WorldWideScience

Sample records for augmented lung injury

  1. BALT development and augmentation of hyperoxic lung injury in mice deficient in NQO1 and NQO2.

    Science.gov (United States)

    Das, Amitava; Kole, Labanyamoy; Wang, Lihua; Barrios, Roberto; Moorthy, Bhagavatula; Jaiswal, Anil K

    2006-05-15

    NAD(P)H/NRH:quinone oxidoreductases (NQO1 and NQO2) protect against oxidative stress and neoplasia. Cross-breeding of NQO1-/- with NQO2-/- mice generated double-knockout (DKO) mice. DKO mice were born normal yet showed myelogenous hyperplasia as observed in single-knockout mice. DKO mice also showed bronchial-associated lymphoid tissue (BALT) that increased in number and size with age. BALT was absent in wild-type and single-knockout mice. Further analysis demonstrated infiltration of neutrophils and macrophages in BALT and significant increases in the serum cytokines TNFalpha, IL-6, and IL-1beta and increased expression of iNOS and higher nitric oxide in lung macrophages. The development of BALT in DKO mice presumably led to the release of cytokines and higher lung macrophage activation, because histologically spleen, thymus, and blood cultures and urine analysis showed absence of infection. Additionally, the DKO mice upon exposure to hyperoxia demonstrated severe intra-alveolar edema and perivascular inflammation and massive infiltration with neutrophils, compared with wild-type mice. These results suggest that NQO1 and NQO2 combined protect mice against lung inflammation, BALT, and hyperoxic lung injury.

  2. Pediatric acute lung injury

    NARCIS (Netherlands)

    Dahlem, P.; van Aalderen, W. M. C.; Bos, A. P.

    2007-01-01

    Among ventilated children, the incidence of acute lung injury (ALI) was 9%; of that latter group 80% developed the acute respiratory distress syndrome (ARDS). The population-based prevalence of pediatric ARDS was 5.5 cases/100.000 inhabitants. Underlying diseases in children were septic shock (34%),

  3. Extravascular Lung Water and Acute Lung Injury

    OpenAIRE

    Ritesh Maharaj

    2012-01-01

    Acute lung injury carries a high burden of morbidity and mortality and is characterised by nonhydrostatic pulmonary oedema. The aim of this paper is to highlight the role of accurate quantification of extravascular lung water in diagnosis, management, and prognosis in “acute lung injury” and “acute respiratory distress syndrome”. Several studies have verified the accuracy of both the single and the double transpulmonary thermal indicator techniques. Both experimental and clinical studies were...

  4. Aortic homograft for pulmonary artery augmentation in single lung transplantation.

    Science.gov (United States)

    Rueda, Pablo; Morales, Jose; Guzman, Enrique; Tellez, Jose L; Niebla, Benito A; Avalos, Alejandro; Patiño, Hilda

    2005-06-01

    We present a case of unilateral lung transplantation in which a segment of the donor's descending aorta was used as a homograft for pulmonary artery augmentation in the donor lung. This technique can be used when the donor's lung artery has been cut at the base of the hilum during the harvesting procedure.

  5. Radionuclide injury to the lung.

    OpenAIRE

    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 ...

  6. Body Temperature Effects on Lung Injury in Ventilated Preterm Lambs

    Science.gov (United States)

    Ball, Molly K.; Hillman, Noah H.; Kallapur, Suhas G.; Polglase, Graeme R.; Jobe, Alan H.; Pillow, J. Jane

    2010-01-01

    Aims: Mechanical ventilation causes lung injury in premature infants. Hypothermia may protect against and hyperthermia may augment lung injury. We tested the effects of hypo- and hyperthermia on ventilation induced acute lung injury in preterm lambs. Methods: Twin sheep fetuses at 128 d GA (term 150 d) were surgically delivered and randomized to unventilated control (UVC), normothermia (38-39 °C) without lung injury (NTNI), or to 1 of 3 injurious ventilation groups: hypothermic (33-34 °C, LT), normothermic (38-39 °C, NT) or hyperthermic (40-41 °C, HT). NT, LT and HT groups had 15 min of injurious ventilation (PEEP 0 cmH2O, VT escalation to 15 mL/kg) following delivery and prior to surfactant. The animals were then gently ventilated (PEEP 5 cmH2O, VT 7.5 mL/kg) for 2 h 45 min. NTNI lambs received surfactant at birth prior to gentle ventilation. The lambs were then euthanized, and bronchoalveolar lavage (BAL) fluid and lung tissue were used to evaluate lung injury, inflammatory cell counts, inflammatory markers and cytokine mRNA. Results: Target temperatures were achieved by 15 min of age and maintained for 3 h. All ventilated groups had increased BAL protein, lung inflammation and increased cytokine mRNA. HT animals developed acidosis, premature death, pneumothoraces, impaired lung function and increased inflammatory mRNA expression. LT animals remained clinically stable without pneumothoraces or death, had improved ventilatory efficiency and trended toward lower inflammatory mRNA expression than NT animals. Conclusion: Hyperthermia exacerbated ventilator induced lung injury, while hypothermia may protect against lung injury in the preterm lamb. PMID:20299144

  7. Dimethylarginine dimethylaminohydrolase II overexpression attenuates LPS-mediated lung leak in acute lung injury.

    Science.gov (United States)

    Aggarwal, Saurabh; Gross, Christine M; Kumar, Sanjiv; Dimitropoulou, Christiana; Sharma, Shruti; Gorshkov, Boris A; Sridhar, Supriya; Lu, Qing; Bogatcheva, Natalia V; Jezierska-Drutel, Agnieszka J; Lucas, Rudolf; Verin, Alexander D; Catravas, John D; Black, Stephen M

    2014-03-01

    Acute lung injury (ALI) is a severe hypoxemic respiratory insufficiency associated with lung leak, diffuse alveolar damage, inflammation, and loss of lung function. Decreased dimethylaminohydrolase (DDAH) activity and increases in asymmetric dimethylarginine (ADMA), together with exaggerated oxidative/nitrative stress, contributes to the development of ALI in mice exposed to LPS. Whether restoring DDAH function and suppressing ADMA levels can effectively ameliorate vascular hyperpermeability and lung injury in ALI is unknown, and was the focus of this study. In human lung microvascular endothelial cells, DDAH II overexpression prevented the LPS-dependent increase in ADMA, superoxide, peroxynitrite, and protein nitration. DDAH II also attenuated the endothelial barrier disruption associated with LPS exposure. Similarly, in vivo, we demonstrated that the targeted overexpression of DDAH II in the pulmonary vasculature significantly inhibited the accumulation of ADMA and the subsequent increase in oxidative/nitrative stress in the lungs of mice exposed to LPS. In addition, augmenting pulmonary DDAH II activity before LPS exposure reduced lung vascular leak and lung injury and restored lung function when DDAH activity was increased after injury. Together, these data suggest that enhancing DDAH II activity may prove a useful adjuvant therapy to treat patients with ALI.

  8. Lung Transplantation for Chronic Humidifier Disinfectant-Associated Lung Injury

    Directory of Open Access Journals (Sweden)

    Won-Young Kim

    2016-05-01

    Full Text Available In the spring of 2011, a cluster of lung injuries caused by humidifier disinfectant (HD usage were reported in Korea. Many patients required mechanical ventilation, extracorporeal membrane oxygenation, and even lung transplantation (LTPL. However, the long-term course of HD-associated lung injury remains unclear because the majority of survivors recovered normal lung function. Here we report a 33-year-old woman who underwent LTPL approximately four years after severe HD-associated lung injury. The patient was initially admitted to the intensive care unit and was supported by a high-flow nasal cannula. Although she had been discharged, she was recurrently admitted to our hospital due to progressive lung fibrosis and a persistent decline in lung function. Finally, sequential double LTPL was successfully performed, and the patient’s clinical and radiological findings showed significant improvement. Therefore, we conclude that LTPL can be a therapeutic option for patients with chronic inhalation injury.

  9. Mechanisms of Enhanced Lung Injury during Sepsis

    Science.gov (United States)

    Czermak, Boris J.; Breckwoldt, Maren; Ravage, Zachary B.; Huber-Lang, Markus; Schmal, Hagen; Bless, Nicolas M.; Friedl, Hans P.; Ward, Peter A.

    1999-01-01

    A major complication in sepsis is progressively impaired lung function and susceptibility to intrapulmonary infection. Why sepsis predisposes the lung to injury is not clear. In the current studies, rats were rendered septic by cecal ligation/puncture and evaluated for increased susceptibility to injury after a direct pulmonary insult (deposition of IgG immune complexes or airway instillation of lipopolysaccharide). By itself, cecal ligation/puncture did not produce evidence of lung injury. However, after a direct pulmonary insult, lung injury in septic animals was significantly enhanced. Enhanced lung injury was associated with increased accumulation of neutrophils in lung, enhanced production of CXC chemokines (but not tumor necrosis factor-α) in bronchoalveolar lavage fluids, and increased expression of lung vascular intercellular adhesion molecule-1 (ICAM-1). Complement depletion or treatment with anti-C5a abolished all evidence of enhanced lung injury in septic animals. When stimulated in vitro, bronchoalveolar lavage macrophages from septic animals had greatly enhanced CXC chemokine responses as compared with macrophages from sham-operated animals or from septic animals that had been complement depleted. These data indicate that the septic state causes priming of lung macrophages and suggest that enhanced lung injury in the septic state is complement dependent and related to increased production of CXC chemokines. PMID:10233844

  10. Toluene-induced acute lung injury

    Directory of Open Access Journals (Sweden)

    Abhishek Singhai

    2013-01-01

    Full Text Available Toluene inhalation is an important occupational health hazard in persons working in factories manufacturing paint, chemicals, pharmaceuticals, and rubber. The present report describes an unusual case of toluene-induced acute lung injury threatening life.

  11. Mechanisms of enhanced lung injury during sepsis

    DEFF Research Database (Denmark)

    Czermak, B J; Breckwoldt, M; Ravage, Z B

    1999-01-01

    A major complication in sepsis is progressively impaired lung function and susceptibility to intrapulmonary infection. Why sepsis predisposes the lung to injury is not clear. In the current studies, rats were rendered septic by cecal ligation/puncture and evaluated for increased susceptibility...

  12. Bleomycin-Induced Lung Injury

    Directory of Open Access Journals (Sweden)

    Tomás Reinert

    2013-01-01

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

  13. Contribution of neutrophils to acute lung injury.

    Science.gov (United States)

    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.

  14. ROS-Mediated NLRP3 Inflammasome Activity Is Essential for Burn-Induced Acute Lung Injury

    OpenAIRE

    Shichao Han; Weixia Cai; Xuekang Yang; Yanhui Jia; Zhao Zheng; Hongtao Wang; Jun Li; Yan Li; Jianxin Gao; Lei Fan; Dahai Hu

    2015-01-01

    The NLRP3 inflammasome is necessary for initiating acute sterile inflammation. However, its role in the pathogenesis of burn-induced acute lung injury (ALI) is unknown. This study aimed to determine the role of the NLRP3 inflammasome and the signaling pathways involved in burn-induced ALI. We observed that the rat lungs exhibited enhanced inflammasome activity after burn, as evidenced by increased levels of NLRP3 expression and Caspase-1 activity and augmented inflammatory cytokines. Inhibiti...

  15. Soluble ICAM-1 activates lung macrophages and enhances lung injury

    DEFF Research Database (Denmark)

    Schmal, H; Czermak, B J; Lentsch, A B

    1998-01-01

    Because of the important role of rat ICAM-1 in the development of lung inflammatory injury, soluble recombinant rat ICAM-1 (sICAM-1) was expressed in bacteria, and its biologic activities were evaluated. Purified sICAM-1 did bind to rat alveolar macrophages in a dose-dependent manner and induced...

  16. Stem cells and repair of lung injuries

    Directory of Open Access Journals (Sweden)

    Randell Scott H

    2004-07-01

    Full Text Available Abstract Fueled by the promise of regenerative medicine, currently there is unprecedented interest in stem cells. Furthermore, there have been revolutionary, but somewhat controversial, advances in our understanding of stem cell biology. Stem cells likely play key roles in the repair of diverse lung injuries. However, due to very low rates of cellular proliferation in vivo in the normal steady state, cellular and architectural complexity of the respiratory tract, and the lack of an intensive research effort, lung stem cells remain poorly understood compared to those in other major organ systems. In the present review, we concisely explore the conceptual framework of stem cell biology and recent advances pertinent to the lungs. We illustrate lung diseases in which manipulation of stem cells may be physiologically significant and highlight the challenges facing stem cell-related therapy in the lung.

  17. Inspiratory resistive breathing induces acute lung injury.

    Science.gov (United States)

    Toumpanakis, Dimitris; Kastis, George A; Zacharatos, Panagiotis; Sigala, Ioanna; Michailidou, Tatiana; Kouvela, Maroussa; Glynos, Constantinos; Divangahi, Maziar; Roussos, Charis; Theocharis, Stamatios E; Vassilakopoulos, Theodoros

    2010-11-01

    Resistive breathing is associated with large negative intrathoracic pressures. Increased mechanical stress induces high-permeability pulmonary edema and lung inflammation. To determine the effects of resistive breathing on the healthy lung. Anesthetized rats breathed through a two-way nonrebreathing valve. The inspiratory line was connected to a resistance setting peak inspiratory tracheal pressure at 50% of maximum (inspiratory resistive breathing), while 100% oxygen was supplied to prevent hypoxemia. Quietly breathing animals (100% oxygen) served as controls. Lung injury was evaluated after 3 and 6 hours of resistive breathing. After both 3 and 6 hours of resistive breathing, lung permeability was increased, as assessed by (99m)Tc-diethylenetriaminepentaacetic acid scintigraphy and Evans blue dye extravasation. Tissue elasticity, measured on the basis of static pressure-volume curves and by the low-frequency forced oscillation technique, was also increased. After both 3 and 6 hours of resistive breathing, gravimetric measurements revealed the presence of pulmonary edema and analysis of bronchoalveolar lavage showed increased total protein content, whereas the total cell count was elevated only after 6 hours of resistive breathing. Cytokine levels were assessed in bronchoalveolar lavage fluid and lung tissue by ELISA and were increased after 6 hours compared with controls. Western blot analysis showed early activation of Src kinase via phosphorylation (at 30 min), and Erk1/2 and IκBα (nuclear factor-κB inhibitor) were phosphorylated at 3 and 6 hours. Pathology revealed the presence of lung injury after resistive breathing. Resistive breathing induces acute lung injury and inflammation.

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

    Energy Technology Data Exchange (ETDEWEB)

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

    2014-08-15

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

  19. Reduced ischemia-reperfusion injury with isoproterenol in non-heart-beating donor lungs.

    Science.gov (United States)

    Jones, D R; Hoffmann, S C; Sellars, M; Egan, T M

    1997-05-01

    Transplantation of lungs retrieved from non-heart-beating donors could expand the donor pool. Recent studies suggest that the ischemia-reperfusion injury (IRI) to the lung can be attenuated by increasing intracellular cAMP concentrations. The purpose of this study was to determine the effect of IRI on capillary permeability, as measured by Kfc, in lungs retrieved from non-heart-beating donors and reperfused with or without isoproterenol (iso). Using an in situ isolated perfused lung model, lungs were retrieved from non-heart-beating donor rats ventilated with O2 or not at varying intervals after death. The lungs were reperfused with or without iso (10 microM). Kfc, lung viability, and pulmonary hemodynamics were measured, and tissue levels of adenine nucleotides and cAMP were measured by HPLC. Iso-reperfusion decreased Kfc significantly (P Kfc in non-iso-reperfused (r = 0.65) and iso-perfused (r = 0.84) lungs. cAMP levels increased significantly with iso-reperfusion. cAMP levels correlated with Kfc (r = 0.87) in iso-reperfused lungs. Iso-reperfusion of lungs retrieved from non-heart-beating donor rats results in decreased capillary permeability and increased lung tissue cAMP levels. Pharmacologic augmentation of tissue TAN and cAMP levels may further ameliorate the increased capillary permeability seen in lungs retrieved from non-heart-beating donors.

  20. Augmented tumor necrosis factor response to lipopolysaccharide after thermal injury is regulated posttranscriptionally.

    Science.gov (United States)

    Minei, J P; Williams, J G; Hill, S J; McIntyre, K; Bankey, P E

    1994-11-01

    Thermal injury has been shown to enhance macrophage sensitivity to lipopolysaccharide (LPS), resulting in augmented tumor necrosis factor alpha (TNF-alpha) production. This study was designed to examine whether enhanced TNF-alpha response after thermal injury and LPS stimulation is regulated at the level of transcription. Tumor necrosis factor alpha release in alveolar macrophages harvested from sham- or thermal-injured Wistar rats was determined using an L929 cytotoxicity bioassay on days 1, 3, and 5 following 40% scald burn and incubation for 24 hours with LPS (0 or 10 micrograms/mL). Separate groups of rats underwent intraperitoneal injection of LPS (5 mg/kg) 3 days following sham or thermal injury. Lung tissue RNA was isolated and probed for TNF-alpha messenger RNA (mRNA), using nuclease protection analysis. Finally, pooled alveolar macrophages were harvested 3 days following sham or thermal injury and cultured in the presence or absence of LPS (10 micrograms/mL) for 4 hours. The RNA from the pooled alveolar macrophages was extracted and probed for TNF-alpha mRNA levels. Thermal injury alone did not significantly increase alveolar macrophage TNF-alpha bioactivity, whole-lung TNF-alpha mRNA levels, or pooled alveolar macrophages TNF-alpha mRNA levels when compared with levels in sham-injured rats. However, alveolar macrophages from postburn day 3 (PBD 3) demonstrated increased sensitivity to LPS (10 micrograms/mL) compared with alveolar macrophages from sham-injured animals undergoing similar LPS treatment (2365 +/- 1011 vs 169 +/- 79 ng/mL; P < .05). Whole-lung mRNA levels in both sham-injured and PBD-3 rats receiving intraperitoneal LPS, while elevated approximately 2.5-fold from those of non-LPS treated rats, were not different from each other. Finally, pooled alveolar macrophages from sham-injured and PBD-3 rats cultured in the presence of LPS had approximately 1.7-fold and threefold increased TNF-alpha mRNA levels, respectively, compared with alveolar

  1. CXCR2 in Acute Lung Injury

    Directory of Open Access Journals (Sweden)

    F. M. Konrad

    2012-01-01

    Full Text Available In pulmonary inflammation, recruitment of circulating polymorphonuclear leukocytes is essential for host defense and initiates the following specific immune response. One pathological hallmark of acute lung injury and acute respiratory distress syndrome is the uncontrolled transmigration of neutrophils into the lung interstitium and alveolar space. Thereby, the extravasation of leukocytes from the vascular system into the tissue is induced by chemokines that are released from the site of inflammation. The most relevant chemokine receptors of neutrophils are CXC chemokine receptor (CXCR 1 and CXCR2. CXCR2 is of particular interest since several studies implicate a pivotal role of this receptor in development and promotion of numerous inflammatory disorders. CXCR2 gets activated by ELR+ chemokines, including MIP-2, KC (rodents and IL-8 (human. Since multiple ELR+ CXC chemokines act on both receptors—CXCR1 and CXCR2—a pharmacologic agent blocking both receptors seems to be advantageous. So far, several CXCR1/2 antagonists have been developed and have been tested successfully in experimental studies. A newly designed CXCR1 and CXCR2 antagonist can be orally administered and was for the first time found efficient in humans. This review highlights the role of CXCR2 in acute lung injury and discusses its potential as a therapeutic target.

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

    LENUS (Irish Health Repository)

    Shields, Conor J

    2012-02-03

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

  3. Effect of corticosteroid on lung parenchyma remodeling at an early phase of acute lung injury.

    Science.gov (United States)

    Rocco, Patricia R M; Souza, Alba B; Faffe, Debora S; Pássaro, Caroline P; Santos, Flávia B; Negri, Elnara M; Lima, Januário G M; Contador, Renata S; Capelozzi, Vera L; Zin, Walter A

    2003-09-15

    In vivo (lung resistive and viscoelastic pressures and static elastance) and in vitro (tissue resistance, elastance, and hysteresivity) respiratory mechanics were analyzed 1 and 30 days after saline (control) or paraquat (P [10 and 25 mg/kg intraperitoneally]) injection in rats. Additionally, P10 and P25 were treated with methylprednisolone (2 mg/kg intravenously) at 1 or 6 hours after acute lung injury (ALI) induction. Collagen and elastic fibers were quantified. Lung resistive and viscoelastic pressures and static elastance were higher in P10 and P25 than in the control. Tissue elastance and resistance augmented from control to P10 (1 and 30 days) and P25. Hysteresivity increased in only P25. Methylprednisolone at 1 or 6 hours attenuated in vivo and in vitro mechanical changes in P25, whereas P10 parameters were similar to the control. Collagen increment was dose and time dependent. Elastic fibers increased in P25 and at 30 days in P10. Corticosteroid prevented collagen increment and avoided elastogenesis. In conclusion, methylprednisolone led to a complete maintenance of in vivo and in vitro respiratory mechanics in mild lesion, whereas it minimized the changes in tissue impedance and extracellular matrix in severe ALI. The beneficial effects of the early use of steroids in ALI remained unaltered at Day 30.

  4. Distributed augmented reality with 3-D lung dynamics--a planning tool concept.

    Science.gov (United States)

    Hamza-Lup, Felix G; Santhanam, Anand P; Imielińska, Celina; Meeks, Sanford L; Rolland, Jannick P

    2007-01-01

    Augmented reality (AR) systems add visual information to the world by using advanced display techniques. The advances in miniaturization and reduced hardware costs make some of these systems feasible for applications in a wide set of fields. We present a potential component of the cyber infrastructure for the operating room of the future: a distributed AR-based software-hardware system that allows real-time visualization of three-dimensional (3-D) lung dynamics superimposed directly on the patient's body. Several emergency events (e.g., closed and tension pneumothorax) and surgical procedures related to lung (e.g., lung transplantation, lung volume reduction surgery, surgical treatment of lung infections, lung cancer surgery) could benefit from the proposed prototype.

  5. Glutamine Attenuates Acute Lung Injury Caused by Acid Aspiration

    Directory of Open Access Journals (Sweden)

    Chih-Cheng Lai

    2014-08-01

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

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

    Science.gov (United States)

    2013-01-01

    Introduction Previous studies have shown that patients with diabetes mellitus appear to have a lower prevalence of acute lung injury. We assumed that insulin prescribed to patients with diabetes has an anti-inflammatory property and pulmonary administration of insulin might exert beneficial effects much more than intravenous administration. Methods Twenty-eight mechanically ventilated rabbits underwent lung injury by saline lavage, and then the animals were allocated into a normoglycemia group (NG), a hyperglycemia group (HG), an HG treated with intravenous insulin (HG-VI) group or an HG treated with aerosolized insulin (HG-AI) group with continuous infusion of different fluid solutions and treatments: normal saline, 50% glucose, 50% glucose with intravenous insulin, or 50% glucose with inhaled aerosolized insulin, respectively. After four hours of treatment, the lungs and heart were excised en bloc, and then high-mobility group B1 concentration in bronchoalveolar lavage fluid, interleukin-8 and toll-like receptor 4 mRNA expression in bronchoalveolar lavage fluid cells, and lung myeloperoxidase activity were measured. Results Treatment with both aerosolized insulin and intravenous insulin attenuated toll-like receptor 4 mRNA expressions in the bronchoalveolar lavage fluid cells. Interleukin-8 and toll-like receptor 4 mRNA expression was significantly lower in the HG-AI group than in the HG-IV group. The lung myeloperoxidase activity in the normal healthy group showed significantly lower levels compared to the NG group but not different compared to those of the HG, HG-VI and HG-AI groups. Conclusions The results suggest that insulin attenuates inflammatory responses in the lungs augmented by hyperglycemia in acute lung injury and the insulin's efficacy may be better when administered by aerosol. PMID:23622115

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

    Science.gov (United States)

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

    2015-01-01

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

  8. Oxidative Stress and Lung Ischemia-Reperfusion Injury

    Directory of Open Access Journals (Sweden)

    Renata Salatti Ferrari

    2015-01-01

    Full Text Available 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.

  9. Dexmedetomidine mitigates CLP-stimulated acute lung injury via restraining the RAGE pathway.

    Science.gov (United States)

    Hu, Hongyi; Shi, Dongsheng; Hu, Chenlu; Yuan, Xiao; Zhang, Juan; Sun, Huaqin

    2017-01-01

    RAGE pathway plays crucial effects in causing acute lung injury (ALI). Dexmedetomidine (DEX) is showed to mitigate sepsis-stimulated ALI. However, its mechanisms have not been verified. The study was to evaluate whether the RAGE pathway participated in the actions of DEX on sepsis-stimulated ALI in rats. Male rats were administrated with intravenously DEX 30 min after sepsis. At 24 h of sepsis, lung myeloperoxidase (MPO) and macrophages in the bronchoalveolarlavage fluid (BALF) were observed. The actions of DEX on pro-inflammatory molecules and related mechanisms were determined by immunological methods. It was indicated that DEX markedly attenuated CLP-stimulated augment of lung inflammatory cells infiltration, along with significantly mitigated MPO activity. Besides, DEX obviously reduced lung wet/dry weight ratio and the levels of HMGB1 and RAGE in BALF and lung tissue. Moreover, DEX post-treatment apparently attenuated the histopathological lung injury compared with CLP model group. Furthermore, western blot analysis revealed that DEX efficiently restrained the activation of IκB-α, NF-κB p65, and MAPK. Our studies demonstrated that DEX attenuates the aggravation of sepsis-stimulated ALI via down regulation of RAGE pathway, which has a potential value in the clinical therapy.

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

    Directory of Open Access Journals (Sweden)

    Cassiano Felippe Gonçalves-de-Albuquerque

    2012-01-01

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

  11. Vascular effects of Endothelin in Experimental lung injury

    OpenAIRE

    Persson, Björn P.

    2012-01-01

    Acute lung injury remains a frequent and life threatening consequence of severe sepsis. This thesis has investigated the role of the endothelin (ET) system in sepsis-induced lung injury, with special reference to its effects on two hallmarks of this syndrome - formation of edema and pulmonary hypertension. This was explored in a porcine endotoxin model of sepsis in vivo, as well as in vitro using isolated porcine pulmonary vessels. In paper I we show that endotoxemia vi...

  12. Obesity, Inflammation, and Lung Injury (OILI): The Good

    OpenAIRE

    Cheryl Wang

    2014-01-01

    Obesity becomes pandemic, predisposing these individuals to great risk for lung injury. In this review, we focused on the anti-inflammatories and addressed the following aspects: adipocytokines and obesity, inflammation and other mechanisms, adipocytokines and lung injury in obesity bridged by inflammation, and potential therapeutic targets. To sum up, the majority of evidence supported that adiponectin, omentin, and secreted frizzled-related protein 5 (SFRP5) were reduced significantly in ob...

  13. RAGE inhibition reduces acute lung injury in mice.

    Science.gov (United States)

    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.

  14. Lung Morphological Changes in Closed Chest Injury (an experimental study

    Directory of Open Access Journals (Sweden)

    A. M. Golubev

    2012-01-01

    Full Text Available Objective: to study lung morphological changes in a closed chest injury model in laboratory animals. Material and methods. Experiments were carried out in 30 male albino nonbred rats weighing 350—380 g. Closed chest injury was simulated, by exposing the chest of anesthetized rats to a 300-g metal cylinder falling from a height of 30 cm. The observation periods were 1, 3, 6, and 24 hours. Results. The signs of evident perivenular edema that was uncharas-teristic to acute respiratory distress syndrome induced by other causes are an important peculiarity of lung morphological changes in this experimental model of closed chest injury. Conclusion. The experimental studies clarified the pattern of lung morphological changes in the early period after closed chest injury. Key words: closed chest injury, pulmonary edema.

  15. Lung Injury and Repair In Search of New Treatment Modalities

    NARCIS (Netherlands)

    J. Tibboel (Jeroen)

    2013-01-01

    markdownabstract__Abstract__ The lung contains the largest surface of our body that is exposed to the environment. Day in, day out, our lungs are being exposed to many injurious components, ranging from noxious gasses and particles caused by traffic and chemical industries to a multitude

  16. Dexmedetomidine effect to lung injury in abdominal hypertension

    Directory of Open Access Journals (Sweden)

    Ozlem Boybeyi and #775;

    2016-06-01

    Conclusion: IAP of 15 mmHg in rats causes mild injury in lung parenchyma. The administration of DEX in clinical doses does not seem to significantly affect the lungs of rats. [Arch Clin Exp Surg 2016; 5(2.000: 100-104

  17. Transfusion-related acute lung injury (TRALI – acase report

    Directory of Open Access Journals (Sweden)

    Anna Łata

    2016-03-01

    Full Text Available Transfusion-related acute lung injury is defined as acute respiratory failure which develops during or within 6 hours after transfusion of a blood component in a patient with no risk factors for respiratory insufficiency. Transfusion-related acute lung injury is diagnosed based on clinical manifestation and by excluding other causes of acute lung injury. Unambiguous diagnosis is difficult. Looking for anti-HLA and/or anti-HNA antibodies in donors and sometimes in recipients plays an important role in lab tests. Negative antibody findings, either in a donor or in a recipient, do not exclude transfusion-related acute lung injury, which, however, does not exempt from performing leukocyte antibody tests since they are extremely important for transfusion-related acute lung injury prophylaxis. The ways to prevent this reaction include: disqualifying donors with anti-HLA/HNA antibodies, screening for antibodies in multiparous women and in individuals after transfusion, modifying the way blood components are prepared and limiting blood transfusion in clinical practice. The paper presents a case of a 38-year-old woman with acute myeloid leukaemia, hospitalised at the Department of Internal Diseases and Haematology of the Military Institute of Medicine for subsequent courses of chemotherapy. During treatment, the patient had red cells and platelets concentrates transfused several times with no transfusion-related reactions. Eight days after the last chemotherapy infusion, the patient developed high temperature and her platelet count was 14 × 103 /mL. Therefore, the patient received a platelet concentrate again. About 1 hour after transfusion, the patient complained about chest pain and dyspnoea. She needed oxygen therapy. Chest X-ray revealed lung oedema with no signs of left ventricular failure. Once other causes of acute lung injury were excluded, transfusion-related acute lung injury was diagnosed.

  18. Obesity, Inflammation, and Lung Injury (OILI: The Good

    Directory of Open Access Journals (Sweden)

    Cheryl Wang

    2014-01-01

    Full Text Available Obesity becomes pandemic, predisposing these individuals to great risk for lung injury. In this review, we focused on the anti-inflammatories and addressed the following aspects: adipocytokines and obesity, inflammation and other mechanisms, adipocytokines and lung injury in obesity bridged by inflammation, and potential therapeutic targets. To sum up, the majority of evidence supported that adiponectin, omentin, and secreted frizzled-related protein 5 (SFRP5 were reduced significantly in obesity, which is associated with increased inflammation, indicated by increase of TNFα and IL-6, through activation of toll-like receptor (TLR4 and nuclear factor light chain κB (NF-κB signaling pathways. Administration of these adipocytokines promotes weight loss and reduces inflammation. Zinc-α2-glycoprotein (ZAG, vaspin, IL-10, interleukin-1 receptor antagonist (IL-1RA, transforming growth factor β (TGF-β1, and growth differentiation factor 15 (GDF15 are also regarded as anti-inflammatories. There were controversial reports. Furthermore, there is a huge lack of studies for obesity related lung injury. The effects of adiponectin on lung transplantation, asthma, chronic obstructive pulmonary diseases (COPD, and pneumonia were anti-inflammatory and protective in lung injury. Administration of IL-10 agonist reduces mortality of acute lung injury in rabbits with acute necrotizing pancreatitis, possibly through inhibiting proinflammation and strengthening host immunity. Very limited information is available for other adipocytokines.

  19. Obesity, inflammation, and lung injury (OILI): the good.

    Science.gov (United States)

    Wang, Cheryl

    2014-01-01

    Obesity becomes pandemic, predisposing these individuals to great risk for lung injury. In this review, we focused on the anti-inflammatories and addressed the following aspects: adipocytokines and obesity, inflammation and other mechanisms, adipocytokines and lung injury in obesity bridged by inflammation, and potential therapeutic targets. To sum up, the majority of evidence supported that adiponectin, omentin, and secreted frizzled-related protein 5 (SFRP5) were reduced significantly in obesity, which is associated with increased inflammation, indicated by increase of TNF α and IL-6, through activation of toll-like receptor (TLR4) and nuclear factor light chain κ B (NF- κ B) signaling pathways. Administration of these adipocytokines promotes weight loss and reduces inflammation. Zinc-α 2-glycoprotein (ZAG), vaspin, IL-10, interleukin-1 receptor antagonist (IL-1RA), transforming growth factor β (TGF-β1), and growth differentiation factor 15 (GDF15) are also regarded as anti-inflammatories. There were controversial reports. Furthermore, there is a huge lack of studies for obesity related lung injury. The effects of adiponectin on lung transplantation, asthma, chronic obstructive pulmonary diseases (COPD), and pneumonia were anti-inflammatory and protective in lung injury. Administration of IL-10 agonist reduces mortality of acute lung injury in rabbits with acute necrotizing pancreatitis, possibly through inhibiting proinflammation and strengthening host immunity. Very limited information is available for other adipocytokines.

  20. KGFR promotes Na+ channel expression in a rat acute lung injury ...

    African Journals Online (AJOL)

    KGFR-adenovirus-transduction reduced damage of the lung injury. To investigate the roles of the KGFR in lung injury, we established a lung injury animal model of four groups as describing in material and method. Thoracotomy showed enlargement of and lesions in the lung tissue, indicating successful establishment of an ...

