oxidative stress in endotoxemia-derived acute lung injury. Growing evidence suggests that endothelial-to-mesenchymal transition (EndMT) could play a pivotal role in various respiratory diseases; however, it remains unclear whether EndMT participates in the injury/repair process of septic acute lung injury. Here, we analyzed lipopolysaccharide (LPS)-treated mice whose total number of pulmonary vascular endothelial cells (PVECs) transiently decreased after production of reactive oxygen species (ROS), while the population of EndMT-PVECs significantly increased. NAD(P)H oxidase inhibition suppressed EndMT of PVECs. Most EndMT-PVECs derived from tissue-resident cells, not from bone marrow, as assessed by mice with chimeric bone marrow. Bromodeoxyuridine-incorporation assays revealed higher proliferation of capillary EndMT-PVECs. In addition, EndMT-PVECs strongly expressed c-kit and CD133. LPS loading to human lung microvascular endothelial cells (HMVEC-Ls) induced reversible EndMT, as evidenced by phenotypic recovery observed after removal of LPS. LPS-induced EndMT-HMVEC-Ls had increased vasculogenic ability, aldehyde dehydrogenase activity, and expression of drug resistance genes, which are also fundamental properties of progenitor cells. Taken together, our results demonstrate that LPS induces EndMT of tissue-resident PVECs during the early phase of acute lung injury, partly mediated by ROS, contributing to increased proliferation of PVECs. Copyright © 2016 the American Physiological Society.

  13. Alterations of lung microbiota in a mouse model of LPS-induced lung injury

    PubMed Central

    Meng, Fanyong; Meliton, Angelo; Afonyushkin, Taras; Ulanov, Alexander; Semenyuk, Ekaterina; Latif, Omar; Tesic, Vera; Birukova, Anna A.; Birukov, Konstantin G.

    2015-01-01

    Acute lung injury (ALI) and the more severe acute respiratory distress syndrome are common responses to a variety of infectious and noninfectious insults. We used a mouse model of ALI induced by intratracheal administration of sterile bacterial wall lipopolysaccharide (LPS) to investigate the changes in innate lung microbiota and study microbial community reaction to lung inflammation and barrier dysfunction induced by endotoxin insult. One group of C57BL/6J mice received LPS via intratracheal injection (n = 6), and another received sterile water (n = 7). Bronchoalveolar lavage (BAL) was performed at 72 h after treatment. Bacterial DNA was extracted and used for qPCR and 16S rRNA gene-tag (V3–V4) sequencing (Illumina). The bacterial load in BAL from ALI mice was increased fivefold (P = 0.03). The community complexity remained unchanged (Simpson index, P = 0.7); the Shannon diversity index indicated the increase of community evenness in response to ALI (P = 0.07). Principal coordinate analysis and analysis of similarity (ANOSIM) test (P = 0.005) revealed a significant difference between microbiota of control and ALI groups. Bacteria from families Xanthomonadaceae and Brucellaceae increased their abundance in the ALI group as determined by Metastats test (P < 0.02). In concordance with the 16s-tag data, Stenotrohomonas maltophilia (Xanthomonadaceae) and Ochrobactrum anthropi (Brucellaceae) were isolated from lungs of mice from both groups. Metabolic profiling of BAL detected the presence of bacterial substrates suitable for both isolates. Additionally, microbiota from LPS-treated mice intensified IL-6-induced lung inflammation in naive mice. We conclude that the morbid transformation of ALI microbiota was attributed to the set of inborn opportunistic pathogens thriving in the environment of inflamed lung, rather than the external infectious agents. PMID:25957290

  14. Alterations of lung microbiota in a mouse model of LPS-induced lung injury.

    PubMed

    Poroyko, Valeriy; Meng, Fanyong; Meliton, Angelo; Afonyushkin, Taras; Ulanov, Alexander; Semenyuk, Ekaterina; Latif, Omar; Tesic, Vera; Birukova, Anna A; Birukov, Konstantin G