  1. Splenectomy exacerbates lung injury after ischemic acute kidney injury in mice

    Science.gov (United States)

    Andrés-Hernando, Ana; Altmann, Christopher; Ahuja, Nilesh; Lanaspa, Miguel A.; Nemenoff, Raphael; He, Zhibin; Ishimoto, Takuji; Simpson, Pete A.; Weiser-Evans, Mary C.; Bacalja, Jasna

    2011-01-01

    Patients with acute kidney injury (AKI) have increased serum proinflammatory cytokines and an increased occurrence of respiratory complications. The aim of the present study was to examine the effect of renal and extrarenal cytokine production on AKI-mediated lung injury in mice. C57Bl/6 mice underwent sham surgery, splenectomy, ischemic AKI, or ischemic AKI with splenectomy and kidney, spleen, and liver cytokine mRNA, serum cytokines, and lung injury were examined. The proinflammatory cytokines IL-6, CXCL1, IL-1β, and TNF-α were increased in the kidney, spleen, and liver within 6 h of ischemic AKI. Since splenic proinflammatory cytokines were increased, we hypothesized that splenectomy would protect against AKI-mediated lung injury. On the contrary, splenectomy with AKI resulted in increased serum IL-6 and worse lung injury as judged by increased lung capillary leak, higher lung myeloperoxidase activity, and higher lung CXCL1 vs. AKI alone. Splenectomy itself was not associated with increased serum IL-6 or lung injury vs. sham. To investigate the mechanism of the increased proinflammatory response, splenic production of the anti-inflammatory cytokine IL-10 was determined and was markedly upregulated. To confirm that splenic IL-10 downregulates the proinflammatory response of AKI, IL-10 was administered to splenectomized mice with AKI, which reduced serum IL-6 and improved lung injury. Our data demonstrate that AKI in the absence of a counter anti-inflammatory response by splenic IL-10 production results in an exuberant proinflammatory response and lung injury. PMID:21677145

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

    Directory of Open Access Journals (Sweden)

    Xue Ying

    2005-05-01

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

  3. Opposite effects of ANP receptors in attenuation of LPS-induced endothelial permeability and lung injury.

    Science.gov (United States)

    Xing, Junjie; Yakubov, Bakhtiyor; Poroyko, Valeriy; Birukova, Anna A

    2012-03-01

    Atrial natriuretic peptide (ANP) has been recently identified as a modulator of acute lung injury (ALI) induced by pro-inflammatory agonists. While previous studies tested effects of exogenous ANP administration, the role of endogenous ANP in the course of ALI remains unexplored. This study examined regulation of ANP and its receptors NPR-A, NPR-B and NPR-C by LPS and involvement of ANP receptors in the modulation of LPS-induced lung injury. Primary cultures of human pulmonary endothelial cells (EC) were used in the in vitro tests. Expression of ANP and its receptors was determined by quantitative RT-PCR analysis. Agonist-induced cytoskeletal remodeling was evaluated by immunofluorescence staining, and EC barrier function was characterized by measurements of transendothelial electrical resistance. In the murine model of ALI, LPS-induced lung injury was assessed by measurements of protein concentration and cell count in bronchoalveolar lavage fluid (BAL). LPS stimulation significantly increased mRNA expression levels of ANP and NPR-A in pulmonary EC. Pharmacological inhibition of NPR-A augmented LPS-induced EC permeability and blocked barrier protective effects of exogenous ANP on LPS-induced intercellular gap formation. In contrast, pharmacological inhibition of ANP clearance receptor NPR-C significantly attenuated LPS-induced barrier disruptive effects. Administration of NPR-A inhibitor in vivo exacerbated LPS-induced lung injury, whereas inhibition of NPR-C suppressed LPS-induced increases in BAL cell count and protein content. These results demonstrate for the first time opposite effects of NPR-A and NPR-C in the modulation of ALI and suggest a compensatory protective mechanism of endogenous ANP in the maintenance of lung vascular permeability in ALI. Copyright © 2011. Published by Elsevier Inc.

  4. NLRP3, a Double-edged Sword in Lung Injury Diseases.

    Science.gov (United States)

    Wu, Jun-Xu; Shi, Kai-Hu

    2015-10-01

    Nucleotide-binding oligomerization domain-like receptor containing pyrin domain 3 (NLRP3) plays a key role in lung injury diseases regulation, and its expression is increased in lung injury diseases. NLRP3 may be a good therapeutic target for lung injury diseases. The molecular mechanisms of NLRP3 in lung injury diseases remain unclear. It is a key to study the potential mechanism of NLRP3 during lung injury diseases, so that to exploit it as a good target for lung injury diseases therapy.

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

    Science.gov (United States)

    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.

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

    OpenAIRE

    Di Nardo Matteo; Perrotta Daniela; Stoppa Francesca; Cecchetti Corrado; Marano Marco; Pirozzi Nicola

    2008-01-01

    Abstract Introduction Independent lung ventilation is a form of protective ventilation strategy used in adult asymmetric acute lung injury, where the application of conventional mechanical ventilation can produce ventilator-induced lung injury and ventilation-perfusion mismatch. Only a few experiences have been published on the use of independent lung ventilation in newborn patients. Case presentation We present a case of independent lung ventilation in a 16-day-old infant of 3.5 kg body weig...

  7. Smoking water pipe is injurious to lungs

    DEFF Research Database (Denmark)

    Sivapalan, Pradeesh; Ringbæk, Thomas; Lange, Peter

    2014-01-01

    This review describes the pulmonary consequences of water pipe smoking. Smoking water pipe affects the lung function negatively, is significantly associated with chronic obstructive pulmonary disease and increases the risk of lung infections. Case reports suggest that regular smokers of water pipe...

  8. Research progression of lung injury after burn-blast combined injury

    Directory of Open Access Journals (Sweden)

    Quan HU

    2013-05-01

    Full Text Available As a result of military conflict, terrorist attacks, industrial and traffic accidents, the incidence of burn-blast combined injury would be escalating. The burn-blast combined injury was a major clinical problem accompanied by multiple complications and high mortality. The lungs were the most severely injured organ in burn-blast combined injury. Dysfunction of ventilation and gas exchange produced by lung damage could affect oxygen supply to organs and systemic tissues, and is one of the pathophysiological changes resulting in shock and other complications. Previous research has indicated that most of alveolar walls were ruptured, capillaries ruptured, and pulmonary capillary endothelial cells were damaged in the lungs after burn-blast combined injury, and they were followed by pulmonary edema and hemorrhage followed by disorders in ventilation and gas exchange, ending in ischemia and hypoxia of systemic organs. So the treatment of lung injury is the major measure for the treatment of burn-blast combined injury. The pathogenesis and treatment of lung injury in burn-blast combined injury are briefly summarized in this article.

  9. Corilagin Attenuates Aerosol Bleomycin-Induced Experimental Lung Injury

    Science.gov (United States)

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

    2014-01-01

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

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

    Science.gov (United States)

    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.

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

    OpenAIRE

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

    2008-01-01

    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 potentia...

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

    Science.gov (United States)

    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.

  13. Modulation of cyclophosphamide-induced early lung injury by allicin.

    Science.gov (United States)

    Ashry, Nora A; Gameil, Nariman M; Suddek, Ghada M

    2013-06-01

    Cyclophosphamide (CP) causes lung injury in rats through its ability to generate free radicals with subsequent epithelial and endothelial cell damage. This study was conducted to assess whether allicin can ameliorate CP-induced early lung injury in rats. Male Sprague Dawely rats were divided into four groups. Group I was the control group. Group II received allicin (50 mg/kg/d, p.o.) for 14 consecutive days. Group III was injected once with CP (150 mg/kg, i.p.). Group IV received allicin for seven consecutive days, before and after CP injection (150 mg/kg, i.p.). The parameters of study were serum biomarkers, lung tissue antioxidant profile and histopathological changes in lung tissue. A single intraperitoneal injection of CP markedly altered the levels of several biomarkers in lung homogenates. Significant increases in lung content of lipid hydroperoxides were seen that paralleled the decreased levels of total reduced glutathione. Superoxide dismutase activity (SOD) was significantly increased. CP increased the level of serum biomarkers; total protein, lactate dehydrogenase (LDH) and tumor necrosis factor-alpha (TNF-α). Pretreatment of rats daily with oral allicin seven days prior to and seven days after CP inject significantly inhibited the development of lung injury, prevented the alterations in lung and serum biomarkers associated with inflammatory reactions, with less lipid peroxidation (LP) and restoration of antioxidants. Moreover, allicin attenuated the secretion of proinflammatory cytokine, TNF-α expression in rat serum. In addition, allicin effectively blunted CP-induced histopathological changes in lung tissue. Our results suggest that allicin is efficient in blunting CP-induced pulmonary damage.

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

    Directory of Open Access Journals (Sweden)

    Di Nardo Matteo

    2008-06-01

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

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

    Directory of Open Access Journals (Sweden)

    Özmert M.A. Özdemir

    2014-10-01

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

  16. Lung ischemia reperfusion injury: a bench-to-bedside review.

    Science.gov (United States)

    Weyker, Paul D; Webb, Christopher A J; Kiamanesh, David; Flynn, Brigid C

    2013-03-01

    Lung ischemia reperfusion injury (LIRI) is a pathologic process occurring when oxygen supply to the lung has been compromised followed by a period of reperfusion. The disruption of oxygen supply can occur either via limited blood flow or decreased ventilation termed anoxic ischemia and ventilated ischemia, respectively. When reperfusion occurs, blood flow and oxygen are reintroduced to the ischemic lung parenchyma, facilitating a toxic environment through the creation of reactive oxygen species, activation of the immune and coagulation systems, endothelial dysfunction, and apoptotic cell death. This review will focus on the mechanisms of LIRI, the current supportive treatments used, and the many therapies currently under research for prevention and treatment of LIRI.

  17. Drosophila melanogaster larvae as a model for blast lung injury.

    Science.gov (United States)

    Bass, Cameron R; Meyerhoff, Kevin P; Damon, Andrew M; Bellizzi, Andrew M; Salzar, Robert S; Rafaels, Karin A

    2010-07-01

    Primary blast injuries, specifically lung injuries, resulting from blast overpressure exposures are a major source of mortality for victims of blast events. However, existing pulmonary injury criteria are inappropriate for common exposure environments. This study uses Drosophila melanogaster larvae to develop a simple phenomenological model for human pulmonary injury from primary blast exposure. Drosophila larvae were exposed to blast overpressures generated by a 5.1-cm internal diameter shock tube and their mortality was observed after the exposure. To establish mortality thresholds, a survival analysis was conducted using survival data and peak incident pressures. In addition, a histologic analysis was performed on the larvae to establish the mechanisms of blast injury. The results of the survival analysis suggest that blast overpressure for 50% Drosophila survival is greater than human threshold lung injury and is similar to human 50% survival levels, in the range of overpressure durations tested (1-5 ms). A "parallel" analysis of the Bass et al. 50% human survival curves indicates that 50% Drosophila survival is equivalent to a human injury resulting in a 69% chance of survival. Histologic analysis of the blast-exposed larvae failed to demonstrate damage to the dorsal trunk of the tracheal system; however, the presence of flocculent material in the larvae body cavities and tracheas suggests tissue damage. This study shows that D. melanogaster survival can be correlated with large animal injury models to approximate a human blast lung injury tolerance. Within the range of durations tested, Drosophila larvae may be used as a simple model for blast injury.

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

    Directory of Open Access Journals (Sweden)

    Duan Yingli

    2012-01-01

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

  19. [Ligament bracing--augmented primary suture repair in multiligamentous knee injuries].

    Science.gov (United States)

    Heitmann, M; Gerau, M; Hötzel, J; Giannakos, A; Frosch, K-H; Preiss, A

    2014-02-01

    Reconstruction of knee stability by primary ligament sutures and additional augmentation after knee dislocation. Acute knee dislocation Schenck type III and IV. Operative treatment should be performed within 7 days after injury. Chronic instability after knee dislocation, refixable bony avulsions, critical soft tissue, infection, lack of compliance. Supine position with electric leg holder. Short arthroscopic assessment of concomitant injuries. Schenck type III medial injuries and Schenck IV injuries: anteromedial parapatellar arthrotomy. Injuries type Schenck III lateral: anteromedian arthrotomy. Armoring of ligament stumps for transosseus sutures. Placement of anterior cruciate ligament (ACL) and posterior cruciate ligament (PCL) drill tunnels. Extracortical diversion of the suture armorings and insertion of augmentation systems. Fixation of the PCL augmentation in 70-90° flexion. Fixation of the ACL augmentation in 20-30° flexion. Knotting of the transosseus ligament sutures. If necessary (postero-)lateral and/or medial stabilization. Limited weight bearing with 20 kg for 6 weeks. Stabilizing brace (e.g., Hypex-Lite®, Albrecht) generally for 12 weeks. Mobilization under tension of the quadriceps muscle for 6 weeks. In total, 20 patients have been treated using the principle of "ligament bracing". So far 8 patients (aged 18-60 years, median 33 years) have been assessed with a follow-up of 10-15 months (median 12 months) postoperatively. In all, 6 patients showed stable knees with good results. Recurrent instability of the ACL was observed in 2 patients; the collateral ligaments and PCL were stable. For the evaluation the following scores were used: IKDC score, Tegner score, and Lysholm score. To objectify the data, stress radiography and physical examination were performed. Using the operative technique mentioned above, no complications occurred. During follow-up 2 patients reported a deficiency of flexion.

  20. Mechanical ventilation guided by electrical impedance tomography in experimental acute lung injury.

    Science.gov (United States)

    Wolf, Gerhard K; Gómez-Laberge, Camille; Rettig, Jordan S; Vargas, Sara O; Smallwood, Craig D; Prabhu, Sanjay P; Vitali, Sally H; Zurakowski, David; Arnold, John H

    2013-05-01

    To utilize real-time electrical impedance tomography to guide lung protective ventilation in an animal model of acute respiratory distress syndrome. Prospective animal study. Animal research center. Twelve Yorkshire swine (15 kg). Lung injury was induced with saline lavage and augmented using large tidal volumes. The control group (n = 6) was ventilated using ARDSnet guidelines, and the electrical impedance tomography-guided group (n = 6) was ventilated using guidance with real-time electrical impedance tomography lung imaging. Regional electrical impedance tomography-derived compliance was used to maximize the recruitment of dependent lung and minimize overdistension of nondependent lung areas. Tidal volume was 6 mL/kg in both groups. Computed tomography was performed in a subset of animals to define the anatomic correlates of electrical impedance tomography imaging (n = 5). Interleukin-8 was quantified in serum and bronchoalveolar lavage samples. Sections of dependent and nondependent regions of the lung were fixed in formalin for histopathologic analysis. Positive end-expiratory pressure levels were higher in the electrical impedance tomography-guided group (14.3 cm H₂O vs. 8.6 cm H₂O; p electrical impedance tomography-guided group (6.9 mL/cm H₂O vs. 4.7 mL/cm H₂O; p = 0.013). Regional electrical impedance tomography-derived compliance of the most dependent lung region was increased in the electrical impedance tomography group (1.78 mL/cm H₂O vs. 0.99 mL/cm H₂O; p = 0.001). Pao₂/FIO₂ ratio was higher and oxygenation index was lower in the electrical impedance tomography-guided group (Pao₂/FIO₂: 388 mm Hg vs. 113 mm Hg, p electrical impedance tomography-guided group (HMEIT 42% samples vs. HMCONTROL 67% samples, p electrical impedance tomography and computed tomography were ± 16%. Electrical impedance tomography-guided ventilation resulted in improved respiratory mechanics, improved gas exchange, and reduced histologic evidence of ventilator

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

    NARCIS (Netherlands)

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

    2014-01-01

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

  2. Maintenance of cAMP in non-heart-beating donor lungs reduces ischemia-reperfusion injury.

    Science.gov (United States)

    Hoffmann, S C; Bleiweis, M S; Jones, D R; Paik, H C; Ciriaco, P; Egan, T M

    2001-06-01

    Studies suggest that pulmonary vascular ischemia-reperfusion injury (IRI) can be attenuated by increasing intracellular cAMP concentrations. The purpose of this study was to determine the effect of IRI on capillary permeability, assessed by capillary filtration coeficient (Kfc), in lungs retrieved from non-heart-beating donors (NHBDs) and reperfused with the addition of the beta(2)-adrenergic receptor agonist isoproterenol (iso), and rolipram (roli), a phosphodiesterase (type IV) inhibitor. Using an in situ isolated perfused lung model, lungs were retrieved from NHBD rats at varying intervals after death and either ventilated with O(2) or not ventilated. The lungs were reperfused with Earle's solution with or without a combination of iso (10 microM) and roli (2 microM). Kfc, lung viability, and pulmonary hemodynamics were measured. Lung tissue levels of adenine nucleotides and cAMP were measured by HPLC. Combined iso and roli (iso/roli) reperfusion decreased Kfc significantly (p Kfc in non-iso/roli-reperfused (r = 0.89) and iso/roli-reperfused (r = 0.97) lungs. cAMP levels correlated with Kfc (r = 0.93) in iso/roli-reperfused lungs. Pharmacologic augmentation of tissue TAN and cAMP levels might ameliorate the increased capillary permeability observed in lungs retrieved from NHBDs.

  3. Semaphorin 7A Aggravates Pulmonary Inflammation during Lung Injury

    Science.gov (United States)

    Schneider, Mariella; Granja, Tiago Folgosa; Rosenberger, Peter

    2016-01-01

    The extent of pulmonary inflammation during lung injury ultimately determines patient outcome. Pulmonary inflammation is initiated by the migration of neutrophils into the alveolar space. Recent work has demonstrated that the guidance protein semaphorin 7A (SEMA7A) influences the migration of neutrophils into hypoxic tissue sites, yet, its role during lung injury is not well understood. Here, we report that the expression of SEMA7A is induced in vitro through pro-inflammatory cytokines. SEMA7A itself induces the production of pro-inflammatory cytokines in endothelial and epithelial cells, enhancing pulmonary inflammation. The induction of SEMA7A facilitates the transendothelial migration of neutrophils. In vivo, animals with deletion of SEMA7A expression showed reduced signs of pulmonary inflammatory changes following lipopolysaccharide challenge. We define here the role of SEMA7A in the development of lung injury and identify a potential pathway to interfere with these detrimental changes. Future anti-inflammatory strategies for the treatment of lung injury might be based on this finding. PMID:26752048

  4. Transfusion-related acute lung injury: a change of perspective

    NARCIS (Netherlands)

    Vlaar, A. P.; Schultz, M. J.; Juffermans, N. P.

    2009-01-01

    Two decades ago, transfusion-related acute lung injury (TRALI) was considered a rare complication of transfusion medicine. Nowadays, TRALI has emerged as the leading cause of transfusion-related mortality, presumably as a consequence of reaching international agreement on defining TRALI with

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

    African Journals Online (AJOL)

    Acute respiratory distress syndrome is the most severe manifestation of acute lung injury and it is associated with high mortality rate. ARDS is characterized by the acute onset of diffuse neutrophilic alveolar infiltrates protein-rich edema due to enhanced alveolar-capillary permeability and hypoxemic respiratory failure.

  6. Augmented Feedback Supports Skill Transfer and Reduces High-Risk Injury Landing Mechanics

    Science.gov (United States)

    Myer, Gregory D.; Stroube, Benjamin W.; DiCesare, Christopher A.; Brent, Jensen L.; Ford, Kevin R.; Heidt, Robert S.; Hewett, Timothy E.

    2014-01-01

    Background There is a current need to produce a simple, yet effective method for screening and targeting possible deficiencies related to increased anterior cruciate ligament (ACL) injury risk. Hypothesis Frontal plane knee angle (FPKA) during a drop vertical jump will decrease upon implementing augmented feedback into a standardized sport training program. Study Design Controlled laboratory study. Methods Thirty-seven female participants (mean ± SD: age, 14.7 ±1.5 years; height, 160.9 ± 6.8 cm; weight, 54.5 ± 7.2 kg) were trained over 8 weeks. During each session, each participant received standardized training consisting of strength training, plyometrics, and conditioning. They were also videotaped running on a treadmill at a standardized speed and performing a repeated tuck jump for 10 seconds. Study participants were randomized into 2 groups and received augmented feedback on either their jumping (AF) or sprinting (CTRL) form. Average (mean of 3 trials) and most extreme (trial with greatest knee abduction) FPKA were calculated from 2-dimensional video captured during performance of the drop vertical jump. Results After testing, a main effect of time was noted, with the AF group reducing their FPKA average by 37.9% over the 3 trials while the CTRL group demonstrated a 26.7% reduction average across the 3 trials (P training. Conclusion Providing athletes with augmented feedback on deficits identified by the tuck jump assessment has a positive effect on their biomechanics during a different drop vertical jump task that is related to increased ACL injury risk. The ability of the augmented feedback to support the transfer of skills and injury risk factor reductions across different tasks provides exciting new evidence related to how neuromuscular training may ultimately cross over into retained biomechanics that reduce ACL injuries during sport. Clinical Relevance The tuck jump assessment’s ease of use makes it a timely and economically favorable method to

  7. Types of Acute Lung Injury and Fat Embolism

    Directory of Open Access Journals (Sweden)

    Ye. A. Kameneva

    2008-01-01

    Full Text Available Objective: to enhance the efficiency of diagnosing acute lung injury (ALI and fat embolism (FE. Subjects and methods: Forty-seven patients with severe concomitant trauma (SCT, divided into three groups by the severity of shock and injury, were examined. The parameters of the scales rating ALI severity, lipid metabolism, hemostatic system, and hemodynamic monitoring were analyzed. Results. Three types of acute lung injury were identified in FE depending on clinical laboratory parameters: the patients having a shockogenicity index of less than 14 scores had significantly activated coagulation hemostasis and suppressed fibrinolytic system. Those with a shockogenicity index of 15 to 22 scores developed hemostatic disorders as activated coagulation hemostasis throughout the study and considerably activated fibrinolytic system, the levels of atherogenic very low density lipoproteins (LVDL and triglycerides increased. The patients with a shockogenicity index of more than 23 scores developed hemostatic disorders, such as pronounced activation of the blood coagulation system and suppression of the fibrinolytic system. The manifestation of ALI increased with the elevated concentrations of LVDL and triglycerides, hypercoagulation by hemo-viscosimetric parameters and reduced platelets, lower oxygenation index, and decreased oxygen consumption. Conclusion. A scheme of development of the types of ALI and FE has been proposed. Key words: severe injury, acute lung injury, fat embolism, types of diagnosis.

  8. Inhibition of adenosine kinase attenuates acute lung injury

    Science.gov (United States)

    Köhler, David; Streißenberger, Ariane; Morote-García, Julio C.; Granja, Tiago F.; Schneider, Mariella; Straub, Andreas; Boison, Detlev; Rosenberger, Peter

    2015-01-01

    Objective Extracellular adenosine has tissue protective potential in several conditions. Adenosine levels are regulated by a close interplay between nucleoside transporters and adenosine kinase (ADK). Based on evidence of the role of ADK in regulating adenosine levels during hypoxia, we evaluated the effect of ADK on lung injury. Furthermore, we tested the influence of a pharmacological approach to blocking ADK on the extent of lung injury. Design Prospective experimental animal study. Setting University based research laboratory. Subjects In vitro cell lines, wildtype (Wt) and ADK+/− mice. Methods We tested the expression of ADK during inflammatory stimulation in vitro and in a model of lipopolysaccharide (LPS) inhalation in vivo. Studies using the ADK promoter were performed in vitro. Wt and ADK+/− mice were subjected to LPS inhalation. Pharmacological inhibition of ADK was performed in vitro, and its effect on adenosine uptake was evaluated. The pharmacological inhibition was also performed in vivo, and the effect on lung injury was assessed. Measurements and Results We observed the repression of ADK by pro-inflammatory cytokines and found a significant influence of NF-κB on regulation of the ADK promoter. Mice with endogenous ADK repression (ADK+/−) showed reduced infiltration of leukocytes into the alveolar space, decreased total protein and myeloperoxidase levels, and lower cytokine levels in the alveolar lavage fluid. The inhibition of ADK by 5-iodotubercidine increased the extracellular adenosine levels in vitro, diminished the transmigration of neutrophils and improved the epithelial barrier function. The inhibition of ADK in vivo showed protective properties, reducing the extent of pulmonary inflammation during lung injury. Conclusions Taken together, these data show that ADK is a valuable target for reducing the inflammatory changes associated with lung injury and should be pursued as a therapeutic option. PMID:26491864

  9. Proton-pump inhibitor omeprazole attenuates hyperoxia induced lung injury.

    Science.gov (United States)

    Richter, Jute; Jimenez, Julio; Nagatomo, Taro; Toelen, Jaan; Brady, Paul; Salaets, Thomas; Lesage, Flore; Vanoirbeek, Jeroen; Deprest, Jan

    2016-08-27

    The administration of supplemental oxygen to treat ventilatory insufficiency may lead to the formation of reactive oxygen species and subsequent tissue damage. Cytochrome P4501A1 (CYP1A1) can modulate hyperoxic lung injury by a currently unknown mechanism. Our objective was to evaluate the effect of administration of omeprazole on the induction of CYP1A1 and its influence on hyperoxic lung injury in an established preterm rabbit model. Omeprazole was administered either (1) directly to the fetus, (2) to the mother or (3) after birth to the pups in different doses (2-10 or 20 mg/kg). Controls were injected with the same amount of saline. Pups were housed in normoxia (21 %) or hyperoxia (>95 %) for 5 days. Outcome parameters were induction of CYP1A1 measured by real-time polymerase chain reaction (RT-PCR) immediately after delivery, at day 3 and day 5 as well as lung function, morphometry and immunohistochemistry assessed at day 5 of life. Transcriptome analysis was used to define the targeted pathways. Daily neonatal injections demonstrated a dose-dependent increase in CYP1A1. Lung function tests showed a significant improvement in tissue damping, tissue elasticity, total lung capacity, static compliance and elastance. Morphometry revealed a more developed lung architecture with thinned septae in animals treated with the highest dose (20 mg/kg) of omeprazole. Surfactant protein B, vascular endothelial growth factor and its receptor were significantly increased on immunohistochemical stainings after omeprazole treatment. Neonatal administration of omeprazole induces CYP1A1 in a dose-dependent matter and combined pre- and postnatal administration attenuates hyperoxic lung injury in preterm rabbits, even with the lowest dose of omeprazole without clear CYP1A1 induction.

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

    Directory of Open Access Journals (Sweden)

    JM Real

    2008-06-01

    Full Text Available The pentraxin 3 (PTX3 is an acute phase proinflammatory protein produced by fibroblasts and alveolar epithelial cells. We have previously demonstrated that PTX3 is a key modulator of inflammation. Mechanical ventilation (MV is a life saving therapeutic approach for patients with acute lung injury that, nevertheless could lead to an inflammatory response and tissue injury (ventilator-induced lung injury: VILI, representing a major cause of iatrogenic lung damage in intensive units. Our objective was to investigate the role of PTX3 in VILI. PTX3 transgenic, knockout and Wt control mice (n = 12/group were ventilated (45ml·kg–1 until respiratory system Elastance increased 50% (Ers150%, an indicator of VILI. Histological analysis demonstrated that using a Ers150% was appropriate for our analysis since identical degrees of inflammation were observed in Tg, KO and Wt mice as assessed by leukocyte infiltration, oedema, alveolar collapse and number of breaks in alveolar septa. However, Tg mice reached Ers150% faster than Wt controls (p = 0.0225. We also showed that the lack of PTX3 does not abolish the occurrence of VILI in KOs. Gene expression profile of PTX3, IL-1beta, IL-6, KC, IFNgamma, TGFbeta and PCIII were investigated by QPCR. MV drastically up modulated PTX3 as well as IL-1beta, IL-6, IFNgamma and KC. Alternatively, mice were ventilated for 20, 40 and 60 min. The faster kinetics of Tg mice to reach Ers150% was accompanied by an earlier augmentation of IL-1b and PTX3 expression. The kinetics of local PTX3 expression in the lungs of ventilated mice strongly suggests the involvement of this pentraxin in the pathogenesis of VILI.

  11. Lung injury induced by Bisphenol A: A food contaminant, is ameliorated by selenium supplementation.

    Science.gov (United States)

    Abedelhaffez, Azza S; El-Aziz, Ebtihal A Abd; Aziz, Mohamed A Abdel; Ahmed, Asmaa M

    2017-06-01

    Bisphenol A (BPA), a widely used industrial chemical, is known to disrupt endocrine function. This study aimed to investigate the impact of chronic exposure to BPA on the lung tissue of adult male rats as well as any possible alleviating effects resulting from selenium (Se) treatment. Chronic exposure to BPA resulted in prominent inflammation and oxidative stress responses as evidenced by an increase in levels of malondialdehyde (MDA), reduced concentrations of superoxide dismutase (SOD), and upregulation of Interleukin-18 (IL-18) expression in lung tissue. In addition, chronic exposure led to modulation of the fibrosis-related gene expression, as we observed augmented follistatin-like1 (FSTL1) expression and diminished a disintegrin and metalloproteinase with thrombospondin motif 5 (ADAMTS5) expression. Se treatment remarkably mitigated changes in the expression of these dysregulated markers of lung injury. The biochemical changes were consistent with the histopathological findings, where cellular infiltration and inflammatory fibrotic changes were observed following BPA administration and a lessening of these effects with concomitant Se treatment. Taken together, the results from the study reveal that chronic exposure to BPA may promote the development of pulmonary inflammatory diseases with possible induction of lung fibrosis. Se treatment effectively suppressed oxidative stress, inflammation, and fibrosis, suggesting that Se has the potential to be used as a therapeutic agent in the treatment of pulmonary inflammatory diseases. Copyright © 2017 Elsevier B.V. All rights reserved.

  12. Obesity-Induced Endoplasmic Reticulum Stress Causes Lung Endothelial Dysfunction and Promotes Acute Lung Injury.

    Science.gov (United States)

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

    2017-08-01

    Obesity is a significant risk factor for acute respiratory distress syndrome. The mechanisms underlying this association are unknown. We recently showed that diet-induced obese mice exhibit pulmonary vascular endothelial dysfunction, which is associated with enhanced susceptibility to LPS-induced acute lung injury. Here, we demonstrate that lung endothelial dysfunction in diet-induced obese mice coincides with increased endoplasmic reticulum (ER) stress. Specifically, we observed enhanced expression of the major sensors of misfolded proteins, including protein kinase R-like ER kinase, inositol-requiring enzyme α, and activating transcription factor 6, in whole lung and in primary lung endothelial cells isolated from diet-induced obese mice. Furthermore, we found that primary lung endothelial cells exposed to serum from obese mice, or to saturated fatty acids that mimic obese serum, resulted in enhanced expression of markers of ER stress and the induction of other biological responses that typify the lung endothelium of diet-induced obese mice, including an increase in expression of endothelial adhesion molecules and a decrease in expression of endothelial cell-cell junctional proteins. Similar changes were observed in lung endothelial cells and in whole-lung tissue after exposure to tunicamycin, a compound that causes ER stress by blocking N-linked glycosylation, indicating that ER stress causes endothelial dysfunction in the lung. Treatment with 4-phenylbutyric acid, a chemical protein chaperone that reduces ER stress, restored vascular endothelial cell expression of adhesion molecules and protected against LPS-induced acute lung injury in diet-induced obese mice. Our work indicates that fatty acids in obese serum induce ER stress in the pulmonary endothelium, leading to pulmonary endothelial cell dysfunction. Our work suggests that reducing protein load in the ER of pulmonary endothelial cells might protect against acute respiratory distress syndrome in obese

  13. Strategies to prevent intraoperative lung injury during cardiopulmonary bypass

    Science.gov (United States)

    2010-01-01

    During open heart surgery the influence of a series of factors such as cardiopulmonary bypass (CPB), hypothermia, operation and anaesthesia, as well as medication and transfusion can cause a diffuse trauma in the lungs. This injury leads mostly to a postoperative interstitial pulmonary oedema and abnormal gas exchange. Substantial improvements in all of the above mentioned factors may lead to a better lung function postoperatively. By avoiding CPB, reducing its time, or by minimizing the extracorporeal surface area with the use of miniaturized circuits of CPB, beneficial effects on lung function are reported. In addition, replacement of circuit surface with biocompatible surfaces like heparin-coated, and material-independent sources of blood activation, a better postoperative lung function is observed. Meticulous myocardial protection by using hypothermia and cardioplegia methods during ischemia and reperfusion remain one of the cornerstones of postoperative lung function. The partial restoration of pulmonary artery perfusion during CPB possibly contributes to prevent pulmonary ischemia and lung dysfunction. Using medication such as corticosteroids and aprotinin, which protect the lungs during CPB, and leukocyte depletion filters for operations expected to exceed 90 minutes in CPB-time appear to be protective against the toxic impact of CPB in the lungs. The newer methods of ultrafiltration used to scavenge pro-inflammatory factors seem to be protective for the lung function. In a similar way, reducing the use of cardiotomy suction device, as well as the contact-time between free blood and pericardium, it is expected that the postoperative lung function will be improved. PMID:20064238

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

    Science.gov (United States)

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

    2012-03-01

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

  15. Lung-protective mechanical ventilation does not protect against acute kidney injury in patients without lung injury at onset of mechanical ventilation

    NARCIS (Netherlands)

    Cortjens, Bart; Royakkers, Annick A. N. M.; Determann, Rogier M.; van Suijlen, Jeroen D. E.; Kamphuis, Stephan S.; Foppen, Jannetje; de Boer, Anita; Wieland, Cathrien W.; Spronk, Peter E.; Schultz, Marcus J.; Bouman, Catherine S. C.

    2012-01-01

    Introduction: Preclinical and clinical studies suggest that mechanical ventilation contributes to the development of acute kidney injury (AKI), particularly in the setting of lung-injurious ventilator strategies. Objective: To determine whether ventilator settings in critically ill patients without

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

    Science.gov (United States)

    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 (Ptherapy. © 2014 by the Society for Experimental Biology and Medicine.