    2015-07-01

    Acute lung injury (ALI) and the more severe acute respiratory distress syndrome are common responses to a variety of infectious and noninfectious insults. We used a mouse model of ALI induced by intratracheal administration of sterile bacterial wall lipopolysaccharide (LPS) to investigate the changes in innate lung microbiota and study microbial community reaction to lung inflammation and barrier dysfunction induced by endotoxin insult. One group of C57BL/6J mice received LPS via intratracheal injection (n = 6), and another received sterile water (n = 7). Bronchoalveolar lavage (BAL) was performed at 72 h after treatment. Bacterial DNA was extracted and used for qPCR and 16S rRNA gene-tag (V3-V4) sequencing (Illumina). The bacterial load in BAL from ALI mice was increased fivefold (P = 0.03). The community complexity remained unchanged (Simpson index, P = 0.7); the Shannon diversity index indicated the increase of community evenness in response to ALI (P = 0.07). Principal coordinate analysis and analysis of similarity (ANOSIM) test (P = 0.005) revealed a significant difference between microbiota of control and ALI groups. Bacteria from families Xanthomonadaceae and Brucellaceae increased their abundance in the ALI group as determined by Metastats test (P < 0.02). In concordance with the 16s-tag data, Stenotrohomonas maltophilia (Xanthomonadaceae) and Ochrobactrum anthropi (Brucellaceae) were isolated from lungs of mice from both groups. Metabolic profiling of BAL detected the presence of bacterial substrates suitable for both isolates. Additionally, microbiota from LPS-treated mice intensified IL-6-induced lung inflammation in naive mice. We conclude that the morbid transformation of ALI microbiota was attributed to the set of inborn opportunistic pathogens thriving in the environment of inflamed lung, rather than the external infectious agents.

  15. Preventive Effects of Dexmedetomidine on the Liver in a Rat Model of Acid-Induced Acute Lung Injury

    PubMed Central

    Şen, Velat; Güzel, Abdulmenap; Selimoğlu Şen, Hadice; Ece, Aydın; Uluca, Ünal; Söker, Sevda; Doğan, Erdal; Kaplan, İbrahim; Deveci, Engin

    2014-01-01

    The aim of this study was to examine whether dexmedetomidine improves acute liver injury in a rat model. Twenty-eight male Wistar albino rats weighing 300–350 g were allocated randomly to four groups. In group 1, normal saline (NS) was injected into the lungs and rats were allowed to breathe spontaneously. In group 2, rats received standard ventilation (SV) in addition to NS. In group 3, hydrochloric acid was injected into the lungs and rats received SV. In group 4, rats received SV and 100 µg/kg intraperitoneal dexmedetomidine before intratracheal HCl instillation. Blood samples and liver tissue specimens were examined by biochemical, histopathological, and immunohistochemical methods. Acute lung injury (ALI) was found to be associated with increased malondialdehyde (MDA), total oxidant activity (TOA), oxidative stress index (OSI), and decreased total antioxidant capacity (TAC). Significantly decreased MDA, TOA, and OSI levels and significantly increased TAC levels were found with dexmedetomidine injection in group 4 (P < 0.05). The highest histologic injury scores were detected in group 3. Enhanced hepatic vascular endothelial growth factor (VEGF) expression and reduced CD68 expression were found in dexmedetomidine group compared with the group 3. In conclusion, the presented data provide the first evidence that dexmedetomidine has a protective effect on experimental liver injury induced by ALI. PMID:25165710

  16. Regulation of alveolar procoagulant activity and permeability in direct acute lung injury by lung epithelial tissue factor.