  17. Vildagliptin-induced acute lung injury: a case report.

    Science.gov (United States)

    Ohara, Nobumasa; Kaneko, Masanori; Sato, Kazuhiro; Maruyama, Ryoko; Furukawa, Tomoyasu; Tanaka, Junta; Kaneko, Kenzo; Kamoi, Kyuzi

    2016-08-12

    Dipeptidyl peptidase-4 inhibitors are a class of oral hypoglycemic drugs and are used widely to treat type 2 diabetes mellitus in many countries. Adverse effects include nasopharyngitis, headache, elevated serum pancreatic enzymes, and gastrointestinal symptoms. In addition, a few cases of interstitial pneumonia associated with their use have been reported in the Japanese literature. Here we describe a patient who developed drug-induced acute lung injury shortly after the administration of the dipeptidyl peptidase-4 inhibitor vildagliptin. A 38-year-old Japanese woman with diabetes mellitus developed acute respiratory failure 1 day after administration of vildagliptin. Chest computed tomography revealed nonsegmental ground-glass opacities in her lungs. There was no evidence of bacterial pneumonia or any other cause of her respiratory manifestations. After discontinuation of vildagliptin, she recovered fully from her respiratory disorder. She received insulin therapy for her diabetes mellitus, and her subsequent clinical course has been uneventful. The period of drug exposure in previously reported cases of patients with drug-induced interstitial pneumonia caused by dipeptidyl peptidase-4 inhibitor varied from several days to over 6 months. In the present case, our patient developed interstitial pneumonia only 1 day after the administration of vildagliptin. The precise mechanism of her vildagliptin-induced lung injury remains uncertain, but physicians should consider that dipeptidyl peptidase-4 inhibitor-induced lung injury, although rare, may appear acutely, even within days after administration of this drug.

  18. Autotaxin and Endotoxin-Induced Acute Lung Injury.

    Directory of Open Access Journals (Sweden)

    Marios-Angelos Mouratis

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

  19. Autotaxin and Endotoxin-Induced Acute Lung Injury

    Science.gov (United States)

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

    2015-01-01

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

  20. Blast injuries to the lung: epidemiology and management.

    Science.gov (United States)

    Mackenzie, Iain M J; Tunnicliffe, Bill

    2011-01-27

    Lung injury is frequently a component of the polytrauma sustained by military personnel surviving blast on the battlefield. This article describes a case series of the military casualties admitted to University Hospital Birmingham's critical care services (role 4 facility), during the period 1 July 2008 to 15 January 2010. Of the 135 casualties admitted, 107 (79.2%) were injured by explosive devices. Plain chest films taken soon after arrival in the role 4 facility were reviewed in 96 of the 107 patients. In 55 (57.3%) films a tracheal tube was present. One or more radiological abnormalities was present in 66 (68.75%) of the films. Five patients met the consensus criteria for the definition of adult respiratory distress syndrome (ARDS). The majority of casualties with blast-related lung injury were successfully managed with conventional ventilatory support employing a lung protective strategy; only a small minority received non-conventional support at any time in the form of high-frequency oscillatory ventilation. Of those casualties who survived to be received by the role 4 facility, none subsequently died as a consequence of lung injury.

  1. Differing Patterns of P-Selectin Expression in Lung Injury

    Science.gov (United States)

    Bless, Nicolas M.; Tojo, Shinichiro J.; Kawarai, Hiroko; Natsume, Yasuhiro; Lentsch, Alex B.; Padgaonkar, Vaishalee A.; Czermak, Boris J.; Schmal, Hagen; Friedl, Hans P.; Ward, Peter A.

    1998-01-01

    Using two models of acute lung inflammatory injury in rats (intrapulmonary deposition of immunoglobulin G immune complexes and systemic activation of complement after infusion of purified cobra venom factor), we have analyzed the requirements and patterns for upregulation of lung vascular P-selectin. In the immune complex model, upregulation of P-selectin was defined by Northern and Western blot analysis of lung homogenates, by immunostaining of lung tissue, and by vascular fixation of 125I-labeled anti-P-selectin. P-selectin protein was detected by 1 hour (long before detection of mRNA) and expression was sustained for the next 7 hours, in striking contrast to the pattern of P-selectin expression in the cobra venom factor model, in which upregulation was very transient (within the 1st hour). In the immune complex model, injury and neutrophil accumulation were P-selectin dependent. Upregulation of P-selectin was dependent on an intact complement system, and the presence of blood neutrophils was susceptible to the antioxidant dimethyl sulfoxide and required C5a but not tumor necrosis factor α. In contrast, in the cobra venom factor model, upregulation of P-selectin, which is C5a dependent, was also dimethyl sulfoxide sensitive but neutrophil independent. Different mechanisms that may explain why upregulation of lung vascular P-selectin is either transient or sustained are discussed. PMID:9777942

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

    Science.gov (United States)

    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  hydrogen-rich saline group than in the normal saline group ( P  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.

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

    Science.gov (United States)

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

    2017-05-01

    Total liquid ventilation (TLV) is an alternative treatment for severe lung injury. High tidal volume is usually required for TLV to maintain adequate CO2 clearance. However, high tidal volume may cause alveolar barotrauma. We aim to investigate the effect of low tidal volume on pulmonary inflammation in piglets with lung injury and under TLV. After the establishment of acute lung injury model by infusing lipopolysaccharide, 12 piglets were randomly divided into two groups, TLV with high tidal volume (25 mL/kg) or with low tidal volume (6 mL/kg) for 240 min, respectively. Extracorporeal CO2 removal was applied in low tidal volume group to improve CO2 clearance and in high tidal volume group as sham control. Gas exchange and hemodynamic status were monitored every 30 min during TLV. At the end of the study, pulmonary mRNA expression and plasmatic concentration of interleukin-6 (IL-6) and interleukin-8 (IL-8) were measured by collecting lung tissue and blood samples from piglets. Arterial blood pressure, PaO2 , and PaCO2 showed no remarkable difference between groups during the observation period. Compared with high tidal volume strategy, low tidal volume resulted in 76% reduction of minute volume and over 80% reduction in peak inspiratory pressure during TLV. In addition, low tidal volume significantly diminished pulmonary mRNA expression and plasmatic level of IL-6 and IL-8. We conclude that during TLV, low tidal volume reduces lung inflammation in piglets with acute lung injury without compromising gas exchange. © 2016 International Center for Artificial Organs and Transplantation and Wiley Periodicals, Inc.

  4. Amiodarone-Induced Lung Injury With Bilateral Lung Pneumonitis and Peripheral Eosinophilia.

    Science.gov (United States)

    Alqaid, Ammar; Baskaran, Gautam; Dougherty, Christopher

    2016-01-01

    Amiodarone is a widely used antiarrhythmic that is used in the management of a variety of atrial and ventricular arrhythmias. Amiodarone-induced lung injury is an adverse effect in 5% of patients taking amiodarone, usually within 12 months of commencing therapy. Different mechanisms of injury and histopathological changes have been proposed and described. Eosinophilic pneumonia is one uncommon presentation of amiodarone-induced lung injury. The following is a case report of a 62-year-old woman who, after taking 400 mg of amiodarone twice daily for 8 months, developed bilateral interstitial pneumonitis with peripheral eosinophilia. After cessation of amiodarone, she had significant improvement in terms of her clinical symptoms and partial regression of pulmonary infiltrates on radiological imaging. The case underlies the importance of vigilance monitoring patients who are taking potentially pneumotoxic drugs as well as describing a classic example of drug-induced pneumonitis.

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

    Science.gov (United States)

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

    2015-03-01

    We describe a case of a 44-year-old woman with a borderline personality disorder and chronic gamma- butyrolactone (GBL) use who presented with progressive dyspnoea and an altered mental status. A high anion gap metabolic acidosis and acute lung injury was diagnosed. We hypothesise this was caused by GBL. In this case report we describe the diagnostic process and possible pathophysiological mechanisms that may have led to this life-threatening condition.

  6. Pathophysiology of pulmonary hypertension in acute lung injury

    Science.gov (United States)

    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

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

    Science.gov (United States)

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

    2018-03-01

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

  8. β2-Adrenoreceptor Agonist Inhalation During Ex Vivo Lung Perfusion Attenuates Lung Injury.

    Science.gov (United States)

    Kondo, Takeshi; Chen, Fengshi; Ohsumi, Akihiro; Hijiya, Kyoko; Motoyama, Hideki; Sowa, Terumasa; Ohata, Keiji; Takahashi, Mamoru; Yamada, Tetsu; Sato, Masaaki; Aoyama, Akihiro; Date, Hiroshi

    2015-08-01

    Attenuation of ischemia reperfusion injury (IRI) is important in lung transplantation. Our group previously reported that β2-adrenoreceptor agonist inhalation during the period before procurement successfully attenuated IRI in donated lungs after cardiac death. We therefore hypothesized that β2-adrenoreceptor agonist inhalation during ex vivo lung perfusion (EVLP) after procurement might also have a protective effect. Cardiac-dead beagles were left at room temperature for 210 minutes, and all lungs were subsequently procured and subjected to EVLP for 240 minutes. The beagles were allocated to 2 groups: the β2 group (receiving an aerosolized β2-adrenoreceptor agonist 20 minutes after initiation of EVLP; n = 7) and the control group (receiving an aerosolized control solvent at the same time point; n = 6). Physiologic data, including lung function, were evaluated during EVLP. The β2 group showed significantly lower peak airway pressure and pulmonary artery pressure than the control group. Dynamic pulmonary compliance was higher, pulmonary vascular resistance (PVR) was lower, and the wet-to-dry lung weight ratio was lower in the β2 group than in the control group. Cyclic adenosine monophosphate (cAMP) and total adenosine nucleotide (TAN) levels in lung tissue after EVLP were higher in the β2 group than in the control group. The β2 group also showed more cystic fibrosis transmembrane conductance regulator (CFTR) gene expression. After procurement, β2-adrenoreceptor agonist inhalation during EVLP attenuates lung injury in a canine model of organ donation after cardiac death. Copyright © 2015 The Society of Thoracic Surgeons. Published by Elsevier Inc. All rights reserved.

  9. Macrophage migration inhibitory factor promotes tumor growth in the context of lung injury and repair.

    Science.gov (United States)

    Arenberg, Douglas; Luckhardt, Tracy R; Carskadon, Shannon; Zhao, Liujian; Amin, Mohammad A; Koch, Alisa E

    2010-10-15

    Tissue injury and repair involve highly conserved processes governed by mechanisms that can be co-opted in tumors. We hypothesized that soluble factors released during the repair response to lung injury would promote orthotopic tumor growth. To determine whether lung injury promoted growth of orthotopic lung tumors and to study the molecular mechanisms. We initiated lung injury in C57Bl6 mice using different stimuli, then injected Lewis lung carcinoma cells during the repair phase. We assessed tumor growth 14 days later. We measured tumor angiogenesis, cytokine expression, proliferation, and apoptosis. Regardless of the mechanism, injured lungs contained more numerous and larger tumors than sham-injured lungs. Tumors from injured lungs were no more vascular, but had higher levels of proliferation and reduced rates of apoptosis. The cytokine macrophage migration inhibitory factor (MIF) was highly expressed in both models of tissue injury. We observed no increase in tumor growth after lung injury in MIF knockout mice. We induced lung-specific overexpression of MIF in a double-transgenic mouse, and observed that MIF overexpression by itself was sufficient to accelerate the growth of orthotopic Lewis lung carcinoma tumors. Lung injury leads to increased expression of the cytokine MIF, which results in protection from apoptosis and increased proliferation in orthotopic tumors injected after the acute phase of injury.

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

    Energy Technology Data Exchange (ETDEWEB)

    Lingappan, Krithika, E-mail: lingappa@bcm.edu [Department of Pediatrics, Section of Neonatology, Texas Children' s Hospital, Baylor College of Medicine, 1102 Bates Avenue, MC: FC530.01, Houston, TX 77030 (United States); Jiang, Weiwu; Wang, Lihua; Couroucli, Xanthi I. [Department of Pediatrics, Section of Neonatology, Texas Children' s Hospital, Baylor College of Medicine, 1102 Bates Avenue, MC: FC530.01, Houston, TX 77030 (United States); Barrios, Roberto [Department of Pathology and Genomic Medicine, The Methodist Hospital Physician Organization, 6565 Fannin Street, Suite M227, Houston, TX 77030 (United States); Moorthy, Bhagavatula [Department of Pediatrics, Section of Neonatology, Texas Children' s Hospital, Baylor College of Medicine, 1102 Bates Avenue, MC: FC530.01, Houston, TX 77030 (United States)

    2013-10-15

    Sex-specific differences in pulmonary morbidity in humans are well documented. Hyperoxia contributes to lung injury in experimental animals and humans. The mechanisms responsible for sex differences in the susceptibility towards hyperoxic lung injury remain largely unknown. In this investigation, we tested the hypothesis that mice will display sex-specific differences in hyperoxic lung injury. Eight week-old male and female mice (C57BL/6J) were exposed to 72 h of hyperoxia (FiO{sub 2} > 0.95). After exposure to hyperoxia, lung injury, levels of 8-iso-prostaglandin F{sub 2} alpha (8-iso-PGF 2α) (LC–MS/MS), apoptosis (TUNEL) and inflammatory markers (suspension bead array) were determined. Cytochrome P450 (CYP)1A expression in the lung was assessed using immunohistochemistry and western blotting. After exposure to hyperoxia, males showed greater lung injury, neutrophil infiltration and apoptosis, compared to air-breathing controls than females. Pulmonary 8-iso-PGF 2α levels were higher in males than females after hyperoxia exposure. Sexually dimorphic increases in levels of IL-6 (F > M) and VEGF (M > F) in the lungs were also observed. CYP1A1 expression in the lung was higher in female mice compared to males under hyperoxic conditions. Overall, our results support the hypothesis that male mice are more susceptible than females to hyperoxic lung injury and that differences in inflammatory and oxidative stress markers contribute to these sex-specific dimorphic effects. In conclusion, this paper describes the establishment of an animal model that shows sex differences in hyperoxic lung injury in a temporal manner and thus has important implications for lung diseases mediated by hyperoxia in humans. - Highlights: • Male mice were more susceptible to hyperoxic lung injury than females. • Sex differences in inflammatory markers were observed. • CYP1A expression was higher in females after hyperoxia exposure.

  11. Aspiration-Induced Acute Lung Injury in Victims with Isolated Severe Brain Injury

    Directory of Open Access Journals (Sweden)

    Yu. A. Gorodovikova

    2009-01-01

    Full Text Available Objective: to determine the time and development rate of acute lung injury (ALI in severe brain injury (SBI complicated by aspiration of gastric contents or blood. Subjects and methods. Twenty-nine patients aged 19 to 70 years, who had isolated SBI, of whom there were 24 males and 5 females, were examined. The patients were divided into 2 groups: those with aspiration of gastric contents (n=9 or blood (n=10. A control group included 10 patients with SBI without aspiration. A PiCCO plus device was used to determine pulmonary extravascular fluid. ALI was diagnosed in accordance with the recommendations of the Research Institute of General Reanimatology, Russian Academy of Medical Sciences. Results. SBI patients with aspiration of gastric contents or blood were found to have significantly increased pulmonary extravascular water (p<0.01 and a lower oxygenation index (<300, which correlated with each other. ALI was recorded in the first hours after injury in about 50% of cases in both patients with gastric contents aspiration and those with blood aspiration. Conclusion. In patients with SBI complicated by aspiration of gastric contents or blood, pulmonary extravascular fluid accumulation concurrent with other signs of injury may be regarded as a criterion for acute lung injury. Key words: severe brain injury, aspiration, acute lung lesion.

  12. Budesonide ameliorates lung injury induced by large volume ventilation.

    Science.gov (United States)

    Ju, Ying-Nan; Yu, Kai-Jiang; Wang, Guo-Nian

    2016-06-04

    Ventilation-induced lung injury (VILI) is a health problem for patients with acute respiratory dysfunction syndrome. The aim of this study was to investigate the effectiveness of budesonide in treating VILI. Twenty-four rats were randomized to three groups: a ventilation group, ventilation/budesonide group, and sham group were ventilated with 30 ml/kg tidal volume or only anesthesia for 4 hor saline or budesonide airway instillation immediately after ventilation. The PaO2/FiO2and wet-to-dry weight ratios, protein concentration, neutrophil count, and neutrophil elastase levels in bronchoalveolar lavage fluid (BALF) and the levels of inflammation-related factors were examined. Histological evaluation of and apoptosis measurement inthe lung were conducted. Compared with that in the ventilation group, the PaO2/FiO2 ratio was significantly increased by treatment with budesonide. The lung wet-to-dry weight ratio, total protein, neutrophil elastase level, and neutrophilcount in BALF were decreased in the budesonide group. The BALF and plasma tumor necrosis factor (TNF)-α, interleukin (IL)-1β, IL-6, intercellular adhesion molecule (ICAM)-1, and macrophage inflammatory protein (MIP)-2 levels were decreased, whereas the IL-10 level was increased in the budesonide group. The phosphorylated nuclear factor (NF)-kBlevels in lung tissue were inhibited by budesonide. The histological changes in the lung and apoptosis were reduced by budesonide treatment. Bax, caspase-3, and cleaved caspase-3 were down-regulated, and Bcl-2 was up-regulated by budesonide. Budesonide ameliorated lung injury induced by large volume ventilation, likely by improving epithelial permeability, decreasing edema, inhibiting local and systemic inflammation, and reducing apoptosis in VILI.

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

    Science.gov (United States)

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

    2015-02-01

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

  14. Hemorrhagic shock augments Nlrp3 inflammasome activation in the lung through impaired pyrin induction.

    Science.gov (United States)

    Xu, Peng; Wen, Zongmei; Shi, Xueyin; Li, Yuehua; Fan, Liyan; Xiang, Meng; Li, Aijun; Scott, Melanie J; Xiao, Guozhi; Li, Song; Billiar, Timothy R; Wilson, Mark A; Fan, Jie

    2013-05-15

    Hemorrhagic shock (HS) promotes the development of systemic inflammatory response syndrome and organ injury by activating and priming the innate immune system for an exaggerated inflammatory response through, as of yet, unclear mechanisms. IL-1β also plays an important role in the development of post-HS systemic inflammatory response syndrome and active IL-1β production is tightly controlled by the inflammasome. Pyrin, a protein of 781 aa with pyrin domain at the N-terminal, negatively regulates inflammasome activation through interaction with nucleotide-binding oligomerization domain-like receptor protein (NLRP). Expression of pyrin can be induced by LPS and cytokines, and IL-10 is a known potent inducer of pyrin expression in macrophages. In the current study, we tested the hypothesis that HS downregulates IL-10 and therefore decreases pyrin expression to promote inflammasome activation and subsequent IL-1β processing and secretion in the lungs. Our results show that LPS, while activating Nlrp3 inflammasome in the lungs, also induced pyrin expression, which in turn suppressed inflammasome activation. More importantly, LPS-mediated upregulation of IL-10 enhanced pyrin expression, which serves, particularly in later phases, as a potent negative-feedback mechanism regulating inflammasome activation. However, HS-mediated suppression of IL-10 expression in alveolar macrophages attenuated the upregulation of pyrin in alveolar macrophages and lung endothelial cells and thereby significantly enhanced inflammasome activation and IL-1β secretion in the lungs. This study demonstrates a novel mechanism by which HS suppresses negative-feedback regulation of Nlrp3 inflammasome to enhance IL-1β secretion in response to subsequent LPS challenge and so primes for inflammation.

  15. Intravenous dexamethasone attenuated inflammation and influenced apoptosis of lung cells in an experimental model of acute lung injury.

    Science.gov (United States)

    Kosutova, P; Mikolka, P; Balentova, S; Adamkov, M; Kolomaznik, M; Calkovska, A; Mokra, D

    2016-12-22

    Acute lung injury (ALI) is characterized by diffuse alveolar damage, inflammation, and transmigration and activation of inflammatory cells. This study evaluated if intravenous dexamethasone can influence lung inflammation and apoptosis in lavage-induced ALI. ALI was induced in rabbits by repetitive saline lung lavage (30 ml/kg, 9+/-3-times). Animals were divided into 3 groups: ALI without therapy (ALI), ALI treated with dexamethasone i.v. (0.5 mg/kg, Dexamed; ALI+DEX), and healthy non-ventilated controls (Control). After following 5 h of ventilation, ALI animals were overdosed by anesthetics. Total and differential counts of cells in bronchoalveolar lavage fluid (BAL) were estimated. Lung edema was expressed as wet/dry weight ratio. Concentrations of IL-1beta, IL-8, esRAGE, S1PR3 in the lung were analyzed by ELISA methods. In right lung, apoptotic cells were evaluated by TUNEL assay and caspase-3 immunohistochemically. Dexamethasone showed a trend to improve lung functions and histopathological changes, reduced leak of neutrophils (P<0.001) into the lung, decreased concentrations of pro-inflammatory IL-1beta (P<0.05) and marker of lung injury esRAGE (P<0.05), lung edema formation (P<0.05), and lung apoptotic index (P<0.01), but increased immunoreactivity of caspase-3 in the lung (P<0.001). Considering the action of dexamethasone on respiratory parameters and lung injury, the results indicate potential of this therapy in ALI.

  16. ROS-Mediated NLRP3 Inflammasome Activity Is Essential for Burn-Induced Acute Lung Injury

    Directory of Open Access Journals (Sweden)

    Shichao Han

    2015-01-01

    Full Text Available The NLRP3 inflammasome is necessary for initiating acute sterile inflammation. However, its role in the pathogenesis of burn-induced acute lung injury (ALI is unknown. This study aimed to determine the role of the NLRP3 inflammasome and the signaling pathways involved in burn-induced ALI. We observed that the rat lungs exhibited enhanced inflammasome activity after burn, as evidenced by increased levels of NLRP3 expression and Caspase-1 activity and augmented inflammatory cytokines. Inhibition of NLRP3 inflammasome by BAY11-7082 attenuated burn-induced ALI, as demonstrated by the concomitant remission of histopathologic changes and the reduction of myeloperoxidase (MPO activity, inflammatory cytokines in rat lung tissue, and protein concentrations in the bronchoalveolar lavage fluid (BALF. In the in vitro experiments, we used AMs (alveolar macrophages challenged with burn serum to mimic the postburn microenvironment and noted that the serum significantly upregulated NLRP3 inflammasome signaling and reactive oxygen species (ROS production. The use of ROS scavenger N-acetylcysteine (NAC partially reversed NLRP3 inflammasome activity in cells exposed to burn serum. These results indicate that the NLRP3 inflammasome plays an essential role in burn-induced ALI and that burn-induced NLRP3 inflammasome activity is a partly ROS-dependent process. Targeting this axis may represent a promising therapeutic strategy for the treatment of burn-induced ALI.

  17. ROS-Mediated NLRP3 Inflammasome Activity Is Essential for Burn-Induced Acute Lung Injury.

    Science.gov (United States)

    Han, Shichao; Cai, Weixia; Yang, Xuekang; Jia, Yanhui; Zheng, Zhao; Wang, Hongtao; Li, Jun; Li, Yan; Gao, Jianxin; Fan, Lei; Hu, Dahai

    2015-01-01

    The NLRP3 inflammasome is necessary for initiating acute sterile inflammation. However, its role in the pathogenesis of burn-induced acute lung injury (ALI) is unknown. This study aimed to determine the role of the NLRP3 inflammasome and the signaling pathways involved in burn-induced ALI. We observed that the rat lungs exhibited enhanced inflammasome activity after burn, as evidenced by increased levels of NLRP3 expression and Caspase-1 activity and augmented inflammatory cytokines. Inhibition of NLRP3 inflammasome by BAY11-7082 attenuated burn-induced ALI, as demonstrated by the concomitant remission of histopathologic changes and the reduction of myeloperoxidase (MPO) activity, inflammatory cytokines in rat lung tissue, and protein concentrations in the bronchoalveolar lavage fluid (BALF). In the in vitro experiments, we used AMs (alveolar macrophages) challenged with burn serum to mimic the postburn microenvironment and noted that the serum significantly upregulated NLRP3 inflammasome signaling and reactive oxygen species (ROS) production. The use of ROS scavenger N-acetylcysteine (NAC) partially reversed NLRP3 inflammasome activity in cells exposed to burn serum. These results indicate that the NLRP3 inflammasome plays an essential role in burn-induced ALI and that burn-induced NLRP3 inflammasome activity is a partly ROS-dependent process. Targeting this axis may represent a promising therapeutic strategy for the treatment of burn-induced ALI.

  18. Lung injury and respiratory mechanics in rugby union.

    Science.gov (United States)

    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 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.

  19. Erythropoietin-Derived Peptide Protects Against Acute Lung Injury After Rat Traumatic Brain Injury

    Directory of Open Access Journals (Sweden)

    Yuan Liu

    2017-04-01

    Full Text Available Background: Traumatic brain injury (TBI can be complicated by TBI-triggered acute lung injury (ALI, in which inflammation plays a central role. It has been reported that an Erythropoietin-derived peptide (pHBSP was able to ameliorate TBI; however, its function in TBI-caused ALI has not been reported yet. Methods: In this study, we studied the effect of pHBSP on TBI-caused ALI by using a weight-drop induced TBI model. At 8 h and 24 h post-TBI, pulmonary edema (PE and bronchoalveolar lavage fluid (BALF proteins were measured, and haematoxylin and eosin (H&E staining of lung sections was carried out. At 24 h following TBI, the lungs were harvested for immunofluorescence staining and qRT-PCR analysis. Results: At 8 h and 24 h post-TBI, pHBSP treatment significantly decreased wet/dry ratios, decreased total BALF protein, and attenuated the histological signs of pulmonary injury. At 24 h post-TBI, pHBSP treatment decreased the accumulation of CD68+ macrophages in the lung and reduced the mRNA levels of TNF-α, IL-6, IL-1β and iNOS in the lung. Conclusions: We identified the protective role that pHBSP played in TBI-caused ALI, suggesting that pHBSP is a potent candidate for systemic therapy in TBI patients.

  20. Lung Surfactant Protein D (SP-D) Response and Regulation During Acute and Chronic Lung Injury

    DEFF Research Database (Denmark)

    Gaunsbaek, Maria Quisgaard; Rasmussen, Karina Juhl; Beers, Michael F.

    2013-01-01

    BACKGROUND: Surfactant protein D (SP-D) is a collection that plays important roles in modulating host defense functions and maintaining phospholipid homeostasis in the lung. The aim of current study was to characterize comparatively the SP-D response in bronchoalveolar lavage (BAL) and serum...... in three murine models of lung injury, using a validated ELISA technology for estimation of SP-D levels. METHODS: Mice were exposed to lipopolysaccharide, bleomycin, or Pneumocystis carinii (Pc) and sacrificed at different time points. RESULTS: In lipopolysaccharide-challenged mice, the level of SP...

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

    Science.gov (United States)

    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

  2. Nintedanib reduces ventilation-augmented bleomycin-induced epithelial-mesenchymal transition and lung fibrosis through suppression of the Src pathway.

    Science.gov (United States)

    Li, Li-Fu; Kao, Kuo-Chin; Liu, Yung-Yang; Lin, Chang-Wei; Chen, Ning-Hung; Lee, Chung-Shu; Wang, Chih-Wei; Yang, Cheng-Ta

    2017-11-01

    Mechanical ventilation (MV) used in patients with acute respiratory distress syndrome (ARDS) can increase lung inflammation and pulmonary fibrogenesis. Src is crucial in mediating the transforming growth factor (TGF)-β1-induced epithelial-mesenchymal transition (EMT) during the fibroproliferative phase of ARDS. Nintedanib, a multitargeted tyrosine kinase inhibitor that directly blocks Src, has been approved for the treatment of idiopathic pulmonary fibrosis. The mechanisms regulating interactions among MV, EMT and Src remain unclear. In this study, we suggested hypothesized that nintedanib can suppress MV-augmented bleomycin-induced EMT and pulmonary fibrosis by inhibiting the Src pathway. Five days after administrating bleomycin to mimic acute lung injury (ALI), C57BL/6 mice, either wild-type or Src-deficient were exposed to low tidal volume (VT ) (6 ml/kg) or high VT (30 ml/kg) MV with room air for 5 hrs. Oral nintedanib was administered once daily in doses of 30, 60 and 100 mg/kg for 5 days before MV. Non-ventilated mice were used as control groups. Following bleomycin exposure in wild-type mice, high VT MV induced substantial increases in microvascular permeability, TGF-β1, malondialdehyde, Masson's trichrome staining, collagen 1a1 gene expression, EMT (identified by colocalization of increased staining of α-smooth muscle actin and decreased staining of E-cadherin) and alveolar epithelial apoptosis (P nintedanib, which simulated genetic downregulation of Src signalling using Src-deficient mice, dampened the MV-augmented profibrotic mediators, EMT profile, epithelial apoptotic cell death and pathologic fibrotic scores (P nintedanib reduces high VT MV-augmented EMT and pulmonary fibrosis after bleomycin-induced ALI, partly by inhibiting the Src pathway. © 2017 The Authors. Journal of Cellular and Molecular Medicine published by John Wiley & Sons Ltd and Foundation for Cellular and Molecular Medicine.

  3. Static inflation attenuates ischemia/reperfusion injury in an isolated rat lung in situ.

    Science.gov (United States)

    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.

  4. Manipulations of core temperatures in ischemia-reperfusion lung injury in rabbits.

    Science.gov (United States)

    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.

  5. Restrictive ventilatory insufficiency and lung injury induced by ischemia/reperfusion of the pancreas in rats.

    Science.gov (United States)

    Chen, C F; Chen, H T; Wang, D; Li, J P; Fong, Y

    2008-09-01

    Ischemia/reperfusion injury (I/R) of the rat pancreas induces acute pancreatitis with a systemic inflammatory response syndrome. Activated inflammatory cells sequestered in the lung and the proteases released from the inflammatory pancreas both induce acute lung injury. Ischemia was induced by clamping the gastroduodenal artery and the splenic artery for 2 hours to induce ischemia of the pancreas, followed by reperfusion for 6 hours. We then observed lung function parameters, such as weight changes, compliance, functional residual capacity (FRC), and respiratory work. This protocol resulted in elevation in the blood concentrations of nitric oxide (P lung compliance (Cchord), but significant increases in respiratory work. The lung weight/body weight ratio also increased significantly. I/R of the pancreas induced lung injury and restrictive ventilatory insufficiency. Inflammatory responses in the lung tissues induced by oxidative stress and nitrosative stress may be major factors inducing lung injury and a restrictive type of ventilatory insufficiency.

  6. Extent and computed tomography appearance of early radiation induced lung injury for non-small cell lung cancer

    DEFF Research Database (Denmark)

    Bernchou, Uffe; Lübeck Christiansen, Rasmus; Asmussen, Jon Thor

    2017-01-01

    BACKGROUND AND PURPOSE: The present study investigates the extent and appearance of radiologic injury in the lung after radiotherapy for non-small cell lung cancer (NSCLC) patients and correlates radiologic response with clinical and dosimetric factors. METHODS AND MATERIALS: Eligible follow-up CT...... scans acquired up to six months after radiotherapy were evaluated for radiologic injuries in 220 NSCLC patients. Radiologic injuries were divided into three categories: (1) interstitial changes, (2) ground-glass opacity, or (3) consolidation. The relationship between the fraction of injured lung of each...... category and clinical or dosimetric factors was investigated. RESULTS: Radiological injuries of category 1-3 were found in 67%, 52%, and 51% of the patients, and the mean (and maximum) fraction of injured lung was 4.4% (85.9%), 2.4% (46.0%), and 2.1% (22.9%), respectively. Traditional lung dose metrics...

  7. Experimental lung injury promotes alterations in energy metabolism and respiratory mechanics in the lungs of rats: prevention by exercise.

    Science.gov (United States)

    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.

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

    Science.gov (United States)

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

    2016-01-01

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

  9. Keratinocyte growth factor-2 is protective in lipopolysaccharide-induced acute lung injury in rats.

    Science.gov (United States)

    Tong, Lin; Bi, Jing; Zhu, Xiaodan; Wang, Guifang; Liu, Jie; Rong, Linyi; Wang, Qin; Xu, Nuo; Zhong, Ming; Zhu, Duming; Song, Yuanlin; Bai, Chunxue

    2014-09-15

    Keratinocyte growth factor-2 (KGF-2) plays a key role in lung development, but its role in acute lung injury has not been well characterized. Lipopolysaccharide instillation caused acute lung injury, which significantly elevated lung wet-to-dry weight ratio, protein and neutrophils in bronchoalveolar lavage fluid (BALF), inhibited surfactant protein A and C expression in lung tissue, and increased pathological injury. Pretreatment with KGF-2 improved the above lung injury parameters, partially restored surfactant protein A and C expression, and KGF-2 given 2-3 days before LPS challenge showed maximum lung injury improvement. Pretreatment with KGF-2 also markedly reduced the levels of TNF-α, MIP-2, IL-1β and IL-6 in BALF and the levels of IL-1β and IL-6 in lung tissue. Histological analysis showed there was increased proliferation of alveolar type II epithelial cells in lung parenchyma, which reached maximal 2 days after KGF-2 instillation. Intratracheal administration of KGF-2 attenuates lung injury induced by LPS, suggesting KGF-2 may be potent in the intervention of acute lung injury. Copyright © 2014 Elsevier B.V. All rights reserved.

  10. Gene Expression Analysis to Assess the Relevance of Rodent Models to Human Lung Injury.

    Science.gov (United States)

    Sweeney, Timothy E; Lofgren, Shane; Khatri, Purvesh; Rogers, Angela J

    2017-08-01

    The relevance of animal models to human diseases is an area of intense scientific debate. The degree to which mouse models of lung injury recapitulate human lung injury has never been assessed. Integrating data from both human and animal expression studies allows for increased statistical power and identification of conserved differential gene expression across organisms and conditions. We sought comprehensive integration of gene expression data in experimental acute lung injury (ALI) in rodents compared with humans. We performed two separate gene expression multicohort analyses to determine differential gene expression in experimental animal and human lung injury. We used correlational and pathway analyses combined with external in vitro gene expression data to identify both potential drivers of underlying inflammation and therapeutic drug candidates. We identified 21 animal lung tissue datasets and three human lung injury bronchoalveolar lavage datasets. We show that the metasignatures of animal and human experimental ALI are significantly correlated despite these widely varying experimental conditions. The gene expression changes among mice and rats across diverse injury models (ozone, ventilator-induced lung injury, LPS) are significantly correlated with human models of lung injury (Pearson r = 0.33-0.45, P human lung injury. Predicted therapeutic targets, peptide ligand signatures, and pathway analyses are also all highly overlapping. Gene expression changes are similar in animal and human experimental ALI, and provide several physiologic and therapeutic insights to the disease.

  11. Microarray meta-analysis identifies acute lung injury biomarkers in donor lungs that predict development of primary graft failure in recipients.

    Directory of Open Access Journals (Sweden)

    Pingzhao Hu

    Full Text Available To perform a meta-analysis of gene expression microarray data from animal studies of lung injury, and to identify an injury-specific gene expression signature capable of predicting the development of lung injury in humans.We performed a microarray meta-analysis using 77 microarray chips across six platforms, two species and different animal lung injury models exposed to lung injury with or/and without mechanical ventilation. Individual gene chips were classified and grouped based on the strategy used to induce lung injury. Effect size (change in gene expression was calculated between non-injurious and injurious conditions comparing two main strategies to pool chips: (1 one-hit and (2 two-hit lung injury models. A random effects model was used to integrate individual effect sizes calculated from each experiment. Classification models were built using the gene expression signatures generated by the meta-analysis to predict the development of lung injury in human lung transplant recipients.Two injury-specific lists of differentially expressed genes generated from our meta-analysis of lung injury models were validated using external data sets and prospective data from animal models of ventilator-induced lung injury (VILI. Pathway analysis of gene sets revealed that both new and previously implicated VILI-related pathways are enriched with differentially regulated genes. Classification model based on gene expression signatures identified in animal models of lung injury predicted development of primary graft failure (PGF in lung transplant recipients with larger than 80% accuracy based upon injury profiles from transplant donors. We also found that better classifier performance can be achieved by using meta-analysis to identify differentially-expressed genes than using single study-based differential analysis.Taken together, our data suggests that microarray analysis of gene expression data allows for the detection of "injury" gene predictors that can

  12. Bench-to-bedside review: Damage-associated molecular patterns in the onset of ventilator-induced lung injury

    NARCIS (Netherlands)

    Kuipers, Maria T.; van der Poll, Tom; Schultz, Marcus J.; Wieland, Catharina W.

    2011-01-01

    Mechanical ventilation (MV) has the potential to worsen pre-existing lung injury or even to initiate lung injury. Moreover, it is thought that injurious MV contributes to the overwhelming inflammatory response seen in patients with acute lung injury or acute respiratory distress syndrome.

  13. Role of Claudin-5 in the Attenuation of Murine Acute Lung Injury by Simvastatin

    Science.gov (United States)

    Chen, Weiguo; Sharma, Rajesh; Rizzo, Alicia N.; Siegler, Jessica H.; Garcia, Joe G. N.

    2014-01-01

    The statins are now recognized to have pleiotropic properties, including augmentation of endothelial barrier function. To explore the mechanisms involved, we investigated the effect of simvastatin on endothelial cell (EC) tight junctions. Western blotting of human pulmonary artery ECs treated with simvastatin (5 μM) confirmed a significant time-dependent increase (16–48 h) in claudin-5 protein expression compared with controls, without detectable alterations in zonula occludens-1 or occludin. These effects were associated with membrane translocation of VE-cadherin, whereas translocation of vascular endothelial cadherin (VE-cadherin; silencing RNA) inhibited simvastatin-induced claudin-5 up-regulation. Moreover, simvastatin treatment of ECs induced increased phosphorylation of both FoxO1 and β-catenin, transcriptional regulators of claudin-5 expression mediated by VE-cadherin. Subsequently, we found no effect of claudin-5 silencing on EC barrier protection by simvastatin in response to thrombin stimulation, as measured by either transendothelial electrical resistance or by EC monolayer flux of FITC-dextran (2,000 kD). However, silencing of claudin-5 did significantly attenuate simvastatin-mediated EC barrier protection in response to thrombin, as measured by monolayer flux of sodium fluorescein (376 Da). Finally, employing a murine model of LPS-induced acute lung injury, there was no effect of claudin-5 silencing in vivo (intratracheal injection) on bronchoalveolar lavage fluid protein or cell counts, but LPS-induced lung tissue extravasation of the small molecular weight markers, sodium fluorescein and Hochst stain (562 Da), were significantly increased in claudin-5–silenced animals compared with simvastatin-treated control animals. These findings implicate a distinct mechanism underlying size-selective endothelial barrier–protective properties of statins, and may ultimately lead to new novel therapeutic targets for patients with acute lung injury. PMID

  14. Time course of early histopathological lung changes in an ovine model of acute lung injury and pulmonary infection.

    Science.gov (United States)

    Lange, Matthias; Cox, Robert A; Traber, Daniel L; Hamahata, Atsumori; Nakano, Yoshimitsu; Traber, Lillian D; Enkhbaatar, Perenlei

    2013-01-01

    Large animal models are valuable tools in biological and medical lung research. Despite the existence of established large animal models, the scientific progress requires more detailed description and expansion of established methods. Previously, we established an ovine model of acute lung injury and subsequent bacterial instillation into the lungs. The current study was designed to assess the time course of early lung histopathological alterations in a large animal model. Injury was induced by smoke inhalation and instillation of live Pseudomonas aeruginosa into the lungs. After 4, 8, 12, 18, and 24 hours, respectively, lung tissue was harvested and histopathological changes were evaluated (n = 4 each). Additional four sheep received no injury and only lung tissue was taken. In injured animals, bronchial obstruction score increased over time and was significantly elevated from 12 to 24 hours (P lung histopathological alterations following acute lung injury and pulmonary infection and may help optimizing the timing of study interventions and evaluation time points in future experiments with this model.

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

    Science.gov (United States)

    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.

  16. Implication of Acute Lung Injury in the Pathogenesis of Hemostatic Disorders

    Directory of Open Access Journals (Sweden)

    S. V. Sinkov

    2008-01-01

    Full Text Available Objective: to estimate the implication of acute lung injury (ALI and acute respiratory distress syndrome (ARDS in the pathogenesis of hemostatic disorders, by studying the arteriovenous difference between hemostatic parameters. Subjects and methods. Venous and arterial hemostases were studied in 95 patients treated in an intensive care unit. Three groups were identified, which included: 1 50 patients with an uncomplicated postoperative period and without any organ incompetence; 2 21 patients with primary lung injury; and 3 24 patients with secondary lung injury. Groups 2 and 3 patients were divided according to the degree of acute lung injury. Results. The arterial blood of patients with the uncomplicated postoperative period shows a lower coagulability than venous blood; there is no arteriovenous difference between fibrinolytic activity and platelet levels. The coagulation activity of arterial blood increases in primary lung injury; the higher fibrinolytic activity of arterial blood is a compensatory mechanism in moderate lung injury. Later on, in evolving ARDS, the hemostasiological balance between the pulmonary and systemic circulations impairs; disseminated intravascular coagulation (DIC develops in both arterial and venous beds. Venous blood coagulability increases in secondary lung injury. By regulating the hemostatic system, the lungs produce a lower coagulation activity of and a higher fibrinolytic activity of arterial blood in ALI. With the development of ARDS, this function triples and DIC spreads to the arterial bed. Conclusion. The lung maintains the hemostasiological balance between the pulmonary and systemic circulations, by holding activated platelets and by enhancing the fibrinolytic activity of the blood flowing from it. The inducer of DIC is the suppressed fibrinolysis of the lesser circulation in patients with primary lung injury and hyperco-agulation in the greater circulation in patients with secondary lung injury. Key words

  17. Inhalable bioresponsive chitosan microspheres of doxorubicin and soluble curcumin augmented drug delivery in lung cancer cells.

    Science.gov (United States)

    Jyoti, Kiran; Pandey, Ravi Shankar; Kush, Preeti; Kaushik, Dinesh; Jain, Upendra Kumar; Madan, Jitender

    2017-05-01

    In present investigation, doxorubicin (Dox) and soluble curcumin (Cur-2-HP-β-CD-complex) combination was simultaneously loaded in inhalable bioresponsive chitosan microspheres (Dox/Cur-2-HP-β-CD-complex-elastin-CMs) bearing a substrate-stimuli, elastin. The mean particle size and mean aerodynamic diameter of inhalable bioresponsive microspheres displayed noteworthy differences after incorporation of elastin. Moreover, combination of Dox and soluble curcumin was molecularly dispersed in microspheres matrix as substantiated by a range of spectral techniques. Inhalable bioresponsive microspheres released astonishingly higher amount of Dox in presence of elastase enzyme at pH∼5.5 in comparison to pH∼7.4. However, the release of soluble curcumin from tailored bioresponsive microspheres in presence of elastase enzyme was independent of pH. Consistently, inhalable bioresponsive microspheres exhibited outstandingly lower IC 50 of 3.4-μM in comparison to 6.5-μM of inhalable drug loaded microspheres (Dox/Cur-2-HP-β-CD-complex-CMs) bearing no elastin, against A549, non-small cell lung cancer cells. The superior therapeutic profile of inhalable bioresponsive microspheres may be attributed to enhanced drug release and consequently augmented drug exposure to A549 cells expressing elastase enzyme. In this way, stimuli triggered drug release from tailored inhalable bioresponsive microspheres boosted the phenomena of apoptosis in A549 cells. In conclusion, Dox/Cur-2-HP-β-CD-complex-elastin-CMs warrant further in-vivo tumor regression study to prove its therapeutic efficacy. Copyright © 2017 Elsevier B.V. All rights reserved.

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

    Science.gov (United States)

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

    2012-12-01

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

  19. Acute lung injury: what have we learned from animal models?

    Science.gov (United States)

    Windsor, A C; Mullen, P G; Fowler, A A

    1993-08-01

    In 1950, Carl John Wiggers, philosopher and physiologist, wrote, "Reactions to definite types of stimulation may be observed or recorded, and concealed phenomena may be revealed by the use of apparatus that transforms them into forms that are recognizable by human senses. But complete understanding of physiological reactions often necessitates extensive operative procedures and sometimes the ultimate sacrifice of life. For this reason experimentation on animals is indispensable." Acute lung injury is still a significant cause of death in the developed world, and modern pharmacology and intensive care have failed to alter the clinical course of this complex condition. In the past decade, there was an explosion in understanding of the pathophysiology of acute lung injury, and with this has come the development of a new generation of agents that may provide a tool with which to combat this disorder. Use of animal model systems led to this greater understanding and is currently at the heart of evaluating the new therapeutic agents. This review briefly addresses the contribution animal model systems have made to what appear to be a watershed in attempts to obviate the effects of this mortal condition.

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

    Directory of Open Access Journals (Sweden)

    Xue-Yuan Chen

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

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

    Directory of Open Access Journals (Sweden)

    Costello Joseph F

    2008-07-01

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

  2. Nebulized anticoagulants limit pulmonary coagulopathy, but not inflammation, in a model of experimental lung injury

    NARCIS (Netherlands)

    Hofstra, Jorrit J; Vlaar, Alexander P; Cornet, Alexander D; Dixon, Barry; Roelofs, Joris J; Choi, Goda; van der Poll, Tom; Levi, Marcel; Schultz, Marcus J

    BACKGROUND: Pulmonary coagulopathy may contribute to an adverse outcome in lung injury. We assessed the effects of local anticoagulant therapy on bronchoalveolar and systemic haemostasis in a rat model of endotoxemia-induced lung injury. METHODS: Male Sprague-Dawley rats were intravenously

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

    Science.gov (United States)

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

  4. Ventilator-related causes of lung injury: the mechanical power.

    Science.gov (United States)

    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 ventilator-related causes of lung injury and of their variations. The equation can be easily implemented in every ventilator's software.

  5. Omeprazole Attenuates Pulmonary Aryl Hydrocarbon Receptor Activation and Potentiates Hyperoxia-Induced Developmental Lung Injury in Newborn Mice.

    Science.gov (United States)

    Shivanna, Binoy; Zhang, Shaojie; Patel, Ananddeep; Jiang, Weiwu; Wang, Lihua; Welty, Stephen E; Moorthy, Bhagavatula

    2015-11-01

    Hyperoxia contributes to the development of bronchopulmonary dysplasia (BPD) in human preterm infants and a similar lung phenotype characterized by alveolar simplification in newborn mice. Omeprazole (OM) is a proton pump inhibitor that is used to treat humans with gastric acid related disorders. OM-mediated aryl hydrocarbon receptor (AhR) activation attenuates acute hyperoxic lung injury (HLI) in adult mice. Whether OM activates pulmonary AhR and protects C57BL/6J newborn mice against hyperoxia-induced developmental lung (alveolar and pulmonary vascular simplification, inflammation, and oxidative stress) injury (HDLI) is unknown. Therefore, we tested the hypothesis that OM will activate pulmonary AhR and mitigate HDLI in newborn mice. Newborn mice were treated daily with i.p. injections of OM at doses of 10 (OM10) or 25 (OM25) mg/kg while being exposed to air or hyperoxia (FiO2 of 85%) for 14 days, following which their lungs were harvested to determine alveolarization, pulmonary vascularization, inflammation, oxidative stress, vascular injury, and AhR activation. To our surprise, hyperoxia-induced alveolar and pulmonary vascular simplification, inflammation, oxidative stress, and vascular injury were augmented in OM25-treated animals. These findings were associated with attenuated pulmonary vascular endothelial growth factor receptor 2 expression and decreased pulmonary AhR activation in the OM25 group. We conclude that contrary to our hypothesis, OM decreases functional activation of pulmonary AhR and potentiates HDLI in newborn mice. These observations are consistent with our previous findings, which suggest that AhR activation plays a protective role in HDLI in newborn mice. © The Author 2015. Published by Oxford University Press on behalf of the Society of Toxicology. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.

  6. Mitochondria Targeted Peptide Attenuates Mitochondrial Dysfunction, Controls Inflammation and Protects Against Spinal Cord Injury-Induced Lung Injury

    Directory of Open Access Journals (Sweden)

    Liu-Long Zhu

    2017-11-01

    Full Text Available Background/Aims: Spinal cord injury (SCI is a common and devastating disease, which results in systemic inflammatory response syndrome and secondary lung injury. Mitochondrial dysfunction and inflammation are closely related to lung injury in diverse disease models. No studies have demonstrated the effects of mitochondrial targeted peptide SS-31 in a mouse model of SCI-induced lung injury. Methods: Immediately after injury, mice in the treatment groups received a daily, single-dose intraperitoneal injection of SS-31 and for the next 2 days. The sham and SCI groups also received a daily single dose of vehicle (DMSO and 0.9% NaCl, 1: 3. The lung tissue of mice was examined after SCI, and tissue damage, apoptosis, inflammation, and mitochondrial dysfunction were recorded. Results: SS-31 treatment attenuated lung edema and tissue damage. Furthermore, SS-31 treatment reduced apoptosis of alveolar type II cells, the number of total macrophages and M1 macrophages, and neutrophil infiltration. Moreover, SS-31 treatment attenuated reactive oxygen species levels, reversed mitochondrial dysfunction and inhibited NLRP3 inflammasome activation. Conclusions: Collectively, our results demonstrate that SS-31 attenuates mitochondrial dysfunction, controls inflammatory responses, and alleviates the severity of lung damage in a mouse model of SCI-induced lung injury.

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

    Energy Technology Data Exchange (ETDEWEB)

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

    2012-05-15

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

  8. Regulatory effects of intrinsic IL-10 in IgG immune complex-induced lung injury

    DEFF Research Database (Denmark)

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

    1995-01-01

    IL-10 has regulatory effects in vitro on cytokine production by activated macrophages. In the IgG immune complex model of lung injury, exogenously administered IL-10 has been shown to suppress in vivo formation of TNF-alpha, up-regulation of vascular ICAM-1, neutrophil recruitment, and ensuing lung...... injury. In the current study, we sought to determine whether endogenous IL-10 is playing a regulatory role in the lung inflammatory response. On the basis of lung mRNA and ELISA measurements, IL-10 induction was found during development of inflammation in the IgG immune complex model of lung injury....... Blocking of IL-10 by Ab resulted in a 52% increase in lung vascular permeability, a 56% increase in TNF-alpha activity in bronchoalveolar lavage fluids, and a 47 to 48% increase in bronchoalveolar lavage neutrophils and lung myeloperoxidase content. These findings suggest that IL-10 is an important natural...

  9. Lung injury and pneumothorax after defibrillation as demonstrated with computed tomography.

    Science.gov (United States)

    Gümüş, Terman; Yıldırım, Düzgün; Uçar, Gökhan

    2013-06-01

    Many patients present for emergency services after electric injuries or require defibrillation during emergency services. Although the defibrillation process is safe, skin burns and myocardial injuries are reported after defibrillation procedures. There are limited data about the complications of defibrillation. In the case reported here, a lung injury and a small pneumothorax were observed after defibrillation. To the best of our knowledge, this is the first reported case in which computed tomography is used to demonstrate that a trace of electric current passed through the lung. Computed tomography may be an excellent diagnostic modality to demonstrate the severity and extent of electric injuries to the lung.

  10. Injurious mechanical ventilation in the normal lung causes a progressive pathologic change in dynamic alveolar mechanics

    OpenAIRE

    Pavone, Lucio A.; Albert, Scott; Carney, David; Gatto, Louis A.; Halter, Jeffrey M; Nieman, Gary F.

    2007-01-01

    Introduction Acute respiratory distress syndrome causes a heterogeneous lung injury, and without protective mechanical ventilation a secondary ventilator-induced lung injury can occur. To ventilate noncompliant lung regions, high inflation pressures are required to 'pop open' the injured alveoli. The temporal impact, however, of these elevated pressures on normal alveolar mechanics (that is, the dynamic change in alveolar size and shape during ventilation) is unknown. In the present study we ...

  11. Hydrogen gas reduces hyperoxic lung injury via the Nrf2 pathway in vivo

    Science.gov (United States)

    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

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

    Directory of Open Access Journals (Sweden)

    Zheng-xin WANG

    2011-11-01

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

  13. Mechanical ventilation injury and repair in extremely and very preterm lungs.

    Directory of Open Access Journals (Sweden)

    Nadine Brew

    Full Text Available BACKGROUND: 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. AIM: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.

  14. [NLRP3 inflammasome induces pyroptosis in lung tissues of radiation-induced lung injury in mice].

    Science.gov (United States)

    Han, Rong; Wu, Dongming; Deng, Shihua; Liu, Teng; Zhang, Ting; Xu, Ying

    2017-09-01

    Objective To establish a radiation-induced lung injury model and investigate the role of caspase-1-dependent programmed cell death (pyroptosis) in the pathogenesis of radiation pneumonitis. Methods BALB/c mice were sacrificed after receiving 5-day 15 Gy X-ray irradiation at chest cavity. The pathological changes of pulmonary tissues were observed by HE staining. The apoptosis of lung tissues cells after irradiation was detected by TUNEL assay. The expressions of γ-H2AX, ki67, NLR family pyrin domain containing 3 (NLRP3), caspase-1, apoptosis-associated speck-like protein containing a CARD (ASC/TMS-1) were detected by Western blot analysis. Real-time quantitative PCR was used to check mRNA levels of interleukin-6 (IL-6), IL-8, tumor necrosis factor α (TNF-α), monocyte chemoattractant protein 1 (MCP-1), NLRP3, caspase-1, IL-1β and IL-18. Immunohistochemical staining was used to determine the expressions of NLRP3, caspase-1 and TMS1 in lung tissues. The activity of caspase-1 was evaluated by caspase-1 assay kit, and the serum levels of IL-1β and IL-18 were detected by ELISA. Results After irradiation, the capillaries of the alveolar wall of the mice were dilated and congested, inflammatory cells infiltrated, the alveolar wall thickened. Positive rate of lung tissue cells was raised in TUNEL staining. The expressions of γ-H2AX and ki67 were elevated, indicating that DNA damage and cell proliferation activity decreased in lung tissues. The mRNA levels of IL-6, IL-8, TNF-α and MCP-1 in lung cells increased; the serum levels of IL-1β and IL-18 increased; the expressions of IL-1β, IL-18, NLRP3, caspase-1 and ASC/TMS-1 in lung tissues were enhanced; and caspase-1 activity increased. Conclusion After irradiation, the pyroptosis caused by the activation of NLRP3 inflammatory body occurred in the lung tissue of mice.

  15. Oleic acid vs saline solution lung lavage-induced acute lung injury: effects on lung morphology, pressure-volume relationships, and response to positive end-expiratory pressure.

    Science.gov (United States)

    Luecke, Thomas; Meinhardt, Juergen P; Herrmann, Peter; Weiss, Andreas; Quintel, Michael; Pelosi, Paolo

    2006-08-01

    To compare two lung injury models (oleic acid [OA] and saline solution washout [SW]) regarding lung morphology, regional inflation, and recruitment during static pressure-volume (PV) curves, and the effects of positive end-expiratory pressure (PEEP) below and above the lower inflection point (Pflex). Fourteen adult pigs underwent OA or SW lung injury. Lung volumes were measured using CT. PV curves were obtained with simultaneous CT scanning at lung apex and base. Fractional inflation and recruitment were compared to data on PEEP above and below Pflex. Severity of lung injury was comparable. At zero PEEP, SW showed an increased amount of edema and poorly aerated lung volume, recruitment during inspiration, and a better oxygenation response with PEEP. Whole-lung PV curves were similar in both models, reflecting changes in alveolar inflation or deflation. On the inspiratory PV limb, recruitment and inflation were on the same line, while there was a substantial difference between deflation and derecruitment on the expiratory limb. PEEP-induced recruitment at lung apex and base was at or above the derecruitment line on the expiratory limb and showed no relationship to the whole-lung expiratory PV curve. The following conclusions were made: (1) OA and SW models are comparable in mechanics but not in lung injury characteristics; (2) neither inspiratory nor expiratory whole-lung PV curves are useful to select PEEP in order to optimize recruitment; and (3) after recruitment, there is no difference in derecruitment between the models at high PEEP, while more collapse occurs at lower PEEP in the basal sections of SW lungs.

  16. Mechanical ventilation with lower tidal volumes and positive end-expiratory pressure prevents alveolar coagulation in patients without lung injury

    NARCIS (Netherlands)

    Choi, Goda; Wolthuis, Esther K.; Bresser, Paul; Levi, Marcel; van der Poll, Tom; Dzoljic, Misa; Vroom, Margreeth B.; Schultz, Marcus J.

    2006-01-01

    BACKGROUND: Alveolar fibrin deposition is a hallmark of acute lung injury, resulting from activation of coagulation and inhibition of fibrinolysis. Previous studies have shown that mechanical ventilation with high tidal volumes may aggravate lung injury in patients with sepsis and acute lung injury.

  17. Microarray analysis of regional cellular responses to local mechanical stress in acute lung injury.

    Science.gov (United States)

    Simon, Brett A; Easley, R Blaine; Grigoryev, Dmitry N; Ma, Shwu-Fan; Ye, Shui Q; Lavoie, Tera; Tuder, Rubin M; Garcia, Joe G N

    2006-11-01

    Human acute lung injury is characterized by heterogeneous tissue involvement, leading to the potential for extremes of mechanical stress and tissue injury when mechanical ventilation, required to support critically ill patients, is employed. Our goal was to establish whether regional cellular responses to these disparate local mechanical conditions could be determined as a novel approach toward understanding the mechanism of development of ventilator-associated lung injury. We utilized cross-species genomic microarrays in a unilateral model of ventilator-associated lung injury in anesthetized dogs to assess regional cellular responses to local mechanical conditions that potentially contribute pathogenic mechanisms of injury. Highly significant regional differences in gene expression were observed between lung apex/base regions as well as between gravitationally dependent/nondependent regions of the base, with 367 and 1,544 genes differentially regulated between these regions, respectively. Major functional groupings of differentially regulated genes included inflammation and immune responses, cell proliferation, adhesion, signaling, and apoptosis. Expression of genes encoding both acute lung injury-associated inflammatory cytokines and protective acute response genes were markedly different in the nondependent compared with the dependent regions of the lung base. We conclude that there are significant differences in the local responses to stress within the lung, and consequently, insights into the cellular responses that contribute to ventilator-associated lung injury development must be sought in the context of the mechanical heterogeneity that characterizes this syndrome.

  18. Differential Expression of Aquaporins in Experimental Models of Acute Lung Injury.

    Science.gov (United States)

    Vassiliou, Alice G; Manitsopoulos, Nikolaos; Kardara, Matina; Maniatis, Nikolaos A; Orfanos, Stylianos E; Kotanidou, Anastasia

    2017-01-01

    The mammalian lung expresses at least three aquaporin (AQP) water channels whose precise role in lung injury or inflammation is still controversial. Three murine models of lung inflammation and corresponding controls were used to evaluate the expression of Aqp1, Aqp4, Aqp5 and Aqp9: lipopolysaccharide (LPS)-induced lung injury; HCl-induced lung injury; and ventilation-induced lung injury (VILI). All models yielded increased lung vascular permeability, and inflammatory cell infiltration in the broncho-alveolar lavage fluid; VILI additionally produced altered lung mechanics. Lung expression of Aqp4 decreased in the models that targeted primarily the alveolar epithelium, i.e. acid aspiration and mechanical ventilation, while Aqp5 expression decreased in the model that appeared to target both the capillary endothelium and alveolar epithelium, i.e. LPS. Participation of aquaporins in the acute inflammatory process depends on localization and the type of lung injury. Copyright© 2017, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.

  19. Acute lung injury: effects of prone positioning on cephalocaudal distribution of lung inflation--CT assessment in dogs.

    Science.gov (United States)

    Lee, Hyun Ju; Im, Jung-Gi; Goo, Jin Mo; Kim, Young Il; Lee, Min Woo; Ryu, Ho-Geol; Bahk, Jae-Hyon; Yoo, Chul-Gyu

    2005-01-01

    To quantify cephalocaudal gradient of lung inflation in acute lung injury in a dog model in prone versus supine position. Experiments were performed in accordance with Guide for the Care and Use of Laboratory Animals, as approved by National Research Council (National Institutes of Health), and were approved by committee on care and use of animals in research at Seoul National University Hospital. After induction of acute lung injury with intravenous injection of oleic acid, dogs were randomized to be ventilated in either prone (n = 6) or supine (n = 6) position. Spiral computed tomography (CT) and hemodynamic measurement were performed sequentially on an hourly basis. Volume and mean attenuation of lung were measured quantitatively by using software to evaluate each CT section. Cephalocaudal gradient of mean lung attenuation, distribution of gas and tissue, and alveolar expansion were assessed. Functional residual capacity and net alveolar expansion of entire lung were measured. Statistical analysis was performed with Friedman, sign, and Mann-Whitney tests. Mean lung attenuation increased gradually from apex to base of lung in supine position. Thus, inflation gradient along cephalocaudal axis was found. Gas was located predominantly in upper lung, whereas tissue was dominant in lower lung in supine position. In supine group, cephalocaudal inflation gradient showed no significant change from baseline up to 4 hours. After prone positioning, cephalocaudal inflation gradient was reduced, and gas and tissue proportions became more uniform along cephalocaudal axis. In prone group, absolute values of cephalocaudal inflation gradient at time points of prone positioning for 1, 2, and 3 hours were significantly lower than baseline values (P lung was not altered significantly. Functional residual capacity was unchanged by prone positioning. In acute lung injury, prone positioning induced more uniform distribution of gas and tissue along cephalocaudal axis by reducing

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

    Science.gov (United States)

    2014-04-01

    chemotherapeutic agents, themselves, cause a syndrome with features of ALI. The pathology and pathophysiology of ALI are very complex and include features...pediatric lung disease, hypothyroidism , and neurological impairment (Krude et al., 2002). Inability to access the presumed very rare, multipo- tent...Schnabel, D., Neitzel, H., Tönnies, H., Weise, D., Lafferty, A., Schwarz, S., et al. (2002). Choreoathetosis, hypothyroidism , and pulmonary

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

    Science.gov (United States)

    2010-07-01

    derived, highly scalable, and since they can be readily derived from individual mice (or humans) they thereby circumvent immune and ethical issues... placentas collected during delivery, and mucosal cells collected by scraping or swab)? N/A Will the research data in this study be gathered through non...is typically depleted in ALI/ARDS, resulting in decreased lung compliance and increased risk of barotrauma. In vivo studies using normal guinea pigs

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

    Science.gov (United States)

    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. Copyright © 2012 Elsevier Inc. All rights reserved.

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

    Directory of Open Access Journals (Sweden)

    Proudfoot Alastair G

    2011-12-01

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

  4. Does airway pressure release ventilation alter lung function after acute lung injury?

    Science.gov (United States)

    Smith, R A; Smith, D B

    1995-03-01

    During airway pressure release ventilation (APRV), tidal ventilation occurs between the increased lung volume established by the application of continuous positive airway pressure (CPAP) and the relaxation volume of the respiratory system. Concern has been expressed that release of CPAP may cause unstable alveoli to collapse and not reinflate when airway pressure is restored. To compare pulmonary mechanics and oxygenation in animals with acute lung injury during CPAP with and without APRV. Experimental, subject-controlled, randomized crossover investigation. Anesthesiology research laboratory, University of South Florida College of Medicine Health Sciences Center. Ten pigs of either sex. Acute lung injury was induced with an intravenous infusion of oleic acid (72 micrograms/kg) followed by randomly alternated 60-min trials of CPAP with and without APRV. Continuous positive airway pressure was titrated to produce an arterial oxyhemoglobin saturation of at least 95% (FIO2 = 0.21). Airway pressure release ventilation was arbitrarily cycled to atmospheric pressure 10 times per minute with a release time titrated to coincide with attainment of respiratory system relaxation volume. Cardiac output, arterial and mixed venous pH, blood gas tensions, hemoglobin concentration and oxyhemoglobin saturation, central venous pressure, pulmonary and systemic artery pressures, pulmonary artery occlusion pressure, airway gas flow, airway pressure, and pleural pressure were measured. Tidal volume (VT), dynamic lung compliance, intrapulmonary venous admixture, pulmonary vascular resistance, systemic vascular resistance, oxygen delivery, oxygen consumption, and oxygen extraction ratio were calculated. Central venous infusion of oleic acid reduced PaO2 from 94 +/- 4 mm Hg to 52 +/- 9 mm Hg (mean +/- 1 SD) (p arterial oxyhemoglobin saturation (96.6 +/- 1.4% vs 96.9 +/- 1.3%) did not. Intrapulmonary venous admixture (9 +/- 3% vs 11 +/- 5%) and oxygen delivery (469 +/- 67 mL/min vs 479

  5. Role of gelatinases MMP-2 and MMP-9 in tissue remodeling following acute lung injury

    Directory of Open Access Journals (Sweden)

    Corbel M.

    2000-01-01

    Full Text Available Acute lung injury is characterized by a severe disruption of alveolo-capillary structures and includes a variety of changes in lung cell populations. Evidence suggests the occurrence of rupture of the basement membranes and interstitial matrix remodeling during acute lung injury. The dynamic equilibrium of the extracellular matrix (ECM under physiological conditions is a consequence of the balance between the regulation of synthesis and degradation of ECM components. Matrix metalloproteinases (MMPs represent a group of enzymes involved in the degradation of most of the components of the ECM and therefore participate in tissue remodeling associated with pathological situations such as acute lung injury. MMP activity is regulated by proteolytic activation of the latent secreted proenzyme and by interaction with specific tissue inhibitors of metalloproteinases. This review details our knowledge of the involvement of MMPs, namely MMP-2 and MMP-9, in acute lung injury and acute respiratory distress syndrome.

  6. VEGF Promotes Malaria-Associated Acute Lung Injury in Mice

    Science.gov (United States)

    Carapau, Daniel; Pena, Ana C.; Ataíde, Ricardo; Monteiro, Carla A. A.; Félix, Nuno; Costa-Silva, Artur; Marinho, Claudio R. F.; Dias, Sérgio; Mota, Maria M.

    2010-01-01

    The spectrum of the clinical presentation and severity of malaria infections is broad, ranging from uncomplicated febrile illness to severe forms of disease such as cerebral malaria (CM), acute lung injury (ALI), acute respiratory distress syndrome (ARDS), pregnancy-associated malaria (PAM) or severe anemia (SA). Rodent models that mimic human CM, PAM and SA syndromes have been established. Here, we show that DBA/2 mice infected with P. berghei ANKA constitute a new model for malaria-associated ALI. Up to 60% of the mice showed dyspnea, airway obstruction and hypoxemia and died between days 7 and 12 post-infection. The most common pathological findings were pleural effusion, pulmonary hemorrhage and edema, consistent with increased lung vessel permeability, while the blood-brain barrier was intact. Malaria-associated ALI correlated with high levels of circulating VEGF, produced de novo in the spleen, and its blockage led to protection of mice from this syndrome. In addition, either splenectomization or administration of the anti-inflammatory molecule carbon monoxide led to a significant reduction in the levels of sera VEGF and to protection from ALI. The similarities between the physiopathological lesions described here and the ones occurring in humans, as well as the demonstration that VEGF is a critical host factor in the onset of malaria-associated ALI in mice, not only offers important mechanistic insights into the processes underlying the pathology related with malaria but may also pave the way for interventional studies. PMID:20502682

  7. Dexmedetomidine Alleviates Hyperoxia-Induced Acute Lung Injury via Inhibiting NLRP3 Inflammasome Activation.

    Science.gov (United States)

    Zhang, Qiuyue; Wu, Di; Yang, Yang; Liu, Tingting; Liu, Hongyu

    2017-01-01

    Dexmedetomidine (Dex), a specific agonist of α2-adrenoceptor, has been reported to have extensive pharmacological effects. In this study, we focused on the protective effect of Dex on hyperoxia-induced acute lung injury and further explored its possible molecular mechanisms. The model of hyperoxia-induced acute lung injury was established by continuous inhalation of oxygen (FiO2= 0.90) for 7 d in neonatal rats in vivo. The in vitro experiments were carried out in LPS/ATP or hyperoxia-treated RAW264.7 cells. ELISA, western blot, TUNEL staining, and immunohistochemistry staining assays were performed and the commercial kits were used to assess the beneficial effect of Dex on hyperoxia-induced acute lung injury. According to our results, Dex treatment attenuated hyperoxia-induced acute lung injury via decreasing the lung wet/dry(W/D) weight ratio and mitigating pathomorphologic changes. Moreover, the oxidative stress injury, inflammatory reaction, and apoptosis in lung epithelial cells were inhibited by Dex treatment. In addition, the activation of NLRP3 inflammasome was restrained by Dex both in lung tissue in vivo and RAW264.7 cells in vitro. These data provide evidence that Dex may ameliorate hyperoxia-induced acute lung injury, which suggests a potential clinical application of Dex in long-term supplemental oxygen therapy. © 2017 The Author(s). Published by S. Karger AG, Basel.