    PubMed

    Shaver, Ciara M; Grove, Brandon S; Putz, Nathan D; Clune, Jennifer K; Lawson, William E; Carnahan, Robert H; Mackman, Nigel; Ware, Lorraine B; Bastarache, Julie A

    2015-11-01

    Tissue factor (TF) initiates the extrinsic coagulation cascade in response to tissue injury, leading to local fibrin deposition. Low levels of TF in mice are associated with increased severity of acute lung injury (ALI) after intratracheal LPS administration. However, the cellular sources of the TF required for protection from LPS-induced ALI remain unknown. In the current study, transgenic mice with cell-specific deletions of TF in the lung epithelium or myeloid cells were treated with intratracheal LPS to determine the cellular sources of TF important in direct ALI. Cell-specific deletion of TF in the lung epithelium reduced total lung TF expression to 39% of wild-type (WT) levels at baseline and to 29% of WT levels after intratracheal LPS. In contrast, there was no reduction of TF with myeloid cell TF deletion. Mice lacking myeloid cell TF did not differ from WT mice in coagulation, inflammation, permeability, or hemorrhage. However, mice lacking lung epithelial TF had increased tissue injury, impaired activation of coagulation in the airspace, disrupted alveolar permeability, and increased alveolar hemorrhage after intratracheal LPS. Deletion of epithelial TF did not affect alveolar permeability in an indirect model of ALI caused by systemic LPS infusion. These studies demonstrate that the lung epithelium is the primary source of TF in the lung, contributing 60-70% of total lung TF, and that lung epithelial, but not myeloid, TF may be protective in direct ALI.

  17. Intratracheal administration of DBcAMP attenuates edema formation in phosgene-induced acute lung injury.

    PubMed

    Sciuto, A M; Strickland, P T; Kennedy, T P; Guo, Y L; Gurtner, G H

    1996-01-01

    Phosgene, a toxic gas widely used as an industrial chemical intermediate, is known to cause life-threatening latent noncardiogenic pulmonary edema. Mechanisms related to its toxicity appear to involve lipoxygenase mediators of arachidonic acid (AA) and can be inhibited by pretreatment with drugs that increase adenosine 3',5'-cyclic monophosphate (cAMP). In the present study, we used the isolated buffer-perfused rabbit lung model to investigate the mechanisms by which cAMP protects against phosgene-induced lung injury. Posttreatment with dibutyryl cAMP (DBcAMP) was given 60-85 min after exposure by an intravascular or intratracheal route. Lung weight gain (LWG) was measured continuously. AA metabolites leukotriene (LT) C4, LTD4, and LTE4 and 6-ketoprostaglandin F1 alpha were measured in the perfusate at 70, 90, 110, 130, and 150 min after exposure. Tissue malondialdehyde and reduced and oxidized glutathione were analyzed 150 min postexposure. Compared with measurements in the lungs of rabbits exposed to phosgene alone, posttreatment with DBcAMP significantly reduced LWG, pulmonary arterial pressure, and inhibited the release of LTC4, LTD4, and LTE4. Intratracheal administration of DBcAMP was more effective than intravascular administration in reducing LWG. Posttreatment also decreased MDA and protected against glutathione oxidation observed with phosgene exposure. We conclude that phosgene causes marked glutathione oxidation, lipid peroxidation, release of AA mediators, and increases LWG. Posttreatment with DBcAMP attenuates these effects, not only by previously described inhibition of pulmonary endothelial or epithelial cell contraction but also by inhibition of AA-mediator production and a novel antioxidant effect.

  18. Stem cell factor improves lung recovery in rats following neonatal hyperoxia-induced lung injury

    PubMed Central

    Miranda, Luis F.; Rodrigues, Claudia O.; Ramachandran, Shalini; Torres, Eneida; Huang, Jian; Klim, Jammie; Hehre, Dorothy; McNiece, Ian; Hare, Joshua M.; Suguihara, Cleide Y.; Young, Karen C.