  8. Evaluation report on the causal association between humidifier disinfectants and lung injury

    Directory of Open Access Journals (Sweden)

    Mina Ha

    2016-08-01

    Full Text Available OBJECTIVES As of November 2011, the Korean government recalled and banned humidifier disinfectants (HDs from the market, because four case-control studies and one retrospective epidemiological study proved the association between HDs and lung injury of unknown cause. The report reviewed the causal role of HDs in lung injury based on scientific evidences. METHODS A careful examination on the association between the HDs and lung injury was based on the criteria of causality inference by Hill and the US Surgeon General Expert Committee. RESULTS We found that all the evidences on the causality fulfilled the criteria (strength of association, consistency, specificity, temporality, biologic gradient, plausibility, coherence, experiment, analogy, consideration of alternative explanations, and cessation of exposure, which proved the unknown cause lung injury reported in 2011 was caused by the HDs. In particular, there was no single reported case of lung injury since the ban in selling HDs in November 2011 as well as before the HDs were sold in markets. CONCLUSIONS Although only a few epidemiological studies in Korea have evaluated the association between lung injury and the use of HDs, those studies contributed to proving the strong association between the use of the HDs and lung injury, based on scientific evidence.

  9. High bias gas flows increase lung injury in the ventilated preterm lamb.

    Directory of Open Access Journals (Sweden)

    Katinka P Bach

    Full Text Available BACKGROUND: Mechanical ventilation of preterm babies increases survival but can also cause ventilator-induced lung injury (VILI, leading to the development of bronchopulmonary dysplasia (BPD. It is not known whether shear stress injury from gases flowing into the preterm lung during ventilation contributes to VILI. METHODS: Preterm lambs of 131 days' gestation (term = 147 d were ventilated for 2 hours with a bias gas flow of 8 L/min (n = 13, 18 L/min (n = 12 or 28 L/min (n = 14. Physiological parameters were measured continuously and lung injury was assessed by measuring mRNA expression of early injury response genes and by histological analysis. Control lung tissue was collected from unventilated age-matched fetuses. Data were analysed by ANOVA with a Tukey post-hoc test when appropriate. RESULTS: High bias gas flows resulted in higher ventilator pressures, shorter inflation times and decreased ventilator efficiency. The rate of rise of inspiratory gas flow was greatest, and pulmonary mRNA levels of the injury markers, EGR1 and CTGF, were highest in lambs ventilated with bias gas flows of 18 L/min. High bias gas flows resulted in increased cellular proliferation and abnormal deposition of elastin, collagen and myofibroblasts in the lung. CONCLUSIONS: High ventilator bias gas flows resulted in increased lung injury, with up-regulation of acute early response genes and increased histological lung injury. Bias gas flows may, therefore, contribute to VILI and BPD.

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

    Science.gov (United States)

    2013-07-01

    original application was to derive new approaches to treat ALI with an emphasis on developing new modes of mechanical ventilation and developing cell...minimizing the known injurious effects of conventional mechanical ventilation in patients with ALI. In this past year, where this grant has been in a...supplemental oxygen and mechanical ventilation to ensure adequate oxygenation. Type I cells, which comprise the vast majority of the gas exchange surface

  11. RITUXIMAB TREATMENT FOR INTERSTITIAL LUNG INJURY IN SCLERODERMA SYSTEMATICA

    Directory of Open Access Journals (Sweden)

    Lidia Petrovna Ananieva

    2013-01-01

    Full Text Available Objective: to study the efficiency and tolerance of rituximab (RTM treatment in patients with scleroderma systematica (SDS with interstitial lung injury (ILI.Subjects and methods. The trial included 27 patients (26 women and 1 man (mean age 45.7±13.0 years, with diffuse (n=13 and circumscribed (n = 14 forms and a disease duration of > 5 years in 63%. All the patients underwent chestcomputed tomography; examination of external respiratory function, including forced vital capacity (FVC and diffusing capacity of the lung (DCL, as well as echocardiographic study. The efficiency of the treatment was evaluated from changes in FVC, skin score, and disease activity index. The indicators were compared prior to the treatment and one year after the first administration of RTM. The latter was injected with premedication (125–500 mg of methylprednisolone intravenously 500–1000 mg per administration. The mean dose of RTM was low and amounted to 1.3 g per year.Results. As estimated by the physician, good, satisfactory, no effects were seen in 81.5, 14.8, and 3.7% of the patients, respectively. There was a significant increase in mean FVC one year after the first administration of RTM and a reduction in the total activity of the disease, including skin syndrome. DCL was substantially unchanged in the entire group. In the diffuse and circumscribed forms of the disease, FVC increased significantly and to the same extent. A clinically significant increase in FVC (by 11% was achieved in patients with a disease duration of ≤5 years and mild lung injury. In people with a more than 5-year disease duration, FVC was initially decreased to a greater extent and the treatment-induced increase was only 3.7%. A significant and permanent decline in peripheral blood B lymphocytes was noted when both the standard dose (2 g of RTM and its lower doses (0.5–1 g were administered. RTM treatment was well tolerated, but complicated by mild intercurrent infections

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

    Science.gov (United States)

    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. Galectin-3 augments tumor initiating property and tumorigenicity of lung cancer through interaction with β-catenin

    Science.gov (United States)

    Chung, Ling-Yen; Tang, Shye-Jye; Wu, Yi-Ching; Sun, Guang-Huan; Liu, Huan-Yun; Sun, Kuang-Hui

    2015-01-01

    Cancer stem cells (CSCs) are comprised of a rare sub-population of cells in tumors that have been proposed to be responsible for high recurrence rates and resistance to chemotherapy. Galectins are highly expressed in cancers that correlate with the aggressiveness of tumors. Galectins may also promote the resistance of cancer cells to chemotherapy. However, the role of galectins in CSCs remains unknown. In this study, sphere formation was used to enrich H1299 human lung CSCs that had self-renewal ability, advanced tumorigenic potential, and that highly expressed stem/progenitor cell markers such as Oct4, Sox2, Nanog, and CD133. A novel candidate molecule, galectin-3, for stemness was found in lung CSCs. The expression of galectin-3 robustly increased in lung cancer spheres over serial passages, but its suppression in the H1299 monolayer or spheres resulted in reduced expression of stemness-related genes, sphere-forming ability, tumorigenicity, chemoresistance, and tumor initiation in mice. Notably, the overexpression of galectin-3 in A549 lung cancer cells, which have low capability to grow as tumor spheres, promoted CSC formation. β-catenin activity was increased in H1299 spheres and counteracted by galectin-3 suppression. Thus, galectin-3 may act as a cofactor by interacting with β-catenin to augment the transcriptional activities of stemness-related genes. Furthermore, galectin-3 expression correlated with tumor progression and expressions of β-catenin and CSC marker CD133 in lung cancer tissues. Targeting galectin-3 signaling may provide a new strategy for lung cancer treatment by inhibiting stem-like properties. PMID:25669973

  14. Electrical impedance tomography (EIT) for quantification of pulmonary edema in acute lung injury.

    Science.gov (United States)

    Trepte, Constantin J C; Phillips, Charles R; Solà, Josep; Adler, Andy; Haas, Sebastian A; Rapin, Michael; Böhm, Stephan H; Reuter, Daniel A

    2016-01-22

    Assessment of pulmonary edema is a key factor in monitoring and guidance of therapy in critically ill patients. To date, methods available at the bedside for estimating the physiologic correlate of pulmonary edema, extravascular lung water, often are unreliable or require invasive measurements. The aim of the present study was to develop a novel approach to reliably assess extravascular lung water by making use of the functional imaging capabilities of electrical impedance tomography. Thirty domestic pigs were anesthetized and randomized to three different groups. Group 1 was a sham group with no lung injury. Group 2 had acute lung injury induced by saline lavage. Group 3 had vascular lung injury induced by intravenous injection of oleic acid. A novel, noninvasive technique using changes in thoracic electrical impedance with lateral body rotation was used to measure a new metric, the lung water ratioEIT, which reflects total extravascular lung water. The lung water ratioEIT was compared with postmortem gravimetric lung water analysis and transcardiopulmonary thermodilution measurements. A significant correlation was found between extravascular lung water as measured by postmortem gravimetric analysis and electrical impedance tomography (r = 0.80; p electrical impedance tomograms during lateral body rotation. The novel lung water ratioEIT holds promise to become a noninvasive bedside measure of pulmonary edema.

  15. Fibroblast Growth Factor-10 (FGF-10) Mobilizes Lung-resident Mesenchymal Stem Cells and Protects Against Acute Lung Injury.

    Science.gov (United States)

    Tong, Lin; Zhou, Jian; Rong, Linyi; Seeley, Eric J; Pan, Jue; Zhu, Xiaodan; Liu, Jie; Wang, Qin; Tang, Xinjun; Qu, Jieming; Bai, Chunxue; Song, Yuanlin

    2016-02-12

    FGF-10 can prevent or reduce lung specific inflammation due to traumatic or infectious lung injury. However, the exact mechanisms are poorly characterized. Additionally, the effect of FGF-10 on lung-resident mesenchymal stem cells (LR-MSCs) has not been studied. To better characterize the effect of FGF-10 on LR-MSCs, FGF-10 was intratracheally delivered into the lungs of rats. Three days after instillation, bronchoalveolar lavage was performed and plastic-adherent cells were cultured, characterized and then delivered therapeutically to rats after LPS intratracheal instillation. Immunophenotyping analysis of FGF-10 mobilized and cultured cells revealed expression of the MSC markers CD29, CD73, CD90, and CD105, and the absence of the hematopoietic lineage markers CD34 and CD45. Multipotency of these cells was demonstrated by their capacity to differentiate into osteocytes, adipocytes, and chondrocytes. Delivery of LR-MSCs into the lungs after LPS injury reduced the inflammatory response as evidenced by decreased wet-to-dry ratio, reduced neutrophil and leukocyte recruitment and decreased inflammatory cytokines compared to control rats. Lastly, direct delivery of FGF-10 in the lungs of rats led to an increase of LR-MSCs in the treated lungs, suggesting that the protective effect of FGF-10 might be mediated, in part, by the mobilization of LR-MSCs in lungs.

  16. Protective effects of Toll-like receptor 4 inhibitor on myocardial injury and lung injury in sepsis rat model

    Directory of Open Access Journals (Sweden)

    Rong-Bing He

    2017-07-01

    Full Text Available Objective: To study the protective effects of Toll-like receptor 4 (TLR4 inhibitor on myocardial injury and lung injury in sepsis rat model. Methods: A total of 18 adult male SD rats were selected as experimental animals and randomly divided into control group, model group and intervention group, with 6 in each group. The sepsis models were established by cecal ligation and given intragastric administration of TLR4 inhibitor C34. Twenty four hours after model establishment, the levels of myocardial injury molecules and lung injury molecules in serum as well as the expression of inflammatory cytokines, the levels of oxidative stress molecules and the expression of apoptosis molecules in myocardial tissue and lung tissue were determined. Results: KL-6, cTnI and CK-MB levels in serum, NF-kB, TNF-α, IL-1β, Bax, Caspase-3 and Caspase-9 mRNA expression as well as MDA and OH﹣ levels in myocardial tissue and lung tissue of model group were significantly higher than those of control group while SOD levels in myocardial tissue and lung tissue were significantly lower than those of control group; KL-6, cTnI and CK-MB levels in serum, NF-kB, TNF-α, IL-1β, Bax, Caspase-3 and Caspase-9 mRNA expression as well as MDA and OH﹣levels in myocardial tissue and lung tissue of intervention group were significantly lower than those of model group while SOD levels in myocardial tissue and lung tissue were significantly higher than those of model group. Conclusions: Toll-like receptor 4 inhibitor has protective effect on myocardial injury and lung injury in model rats with sepsis.

  17. C5-derived activity is required for complement neutrophil-mediated lung injury

    Energy Technology Data Exchange (ETDEWEB)

    Morganroth, M.L.; Till, G.O.; Ward, P.A.

    1986-03-05

    Cobra venom factor (CVF) derived from the cobra species Naja naja (NN) is a complement activator (cleaves C3, C5 and terminal components) which causes neutrophil dependent acute lung injury and pulmonary hypertension in rats. CVF, derived from the cobra species Naja haje (NH), differs from NN-CVF in that only C3 is cleaved. The authors investigated in isolated blood perfused rat lungs if NH-CVF (n=5), a complement activator which does not generate C5 derived peptides, causes pulmonary hypertension and acute lung injury. NN-CVF (n=5) caused a transient increase in mean pulmonary artery pressure (PA) which returned toward baseline by 30 min (Peak ..delta.. PA = 17 +/- 6 mmHg). Lung injury occurred and was quantitated by the leak of /sup 125/I bovine serum albumin (/sup 125/I-BSA added 30 min post CVF) into lung parenchyma (lung/perfusate /sup 125/I-BSA counts: control = .09 +/- .01, NN-CVF = .48 +/- .11, p < .05). NH-CVF, in an amount which caused equipotent in vitro hemolysis of nonsensitized rabbit erythrocytes, did not cause a PA pressor response (3.5 +/- 1.1 mm Hg, p=NS) or acute lung injury (lung/perfusate /sup 125/I-BSA counts .11 +/- .01, p=NS). Similarly, NH-CVF did not appear to cause lung injury in intact rats (lung perfusate /sup 125/I-BSA counts: control .20 +/- .01, n=3; NH-CVF .25 +/- .05, n=3; NN-CVF .83 +/- .27, n=2). Thus, C3 cleavage alone without the generation of C5 derived peptides is an inadequate stimulus to elicit neutrophil-mediated acute lung injury.

  18. Ischemic postconditioning alleviates lung injury and maintains a better expression of aquaporin-1 during cardiopulmonary bypass.

    Science.gov (United States)

    Cheng, Chi; Li, Shanshan; Wang, Yong; Chen, Song; You, Lu; Zhang, Hong

    2014-01-01

    It has found that ischemic postconditioning (IPO) might decrease pulmonary ischemia/reperfusion (I/R) injury, which is one of the main reasons of lung injury caused by cardiopulmonary bypass (CPB). It was found that aquaporins (AQPs) play a role in the maintenance of fluid homeostasis. But it is still unclear whether IPO influences the expression of aquaporin-1 (AQP1). This study was designed to investigate whether IPO can reduce CPB-related lung injury and affect the expression of AQP1 of lungs. Twelve healthy dogs were divided into control group (C group) and ischemia postconditioning group (IPO group). CPB procedures were implemented. Ten minutes later, the left pulmonary artery was separated and blocked. Postconditioning consisted of two cycles of 5-minute pulmonary artery reperfusion/5-minute reocclusion starting at the beginning of reperfusion. The 2×4 cm tissues of both sides of pulmonary apex, superior, middle and inferior lobe were taken before CPB (T1), before occlusion and reopening of left pulmonary artery (T2, T3), and 2 hours after CPB (T4). Samples were used to evaluate lung injury degrees and to detect the expression of AQP1. At T1 and T4, blood was collected from femoral artery to calculate pulmonary function. At T4, each pulmonary function showed significant deterioration compared with T1. Lung injury could be found at the onset of CPB. However, the expression of AQP1 decreased and wet to dry weight ratio (W/D) increased after T2. In the left lung of C group, the worst pulmonary function and structures were detected. The slightest changes were discovered in the right lung of C group. A close relationship between W/D and lung injury score was found. The lung injury score was negatively related with the expression of AQP1. It was found that the expression of AQP1 was negatively connected with W/D. In dog CPB models, lung injury induced by CPB was related with down regulated expression of AQP1. AQP1 is believed to be involved in the mechanisms of

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

    Energy Technology Data Exchange (ETDEWEB)

    Bakkal, B.H. [Department of Radiation Oncology, School of Medicine, Bulent Ecevit University, Kozlu, Zonguldak (Turkey); Gultekin, F.A. [Department of General Surgery, School of Medicine, Bulent Ecevit University, Kozlu, Zonguldak (Turkey); Guven, B. [Department of Biochemistry, School of Medicine, Bulent Ecevit University, Kozlu, Zonguldak (Turkey); Turkcu, U.O. [Mugla School of Health Sciences, Mugla Sitki Kocman University, Mugla (Turkey); Bektas, S. [Department of Pathology, School of Medicine, Bulent Ecevit University, Kozlu, Zonguldak (Turkey); Can, M. [Department of Biochemistry, School of Medicine, Bulent Ecevit University, Kozlu, Zonguldak (Turkey)

    2013-09-27

    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.

  20. THE 5-LIPOXYGENASE PATHWAY IS REQUIRED FOR ACUTE LUNG INJURY FOLLOWING HEMORRHAGIC SHOCK

    Science.gov (United States)

    Eun, John C.; Moore, Ernest E.; Mauchley, David C.; Johnson, Chris A.; Meng, Xianzhong; Banerjee, Anirban; Wohlauer, Max V.; Zarini, Simona; Gijón, Miguel A.; Murphy, Robert C.

    2012-01-01

    The cellular and biochemical mechanisms leading to acute lung injury and subsequent multiple organ failure are only partially understood. In order to study the potential role of eicosanoids, particularly leukotrienes, as possible mediators of acute lung injury, we used a murine experimental model of acute lung injury induced by hemorrhagic shock after blood removal via cardiac puncture. Neutrophil sequestration as shown by immunofluorescence, and protein leakage into the alveolar space, were measured as markers of injury. We used liquid chromatography coupled to tandem mass spectrometry to unequivocally identify several eicosanoids in the bronchoalveolar lavage fluid of experimental animals. MK886, a specific inhibitor of the 5-lipoxygenase pathway, as well as transgenic mice deficient in 5-lipoxygenase, were used to determine the role of this enzymatic pathway in this model. Leukotriene B4 and leukotriene C4 were consistently elevated in shock-treated mice compared to sham-treated mice. MK886 attenuated neutrophil infiltration and protein extravasation induced by hemorrhagic shock. 5-lipoxygenase-deficient mice showed reduced neutrophil infiltration and protein extravasation after shock treatment, indicating greatly reduced lung injury. These results support the hypothesis that 5-lipoxygenase, most likely through the generation of leukotrienes, plays an important role in the pathogenesis of acute lung injury induced by hemorrhagic shock in mice. This pathway could represent a new target for pharmacological intervention to reduce lung damage following severe primary injury. PMID:22392149

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

    NARCIS (Netherlands)

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

    2014-01-01

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

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

    NARCIS (Netherlands)

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

    2014-01-01

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

  3. Development and Assessment of Countermeasure Formulations for Treatment of Lung Injury Induced by Chlorine Inhalation

    Science.gov (United States)

    Hoyle, Gary W.; Chen, Jing; Schlueter, Connie F.; Mo, Yiqun; Humphrey, David M.; Rawson, Greg; Niño, Joe A.; Carson, Kenneth H.

    2016-01-01

    Chlorine is a commonly used, reactive compound to which humans can be exposed via accidental or intentional release resulting in acute lung injury. Formulations of rolipram (a phosphodiesterase inhibitor), triptolide (a natural plant product with anti-inflammatory properties), and budesonide (a corticosteroid), either neat or in conjunction with poly(lactic:glycolic acid) (PLGA), were developed for treatment of chlorine-induced acute lung injury by intramuscular injection. Formulations were produced by spray-drying, which generated generally spherical microparticles that were suitable for intramuscular injection. Multiple parameters were varied to produce formulations with a wide range of in vitro release kinetics. Testing of selected formulations in chlorine-exposed mice demonstrated efficacy against key aspects of acute lung injury. The results show the feasibility of developing microencapsulated formulations that could be used to treat chlorine-induced acute lung injury by intramuscular injection, which represents a preferred route of administration in a mass casualty situation. PMID:26952014

  4. Nebulized anticoagulants for acute lung injury - a systematic review of preclinical and clinical investigations

    NARCIS (Netherlands)

    Tuinman, Pieter R.; Dixon, Barry; Levi, Marcel; Juffermans, Nicole P.; Schultz, Marcus J.

    2012-01-01

    Data from interventional trials of systemic anticoagulation for sepsis inconsistently suggest beneficial effects in case of acute lung injury (ALI). Severe systemic bleeding due to anticoagulation may have offset the possible positive effects. Nebulization of anticoagulants may allow for improved

  5. Monitoring of recruitment and derecruitment by electrical impedance tomography in a model of acute lung injury

    NARCIS (Netherlands)

    Kunst, P. W.; Vazquez de Anda, G.; Böhm, S. H.; Faes, T. J.; Lachmann, B.; Postmus, P. E.; de Vries, P. M.

    2000-01-01

    OBJECTIVE: To evaluate a noninvasive system for obtaining information about alveolar recruitment and derecruitment in a model of acute lung injury. DESIGN: Prospective experimental study. SETTING: Animal research laboratory. SUBJECTS: Nine anesthetized pigs. INTERVENTIONS: Electrical impedance

  6. Hypercapnic acidosis attenuates shock and lung injury in early and prolonged systemic sepsis.

    Science.gov (United States)

    Costello, Joseph; Higgins, Brendan; Contreras, Maya; Chonghaile, Martina Ni; Hassett, Patrick; O'Toole, Daniel; Laffey, John G

    2009-08-01

    To investigate whether acute hypercapnic acidosis--induced by adding CO2 to inspired gas--would protect against severe systemic sepsis-induced lung and systemic organ injury resulting from cecal ligation and puncture. Acute hypercapnic acidosis protects against lung injury after both nonseptic and early pneumonia-induced lung injury. In contrast, prolonged hypercapnia worsens pneumonia-induced lung injury. The effects of hypercapnia and acidosis in the setting of systemic sepsis remain to be determined. Prospective randomized animal study. University research laboratory. Adult male Sprague-Dawley rats. In the early systemic sepsis series, post induction of anesthesia and tracheostomy placement, animals were randomized to normocapnia (Fico2 = 0.00, n = 12) or hypercapnic acidosis (Fico2 = 0.05, n = 12). Cecal ligation and puncture were performed and the animals were ventilated for 3 hrs. In the prolonged systemic sepsis series, rats were anesthetized, cecal ligation and puncture were performed, and the animals were allowed to recover. The animals were then randomized to housing under conditions of environmental normocapnia (Fico2 = 0.00, n = 20) or hypercapnia (Fico2 = 0.08, n = 20). After 96 hrs, the animals were reanesthetized, and the severity of lung and hemodynamic injury was assessed. In early systemic sepsis, hypercapnic acidosis attenuated the development and severity of hypotension, and reduced lactate accumulation and the decrement in central venous oxyhemoglobin levels, compared with normocapnia. Hypercapnic acidosis reduced bronchoalveolar lavage neutrophil infiltration, and lung wet/dry weight ratios. In prolonged systemic sepsis, hypercapnic acidosis reduced histologic indices of lung injury. There was no evidence that hypercapnia worsened prolonged systemic sepsis-induced lung injury. Hypercapnic acidosis did not alter lung or systemic bacterial loads in early or prolonged systemic sepsis. Hypercapnic acidosis exerts beneficial effects in early and

  7. Xenon Treatment Protects against Remote Lung Injury after Kidney Transplantation in Rats.

    Science.gov (United States)

    Zhao, Hailin; Huang, Han; Ologunde, Rele; Lloyd, Dafydd G; Watts, Helena; Vizcaychipi, Marcela P; Lian, Qingquan; George, Andrew J T; Ma, Daqing

    2015-06-01

    Ischemia-reperfusion injury (IRI) of renal grafts may cause remote organ injury including lungs. The authors aimed to evaluate the protective effect of xenon exposure against remote lung injury due to renal graft IRI in a rat renal transplantation model. For in vitro studies, human lung epithelial cell A549 was challenged with H2O2, tumor necrosis factor-α, or conditioned medium from human kidney proximal tubular cells (HK-2) after hypothermia-hypoxia insults. For in vivo studies, the Lewis renal graft was stored in 4°C Soltran preserving solution for 24 h and transplanted into the Lewis recipient, and the lungs were harvested 24 h after grafting. Cultured lung cells or the recipient after engraftment was exposed to 70% Xe or N2. Phospho (p)-mammalian target of rapamycin (mTOR), hypoxia-inducible factor-1α (HIF-1α), Bcl-2, high-mobility group protein-1 (HMGB-1), TLR-4, and nuclear factor κB (NF-κB) expression, lung inflammation, and cell injuries were assessed. Recipients receiving ischemic renal grafts developed pulmonary injury. Xenon treatment enhanced HIF-1α, which attenuated HMGB-1 translocation and NF-κB activation in A549 cells with oxidative and inflammatory stress. Xenon treatment enhanced p-mTOR, HIF-1α, and Bcl-2 expression and, in turn, promoted cell proliferation in the lung. Upon grafting, HMGB-1 translocation from lung epithelial nuclei was reduced; the TLR-4/NF-κB pathway was suppressed by xenon treatment; and subsequent tissue injury score (nitrogen vs. xenon: 26 ± 1.8 vs. 10.7 ± 2.6; n = 6) was significantly reduced. Xenon treatment confers protection against distant lung injury triggered by renal graft IRI, which is likely through the activation of mTOR-HIF-1α pathway and suppression of the HMGB-1 translocation from nuclei to cytoplasm.

  8. APRV Mode in Ventilator Induced Lung Injury (VILI

    Directory of Open Access Journals (Sweden)

    Ata Mahmoodpoor

    2014-01-01

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

  9. Targeting Extracellular Histones with Novel RNA Bio drugs for the Treatment of Acute Lung Injury

    Science.gov (United States)

    2017-10-01

    AWARD NUMBER: W81XWH-16-1-0179 TITLE: Targeting Extracellular Histones with Novel RNA Bio- drugs for the Treatment of Acute Lung Injury...4. TITLE AND SUBTITLE Targeting Extracellular Histones with Novel RNA Bio- drugs for the Treatment of Acute Lung Injury 5a. CONTRACT NUMBER 5b...preclinical animal models and human clinical trials. Furthermore, as a drug to prevent the development of MODS/ARDS and ALI in high risk patients, these bio

  10. Mechanisms and Treatment of Deployment-Related Lung Injury: Repair of the Injured Epithelium

    Science.gov (United States)

    2017-10-01

    AWARD NUMBER: W81XWH-16-2-0018 TITLE: Mechanisms and Treatment of Deployment-Related Lung Injury: Repair of the Injured Epithelium PRINCIPAL...AND SUBTITLE Mechanisms and Treatment of Deployment-Related Lung Injury: Repair of the Injured Epithelium 5a. CONTRACT NUMBER 5b. GRANT NUMBER...initial experiments confirm our preliminary data that pretreatment with PM from Iraq or Afghanistan (5- 10 µg/cm2) significantly delay wound closure in

  11. Tanshinone IIA ameliorates seawater exposure-induced lung injury by inhibiting aquaporins (AQP) 1 and AQP5 expression in lung.

    Science.gov (United States)

    Li, Jiahuan; Xu, Min; Fan, Qixin; Xie, Xiaoyan; Zhang, Yong; Mu, Deguang; Zhao, Pengtao; Zhang, Bo; Cao, Fale; Wang, Yanxia; Jin, Faguang; Li, Zhichao

    2011-04-30

    Aquaporins (AQPs), a family of transmembrane water channels, mediate physiological response to changes of fluid volume and osmolarity. It is still unknown what role of AQPs plays in seawater drowning-induced acute lung injury (ALI) and whether pharmacologic modulation of AQPs could alleviate the severity of ALI caused by seawater aspiration. In our study, the results from RT-PCR and Western blotting showed that intratracheal installation of seawater up-regulated the mRNA and protein levels of AQP1 and AQP5 in lung tissues. Furthermore, we found that treatment of tanshinone IIA (TIIA, one of the main active components from Chinese herb Danshen) significantly reduced the elevation of AQP1 and AQP5 expression induced by seawater in rats, A549 cells and primary alveolar type II cells. Treatment of TIIA also improved lung histopathologic changes and blood-gas indices, and reduced lung edema and vascular leakage. These findings demonstrated that AQP1 and AQP5 might play an important role in the development of lung edema and lung injury, and that treatment with TIIA could significantly alleviate seawater exposure-induced ALI, which was probably through the inhibition of AQP1 and AQP5 over-expression in lungs. Copyright © 2011 Elsevier B.V. All rights reserved.

  12. Distribution of regional lung aeration and perfusion during conventional and noisy pressure support ventilation in experimental lung injury.

    Science.gov (United States)

    Carvalho, Alysson R; Spieth, Peter M; Güldner, Andreas; Cuevas, Maximilano; Carvalho, Nadja C; Beda, Alessandro; Spieth, Stephanie; Stroczynski, Christian; Wiedemann, Bärbel; Koch, Thea; Pelosi, Paolo; de Abreu, Marcelo Gama

    2011-04-01

    In acute lung injury (ALI), pressure support ventilation (PSV) may improve oxygenation compared with pressure-controlled ventilation (PCV), and benefit from random variation of pressure support (noisy PSV). We investigated the effects of PCV, PSV, and noisy PSV on gas exchange as well as the distribution of lung aeration and perfusion in 12 pigs with ALI induced by saline lung lavage in supine position. After injury, animals were mechanically ventilated with PCV, PSV, and noisy PSV for 1 h/mode in random sequence. The driving pressure was set to a mean tidal volume of 6 ml/kg and positive end-expiratory pressure to 8 cmH₂O in all modes. Functional variables were measured, and the distribution of lung aeration was determined by static and dynamic computed tomography (CT), whereas the distribution of pulmonary blood flow (PBF) was determined by intravenously administered fluorescent microspheres. PSV and noisy PSV improved oxygenation and reduced venous admixture compared with PCV. Mechanical ventilation with PSV and noisy PSV did not decrease nonaerated areas but led to a redistribution of PBF from dorsal to ventral lung regions and reduced tidal reaeration and hyperinflation compared with PCV. Noisy PSV further improved oxygenation and redistributed PBF from caudal to cranial lung regions compared with conventional PSV. We conclude that assisted ventilation with PSV and noisy PSV improves oxygenation compared with PCV through redistribution of PBF from dependent to nondependent zones without lung recruitment. Random variation of pressure support further redistributes PBF and improves oxygenation compared with conventional PSV.

  13. The effects of morin on lipopolysaccharide-induced acute lung injury by suppressing the lung NLRP3 inflammasome.

    Science.gov (United States)

    Tianzhu, Zhang; Shihai, Yang; Juan, Du

    2014-12-01

    In previous study, the anti-inflammatory effect of morin had been found. In this study, we investigated anti-inflammatory effects of morin on acute lung injury using lipopolysaccharide (LPS)-induced acute lung injury (ALI) mouse model. The cell counting in the bronchoalveolar lavage fluid (BALF) was measured. The animal lung edema degree was evaluated by wet/dry weight (W/D) ratio. The superoxidase dismutase (SOD) activity and myeloperoxidase (MPO) activity were assayed by SOD and MPO kits, respectively. The levels of inflammatory mediators including tumor necrosis factor-α (TNF-α), interleukin (IL)-1β, IL-18, and IL-6 were assayed by enzyme-linked immunosorbent assay method. Pathological changes of lung tissues were observed by hematoxylin and eosin (HE) staining. The protein level of lung NACHT, LRR, and PYD domains-containing protein 3 (NLRP3) inflammasome was measured by Western blotting. The data showed that treatment with the morin markedly attenuated inflammatory cell numbers in the BALF, decreased lung NLRP3 inflammasome protein level, and improved SOD activity and inhibited MPO activity. Histological studies demonstrated that morin substantially inhibited LPS-induced neutrophils in lung tissue compared with model group. The results indicated that the morin had a protective effect on LPS-induced ALI in mice.

  14. Lung injury after cigarette smoking is particle related

    Directory of Open Access Journals (Sweden)

    Rahul G Sangani

    2011-03-01

    Full Text Available Rahul G Sangani, Andrew J GhioEnvironmental Public Health Division, National Health and Environmental Effects Research Laboratory, US Environmental Protection Agency, Chapel Hill, NC, USAAbstract: 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.Keywords: particulate matter, smoking, oxidants, oxidative stress, air pollution

  15. Mild hypothermia reduces ventilator-induced lung injury, irrespective of reducing respiratory rate

    NARCIS (Netherlands)

    Aslami, Hamid; Kuipers, Maria T.; Beurskens, Charlotte J. P.; Roelofs, Joris J. T. H.; Schultz, Marcus J.; Juffermans, Nicole P.