    2016-01-01

    BACKGROUND Stem cell factor (SCF) and its receptor, c-kit, are modulators of angiogenesis. Neonatal hyperoxia-induced lung injury (HILI) is characterized by disordered angiogenesis. The objective of this study was to determine whether exogenous SCF improves recovery from neonatal HILI by improving angiogenesis. METHODS Newborn rats assigned to normoxia (RA: 20.9% O2) or hyperoxia (90% O2) from postnatal day (P) 2 to 15, received daily injections of SCF 100 µg/kg or placebo (PL) from P15 to P21. Lung morphometry was performed at P28. Capillary tube formation in SCF-treated hyperoxia-exposed pulmonary microvascular endothelial cells (HPMECs) was determined by Matrigel assay. RESULTS As compared with RA, hyperoxic-PL pups had decrease in alveolarization and in lung vascular density, and this was associated with increased right ventricular systolic pressure (RVSP), right ventricular hypertrophy, and vascular remodeling. In contrast, SCF-treated hyperoxic pups had increased angiogenesis, improved alveolarization, and attenuation of pulmonary hypertension as evidenced by decreased RVSP, right ventricular hypertrophy, and vascular remodeling. Moreover, in an in vitro model, SCF increased capillary tube formation in hyperoxia-exposed HPMECs. CONCLUSION Exogenous SCF restores alveolar and vascular structure in neonatal rats with HILI by promoting neoangiogenesis. These findings suggest a new strategy to treat lung diseases characterized by dysangiogenesis. PMID:24153399

  19. Hydrogen gas reduces hyperoxic lung injury via the Nrf2 pathway in vivo

    PubMed Central

    Kawamura, Tomohiro; Wakabayashi, Nobunao; Shigemura, Norihisa; Huang, Chien-Sheng; Masutani, Kosuke; Tanaka, Yugo; Noda, Kentaro; Peng, Ximei; Takahashi, Toru; Billiar, Timothy R.; Okumura, Meinoshin; Toyoda, Yoshiya; Kensler, Thomas W.

    2013-01-01

    Hyperoxic lung injury is a major concern in critically ill patients who receive high concentrations of oxygen to treat lung diseases. Successful abrogation of hyperoxic lung injury would have a huge impact on respiratory and critical care medicine. Hydrogen can be administered as a therapeutic medical gas. We recently demonstrated that inhaled hydrogen reduced transplant-induced lung injury and induced heme oxygenase (HO)-1. To determine whether hydrogen could reduce hyperoxic lung injury and investigate the underlying mechanisms, we randomly assigned rats to four experimental groups and administered the following gas mixtures for 60 h: 98% oxygen (hyperoxia), 2% nitrogen; 98% oxygen (hyperoxia), 2% hydrogen; 98% balanced air (normoxia), 2% nitrogen; and 98% balanced air (normoxia), 2% hydrogen. We examined lung function by blood gas analysis, extent of lung injury, and expression of HO-1. We also investigated the role of NF-E2-related factor (Nrf) 2, which regulates HO-1 expression, by examining the expression of Nrf2-dependent genes and the ability of hydrogen to reduce hyperoxic lung injury in Nrf2-deficient mice. Hydrogen treatment during exposure to hyperoxia significantly improved blood oxygenation, reduced inflammatory events, and induced HO-1 expression. Hydrogen did not mitigate hyperoxic lung injury or induce HO-1 in Nrf2-deficient mice. These findings indicate that hydrogen gas can ameliorate hyperoxic lung injury through induction of Nrf2-dependent genes, such as HO-1. The findings suggest a potentially novel and applicable solution to hyperoxic lung injury and provide new insight into the molecular mechanisms and actions of hydrogen. PMID:23475767

  20. Effect of Valproic Acid on Acute Lung Injury in a Rodent Model of Intestinal Ischemia Reperfusion

    PubMed Central

    Kim, Kyuseok; Li, Yongqing; Jin, Guang; Chong, Wei; Liu, Baoling; Lu, Jennifer; Lee, Kyoungbun; deMoya, Marc; Velmahos, George; Alam, Hasan B.