    2012-01-01

    In the era of lung-protective mechanical ventilation using limited tidal volumes, higher respiratory rates are applied to maintain adequate minute volume ventilation. However, higher respiratory rates may contribute to ventilator-induced lung injury (VIII). Induced hypothermia reduces carbon dioxide

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

    NARCIS (Netherlands)

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

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

  17. Comparison of three rat strains for development of radiation-induced lung injury after hemithoracic irradiation

    NARCIS (Netherlands)

    van Eerde, MR; Kampinga, HH; Szabo, BG; Vujaskovic, Z

    The purpose of this study is to define differences in radiation sensitivity among rat strains using breathing frequency and lung perfusion as end points of radiation-induced lung injury. The results have confirmed previous findings in mice showing that-under stringently controlled iso-dose/volume

  18. Antenatal betamethasone attenuates intrauterine infection-aggravated hyperoxia-induced lung injury in neonatal rats.

    Science.gov (United States)

    Yoo, Hye Soo; Chang, Yun Sil; Kim, Jin Kyu; Ahn, So Yoon; Kim, Eun Sun; Sung, Dong Kyung; Jeon, Ga Won; Hwang, Jong Hee; Shim, Jae Won; Park, Won Soon

    2013-06-01

    Intrauterine infection can exacerbate postnatal hyperoxic lung injury. We hypothesized that antenatal betamethasone treatment attenuates hyperoxic lung injury aggravated by intrauterine infection in neonatal rats. Newborn Sprague-Dawley rats were divided into eight experimental groups according to (i) whether rats were exposed to normoxia (N) or hyperoxia (H, 85% oxygen) from postnatal day (P)1 to P14, (ii) whether antenatal betamethasone (0.2 mg/dose) or vehicle was administered to pregnant rats at gestation days (E)19 and E20, and (iii) whether intrauterine infection was induced or not antenatally. Intrauterine infection was induced by intracervical inoculation of Escherichia coli into pregnant rats on E19. We measured cytokine levels of tumor necrosis factor-α (TNF-α), interleukin (IL)-6, and IL-1β in P1 rat lungs and performed morphometric analyses and assessed inflammatory responses in lung tissue and bronchoalveolar lavage (BAL) at P14 by terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick end labeling (TUNEL) staining and measurement of myeloperoxidase activity, collagen, and cytokine levels. Cytokine levels in P1 rat lungs were increased by intrauterine infection, and these increases were attenuated by antenatal betamethasone. Hyperoxic lung injuries, indicated by morphometric changes and an inflammatory response in the lung and BAL fluid, were aggravated by intrauterine infection at P14. This aggravation was significantly attenuated by antenatal betamethasone. Antenatal betamethasone attenuated aggravated hyperoxic lung injuries induced by intrauterine infection in neonatal rats via its anti-inflammatory actions.

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

    NARCIS (Netherlands)

    Peters, A.L.

    2017-01-01

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

  20. Autophagy in pulmonary macrophages mediates lung inflammatory injury via NLRP3 inflammasome activation during mechanical ventilation.

    Science.gov (United States)

    Zhang, Yang; Liu, Gongjian; Dull, Randal O; Schwartz, David E; Hu, Guochang

    2014-07-15

    The inflammatory response is a primary mechanism in the pathogenesis of ventilator-induced lung injury. Autophagy is an essential, homeostatic process by which cells break down their own components. We explored the role of autophagy in the mechanisms of mechanical ventilation-induced lung inflammatory injury. Mice were subjected to low (7 ml/kg) or high (28 ml/kg) tidal volume ventilation for 2 h. Bone marrow-derived macrophages transfected with a scrambled or autophagy-related protein 5 small interfering RNA were administered to alveolar macrophage-depleted mice via a jugular venous cannula 30 min before the start of the ventilation protocol. In some experiments, mice were ventilated in the absence and presence of autophagy inhibitors 3-methyladenine (15 mg/kg ip) or trichostatin A (1 mg/kg ip). Mechanical ventilation with a high tidal volume caused rapid (within minutes) activation of autophagy in the lung. Conventional transmission electron microscopic examination of lung sections showed that mechanical ventilation-induced autophagy activation mainly occurred in lung macrophages. Autophagy activation in the lungs during mechanical ventilation was dramatically attenuated in alveolar macrophage-depleted mice. Selective silencing of autophagy-related protein 5 in lung macrophages abolished mechanical ventilation-induced nucleotide-binding oligomerization domain-like receptor containing pyrin domain 3 (NLRP3) inflammasome activation and lung inflammatory injury. Pharmacological inhibition of autophagy also significantly attenuated the inflammatory responses caused by lung hyperinflation. The activation of autophagy in macrophages mediates early lung inflammation during mechanical ventilation via NLRP3 inflammasome signaling. Inhibition of autophagy activation in lung macrophages may therefore provide a novel and promising strategy for the prevention and treatment of ventilator-induced lung injury. Copyright © 2014 the American Physiological Society.

  1. Effect of Thoracentesis on Intubated Patients with Acute Lung Injury.

    Science.gov (United States)

    Bloom, Matthew B; Serna-Gallegos, Derek; Ault, Mark; Khan, Ahsan; Chung, Rex; Ley, Eric J; Melo, Nicolas; Margulies, Daniel R

    2016-03-01

    Pleural effusions occur frequently in mechanically ventilated patients, but no consensus exists regarding the clinical benefit of effusion drainage. We sought to determine the impact of thoracentesis on gas exchange in patients with differing severities of acute lung injury (ALI). A retrospective analysis was conducted on therapeutic thoracenteses performed on intubated patients in an adult surgical intensive care unit of a tertiary center. Effusions judged by ultrasound to be 400 mL or larger were drained. Subjects were divided into groups based on their initial P:F ratios: normal >300, ALI 200 to 300, and acute respiratory distress syndrome (ARDS) gases, and ventilator settings before and after the intervention were analyzed. The primary end point was the change in measures of oxygenation. Significant improvements in P:F ratios (mean ± SD) were seen only in patients with ARDS (50.4 ± 38.5, P = 0.001) and ALI (90.6 ± 161.7, P = 0.022). Statistically significant improvement was observed in the pO2 (31.1, P = 0.005) and O2 saturation (4.1, P < 0.001) of the ARDS group. The volume of effusion removed did not correlate with changes in individual patient's oxygenation. These data support the role of therapeutic thoracentesis for intubated patients with abnormal P:F ratios.

  2. Protection against lung graft injury from brain-dead donors with carbon monoxide, biliverdin, or both.

    Science.gov (United States)

    Zhou, Huacheng; Qian, Hua; Liu, Jinfeng; Zhu, Daling; Ding, Wengang; Pan, Peng; Jin, Di; Wang, Juan; Li, Wenzhi

    2011-04-01

    The process of brain death can induce acute lung injury in donors and aggravate ischemia-reperfusion injury in grafts. Carbon monoxide (CO) and biliverdin (BV) have been shown to attenuate ischemia-reperfusion injury. We therefore examined if the administration of both CO and BV provide enhanced cytoprotection against lung graft injury from brain-dead (BD) rat donors. Brain death was induced in all donors, after which they were observed for 1.5 hours and then underwent lung transplantation. The recipients were ventilated with 40% oxygen (control group), ventilated with 250 ppm CO in 40% oxygen (CO group), treated with BV (35 mg/kg) intraperitoneally (BV group), or treated with CO and BV conjointly (COBV group) before transplantation (n = 8 each group). The recipients were sacrificed 2 hours after lung transplantation by exsanguination. Serum levels of interleukin (IL)-8 and tumor necrosis factor (TNF)-α were measured by enzyme-linked immunosorbent assay. CO and/or BV treatment attenuated partial pressure of arterial oxygen (Pao(2))/fraction of inspired oxygen (Fio(2)) aggravation in the recipients after reperfusion, reduced the wet weight/dry weight ratio, decreased the lung injury score, inhibited the activity of myeloperoxidase in grafts, and decreased serum levels of IL-8 and TNF-α compared with the control group (p < 0.05). The COBV group had significantly decreased malonaldehyde levels and increased superoxide dismutase levels in lung grafts compared with the CO group (p < 0.05). The static pressure-volume curve of the lungs was ameliorated in the CO group, BV group, and COBV group compared with the control group (p < 0.05). CO and BV exert protective effects through anti-inflammatory and anti-oxidant mechanisms, and dual treatment provided enhanced cytoprotection against lung graft injury from BD rat donors. Copyright © 2011 International Society for Heart and Lung Transplantation. Published by Elsevier Inc. All rights reserved.

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

    Science.gov (United States)

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

    2013-06-15

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

  4. Penetrating injury of the lungs and multiple injuries of lower extremities caused by aircraft bombs splinters

    Directory of Open Access Journals (Sweden)

    Golubović Zoran

    2010-01-01

    Full Text Available Introduction. Injuries caused by aircraft bombs cause severe damages to the human body. They are characterized by massive destruction of injured tissues and organs, primary contamination by polymorph bacterial flora and modified reactivity of the body. Upon being wounded by aircraft bombs projectiles a victim simultaneously sustains severe damages of many organs and organ systems due to the fact that a large number of projectiles at the same time injure the chest, stomach, head and extremities. Case report. We presented a patient, 41 years of age, injured by aircraft bomb with hemo-pneumothorax and destruction of the bone and soft tissue structures of the foot, as well as the treatment result of such heavy injuries. After receiving thoracocentesis and short reanimation, the patient underwent surgical procedure. The team performed thoracotomy, primary treatment of the wound and atypical resection of the left lung. Thoracic drains were placed. The wounds on the lower leg and feet were treated primarily. Due to massive destruction of bone tissue of the right foot by cluster bomb splinters, and impossibility of reconstruction of the foot, guillotine amputation of the right lower leg was performed. Twelve days after the wounding caused by cluster bomb splinters, soft tissue of the left lower leg was covered by Tirsch free transplantant and the defect in the area of the left foot was covered by dorsalis pedis flap. The transplant and flap were accepted and the donor sites were epithelized. Twenty-six days following the wounding reamputation was performed and amputation stump of the right lower leg was closed. The patient was given a lower leg prosthesis with which he could move. Conclusion. Upon being wounded by aircraft bomb splinters, the injured person sustains severe wounds of multiple organs and organ systems due to simultaneous injuries caused by a large number of projectiles. It is necessary to take care of the vital organs first because they

  5. Intravenous alpha-1 antitrypsin augmentation therapy for treating patients with alpha-1 antitrypsin deficiency and lung disease

    DEFF Research Database (Denmark)

    Gøtzsche, Peter C; Johansen, Helle Krogh

    2016-01-01

    BACKGROUND: Alpha-1 antitrypsin deficiency is an inherited disorder that can cause chronic obstructive pulmonary disease (COPD). People who smoke are more seriously affected and have a greater risk of dying from the disease. Therefore, the primary treatment is to help people give up smoking....... There are now also preparations available that contain alpha-1 antitrypsin, but it is uncertain what their clinical effect is. OBJECTIVES: To review the benefits and harms of augmentation therapy with intravenous alpha-1 antitrypsin in patients with alpha-1 antitrypsin deficiency and lung disease. SEARCH...... review authors independently selected trials, extracted outcome data and assessed the risk of bias. MAIN RESULTS: We included three trials (283 participants in the analyses) that ran for two to three years. All participants were ex- or never-smokers and had genetic variants that carried a high risk...

  6. Reproduction and evaluation of a rat model of inhalation lung injury caused by black gunpowder smog

    OpenAIRE

    Yi-fan LIU; Hong-wei TANG; Xiao-li WU; Yin-jing XIE; Hong-rui ZHANG; Jin-yan DUAN; Dai-jun XIANG; Xiao-mei LAN; Mian-yang LI; Cheng-bin WANG; Deng-qing LI

    2013-01-01

    Objective To reproduce and evaluate a rat model of inhalation lung injury caused by black gunpowder smog. Methods The smog composition was analyzed and a rat model of inhalation lung injury was reproduced. Forty two healthy male Wistar rats were randomly divided into normal control (NC) group and 1h, 2h, 6h, 24h, 48h and 96h after inhalation group (n=6). The arterial blood gas, wet to dry weight ratio (W/D) of lung, leukocyte count, and protein concentration in broncho-alveolar lavage fluid (...

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

    Science.gov (United States)

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

    2017-04-01

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

  8. Intravenous augmentation treatment and lung density in severe α1 antitrypsin deficiency (RAPID)

    DEFF Research Database (Denmark)

    Chapman, Kenneth R; Burdon, Jonathan G W; Piitulainen, Eeva

    2015-01-01

    transplantation, lobectomy, or lung volume-reduction surgery, or had selective IgA deficiency. We randomly assigned patients (1:1; done by Accovion) using a computerised pseudorandom number generator (block size of four) with centre stratification to receive A1PI intravenously 60 mg/kg per week or placebo for 24...... months, analysed by modified intention to treat (patients needed at least one evaluable lung density measurement). This study is registered with ClinicalTrials.gov, number NCT00261833. A 2-year open-label extension study was also completed (NCT00670007). FINDINGS: Between March 1, 2006, and Nov 3, 2010...

  9. The Epidemiology of Transfusion-related Acute Lung Injury Varies According to the Applied Definition of Lung Injury Onset Time.

    Science.gov (United States)

    Vande Vusse, Lisa K; Caldwell, Ellen; Tran, Edward; Hogl, Laurie; Dinwiddie, Steven; López, José A; Maier, Ronald V; Watkins, Timothy R

    2015-09-01

    Research that applies an unreliable definition for transfusion-related acute lung injury (TRALI) may draw false conclusions about its risk factors and biology. The effectiveness of preventive strategies may decrease as a consequence. However, the reliability of the consensus TRALI definition is unknown. To prospectively study the effect of applying two plausible definitions of acute respiratory distress syndrome onset time on TRALI epidemiology. We studied 316 adults admitted to the intensive care unit and transfused red blood cells within 24 hours of blunt trauma. We identified patients with acute respiratory distress syndrome, and defined acute respiratory distress syndrome onset time two ways: (1) the time at which the first radiographic or oxygenation criterion was met, and (2) the time both criteria were met. We categorized two corresponding groups of TRALI cases transfused in the 6 hours before acute respiratory distress syndrome onset. We used Cohen's kappa to measure agreement between the TRALI cases and implicated blood components identified by the two acute respiratory distress syndrome onset time definitions. In a nested case-control study, we examined potential risk factors for each group of TRALI cases, including demographics, injury severity, and characteristics of blood components transfused in the 6 hours before acute respiratory distress syndrome onset. Forty-two of 113 patients with acute respiratory distress syndrome were TRALI cases per the first acute respiratory distress syndrome onset time definition and 63 per the second definition. There was slight agreement between the two groups of TRALI cases (κ = 0.16; 95% confidence interval, -0.01 to 0.33) and between the implicated blood components (κ = 0.15, 95% confidence interval, 0.11-0.20). Age, Injury Severity Score, high plasma-volume components, and transfused plasma volume were risk factors for TRALI when applying the second acute respiratory distress syndrome onset time definition

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

    Science.gov (United States)

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

    2013-12-01

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

  11. Airway epithelium controls lung inflammation and injury through the NF-kappa B pathway.

    Science.gov (United States)

    Cheng, Dong-sheng; Han, Wei; Chen, Sabrina M; Sherrill, Taylor P; Chont, Melissa; Park, Gye-Young; Sheller, James R; Polosukhin, Vasiliy V; Christman, John W; Yull, Fiona E; Blackwell, Timothy S

    2007-05-15

    Although airway epithelial cells provide important barrier and host defense functions, a crucial role for these cells in development of acute lung inflammation and injury has not been elucidated. We investigated whether NF-kappaB pathway signaling in airway epithelium could decisively impact inflammatory phenotypes in the lungs by using a tetracycline-inducible system to achieve selective NF-kappaB activation or inhibition in vivo. In transgenic mice that express a constitutively active form of IkappaB kinase 2 under control of the epithelial-specific CC10 promoter, treatment with doxycycline induced NF-kappaB activation with consequent production of a variety of proinflammatory cytokines, high-protein pulmonary edema, and neutrophilic lung inflammation. Continued treatment with doxycycline caused progressive lung injury and hypoxemia with a high mortality rate. In contrast, inducible expression of a dominant inhibitor of NF-kappaB in airway epithelium prevented lung inflammation and injury resulting from expression of constitutively active form of IkappaB kinase 2 or Escherichia coli LPS delivered directly to the airways or systemically via an osmotic pump implanted in the peritoneal cavity. Our findings indicate that the NF-kappaB pathway in airway epithelial cells is critical for generation of lung inflammation and injury in response to local and systemic stimuli; therefore, targeting inflammatory pathways in airway epithelium could prove to be an effective therapeutic strategy for inflammatory lung diseases.

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

    Science.gov (United States)

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

    2016-02-01

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

  13. Bioinformatic approaches to augment study of epithelial-to-mesenchymal transition in lung cancer.

    Science.gov (United States)

    Beck, Tim N; Chikwem, Adaeze J; Solanki, Nehal R; Golemis, Erica A

    2014-10-01

    Bioinformatic approaches are intended to provide systems level insight into the complex biological processes that underlie serious diseases such as cancer. In this review we describe current bioinformatic resources, and illustrate how they have been used to study a clinically important example: epithelial-to-mesenchymal transition (EMT) in lung cancer. Lung cancer is the leading cause of cancer-related deaths and is often diagnosed at advanced stages, leading to limited therapeutic success. While EMT is essential during development and wound healing, pathological reactivation of this program by cancer cells contributes to metastasis and drug resistance, both major causes of death from lung cancer. Challenges of studying EMT include its transient nature, its molecular and phenotypic heterogeneity, and the complicated networks of rewired signaling cascades. Given the biology of lung cancer and the role of EMT, it is critical to better align the two in order to advance the impact of precision oncology. This task relies heavily on the application of bioinformatic resources. Besides summarizing recent work in this area, we use four EMT-associated genes, TGF-β (TGFB1), NEDD9/HEF1, β-catenin (CTNNB1) and E-cadherin (CDH1), as exemplars to demonstrate the current capacities and limitations of probing bioinformatic resources to inform hypothesis-driven studies with therapeutic goals. Copyright © 2014 the American Physiological Society.

  14. High-dose heparin fails to improve acute lung injury following smoke inhalation in sheep.

    Science.gov (United States)

    Murakami, Kazunori; Enkhbaatar, Perenlei; Shimoda, Katsumi; Mizutani, Akio; Cox, Robert A; Schmalstieg, Frank C; Jodoin, Jeffrey M; Hawkins, Hal K; Traber, Lillian D; Traber, Daniel L

    2003-04-01

    Thrombin is involved in various inflammatory responses. In sepsis, coagulation abnormalities are major complications. Acute lung injury is one of the most life-threatening problems that can result from sepsis. We hypothesized that high-dose heparin might be effective in attenuating acute lung injury in our sepsis model. Female sheep ( n =16) were surgically prepared for the study. After a tracheotomy, 48 breaths of cotton smoke (heparin infusion group ( n =6), a Ringer's lactate infusion group ( n =6), and a sham-injury group ( n =4; surgically prepared in the same fashion but receiving no inhalation injury or bacteria). The treatment was started 1 h after the insult, and was continued thereafter for 24 h. The dose of heparin was adjusted by monitoring to target an activated clotting time of between 300 and 400 s (baseline=approx. 150 s). Sheep exposed to lung injury presented with typical hyperdynamic cardiovascular changes, including an increased cardiac output and a fall in systemic vascular resistance. There was a decrease in the arterial partial pressure of O(2). In conclusion, high-dose heparin did not prevent lung dysfunction in this model, in which acute lung injury was induced by combined smoke and septic challenge.

  15. Heparin nebulization attenuates acute lung injury in sepsis following smoke inhalation in sheep.

    Science.gov (United States)

    Murakami, Kazunori; McGuire, Roy; Cox, Robert A; Jodoin, Jeffrey M; Bjertnaes, Lars J; Katahira, Jiro; Traber, Lillian D; Schmalstieg, Frank C; Hawkins, Hal K; Herndon, David N; Traber, Daniel L

    2002-09-01

    Pseudomonas pneumonia is a common complication of smoke inhalation injury. Airway casts formed from clotted mucous occur frequently in this condition. A recent report shows that intravenous heparin improves oxygenation and reduces lung damage in a sheep model of smoke inhalation. We hypothesized that nebulized heparin could be an effective means of reducing cast formation. Female sheep (n = 19) were surgically prepared for a study of acute lung injury (ALI). After a tracheotomy, 48 breaths of cotton smoke (heparin-nebulized group (n = 5; animals received aerosolized heparin [10,000 I.U.] 1 h after the bacterial instillation and subsequently every 4 h thereafter), an intravenous heparin group (n = 5,300 U/kg/23 h, infusion was started 1 h after the injury), a saline-nebulization group (n = 5; animals received inhaled nebulized saline), and a sham injury group (n = 4, treated in the same fashion, but no injury). The animals were sacrificed after 24 h of mechanical ventilation, and lung samples were harvested. Sheep exposed to lung injury presented with typical hyperdynamic cardiovascular changes and a corresponding drop in PaO2. These changes were significantly attenuated in the heparin groups. Histological changes consisting of cellular infiltrates, lung edema, congestion, and cast formation were reduced by heparin. These data suggest that nebulized inhaled heparin is a beneficial therapy for sepsis-induced ALI.

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

    Directory of Open Access Journals (Sweden)

    Kallapur Suhas G

    2009-12-01

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

  17. Effects of adiponectin on acute lung injury in cecal ligation and puncture-induced sepsis rats.

    Science.gov (United States)

    Xu, Li; Bao, Hong-Guang; Si, Yan-Na; Han, Liu; Zhang, Rui; Cai, Meng-Meng; Shen, Yan

    2013-08-01

    The purpose of this study was to elucidate the possible beneficial effects of adiponectin (APN) on acute lung injury in a rat model of sepsis. We subjected male Sprague-Dawley rats to cecal ligation and puncture (CLP) to establish sepsis models. We randomly animals divided into four groups: control (C), model (CLP), preemptive APN administration (APN plus CLP), and delayed APN administration (CLP plus APN). We killed the animals 24 h after CLP and collected blood samples to determine PaO2 and PaCO2. Lung samples were taken for histologic assessment and measurement of myeloperoxidase activity. We measured neutrophil and macrophage count and cytokine production (tumor necrosis factor-α and macrophage inflammatory protein-2) in bronchoalveolar lavage fluid. Histology findings and lung injury score analysis revealed acute lung injury in rats in the CLP group, whereas those in the APN-treated group had mild lung injury. The effects of sepsis on the increasing cell number in bronchoalveolar lavage fluid as well as the wet/dry weight ratio, neutrophil infiltration, and myeloperoxidase activity of lung tissue were significantly attenuated by APN administration. Adiponectin also significantly alleviated hypoxemia and hypercapnia resulting from the development of lung injury. In addition, in APN-treated rats, the levels of pulmonary inflammatory molecule (macrophage inflammatory protein-2) and cytokine (tumor necrosis factor-α) were down-regulated compared with the CLP group. Adiponectin administration ameliorates acute lung injury in a rat model of sepsis induced by CLP, no matter whether it is administrated before or after the onset of sepsis. Copyright © 2013. Published by Elsevier Inc.

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

    Directory of Open Access Journals (Sweden)

    Yung-Yang Liu

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

  19. Reproduction and evaluation of a rat model of inhalation lung injury caused by black gunpowder smog

    Directory of Open Access Journals (Sweden)

    Yi-fan LIU

    2013-09-01

    Full Text Available Objective To reproduce and evaluate a rat model of inhalation lung injury caused by black gunpowder smog. Methods The smog composition was analyzed and a rat model of inhalation lung injury was reproduced. Forty two healthy male Wistar rats were randomly divided into normal control (NC group and 1h, 2h, 6h, 24h, 48h and 96h after inhalation group (n=6. The arterial blood gas, wet to dry weight ratio (W/D of lung, leukocyte count, and protein concentration in broncho-alveolar lavage fluid (BALF were determined. Macroscopic and microscopic changes in lung tissue were observed. Results The composition of black gunpowder smog was composed mainly of CO2 and CO, and their concentrations remained stable within 12 minutes. Smog inhalation caused a significant hypoxemia, the concentration of blood COHb reached a peak value 1h, and the W/D of lung reached peak value 2h after inhalation (P<0.05. The amount of leukocytes and content of protein in BALF increased significantly within 24h after inhalation (P<0.05. Histopathological observation showed diffuse hemorrhage, edema and inflammatory cell infiltration in lung tissue as manifestations of acute lung injury, and the injury did not recover at 96h after inhalation. Conclusion The rat model of inhalation lung injury can be reproduced using black gunpowder smog, and it has the advantages of its readiness for reproduction, reliability and stability, and it could be used for the experiment of inhalation injury in a battlefield environment.

  20. Role of NLRP3 inflammasomes in lung injury induced by gut hypoxic stress and its mechanism

    Directory of Open Access Journals (Sweden)

    Shi-qiang XIONG

    2015-01-01

    Full Text Available Hypoxic stress of the gut may induce impairment of gut barrier function, ensuing translocation of gutderived factors which can damage the function of remote organs, especially the development of acute lung injury (ALI. High altitude pulmonary edema (HAPE is a non-cardiogenic pulmonary injury caused by hypoxia, while inflammation involved in the pathogenesis of HAPE has been gradually recognized. It has been also recognized that the cleavage and maturation of proinflammatory cytokines mediated by NLRP3 inflammasome play a crucial role in the pathogenesis of lung injury. Further investigation on the role of NLRP3 inflammasome in lung injury induced by gut hypoxic stress is of an important clinical significance for further improvement in the treatment of hypoxic inflammatory diseases. DOI: 10.11855/j.issn.0577-7402.2014.11.14

  1. Pseudomonas aeruginosa colonization enhances ventilator-associated pneumonia-induced lung injury.

    Science.gov (United States)

    Tsay, Tzyy-Bin; Jiang, Yu-Zhen; Hsu, Ching-Mei; Chen, Lee-Wei

    2016-08-09

    Pseudomonas aeruginosa (PA) is the single-most common pathogen of ventilator-associated pneumonia (VAP). Large quantities of PA in the trachea of ventilated patients are associated with an increased risk of death. However, the role of PA colonization in PA VAP-induced lung injury remains elusive. This study examined the effect and mechanism of PA colonization in VAP-induced lung injury. C57BL/6 wild-type (WT) and c-Jun N-terminal kinase knockout (JNK1(-/-)) mice received mechanical ventilation for 3 h at 2 days after receiving nasal instillation of PA (1 × 10(6) colony forming unit) or normal saline. Intranasal instillation of PA or mechanical ventilation induced the expression of interleukin-6 (IL-6) in the lungs. Phospho-JNK protein expression in the lungs was significantly increased in mice receiving mechanical ventilation after PA instillation as compared with those receiving ventilation alone. Mechanical ventilation after PA instillation significantly increased the expression of tumor necrosis factor-α (TNF-α), IL-1β, and macrophage inflammatory protein-2 (MIP-2) proteins; neutrophil sequestration; and TNF-α, IL-1β, and IL-6 levels in the lungs of WT mice, but not in JNK1(-/-) mice. PA colonization plays an important role in PA VAP-induced lung injury through the induction of JNK1-mediated inflammation. PA-induced VAP causes lung injury through JNK signaling pathway in the lungs. JNK inhibition in ICU patients with higher percentages of PA colonization may reduce VAP-induced lung injury and mortality.

  2. Ischemia-reperfusion injury in the isolated rat lung. Role of flow and endogenous leukocytes.

    Science.gov (United States)

    Seibert, A F; Haynes, J; Taylor, A

    1993-02-01

    Microvascular lung injury caused by ischemia-reperfusion (IR) may occur via leukocyte-dependent and leukocyte-independent pathways. Leukocyte-endothelial adhesion may be a rate-limiting step in IR lung injury. Leukocyte adhesion to microvascular endothelium occurs when the attractant forces between leukocyte and endothelium are greater than the kinetic energy of the leukocyte and the vascular wall shear rate. We hypothesized (1) that isolated, buffer-perfused rat lungs are not free of endogenous leukocytes, (2) that endogenous leukocytes contribute to IR-induced microvascular injury as measured by the capillary filtration coefficient (Kfc), and (3) that a reduction of perfusate flow rate would potentiate leukocyte-dependent IR injury. Sixty lungs were divided into four groups: (1) low-flow controls, (2) high-flow controls, (3) low-flow IR, and (4) high-flow IR. Microvascular injury was linearly related to baseline perfusate leukocyte concentrations at both low (r = 0.78) and high (r = 0.82) flow rates. Kfc in the high-flow IR group (0.58 +/- 0.03 ml/min/cm H2O/100 g) was less (p Kfc in the low-flow IR group (0.82 +/- 0.07), and in both groups Kfc values were significantly greater than low-flow (0.34 +/- 0.03) and high-flow (0.31 +/- 0.01) control Kfc values after 75 min. Retention of leukocytes in the lung, evaluated by a tissue myeloperoxidase assay, was greatest in the low-flow IR group. We conclude (1) that isolated, buffer-perfused rat lungs contain significant quantities of leukocytes and that these leukocytes contribute to IR lung injury, and (2) that IR-induced microvascular injury is potentiated by low flow.

  3. Mitigation of chlorine gas lung injury in rats by postexposure administration of sodium nitrite.

    Science.gov (United States)

    Yadav, Amit K; Doran, Stephen F; Samal, Andrey A; Sharma, Ruchita; Vedagiri, Kokilavani; Postlethwait, Edward M; Squadrito, Giuseppe L; Fanucchi, Michelle V; Roberts, L Jackson; Patel, Rakesh P; Matalon, Sadis

    2011-03-01

    Nitrite (NO(2)(-)) has been shown to limit injury to the heart, liver, and kidneys in various models of ischemia-reperfusion injury. Potential protective effects of systemic NO(2)(-) in limiting lung injury or enhancing repair have not been documented. We assessed the efficacy and mechanisms by which postexposure intraperitoneal injections of NO(2)(-) mitigate chlorine (Cl(2))-induced lung injury in rats. Rats were exposed to Cl(2) (400 ppm) for 30 min and returned to room air. NO(2)(-) (1 mg/kg) or saline was administered intraperitoneally at 10 min and 2, 4, and 6 h after exposure. Rats were killed at 6 or 24 h. Injury to airway and alveolar epithelia was assessed by quantitative morphology, protein concentrations, number of cells in bronchoalveolar lavage (BAL), and wet-to-dry lung weight ratio. Lipid peroxidation was assessed by measurement of lung F(2)-isoprostanes. Rats developed severe, but transient, hypoxemia. A significant increase of protein concentration, neutrophil numbers, airway epithelia in the BAL, and lung wet-to-dry weight ratio was evident at 6 h after Cl(2) exposure. Quantitative morphology revealed extensive lung injury in the upper airways. Airway epithelial cells stained positive for terminal deoxynucleotidyl-mediated dUTP nick end labeling (TUNEL), but not caspase-3. Administration of NO(2)(-) resulted in lower BAL protein levels, significant reduction in the intensity of the TUNEL-positive cells, and normal lung wet-to-dry weight ratios. F(2)-isoprostane levels increased at 6 and 24 h after Cl(2) exposure in NO(2)(-)- and saline-injected rats. This is the first demonstration that systemic NO(2)(-) administration mitigates airway and epithelial injury.

  4. Ventilation-induced lung injury is not exacerbated by growth restriction in preterm lambs.

    Science.gov (United States)

    Allison, Beth J; Hooper, Stuart B; Coia, Elise; Zahra, Valerie A; Jenkin, Graham; Malhotra, Atul; Sehgal, Arvind; Kluckow, Martin; Gill, Andrew W; Sozo, Foula; Miller, Suzanne L; Polglase, Graeme R

    2016-02-01

    Intrauterine growth restriction (IUGR) and preterm birth are frequent comorbidities and, combined, increase the risk of adverse respiratory outcomes compared with that in appropriately grown (AG) infants. Potential underlying reasons for this increased respiratory morbidity in IUGR infants compared with AG infants include altered fetal lung development, fetal lung inflammation, increased respiratory requirements, and/or increased ventilation-induced lung injury. IUGR was surgically induced in preterm fetal sheep (0.7 gestation) by ligation of a single umbilical artery. Four weeks later, preterm lambs were euthanized at delivery or delivered and ventilated for 2 h before euthanasia. Ventilator requirements, lung inflammation, early markers of lung injury, and morphological changes in lung parenchymal and vascular structure and surfactant composition were analyzed. IUGR preterm lambs weighed 30% less than AG preterm lambs, with increased brain-to-body weight ratio, indicating brain sparing. IUGR did not induce lung inflammation or injury or alter lung parenchymal and vascular structure compared with AG fetuses. IUGR and AG lambs had similar oxygenation and respiratory requirements after birth and had significant, but similar, increases in proinflammatory cytokine expression, lung injury markers, gene expression, and surfactant phosphatidylcholine species compared with unventilated controls. IUGR does not induce pulmonary structural changes in our model. Furthermore, IUGR and AG preterm lambs have similar ventilator requirements in the immediate postnatal period. This study suggests that increased morbidity and mortality in IUGR infants is not due to altered lung tissue or vascular structure, or to an altered response to early ventilation. Copyright © 2016 the American Physiological Society.

  5. CORM-2 inhibits TXNIP/NLRP3 inflammasome pathway in LPS-induced acute lung injury.

    Science.gov (United States)

    Jiang, Lei; Fei, Dongsheng; Gong, Rui; Yang, Wei; Yu, Wei; Pan, Shangha; Zhao, Mingran; Zhao, Mingyan

    2016-11-01

    Accumulated studies suggest that exogenously administered carbon monoxide is beneficial for the resolution of acute lung inflammation. The present study aimed to examine the effects and the underlying mechanisms of CORM-2 on thioredoxin-interacting protein (TXNIP)/NLRP3 inflammasome pathway in lipopolysaccharide (LPS)-induced acute lung injury (ALI). ALI was intratracheally induced by LPS in C57BL6 mice. CORM-2 or iCORM-2 (30mg/kg i.p.) was administered immediately before LPS instillation. 6 h later, lung bronchoalveolar lavage (BAL) fluids were acquired for IL-18, IL-1β, and cell measurement, and lung issues were collected for histologic examination, wet/dry weight ratio, and determination of TXNIP/NLRP3 inflammasome expression, NLRP3 inflammasome and NF-ΚB activity, and reactive oxygen species (ROS) production. LPS triggered significant lung edema, lung injury, and leukocyte infiltration, and elevated the levels of IL-1β and IL-18 in lung BAL fluids. CORM-2 pretreatment resulted in a marked amelioration of lung injury and reduced IL-1β and IL-18 secretion in BAL fluids. In lung tissues; CORM-2 down-regulated mRNA and protein level of TXNIP, NLRP3, ASC, and caspase-1. Furthermore, CORM-2 reduced ROS production, inhibited NLRP3 inflammasome and NF-κB activity, and interaction of TXNIP-NLRP3. However, no significant differences were detected between the LPS and iCORM-2 (an inactive variant of CORM-2) group. CORM-2 suppresses TXNIP/NLRP3 inflammasome pathway and protects against LPS-induced lung injury.

  6. Lung stress, strain, and energy load: engineering concepts to understand the mechanism of ventilator-induced lung injury (VILI).