    2011-01-01

    Objectives Acute lung injury (ALI) is developed in many clinical situations and associated with significant morbidity and mortality. Valproic acid (VPA), a well-known anti-epileptic drug, has been shown to have anti-oxidant and anti-inflammatory effects in various ischemia/reperfusion (I/R) models. The purpose of this study was to investigate whether VPA could affect survival and development of ALI in a rat model of intestinal I/R. Methods Two experiments were performed. Experiment I: Male Sprague-Dawley rats (250–300 g) were subjected to intestinal ischemia (1 hour) and reperfusion (3 hours). They were randomized into 2 groups (n=7/group) 30 min after ischemia: Vehicle (Veh) and VPA (300 mg/kg, IV). Primary end-point for this study was survival over 4 hours from the start of ischemia. Experiment II: The histological and biochemical effects of VPA treatment on lungs were examined 3 hours (1 hr ischemia + 2 hrs reperfusion) after intestinal I/R injury (Veh vs. VPA, n = 9/group). An objective histological score was used to grade the degree of ALI. Enzyme linked immunosorbent assay (ELISA) was performed to measure serum levels of cytokine interleukins (IL-6 and 10), and lung tissue of cytokine-induced neutrophil chemoattractant (CINC) and myeloperoxidase (MPO). In addition, the activity of 8-isoprostane was analyzed for pulmonary oxidative damage. Results In Experiment I, four-hour survival rate was significantly higher in VPA treated animals compared to Veh animals (71.4% vs. 14.3%, p = 0.006). In Experiment II, ALI was apparent in all of the Veh group animals. Treatment with VPA prevented the development of ALI, with a reduction in the histological score (3.4 ± 0.3 vs. 5.3 ± 0.6, p = 0.025). Moreover, compared to the Veh control group the animals from the VPA group displayed decreased serum levels of IL-6 (952 ± 213 vs. 7709 ± 1990 pg/ml, p = 0.011), and lung tissue concentrations of CINC (1188 ± 28 vs. 1298 ± 27, p < 0.05), MPO activity (368 ± 23 vs. 490

  1. Mechanical ventilation injury and repair in extremely and very preterm lungs.

    PubMed

    Brew, Nadine; Hooper, Stuart B; Zahra, Valerie; Wallace, Megan; Harding, Richard

    2013-01-01

    Extremely preterm infants often receive mechanical ventilation (MV), which can contribute to bronchopulmonary dysplasia (BPD). However, the effects of MV alone on the extremely preterm lung and the lung's capacity for repair are poorly understood. To characterise lung injury induced by MV alone, and mechanisms of injury and repair, in extremely preterm lungs and to compare them with very preterm lungs. Extremely preterm lambs (0.75 of term) were transiently exposed by hysterotomy and underwent 2 h of injurious MV. Lungs were collected 24 h and at 15 d after MV. Immunohistochemistry and morphometry were used to characterise injury and repair processes. qRT-PCR was performed on extremely and very preterm (0.85 of term) lungs 24 h after MV to assess molecular injury and repair responses. 24 h after MV at 0.75 of term, lung parenchyma and bronchioles were severely injured; tissue space and myofibroblast density were increased, collagen and elastin fibres were deformed and secondary crest density was reduced. Bronchioles contained debris and their epithelium was injured and thickened. 24 h after MV at 0.75 and 0.85 of term, mRNA expression of potential mediators of lung repair were significantly increased. By 15 days after MV, most lung injury had resolved without treatment. Extremely immature lungs, particularly bronchioles, are severely injured by 2 h of MV. In the absence of continued ventilation these injured lungs are capable of repair. At 24 h after MV, genes associated with injurious MV are unaltered, while potential repair genes are activated in both extremely and very preterm lungs.

  2. Oxidative stress and anti-oxidative mobilization in burn injury.

    PubMed

    Parihar, Arti; Parihar, Mordhwaj S; Milner, Stephen; Bhat, Satyanarayan

    2008-02-01

    A severe burn is associated with release of inflammatory mediators which ultimately cause local and distant pathophysiological effects. Mediators including Reactive Oxygen Species (ROS) and Reactive Nitrogen Species (RNS) are increased in affected tissue, which are implicated in pathophysiological events observed in burn patients. The purpose of this article is to understand the role of oxidative stress in burns, in order to develop therapeutic strategies. All peer-reviewed, original and review articles published in the English language literature relevant to the topic of oxidative stress in burns in animals and human subjects were selected for this review and the possible roles of ROS and RNS in the pathophysiology of burns are discussed. Both increased xanthine oxidase and neutrophil activation appear to be the oxidant sources in burns. Free radicals have been found to have beneficial effects on antimicrobial action and wound healing. However following a burn, there is an enormous production of ROS which is harmful and implicated in inflammation,