    Science.gov (United States)

    Nieman, Gary F; Satalin, Joshua; Andrews, Penny; Habashi, Nader M; Gatto, Louis A

    2016-12-01

    It was recently shown that acute respiratory distress syndrome (ARDS) mortality has not been reduced in over 15 years and remains ~40 %, even with protective low tidal volume (LVt) ventilation. Thus, there is a critical need to develop novel ventilation strategies that will protect the lung and reduce ARDS mortality. Protti et al. have begun to analyze the impact of mechanical ventilation on lung tissue using engineering methods in normal pigs ventilated for 54 h. They used these methods to assess the impact of a mechanical breath on dynamic and static global lung strain and energy load. Strain is the change in lung volume in response to an applied stress (i.e., Tidal Volume-Vt). This study has yielded a number of exciting new concepts including the following: (1) Individual mechanical breath parameters (e.g., Vt or Plateau Pressure) are not directly correlated with VILI but rather any combination of parameters that subject the lung to excessive dynamic strain and energy/power load will cause VILI; (2) all strain is not equal; dynamic strain resulting in a dynamic energy load (i.e., kinetic energy) is more damaging to lung tissue than static strain and energy load (i.e., potential energy); and (3) a critical consideration is not just the size of the Vt but the size of the lung that is being ventilated by this Vt. This key concept merits attention since our current protective ventilation strategies are fixated on the priority of keeping the Vt low. If the lung is fully inflated, a large Vt is not necessarily injurious. In conclusion, using engineering concepts to analyze the impact of the mechanical breath on the lung is a novel new approach to investigate VILI mechanisms and to help design the optimally protective breath. Data generated using these methods have challenged some of the current dogma surrounding the mechanisms of VILI and of the components in the mechanical breath necessary for lung protection.

  7. High tacrolimus blood concentrations early after lung transplantation and the risk of kidney injury.

    Science.gov (United States)

    Sikma, M A; Hunault, C C; van de Graaf, E A; Verhaar, M C; Kesecioglu, J; de Lange, D W; Meulenbelt, J

    2017-05-01

    Lung transplant recipients often develop acute kidney injury (AKI) evolving into chronic kidney disease (CKD). The immunosuppressant tacrolimus might be associated with the emergence of AKI. We analyzed the development and recovery of kidney injury after lung transplantation and related AKI to whole-blood tacrolimus trough concentrations and other factors causing kidney injury. We retrospectively studied kidney injury in 186 lung-transplantation patients at the UMC Utrecht between 2001 and 2011. Kidney function and whole-blood tacrolimus trough concentrations were determined from day 1 to 14 and at 1, 3, 6, and 12 months postoperative. Systemic inflammatory response syndrome (SIRS), septic shock, and nephrotoxic medications were evaluated as covariates for AKI. We analyzed liver injury and drug-drug interactions. AKI was present in 85 (46%) patients. Tacrolimus concentrations were supra-therapeutic in 135 of 186 patients (73%). AKI in the first week after transplantation was related to supra-therapeutic tacrolimus concentrations (OR 1.55; 95% CI 1.06-2.27), ≥3 other nephrotoxic drugs (OR 1.96; 95% CI 1.02-3.77), infection (OR 2.48; 95% CI 1.31-4.70), and cystic fibrosis (OR 2.17; 95% CI 1.16-4.06). Recovery rate of AKI was lower than expected (19%), and the cumulative incidence of severe CKD at 1 year was 15%. After lung transplantation, AKI is common and often evolves into severe CKD, which is a known cause of morbidity and mortality. Supra-therapeutic whole-blood tacrolimus trough concentrations are related to the early onset of AKI. Conscientious targeting tacrolimus blood concentrations might be vital in the early phase after lung transplantation. What is known about this subject? • Lung transplant recipients often develop acute kidney injury evolving into chronic kidney disease increasing both morbidity and mortality. • To date, the pathophysiology of kidney injury after lung transplantation has not been fully elucidated. • The immunosuppressant

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

    Science.gov (United States)

    Kosaka, Junko; Morimatsu, Hiroshi; Takahashi, Toru; Shimizu, Hiroko; Kawanishi, Susumu; Omori, Emiko; Endo, Yasumasa; Tamaki, Naofumi; Morita, Manabu; Morita, Kiyoshi

    2013-01-01

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

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

    Directory of Open Access Journals (Sweden)

    Junko Kosaka

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

  10. Nebulized anticoagulants for acute lung injury - a systematic review of preclinical and clinical investigations.

    Science.gov (United States)

    Tuinman, Pieter R; Dixon, Barry; Levi, Marcel; Juffermans, Nicole P; Schultz, Marcus J

    2012-12-12

    Data from interventional trials of systemic anticoagulation for sepsis inconsistently suggest beneficial effects in case of acute lung injury (ALI). Severe systemic bleeding due to anticoagulation may have offset the possible positive effects. Nebulization of anticoagulants may allow for improved local biological availability and as such may improve efficacy in the lungs and lower the risk of systemic bleeding complications. We performed a systematic review of preclinical studies and clinical trials investigating the efficacy and safety of nebulized anticoagulants in the setting of lung injury in animals and ALI in humans. The efficacy of nebulized activated protein C, antithrombin, heparin and danaparoid has been tested in diverse animal models of direct (for example, pneumonia-, intra-pulmonary lipopolysaccharide (LPS)-, and smoke inhalation-induced lung injury) and indirect lung injury (for example, intravenous LPS- and trauma-induced lung injury). Nebulized anticoagulants were found to have the potential to attenuate pulmonary coagulopathy and frequently also inflammation. Notably, nebulized danaparoid and heparin but not activated protein C and antithrombin, were found to have an effect on systemic coagulation. Clinical trials of nebulized anticoagulants are very limited. Nebulized heparin was found to improve survival of patients with smoke inhalation-induced ALI. In a trial of critically ill patients who needed mechanical ventilation for longer than two days, nebulized heparin was associated with a higher number of ventilator-free days. In line with results from preclinical studies, nebulization of heparin was found to have an effect on systemic coagulation, but without causing systemic bleedings. Local anticoagulant therapy through nebulization of anticoagulants attenuates pulmonary coagulopathy and frequently also inflammation in preclinical studies of lung injury. Recent human trials suggest nebulized heparin for ALI to be beneficial and safe, but data

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

    Directory of Open Access Journals (Sweden)

    Masahiro Hashizume

    2014-08-01

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

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

    Science.gov (United States)

    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.

  13. Calcium dobesilate ameliorates lung injury following lower limb ischemia/reperfusion.

    Science.gov (United States)

    Bozkurt, A K; Konukoğlu, D; Ustündağ, N; Yüceyar, L; Mayda, A S

    2002-01-01

    We examined the effects of calcium dobesilate on ameliorating the lung damage following ischemia-reperfusion injury in skeletal muscle of rats. A well known antioxidant, dimethyl sulfoxide, was also tested for comparison. The study included three groups: normal saline, dimethyl sulfoxide and calcium dobesilate. Plasma bicarbonate, creatine kinase, lactate dehydrogenase, thiobarbituric acid reactive substances (TBARS), as well as muscle and lung tissue TBARS levels were measured. Lung tissue samples were taken for histological examination. The dimethyl sulfoxide group showed significant amelioration of plasma (p = 0.004), skeletal muscle (p = 0.006) and lung TBARS (p = 0.004) levels, compared with controls. Calcium dobesilate-treated rats showed significantly low level muscle (p = 0.025) and lung TBARS (p = 0.004), compared with the control group. The extent of lung injury according to the histological findings was less in the dimethyl sulfoxide (p = 0.004) and calcium dobesilate (p = 0.003) groups. These observations indicated that calcium dobesilate acted effectively in the prevention of lung damage following ischemia-reperfusion injury in the rat skeletal muscle.

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

    Directory of Open Access Journals (Sweden)

    Inoue Takehiro

    2010-04-01

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

  15. Detection of lung injury with conventional and neural network-based analysis of continuous data.

    Science.gov (United States)

    Räsänen, J; León, M A

    1998-08-01

    To test if analysis of pressure and flow waveform patterns with an artificial intelligence neural network could distinguish between normal and injured lungs. Acute lung injury was induced in ten healthy anesthetized, mechanically ventilated dogs with repeated injections of oleic acid, until arterial blood oxyhemoglobin saturation reached 85% breathing room air. Airway pressure, esophageal pressure, airway flow, and arterial and mixed venous saturation signals were stored at 2 min intervals. Hemodynamic and blood gas data were collected every 10 min. Back-propagation neural networks were trained with normalized airway pressure and flow waveforms from normal and fully injured lungs. The networks scored lung injury on a continuous scale from +1 (normal) to -1 (injured). Network scores unequivocally distinguished between normal and fully injured lungs and suggested a gradual transition from normal to injury pattern. However, the response of the network was slow compared to compliance, resistance and venous admixture. Normal and fully injured lungs display distinct flow and pressure waveform patterns which are independent of changes in calculated pulmonary mechanics variables. These patterns can be recognized by a neural network. Further research is needed to determine the full potential of automated pattern recognition for lung monitoring.

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

    Directory of Open Access Journals (Sweden)

    REYHANEH SEPEHR

    2013-07-01

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

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

    Energy Technology Data Exchange (ETDEWEB)

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

    2014-01-01

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

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

    Directory of Open Access Journals (Sweden)

    Xun Liang

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

  19. Cell Therapy Augments Functional Recovery Subsequent to Spinal Cord Injury under Experimental Conditions

    Directory of Open Access Journals (Sweden)

    Vikram Sabapathy

    2015-01-01

    Full Text Available The spinal cord injury leads to enervation of normal tissue homeostasis ultimately leading to paralysis. Until now there is no proper cure for the treatment of spinal cord injury. Recently, cell therapy in animal spinal cord injury models has shown some progress of recovery. At present, clinical trials are under progress to evaluate the efficacy of cell transplantation for the treatment of spinal cord injury. Different types of cells such as pluripotent stem cells derived neural cells, mesenchymal stromal cells, neural stem cells, glial cells are being tested in various spinal cord injury models. In this review we highlight both the advances and lacuna in the field of spinal cord injury by discussing epidemiology, pathophysiology, molecular mechanism, and various cell therapy strategies employed in preclinical and clinical injury models and finally we discuss the limitations and ethical issues involved in cell therapy approach for treating spinal cord injury.

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

    Directory of Open Access Journals (Sweden)

    Guo Li

    2015-01-01

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

  1. Cell Therapy Augments Functional Recovery Subsequent to Spinal Cord Injury under Experimental Conditions

    OpenAIRE

    Vikram Sabapathy; George Tharion; Sanjay Kumar

    2015-01-01

    The spinal cord injury leads to enervation of normal tissue homeostasis ultimately leading to paralysis. Until now there is no proper cure for the treatment of spinal cord injury. Recently, cell therapy in animal spinal cord injury models has shown some progress of recovery. At present, clinical trials are under progress to evaluate the efficacy of cell transplantation for the treatment of spinal cord injury. Different types of cells such as pluripotent stem cells derived neural cells, mesenc...

  2. Differing patterns of P-selectin expression in lung injury

    DEFF Research Database (Denmark)

    Bless, N M; Tojo, S J; Kawarai, H

    1998-01-01

    -selectin. In the immune complex model, upregulation of P-selectin was defined by Northern and Western blot analysis of lung homogenates, by immunostaining of lung tissue, and by vascular fixation of 125I-labeled anti-P-selectin. P-selectin protein was detected by 1 hour (long before detection of mRNA) and expression...

  3. Losartan attenuated lipopolysaccharide-induced lung injury by suppression of lectin-like oxidized low-density lipoprotein receptor-1.

    Science.gov (United States)

    Deng, Wang; Deng, Yue; Deng, Jia; Wang, Dao-Xin; Zhang, Ting

    2015-01-01

    Recent study has shown that renin-angiotensin system plays an important role in the development of acute lung injury (ALI) with high level of angiotensin II (AngII) generated form AngI catalyzed by angiotensin-converting enzyme. AngII plays a major effect mainly through AT1 receptor. Therefore, we speculate inhibition of AT1 receptor may possibly attenuate the lung injury. Losartan, an antagonist of AT1 receptor for angiotensin II, attenuated lung injury by alleviation of the inflammation response in ALI, but the mechanism of losartan in ALI still remains unclear. Thirty male Sprague-Dawley rats were randomly divided into Control group, ALI group (LPS), and Losartan group (LPS + Losartan). Bronchoalveolar lavage fluid (BALF) and lung tissue were obtained for analysis. The expressions of lectin-like oxidized low-density lipoprotein receptor-1 (LOX-1), intercellular adhesion molecule-1 (ICAM-1) and caspase-3 were detected by reverse transcriptase polymerase chain reaction (RT-PCR) and western blotting. In ALI group, TNF-α and protein level in BALF, MPO activity in lung tissue, pulmonary edema and lung injury were significantly increased. Losartan significantly reduced LPS-induced increase in TNF-α and protein level in BALF, MPO activity, pulmonary edema and lung injury in LPS-induced lung injury. The mRNA and protein expression levels of LOX-1 were significantly decreased with the administration of losartan in LPS-induced lung injury. Also, losartan blocked the protein levels of caspase-3 and ICAM-1 mediated by LOX-1 in LPS-induced lung injury. Losartan attenuated lung injury by alleviation of the inflammation and cell apoptosis by inhibition of LOX-1 in LPS-induced lung injury.

  4. Protective agents used as additives in University of Wisconsin solution to promote protection against ischaemia-reperfusion injury in rat lung.

    Science.gov (United States)

    Chiang, C H; Wu, K; Yu, C P; Perng, W C; Yan, H C; Wu, C P; Chang, D M; Hsu, K

    1998-09-01

    protection in our ischaemia-reperfusion lung injury model. UW modified with an additive of PGE1, Dex or Bt2-cAMP attenuated ischaemia-reperfusion injury. Furthermore, UW containing two of these protective agents augmented the protection. Among the modified solutions, it appears that UW+PGE1+Bt2-cAMP protects the lungs to a greater extent than all other solutions used in our study. We suggest that preservation solutions containing PGE1-Bt2-cAMP will provide additional protective effects to organs stored for transplantation.

  5. Influence of nebulized unfractionated heparin and N-acetylcysteine in acute lung injury after smoke inhalation injury.

    Science.gov (United States)

    Miller, Andrew C; Rivero, Abel; Ziad, Sophia; Smith, David J; Elamin, Elamin M

    2009-01-01

    To determine whether the combination of aerosolized unfractionated heparin and N-acetylcystine reduces 28-days mortality and lung injury scores (LISs) in adult patients with smoke inhalation injury requiring mechanical ventilation. The study was a single-center retrospective study with historical control. The authors included 30 mechanically ventilated adult subjects who were admitted within 48 hours of their bronchoscopy confirmed smoke inhalation injury over a 5-year period. The experimental group was treated with nebulized heparin sulfate, N-acetylcystine, and albuterol sulfate. Controls received ventilation support and albuterol sulfate. The authors calculated acute physiology and chronic health evaluation (APACHE)-III scores on admission in addition to daily LIS for 7 days. The experimental group was divided into five APACHE-III subgroups and matched with inhalation lung injury patients in the historical control group. There was no significant difference in initial APACHE-III scores or LISs between groups (alpha = 0.05) upon entry to the study. The experimental group showed significant improvement in LISs, respiratory resistance and compliance measurements, and hypoxia scores as compared with controls throughout the duration of the study. There was a statistically significant survival benefit in the experimental group that was most pronounced in patients with APACHE-III scores >35. Survival for the control vs experimental group was 0.5714 +/- 0.1497 vs 0.9375 +/- 0.0605, respectively, (risk ratio -0.0055; 95% confidence interval -0.0314-0.0204; hazard ratio 1.003; number needed to treat 2.7). The use of aerosolized unfractionated heparin and N-acetylcystine attenuates lung injury and the progression of acute respiratory distress syndrome in ventilated adult patients with acute lung injury following smoke inhalation.

  6. NLRP3 deletion protects from hyperoxia-induced acute lung injury.

    Science.gov (United States)

    Fukumoto, Jutaro; Fukumoto, Itsuko; Parthasarathy, Prasanna Tamarapu; Cox, Ruan; Huynh, Bao; Ramanathan, Gurukumar Kollongod; Venugopal, Rajan Babu; Allen-Gipson, Diane S; Lockey, Richard F; Kolliputi, Narasaiah

    2013-07-15

    Inspiration of a high concentration of oxygen, a therapy for acute lung injury (ALI), could unexpectedly lead to reactive oxygen species (ROS) production and hyperoxia-induced acute lung injury (HALI). Nucleotide-binding domain and leucine-rich repeat PYD-containing protein 3 (NLRP3) senses the ROS, triggering inflammasome activation and interleukin-1β (IL-1β) production and secretion. However, the role of NLRP3 inflammasome in HALI is unclear. The main aim of this study is to determine the effect of NLRP3 gene deletion on inflammatory response and lung epithelial cell death. Wild-type (WT) and NLRP3(-/-) mice were exposed to 100% O2 for 48-72 h. Bronchoalveolar lavage fluid and lung tissues were examined for proinflammatory cytokine production and lung inflammation. Hyperoxia-induced lung pathological score was suppressed in NLRP3(-/-) mice compared with WT mice. Hyperoxia-induced recruitment of inflammatory cells and elevation of IL-1β, TNFα, macrophage inflammatory protein-2, and monocyte chemoattractant protein-1 were attenuated in NLRP3(-/-) mice. NLRP3 deletion decreased lung epithelial cell death and caspase-3 levels and a suppressed NF-κB levels compared with WT controls. Taken together, this research demonstrates for the first time that NLRP3-deficient mice have suppressed inflammatory response and blunted lung epithelial cell apoptosis to HALI.

  7. TGFβ signaling in lung epithelium regulates bleomycin-induced alveolar injury and fibroblast recruitment.

    Science.gov (United States)

    Degryse, Amber L; Tanjore, Harikrishna; Xu, Xiaochuan C; Polosukhin, Vasiliy V; Jones, Brittany R; Boomershine, Chad S; Ortiz, Camila; Sherrill, Taylor P; McMahon, Frank B; Gleaves, Linda A; Blackwell, Timothy S; Lawson, William E

    2011-06-01

    The response of alveolar epithelial cells (AECs) to lung injury plays a central role in the pathogenesis of pulmonary fibrosis, but the mechanisms by which AECs regulate fibrotic processes are not well defined. We aimed to elucidate how transforming growth factor-β (TGFβ) signaling in lung epithelium impacts lung fibrosis in the intratracheal bleomycin model. Mice with selective deficiency of TGFβ receptor 2 (TGFβR2) in lung epithelium were generated and crossed to cell fate reporter mice that express β-galactosidase (β-gal) in cells of lung epithelial lineage. Mice were given intratracheal bleomycin (0.08 U), and the following parameters were assessed: AEC death by terminal deoxynucleotidyl transferase dUTP-mediated nick-end labeling assay, inflammation by total and differential cell counts from bronchoalveolar lavage, fibrosis by scoring of trichrome-stained lung sections, and total lung collagen content. Mice with lung epithelial deficiency of TGFβR2 had improved AEC survival, despite greater lung inflammation, after bleomycin administration. At 3 wk after bleomycin administration, mice with epithelial TGFβR2 deficiency showed a significantly attenuated fibrotic response in the lungs, as determined by semiquantitatve scoring and total collagen content. The reduction in lung fibrosis in these mice was associated with a marked decrease in the lung fibroblast population, both total lung fibroblasts and epithelial-to-mesenchymal transition-derived (S100A4(+)/β-gal(+)) fibroblasts. Attenuation of TGFβ signaling in lung epithelium provides protection from bleomycin-induced fibrosis, indicating a critical role for the epithelium in transducing the profibrotic effects of this cytokine.

  8. Multislice spiral computed tomography to determine the effects of a recruitment maneuver in experimental lung injury

    Energy Technology Data Exchange (ETDEWEB)

    Henzler, Dietrich; Rossaint, Rolf [University Hospital, RWTH Aachen, Anesthesiology Department, Aachen (Germany); Mahnken, Andreas H.; Wildberger, Joachim E.; Guenther, Rolf W. [University Hospital of the RWTH Aachen, Clinic of Diagnostic Radiology, Aachen (Germany); Kuhlen, Ralf [University Hospital of the RWTH Aachen, Operative Intensive Care Department, Aachen (Germany)

    2006-06-15

    Although recruitment of atelectatic lung is a common aim in acute respiratory distress syndrome (ARDS), the effects of a recruitment maneuver have not been assessed quantitatively. By multislice spiral CT (MSCT), we analyzed the changes in lung volumes calculated from the changes in the CT values of hyperinflated (V{sub HYP}), normally (V{sub NORM}), poorly (V{sub POOR}) and nonaerated (V{sub NON}) lung in eight mechanically ventilated pigs with saline lavage-induced acute lung injury before and after a recruitment maneuver. This was compared to single slice analysis near the diaphragm. The increase in aerated lung was mainly for V{sub POOR} and the less in V{sub NORM}. Total lung volume and intrathoracic gas increased. No differences were found for tidal volumes measured by spirometry or determined by CT. The inspiratory-expiratory volume differences were not different after the recruitment maneuver in V{sub NON} (from 62{+-}18 ml to 43{+-}26 ml, P=0.114), and in V{sub NORM} (from 216{+-}51 ml to 251{+-}37 ml, P=0.102). Single slice analysis significantly underestimated the increase in normally and poorly aerated lung. Quantitative analysis of lung volumes by whole lung MSCT revealed the increase of poorly aerated lung as the main mechanism of a standard recruitment maneuver. MSCT can provide additional information as compared to single slice CT. (orig.)

  9. Acute lung injury after inhalation of water-proofing spray while smoking a cigarette.

    Science.gov (United States)

    Jinn, Y; Akizuki, N; Ohkouchi, M; Inase, N; Ichioka, M; Marumo, F

    1998-01-01

    A 34-year-old Japanese woman developed acute lung injury soon after inhaling a water-proofing spray which she applied onto her ski suit while smoking a cigarette at the same time. She initially demonstrated arterial hypoxemia (PaO2 = 59 mm Hg) and ground-glass opacities in both lung fields on the CT scan, which both returned to normal without any medication. Several water-proofing sprays, which are easily obtainable in Japan, contain 1,1,1-trichloroethane, liquefied petroleum gas and fluoride resin. Although these components have not been reported to be toxic to the lung yet, high concentrations of these components and/or the pyrolytic products of fluoride resin may have caused acute lung injury in this case.

  10. Mitigation of Lung Injury after Accidental Exposure to Radiation

    Science.gov (United States)

    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

  11. Targeting myeloid-derived suppressor cells augments antitumor activity against lung cancer

    Directory of Open Access Journals (Sweden)

    Srivastava MK

    2012-10-01

    Full Text Available Minu K Srivastava,1,2 Li Zhu,1,2 Marni Harris-White,2 Min Huang,1–3 Maie St John,1,3 Jay M Lee,1,3 Ravi Salgia,4 Robert B Cameron,1,3,5 Robert Strieter,6 Steven Dubinett,1–3 Sherven Sharma1–31Department of Medicine, UCLA Lung Cancer Research Program, David Geffen School of Medicine at UCLA, Los Angeles, CA, 2Molecular Gene Medicine Laboratory, Veterans Affairs Greater Los Angeles Healthcare System, Los Angeles, CA, 3Jonsson Comprehensive Cancer Center, David Geffen School of Medicine at UCLA, Los Angeles, CA, 4Department of Medicine, University of Chicago, Chicago, IL, 5Department of Surgery, Veterans Affairs Greater Los Angeles Healthcare System, Los Angeles, CA, 6Department of Medicine, University of Virginia, Charlottesville, VA, USAAbstract: Lung cancer evades host immune surveillance by dysregulating inflammation. Tumors and their surrounding stromata produce growth factors, cytokines, and chemokines that recruit, expand, and/or activate myeloid-derived suppressor cells (MDSCs. MDSCs regulate immune responses and are frequently found in malignancy. In this review the authors discuss tumor-MDSC interactions that suppress host antitumor activities and the authors' recent findings regarding MDSC depletion that led to improved therapeutic vaccination responses against lung cancer. Despite the identification of a repertoire of tumor antigens, hurdles persist for immune-based anticancer therapies. It is likely that combined therapies that address the multiple immune deficits in cancer patients will be required for effective therapy. MDSCs play a major role in the suppression of T-cell activation and they sustain tumor growth, proliferation, and metastases. Regulation of MDSC recruitment, differentiation or expansion, and inhibition of the MDSC suppressive function with pharmacologic agents will be useful in the control of cancer growth and progression. Pharmacologic agents that regulate MDSCs may be more effective when combined with

  12. Translational toxicological research: investigating and preventing acute lung injury in organophosphorus insecticide poisoning.

    Science.gov (United States)

    Hulse, Elspeth J; Clutton, R E; Drummond, G; Eddleston, M

    2014-06-01

    Poisoning through ingestion of organophosphorus (OP) insecticide is a leading cause of suicide globally. Severe poisoning with OP compounds creates an unconscious, paralysed patient with respiratory failure. These symptoms make pulmonary aspiration of stomach contents highly likely, potentially causing an acute lung injury. To explore this hypothesis, we created a Gottingen minipig pulmonary aspiration model (n=26) to investigate the mechanism and severity of lung injury created through pulmonary instillation of 0.5 mL/kg mixtures of porcine gastric juice (GJ), OP and/or its solvent. Early results show that aspiration of OP and GJ causes pulmonary neutrophil sequestration, alveolar haemorrhage and interstitial oedema, with disruption of the alveolar-capillary membrane. Further measurements will include quantitative CT imaging, histopathology scoring, acute lung injury biomarkers and respiratory function. In order to test the validity of the minipig model, a pilot study in Sri Lanka has been devised to observe signs of lung injury in human patients who have ingested OP insecticide with or without clinical evidence of pulmonary aspiration. Lung injury will be assessed with PaO2/FIO2 ratios and physiological dead space measurement. Blood, bronchoalveolar lavage and urine will be taken at 24 and 48 h after poisoning and at 3-4 h in surgical control patients to measure acute lung injury biomarkers. An unpublished toxicology study from Sri Lanka, 2011-2012, showed that over 40% of unconscious poisoned patients with a GCS poisoned patients. We hypothesise that non-drug assisted placement of supraglottic airways may be a good tool for use in unconscious poisoned patients requiring transfer from small rural hospitals in Asia. They could confer better airway protection than no airway intervention and reduce both morbidity and mortality. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.

  13. Nebulised heparin: a new approach to the treatment of acute lung injury?

    OpenAIRE

    Suter, Peter M

    2008-01-01

    The administration of heparin by nebulisation has been proposed for the 'local' treatment of pulmonary coagulation disturbances in acute lung injury (ALI). Alveolar and lung micro-vascular fibrin accumulation and breakdown inhibition indeed play a central role in the development and clinical course of this disease. Preclinical studies provide some evidence of the beneficial effects of heparin inhalation in several animal models of ALI. Clinical investigations are sparse, and trials such as th...

  14. Nebulized anticoagulants for acute lung injury - a systematic review of preclinical and clinical investigations

    OpenAIRE

    Tuinman, Pieter R; Dixon, Barry; Levi, Marcel; Juffermans, Nicole P; Schultz, Marcus J

    2012-01-01

    Background Data from interventional trials of systemic anticoagulation for sepsis inconsistently suggest beneficial effects in case of acute lung injury (ALI). Severe systemic bleeding due to anticoagulation may have offset the possible positive effects. Nebulization of anticoagulants may allow for improved local biological availability and as such may improve efficacy in the lungs and lower the risk of systemic bleeding complications. Method We performed a systematic review of preclinical st...

  15. FIRST REPORT OF TRANSFUSION-RELATED ACUTE LUNG INJURY (TRALI)IN SLOVENIA

    OpenAIRE

    Vesna Galvani; Slavica Maver; Gordana Soldatović; Irena Kramar

    2008-01-01

    BACKGROUND Transfusion-related acute lung injury (TRALI) is a major cause of lethal side effects associated with transfusion of blood and blood components. TRALI is defined as a new acutenoncardiogenic pulmonary oedema as seen on the frontal radiography of lungs, manifested with the shortness of breath, hypoxemia, hypotension and fever, all occurring duringor within 6 h after transfusion.TRALI is rarely diagnosed and can be confused with other causes of acute respiratoryfailure. It occurs ...

  16. Isoproterenol reduces ischemia-reperfusion lung injury despite beta-blockade.

    Science.gov (United States)

    Takashima, Seiki; Schlidt, Scott A; Koukoulis, Giovanna; Sevala, Mayura; Egan, Thomas M

    2005-06-01

    If lungs could be retrieved from non-heart-beating donors (NHBDs), the shortage of lungs for transplantation could be alleviated. The use of lungs from NHBDs is associated with a mandatory warm ischemic interval, which results in ischemia-reperfusion injury upon reperfusion. In an earlier study, rat lungs retrieved 2-h postmortem from NHBDs had reduced capillary leak measured by filtration coefficient (Kfc) when reperfused with isoproterenol (iso), associated with an increase in lung tissue levels of cyclic AMP (cAMP). The objective was to determine if this decrease in Kfc was because of beta-stimulation, or would persist despite beta-blockade. Donor rats were treated intraperitoneally with beta-blockade (propranolol or pindolol) or carrier, sacrificed, and lungs were retrieved immediately or 2 h postmortem. The lungs were reperfused with or without iso and the beta-blockers in the reperfusate. Outcome measures were Kfc, wet:dry weight ratio (W/D), lung levels of adenine nucleotides and cAMP. Lungs retrieved immediately after death had normal Kfc and W/D. After 2 h of ischemia, Kfc and W/D were markedly elevated in controls (no drug) and lungs reperfused with beta-blockers alone. Isoproterenol-reperfusion decreased Kfc and W/D significantly (P < 0.01) even in the presence of beta-blockade. Lung cAMP levels were increased only with iso in the absence of beta-blockade. The attenuation of ischemia-reperfusion injury because of iso occurs even in the presence of beta-blockade, and may not be a result of beta-stimulated increased cAMP.

  17. Parecoxib reduces systemic inflammation and acute lung injury in burned animals with delayed fluid resuscitation.

    Science.gov (United States)

    Chong, Si Jack; Wong, Yong Chiat; Wu, Jian; Tan, Mui Hong; Lu, Jia; Moochhala, Shabbir M

    2014-01-01

    Burn injuries result in the release of proinflammatory mediators causing both local and systemic inflammation. Multiple organ dysfunctions secondary to systemic inflammation after severe burn contribute to adverse outcome, with the lungs being the first organ to fail. In this study, we evaluate the anti-inflammatory effects of Parecoxib, a parenteral COX-2 inhibitor, in a delayed fluid resuscitation burned rat model. Anaesthetized Sprague Dawley rats were inflicted with 45% total body surface area full-thickness scald burns and subsequently subjected to delayed resuscitation with Hartmann's solution. Parecoxib (0.1, 1.0, and 10 mg/kg) was delivered intramuscularly 20 min after injury followed by 12 h interval and the rats were sacrificed at 6 h, 24 h, and 48 h. Burn rats developed elevated blood cytokines, transaminase, creatinine, and increased lung MPO levels. Animals treated with 1 mg/kg Parecoxib showed significantly reduced plasma level of CINC-1, IL-6, PGEM, and lung MPO. Treatment of 1 mg/kg Parecoxib is shown to mitigate systemic and lung inflammation without significantly affecting other organs. At present, no specific therapeutic agent is available to attenuate the systemic inflammatory response secondary to burn injury. The results suggest that Parecoxib may have the potential to be used both as an analgesic and ameliorate the effects of lung injury following burn.

  18. NLRP3 deletion protects from hyperoxia-induced acute lung injury

    OpenAIRE

    Fukumoto, Jutaro; Fukumoto, Itsuko; Parthasarathy, Prasanna Tamarapu; Cox, Ruan; Huynh, Bao; Ramanathan, Gurukumar Kollongod; Venugopal, Rajan Babu; Allen-Gipson, Diane S.; Lockey, Richard F.; Kolliputi, Narasaiah

    2013-01-01

    Inspiration of a high concentration of oxygen, a therapy for acute lung injury (ALI), could unexpectedly lead to reactive oxygen species (ROS) production and hyperoxia-induced acute lung injury (HALI). Nucleotide-binding domain and leucine-rich repeat PYD-containing protein 3 (NLRP3) senses the ROS, triggering inflammasome activation and interleukin-1β (IL-1β) production and secretion. However, the role of NLRP3 inflammasome in HALI is unclear. The main aim of this study is to determine the e...

  19. Preventive effects of valnemulin on lipopolysaccharide-induced acute lung injury in mice.

    Science.gov (United States)

    Chen, Zhibao; Zhang, Xuemei; Chu, Xiao; Zhang, Xiaozhe; Song, Keji; Jiang, Youshuai; Yu, Lu; Deng, Xuming

    2010-10-01

    Valnemulin reportedly regulates inflammatory responses in addition to its in vitro antibacterial activity. In this study, we established a mouse model of lipopolysaccharide (LPS)-induced inflammatory lung injury and investigated the effect of valnemulin (100 mg/kg) on acute lung injury (ALI) 8 h after LPS challenge. We prepared bronchoalveolar lavage fluid (BALF) for measuring protein concentrations, cytokine levels, and superoxidase dismutase (SOD) activity, and collected lungs for assaying wet-to-dry weight (W/D) ratios, myeloperoxidase (MPO) activity, cytokine mRNA expression, and histological change. We found that the pre-administration of valnemulin significantly decreases the W/D ratio of lungs, protein concentrations, and the number of total cells, neutrophils, macrophages, and leukomonocytes, and histologic analysis indicates that valnemulin significantly attenuates tissue injury. Furthermore, valnemulin significantly increases LPS-induced SOD activity in BALF and decreases lung MPO activity as well. In addition, valnemulin also inhibits the production of tumor necrosis factor-alpha, interleukin-6, and interleukin-1beta, which is consistent with mRNA expression in lung. The results showed that valnemulin had a protective effect on LPS-induced ALI in mice.

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

    Directory of Open Access Journals (Sweden)

    Crimi Nunzio

    2006-11-01

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

  1. Oxidative lung injury correlates with one-lung ventilation time during pulmonary lobectomy: a study of exhaled breath condensate and blood.

    Science.gov (United States)

    García-de-la-Asunción, José; García-del-Olmo, Eva; Perez-Griera, Jaume; Martí, Francisco; Galan, Genaro; Morcillo, Alfonso; Wins, Richard; Guijarro, Ricardo; Arnau, Antonio; Sarriá, Benjamín; García-Raimundo, Miguel; Belda, Javier

    2015-09-01

    During lung lobectomy, the operated lung is collapsed and hypoperfused; oxygen deprivation is accompanied by reactive hypoxic pulmonary vasoconstriction. After lung lobectomy, ischaemia present in the collapsed state is followed by expansion-reperfusion and lung injury attributed to the production of reactive oxygen species. The primary objective of this study was to investigate the time course of several markers of oxidative stress simultaneously in exhaled breath condensate and blood and to determine the relationship between oxidative stress and one-lung ventilation time in patients undergoing lung lobectomy. This single-centre, observational, prospective study included 28 patients with non-small-cell lung cancer who underwent lung lobectomy. We measured the levels of hydrogen peroxide, 8-iso-PGF2α, nitrites plus nitrates and pH in exhaled breath condensate (n = 25). The levels of 8-iso-PGF2α and nitrites plus nitrates were also measured in blood (n = 28). Blood samples and exhaled breath condensate samples were collected from all patients at five time points: preoperatively; during one-lung ventilation, immediately before resuming two-lung ventilation; immediately after resuming two-lung ventilation; 60 min after resuming two-lung ventilation and 180 min after resuming two-lung ventilation. Both exhaled breath condensate and blood exhibited significant and simultaneous increases in oxidative-stress markers immediately before two-lung ventilation was resumed. However, all these values underwent larger increases immediately after resuming two-lung ventilation. In both exhaled breath condensate and blood, marker levels significantly and directly correlated with the duration of one-lung ventilation immediately before resuming two-lung ventilation and immediately after resuming two-lung ventilation. Although pH significantly decreased in exhaled breath condensate immediately after resuming two-lung ventilation, these pH values were inversely correlated with the

  2. Transfusion of 35-Day Stored RBCs in the Presence of Endotoxemia Does Not Result in Lung Injury in Humans

    NARCIS (Netherlands)

    Peters, Anna L.; van Hezel, Maike E.; Cortjens, Bart; Tuip-de Boer, Anita M.; van Bruggen, Robin; de Korte, Dirk; Jonkers, René E.; Bonta, Peter I.; Zeerleder, Sacha S.; Lutter, Rene; Juffermans, Nicole P.; Vlaar, Alexander P. J.

    2016-01-01

    Transfusion-related acute lung injury is the leading cause of transfusion-related mortality. Preclinical studies have shown that aged RBCs can induce transfusion-related acute lung injury in the presence of a "first hit" (e.g., sepsis). Clinical studies, however, show conflicting results on this

  3. Time-courses of lung function and respiratory muscle pressure generating capacity after spinal cord injury: A prospective cohort study.

    NARCIS (Netherlands)

    Mueller, G.; de Groot, S.; van der Woude, L.H.V.; Hopman, M.T.

    2008-01-01

    Objective: To investigate the time-courses of lung function and respiratory muscle pressure generating capacity after spinal cord injury. Design: Multi-centre, prospective cohort study. Subjects: One hundred and nine subjects with recent, motor complete spinal cord injury. Methods: Lung function and

  4. Time-courses of lung function and respiratory muscle pressure generating capacity after spinal cord injury : a prospective cohort study

    NARCIS (Netherlands)

    Mueller, Gabi; de Groot, Sonja; van der Woude, Lucas; Hopman, Maria T E

    OBJECTIVE: To investigate the time-courses of lung function and respiratory muscle pressure generating capacity after spinal cord injury. DESIGN: Multi-centre, prospective cohort study. SUBJECTS: One hundred and nine subjects with recent, motor complete spinal cord injury. METHODS: Lung function and

  5. Time-courses of lung function and respiratory muscle pressure generating capacity after spinal cord injury: a prospective cohort study.

    NARCIS (Netherlands)

    Mueller, G.; Groot, S de; Woude, L van der; Hopman, M.T.E.

    2008-01-01

    OBJECTIVE: To investigate the time-courses of lung function and respiratory muscle pressure generating capacity after spinal cord injury. DESIGN: Multi-centre, prospective cohort study. SUBJECTS: One hundred and nine subjects with recent, motor complete spinal cord injury. METHODS: Lung function and

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

    Directory of Open Access Journals (Sweden)

    Diego C Reino

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

  7. Fluorometry of ischemia reperfusion injury in rat lungs in vivo

    Science.gov (United States)

    Sepehr, R.; Staniszewski, K.; Jacobs, E. R.; Audi, S.; Ranji, Mahsa

    2013-02-01

    Previously we demonstrated the utility of optical fluorometry to evaluate lung tissue mitochondrial redox state in isolated perfused rats lungs under various chemically-induced respiratory states. The objective of this study was to evaluate the effect of acute ischemia on lung tissue mitochondrial redox state in vivo using optical fluorometry. Under ischemic conditions, insufficient oxygen supply to the mitochondrial chain should reduce the mitochondrial redox state calculated from the ratio of the auto-fluorescent mitochondrial metabolic coenzymes NADH (Nicotinamide Adenine Dinucleotide) and FAD (Flavoprotein Adenine Dinucleotide). The chest of anesthetized, and mechanically ventilated Sprague-Dawley rat was opened to induce acute ischemia by clamping the left hilum to block both blood flow and ventilation to one lung for approximately 10 minutes. NADH and FAD fluorescent signals were recorded continuously in a dark room via a fluorometer probe placed on the pleural surface of the left lung. Acute ischemia caused a decrease in FAD and an increase in NADH, which resulted in an increase in the mitochondrial redox ratio (RR=NADH/FAD). Restoration of blood flow and ventilation by unclamping the left hilum returned the RR back to its baseline. These results (increase in RR under ischemia) show promise for the fluorometer to be used in a clinical setting for evaluating the effect of pulmonary ischemia-reperfusion on lung tissue mitochondrial redox state in real time.

  8. A Direct Comparison Between Norepinephrine and Phenylephrine for Augmenting Spinal Cord Perfusion in a Porcine Model of Spinal Cord Injury.

    Science.gov (United States)

    Streijger, Femke; So, Kitty; Manouchehri, Neda; Gheorghe, Ana; Okon, Elena B; Chan, Ryan M; Ng, Benjamin; Shortt, Katelyn; Sekhon, Mypinder Singh; Griesdale, Donald E; Kwon, Brian K

    2018-01-16

    Current clinical guidelines recommend elevating the mean arterial blood pressure (MAP) to increase spinal cord perfusion in patients with acute spinal cord injury (SCI). This is typically achieved with vasopressors such as norepinephrine (NE) and phenylephrine (PE). These drugs differ in their pharmacologic properties and potentially have different effects on spinal cord blood flow (SCBF), oxygenation (PO2), and downstream metabolism after injury. Using a porcine model of thoracic SCI, we evaluated how these vasopressors influenced intraparenchymal SCBF, PaPO2, hydrostatic pressure, and metabolism within the spinal cord adjacent to the injury site. Yorkshire pigs underwent a contusion/compression SCI at T10 and were randomized to receive either NE or PE for MAP elevation of 20 mm Hg, or no MAP augmentation. Prior to injury, a combined SCBF/PO2 sensor, a pressure sensor, and a microdialysis probe were inserted into the spinal cord adjacent to T10 at two locations: a 'proximal' site and 'distal' site, 2 mm and 22 mm from the spinal cord injury, respectively. At the proximal site, NE and PE resulted in little improvement in SCBF during cord compression. Following decompression, NE resulted in increased SCBF and PO2, while decreased levels were observed for PE. However, both NE and PE were associated with a gradual decrease in the L/P ratio after decompression. PE was associated with greater hemorrhage through the injury site than control animals. Combined, our results suggest that NE promotes better restoration of blood flow and oxygenation than PE in the traumatically injured spinal cord, thus providing a physiologic rationale for selecting NE over PE in the hemodynamic management of acute SCI.

  9. [Losartan regulates oxidative stress via caveolin-1 and NOX4 in mice with ventilator- induced lung injury].

    Science.gov (United States)

    Ling, Xuguang; Lou, Anni; Li, Yang; Yang, Renqiang; Ning, Zuowei; Li, Xu

    2015-12-01

    To investigate the effect of losartan in regulating oxidative stress and the underlying mechanism in mice with ventilator-induced lung injury. Thirty-six male C57 mice were randomly divided into control group, losartan treatment group, mechanical ventilation model group, and ventilation plus losartan treatment group. After the corresponding treatments, the lung injuries in each group were examined and the expressions of caveolin-1 and NOX4 in the lung tissues were detected. The mean Smith score of lung injury was significantly higher in mechanical ventilation model group (3.3) than in the control group (0.4), and losartan treatment group (0.3); the mean score was significantly lowered in ventilation plus losartan treatment group (2.3) compared with that in the model group (Plosartan treatment groups (Plosartan treatment (Plosartan treatment. Losartan can alleviate ventilator-induced lung injury in mice and inhibit the expression of caveolin-1 and NOX4 and their interaction in the lungs.

  10. Protective effects of an aptamer inhibitor of neutrophil elastase in lung inflammatory injury

    DEFF Research Database (Denmark)

    Bless, N M; Smith, D; Charlton, J

    1997-01-01

    (SLPI) [8-10]. A disturbed balance between neutrophil elastase and these inhibitors has been found in various acute clinical conditions (such as adult respiratory syndrome and ischemia-reperfusion injury) and in chronic diseases. We investigated the effect of NX21909, a selected oligonucleotide (aptamer...... show that NX21909 inhibits lung injury and neutrophil influx in a dose-dependent manner, the first demonstration of efficacy by an aptamer in an animal disease model....

  11. Lung ischemia reperfusion injury: the therapeutic role of dipeptidyl peptidase 4 inhibition

    OpenAIRE

    Beckers, Paul A. J.; Gielis, Jan F.; Van Schil, Paul E.; Adriaensen, Dirk

    2017-01-01

    Dipeptidyl peptidase 4 (DPP4) is a cell surface protease that has been reported to play a role in glucose homeostasis, cancer, HIV, autoimmunity, immunology and inflammation. A role for DPP4 in ischemia-reperfusion injury (IRI) in the heart has been established. Dipeptidyl peptidase 4 inhibition (DPP4i) appeared to decrease infarct size, improves cardiac function and promotes myocardial regeneration. Lung ischemia reperfusion injury is caused by a complex mechanism in which macrophages and ne...

  12. Lung function in patients with lung injury due to household chemical inhalation: Post hoc analysis of a prospective nationwide cohort.

    Science.gov (United States)

    Kim, Won-Young; Park, Soonyoung; Kim, Hwa Jung; Chae, Eun Jin; Do, Kyung-Hyun; Huh, Jin Won; Lim, Chae-Man; Koh, Younsuck; Hong, Sang-Bum

    2017-02-01

    Inhalation exposure to household chemicals can result in serious health problems, although the long-term outcomes are unclear. We evaluated the changes in lung function after home humidifier disinfectant (HD) exposure. This post hoc analysis of a prospective nationwide cohort involved patients with inhalation lung injury due to HD. Patients underwent spirometric measurements at onset and annually thereafter. Forty subjects met the eligibility criteria. Overall, mean forced vital capacity (FVC) increased significantly during the first 3 years from 2.10 ± 0.74 to 3.06 ± 1.08 L. Mean forced expiratory volume in 1 s (FEV 1 ) also rose from 1.84 ± 0.63 to 2.62 ± 0.88 L. Both variables then stabilized. However, in 19 (48%) patients, the FVCs did not normalize. Compared to subjects with an FVC at onset of lung function within several years of onset. However, lung function was impaired in the remaining patients. This impairment associated with lung function at onset and exposure intensity. © 2016 Asian Pacific Society of Respirology.

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

    Science.gov (United States)

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

    2010-04-05

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

  14. Apneic oxygenation combined with extracorporeal arteriovenous carbon dioxide removal provides sufficient gas exchange in experimental lung injury

    DEFF Research Database (Denmark)

    Nielsen, Niels Dalsgaard; Kjærgaard, Benedict; Koefoed-Nielsen, Jacob

    2008-01-01

    We hypothesized that apneic oxygenation, using an open lung approach, combined with extracorporeal CO2 removal, would provide adequate gas exchange in acute lung injury. We tested this hypothesis in nine anesthetized and mechanically ventilated pigs (85-95 kg), in which surfactant was depleted from....../min. Thus, the method provided adequate gas exchange in this experimental model, suggesting that it might have potential as an alternative treatment modality in acute lung injury....

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

    Science.gov (United States)

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

    2015-08-01

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

  16. Resolution of pulmonary edema with variable mechanical ventilation in a porcine model of acute lung injury.

    Science.gov (United States)

    Graham, M Ruth; Gulati, Harleena; Kha, Lan; Girling, Linda G; Goertzen, Andrew; Mutch, W Alan C

    2011-08-01

    Resolution of the acute respiratory distress syndrome (ARDS) requires clearance of pulmonary edema. Biologically variable ventilation (BVV) strategies that improve gas exchange, lung mechanics, and inflammatory mediators in ARDS may be beneficial in this regard. We used quantitative computed tomography (CT), a single indicator thermodilution system (PiCCO®) to determine extravascular lung water (EVLW), and the change in edema protein concentration over time to compare edema clearance with BVV vs conventional mechanical ventilation (CMV) in a porcine ARDS model. Sixteen pigs with oleic acid lung injury were randomized to four hours of ventilation with either CMV (n = 8) or BVV (n = 8) at identical low tidal volume and minute ventilation over time. Hemodynamic variables, gas exchange, lung mechanics, and PiCCO derived EVLW were determined hourly. Computed tomography images and edema fluid samples were obtained at baseline lung injury and after four hours of ventilation. Wet and dry lung weights were determined postmortem. At four hours with BVV, peak airway pressure was decreased significantly and lung compliance improved compared with CMV (P = 0.003; P lung weight and global lung density (P = 0.005; P = 0.04 respectively) with BVV. These findings were associated with a significant increase in the gas volume of normally aerated lung regions (P lung regions (P = 0.001). No change in any CT parameter occurred with CMV. The lung weights derived from computed tomography correlated well with postmortem wet weights (R(2) = 0.79; P lung water showed no correlation with postmortem wet weights and significantly underestimated lung water. Average alveolar fluid clearance rates were positive (1.4%·hr(-1) (3%)) with BVV and negative with CMV (-2.0%·hr(-1) (4%)). In a comparison between BVV and CMV, computed tomography evidence suggests that BVV facilitates enhanced clearance and/or redistribution of edema fluid with improved recruitment of atelectatic and

  17. Immature monocytes contribute to cardiopulmonary bypass-induced acute lung injury by generating inflammatory descendants.

    Science.gov (United States)

    Xing, Zhichen; Han, Junyan; Hao, Xing; Wang, Jinhong; Jiang, Chunjing; Hao, Yu; Wang, Hong; Wu, Xueying; Shen, Liwei; Dong, Xiaojun; Li, Tong; Li, Guoli; Zhang, Jianping; Hou, Xiaotong; Zeng, Hui

    2017-03-01

    As immune regulatory and effector cells, monocytes play an important role in the blood-extracorporeal circuit contact-related acute lung injury in patients undergoing cardiopulmonary bypass (CPB). However, circulating monocytes are phenotypically and functionally heterogeneous, so we characterised how immature monocytes affect acute lung injury induced by CPB. The identification and dynamic changes in monocyte subsets were monitored by flow cytometry in patients undergoing CPB and in a rat model of CPB. The differentiation and migration of monocyte subsets were explored by in vitro cultures and adoptive transfer in the CPB rat model. We observed a dramatic increase of two monocyte subsets in the peripheral blood of patients undergoing CPB, involving tumour necrosis factor (TNF)-α-producing, mature intermediate CD14(high)CD16(+) monocytes and a novel immature CD14(low)CD16(-) subset. The immature CD14(low)CD16(-) monocytes possessed limited ability for TNF-α production, and failed to suppress T-cell proliferation mediated by T-cell receptor signalling. However, these immature cells were highly proliferative and could differentiate into TNF-α producing, mature CD14(high)CD16(+) monocytes. In the rat model of CPB, we further demonstrated that CPB induced migration of immature monocytes into the lungs, either from the bone marrow or from the spleen. Moreover, we confirmed the hypothesis that immature subsets could contribute to CPB-induced acute lung injury by giving rise to TNF-α producing descendants. The immature CD14(low)CD16(-) monocytes might contribute to blood-circuit contact-induced acute lung injury by generating TNF-α-producing, mature monocytes. New strategies based on monocyte manipulation could be a promising therapeutic approach for minimising CPB-related lung injury. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/.

  18. Quantification of ventilation distribution in regional lung injury by electrical impedance tomography and xenon computed tomography.

    Science.gov (United States)

    Elke, Gunnar; Fuld, Matthew K; Halaweish, Ahmed F; Grychtol, Bartłomiej; Weiler, Norbert; Hoffman, Eric A; Frerichs, Inéz

    2013-10-01

    Validation studies of electrical impedance tomography (EIT) based assessment of regional ventilation under pathological conditions are required to prove that EIT can reliably quantify heterogeneous ventilation distribution with sufficient accuracy. The objective of our study was to validate EIT measurements of regional ventilation through a comparison with xenon-multidetector-row computed tomography (XeCT) in an animal model of sub-lobar lung injury. Nine anesthetized mechanically ventilated supine pigs were examined before and after the induction of lung injury in two adjacent sub-lobar segments of the right lung by saline lavage or endotoxin instillation. Regional ventilation was determined in 32 anteroposterior regions of interest in the right and left lungs and the ventilation change quantified by difference images between injury and control. Six animals were included in the final analysis. Measurements of regional ventilation by EIT and XeCT correlated well before (rs = 0.89 right, rs = 0.90 left lung) and after local injury (rs = 0.79 and 0.92, respectively). No bias and narrow limits of agreement were found during both conditions. The ventilation decrease in the right injured lung was correspondingly measured by both modalities (5.5%±1.1% by EIT and 5.4%±1.9% by XeCT, p = 0.94). EIT was inferior to clearly separate the exact anatomical location of the regional injuries. Regional ventilation was overestimated (<2%) in the most ventral and dorsal regions and underestimated (2%) in the middle regions by EIT compared to XeCT. This study shows that EIT is able to reliably discern even small ventilation changes on sub-lobar level.

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

    Directory of Open Access Journals (Sweden)

    Chou-Chin Lan

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

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

    Science.gov (United States)

    Lan, Chou-Chin; Peng, Chung-Kan; Tang, Shih-En; Huang, Kun-Lun; Wu, Chin-Pyng

    2017-01-01

    Ischemia-reperfusion (IR)-induced acute lung injury (ALI) is implicated in several clinical conditions including lung transplantation, cardiopulmonary bypass surgery, re-expansion of collapsed lung from pneumothorax or pleural effusion and etc. IR-induced ALI remains a challenge in the current treatment. Carbonic anhydrase has important physiological function and influences on transport of CO2. Some investigators suggest that CO2 influences lung injury. Therefore, carbonic anhydrase should have the role in ALI. This study was undertaken to define the effect of a carbonic anhydrase inhibitor, acetazolamide (AZA), in IR-induced ALI, that was conducted in a rat model of isolated-perfused lung with 30 minutes of ischemia and 90 minutes of reperfusion. The animals were divided into six groups (n = 6 per group): sham, sham + AZA 200 mg/kg body weight (BW), IR, IR + AZA 100 mg/kg BW, IR + AZA 200 mg/kg BW and IR+ AZA 400 mg/kg BW. IR caused significant pulmonary micro-vascular hyper-permeability, pulmonary edema, pulmonary hypertension, neutrophilic sequestration, and an increase in the expression of pro-inflammatory cytokines. Increases in carbonic anhydrase expression and perfusate pCO2 levels were noted, while decreased Na-K-ATPase expression was noted after IR. Administration of 200mg/kg BW and 400mg/kg BW AZA significantly suppressed the expression of pro-inflammatory cytokines (TNF-α, IL-1, IL-6 and IL-17) and attenuated IR-induced lung injury, represented by decreases in pulmonary hyper-permeability, pulmonary edema, pulmonary hypertension and neutrophilic sequestration. AZA attenuated IR-induced lung injury, associated with decreases in carbonic anhydrase expression and pCO2 levels, as well as restoration of Na-K-ATPase expression. PMID:28644844

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

    Energy Technology Data Exchange (ETDEWEB)

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

    2013-11-01

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

  2. Closed-loop mechanical ventilation for lung injury: a novel physiological-feedback mode following the principles of the open lung concept.

    Science.gov (United States)

    Schwaiberger, David; Pickerodt, Philipp A; Pomprapa, Anake; Tjarks, Onno; Kork, Felix; Boemke, Willehad; Francis, Roland C E; Leonhardt, Steffen; Lachmann, Burkhard

    2017-06-26

    Adherence to low tidal volume (V T ) ventilation and selected positive end-expiratory pressures are low during mechanical ventilation for treatment of the acute respiratory distress syndrome. Using a pig model of severe lung injury, we tested the feasibility and physiological responses to a novel fully closed-loop mechanical ventilation algorithm based on the "open lung" concept. Lung injury was induced by surfactant washout in pigs (n = 8). Animals were ventilated following the principles of the "open lung approach" (OLA) using a fully closed-loop physiological feedback algorithm for mechanical ventilation. Standard gas exchange, respiratory- and hemodynamic parameters were measured. Electrical impedance tomography was used to quantify regional ventilation distribution during mechanical ventilation. Automatized mechanical ventilation provided strict adherence to low V T -ventilation for 6 h in severely lung injured pigs. Using the "open lung" approach, tidal volume delivery required low lung distending pressures, increased recruitment and ventilation of dorsal lung regions and improved arterial blood oxygenation. Physiological feedback closed-loop mechanical ventilation according to the principles of the open lung concept is feasible and provides low tidal volume ventilation without human intervention. Of importance, the "open lung approach"-ventilation improved gas exchange and reduced lung driving pressures by opening atelectasis and shifting of ventilation to dorsal lung regions.

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

    Energy Technology Data Exchange (ETDEWEB)

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

    2012-09-01

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

  4. FOXF1 maintains endothelial barrier function and prevents edema after lung injury.

    Science.gov (United States)

    Cai, Yuqi; Bolte, Craig; Le, Tien; Goda, Chinmayee; Xu, Yan; Kalin, Tanya V; Kalinichenko, Vladimir V

    2016-04-19

    Multiple signaling pathways, structural proteins, and transcription factors are involved in the regulation of endothelial barrier function. The forkhead protein FOXF1 is a key transcriptional regulator of embryonic lung development, and we used a conditional knockout approach to examine the role of FOXF1 in adult lung homeostasis, injury, and repair. Tamoxifen-regulated deletion of both Foxf1 alleles in endothelial cells of adult mice (Pdgfb-iCreER/Foxf1(-/-)) caused lung inflammation and edema, leading to respiratory insufficiency and death. Deletion of a single Foxf1 allele made heterozygous Pdgfb-iCreER/Foxf1(+/-)mice more susceptible to acute lung injury. FOXF1 abundance was decreased in pulmonary endothelial cells of human patients with acute lung injury. Gene expression analysis of pulmonary endothelial cells with homozygous FOXF1 deletion indicated reduced expression of genes critical for maintenance and regulation of adherens junctions. FOXF1 knockdown in vitro and in vivo disrupted adherens junctions, enhanced lung endothelial permeability, and increased the abundance of the mRNA and protein for sphingosine 1-phosphate receptor 1 (S1PR1), a key regulator of endothelial barrier function. Chromatin immunoprecipitation and luciferase reporter assays demonstrated that FOXF1 directly bound to and induced the transcriptional activity of the S1pr1 promoter. Pharmacological administration of S1P to injured Pdgfb-iCreER/Foxf1(+/-)mice restored endothelial barrier function, decreased lung edema, and improved survival. Thus, FOXF1 promotes normal lung homeostasis and repair, in part, by enhancing endothelial barrier function through activation of the S1P/S1PR1 signaling pathway. Copyright © 2016, American Association for the Advancement of Science.

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

    Science.gov (United States)

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

    2016-08-01

    Micro-RNA (miR)-155 is a novel gene regulator with important roles in inflammation. Herein, our study aimed to explore the role of miR-155 in LPS-induced acute lung injury(ALI). ALI in mice was induced by intratracheally delivered LPS. Loss-of-function experiments performed on miR-155 knockout mice showed that miR-155 gene inactivation protected mice from LPS-induced ALI, as manifested by preserved lung permeability and reduced lung inflammation compared with wild-type controls. Bone marrow transplantation experiments identified leukocytes, but not lung parenchymal-derived miR-155-promoted acute lung inflammation. Real-time PCR analysis showed that the expression of miR-155 in lung tissue was greatly elevated in wild-type mice after LPS stimulation. In situ hybridization showed that miR-155 was mainly expressed in alveolar macrophages. In vitro experiments performed in isolated alveolar macrophages and polarized bone marrow-derived macrophages confirmed that miR-155 expression in macrophages was increased in response to LPS stimulation. Conversely, miR-155 gain-of-function in alveolar macrophages remarkably exaggerated LPS-induced acute lung injury. Molecular studies identified the inflammation repressor suppressor of cytokine signaling (SOCS-1) as the downstream target of miR-155. By binding to the 3'-UTR of the SOCS-1 mRNA, miR-155 downregulated SOCS-1 expression, thus, permitting the inflammatory response during lung injury. Finally, we generated a novel miR-155 knockout rat strain and showed that the proinflammatory role of miR-155 was conserved in rats. Our study identified miR-155 as a proinflammatory factor after LPS stimulation, and alveolar macrophages-derived miR-155 has an important role in LPS-induced ALI. Copyright © 2016 the American Physiological Society.

  6. Partial liquid ventilation improves lung function in ventilation-induced lung injury

    NARCIS (Netherlands)

    G.F. Vazquez de Anda; R.A. Lachmann; S.J.C. Verbrugge (Serge); D.A.M.P.J. Gommers (Diederik); J.J. Haitsma (Jack); B.F. Lachmann (Burkhard)

    2001-01-01

    textabstractDisturbances in lung function and lung mechanics are present after ventilation with high peak inspiratory pressures (PIP) and low levels of positive end-expiratory pressure (PEEP). Therefore, the authors investigated whether partial liquid ventilation can re-establish

  7. Treatment with H2S-releasing diclofenac protects mice against acute pancreatitis-associated lung injury.

    Science.gov (United States)

    Bhatia, Madhav; Sidhapuriwala, Jenab N; Sparatore, Anna; Moore, Philip K

    2008-01-01

    Impaired lung function in severe acute pancreatitis is the primary cause of morbidity and mortality in this condition. Hydrogen sulfide (H(2)S) is a naturally occurring gas that has been shown to be a potent vasodilator. Diclofenac is a nonsteroidal anti-inflammatory drug and has been shown to have anti-inflammatory, analgesic, and antipyretic activity. ACS15 is an H(2)S-releasing derivative of diclofenac. Little is known about its effectiveness as an anti-inflammatory drug. In this report, we describe the effect of diclofenac and its H(2)S-releasing derivative on acute pancreatitis and associated lung injury in the mouse. Acute pancreatitis was induced in mice by hourly i.p. injections of cerulein. Diclofenac and ACS15 were administered either 1 hour before or 1 hour after starting cerulein injections, and the severity of acute pancreatitis and associated lung injury was assessed. The severity of acute pancreatitis was determined by hyperamylasemia, neutrophil sequestration in the pancreas (pancreatic myeloperoxidase activity), and pancreatic acinar cell injury/necrosis on histological examination of pancreas sections. The severity of acute pancreatitis-associated lung injury was assessed by neutrophil sequestration in the lungs (lung myeloperoxidase activity) and by histological examination of lung sections. ACS15, given prophylactically and therapeutically, significantly reduced lung inflammation without having any significant effect on pancreatic injury. These results suggest the usefulness of H(2)S-releasing nonsteroidal anti-inflammatory drugs as potential treatments for pancreatitis-associated lung injury.

  8. Effects of S-Nitroso-N-Acetyl-Penicillamine (SNAP) on Inflammation, Lung Tissue Apoptosis and iNOS Activity in a Rabbit Model of Acute Lung Injury.

    Science.gov (United States)

    Kosutova, P; Mikolka, P; Kolomaznik, M; Balentova, S; Calkovska, A; Mokra, D

    2016-01-01

    Acute lung injury is characterized by lung edema, surfactant dysfunction, and inflammation. The main goal of our study was to evaluate effects of S-nitroso-N-acetyl-penicillamine (SNAP) on migration of cells into the lung and their activation, inducible NO synthase (iNOS) activity, and apoptosis in experimental acute lung injury (ALI) in rabbits. ALI was induced by repetitive lung lavage with saline. The animals were divided into the following groups: (1) ALI without therapy, (2) lung injury treated with SNAP (ALI + SNAP), and (3) healthy animals (Control). After 5 h of ventilation, total and differential counts of cells in the bronchoalveolar lavage fluid (BALF) were assessed. Concentrations of interleukins (IL)-1ß, IL-6, and IL-8, endogenous secretory receptor for advanced glycation endproducts (esRAGE), sphingosine-1-phosphate receptor (S1PR)3, caspase-3, and mRNA expression of inducible NO synthase (iNOS) in lung tissue and nitrite/nitrate in plasma were analyzed. In the right lung, apoptotic cells were evaluated by TUNEL assay. In the animals with ALI, higher counts of cells, mainly neutrophils, in BALF and increased production of pro-inflammatory substances were observed compared with controls. SNAP therapy reduced a leak of cells into the lung and decreased concentrations of pro-inflammatory and apoptotic markers, reduced mRNA expression of iNOS, and decreased apoptotic index in the lung.

  9. Toll-like receptor 4 dependent responses to lung injury in a murine model of pulmonary contusion

    OpenAIRE

    Hoth, J. Jason; Wells, Jonathan D.; Brownlee, Noel A.; Hiltbold, Elizabeth M.; Meredith, J. Wayne; McCall, Charles E.; Yoza, Barbara K.

    2009-01-01

    Blunt chest trauma resulting in pulmonary contusion with an accompanying acute inflammatory response is a common but poorly understood injury. We previously demonstrated that toll-like receptor 2 participates in the inflammatory response to lung injury. We hypothesized that the toll-like receptor 4, in a MyD88-dependent manner, may also participate in the response to lung injury. To investigate this, we used a model of pulmonary contusion in the mouse that is similar to that observed clinical...

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

    Science.gov (United States)

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

    2017-04-01

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

  11. Mesenchymal stem cells: A double-edged sword in radiation-induced lung injury.

    Science.gov (United States)

    Yao, Yi; Zheng, Zhongliang; Song, Qibin

    2017-12-13

    Radiation therapy is an important treatment modality for multiple thoracic malignancies. However, radiation-induced lung injury (RILI), which is the term generally used to describe damage to the lungs caused by exposure to ionizing radiation, remains a critical issue affecting both tumor control and patient quality of life. Despite tremendous effort, there is no current consensus regarding the optimal treatment approach for RILI. Because of a number of functional advantages, including self-proliferation, multi-differentiation, injury foci chemotaxis, anti-inflammation, and immunomodulation, mesenchymal stem cells (MSCs) have been a focus of research for many years. Accumulating evidence indicates the therapeutic potential of transplantation of MSCs derived from adipose tissue, umbilical cord blood, and bone marrow for inflammatory diseases, including RILI. However, reports have also shown that MSCs, including fibrocytes, lung hematopoietic progenitor cells, and ABCG2+ MSCs, actually enhance the progression of lung injuries. These contradictory results suggest that MSCs may have dual effects and that caution should be taken when using MSCs to treat RILI. In this review, we present and discuss recent evidence of the double-edged function of MSCs and provide comments on the prospects of these findings. © 2017 The Authors. Thoracic Cancer published by China Lung Oncology Group and John Wiley & Sons Australia, Ltd.

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

    Directory of Open Access Journals (Sweden)

    Qiao Wang

    2015-01-01

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

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

    Science.gov (United States)

    Gupta, Arjun; Sen, Shiraj; Naina, Harris

    2016-04-06

    Bleomycin-induced lung injury is the most common chemotherapy-associated lung disease, and is linked with several histopathological patterns. Acute fibrinous and organising pneumonia (AFOP) is a relatively new and rare histological pattern of diffuse lung injury. We report the first known case of bleomycin-induced AFOP. A 36-year-old man with metastatic testicular cancer received three cycles of bleomycin, etoposide and cisplatin, before being transitioned to paclitaxel, ifosfamide and cisplatin. He subsequently presented with exertional dyspnoea, cough and pleuritic chest pain. CT of the chest demonstrated bilateral ground glass opacities with peribronchovascular distribution and pulmonary function tests demonstrated a restrictive pattern of lung disease with impaired diffusion. Transbronchial biopsy revealed intra-alveolar fibrin deposits with organising pneumonia, consisting of intraluminal loose connective tissue consistent with AFOP. The patient received high-dose corticosteroids with symptomatic and radiographic improvement. AFOP should be recognised as a histopathological variant of bleomycin-induced lung injury. 2016 BMJ Publishing Group Ltd.

  14. [Effects of high dose ambroxol on lung injury induced by paraquat in rats].

    Science.gov (United States)

    Ma, Yu-teng; Tian, Ying-ping; Shi, Han-wen; Lv, Cui-huan; Liu, Jian-hui; Sun, Zhi-ping

    2007-09-01

    To evaluate the protective effect of high dose ambroxol, a mucoactive drug, on acute lung injury caused by paraquat in rats. One hundred and thirty-six healthy male Sprague-Dawley rats were randomly divided into three groups: control group (n = 24) injected with normal saline intraperitoneally, PQ group (n = 56) [(2% paraquat (25 mg/kg) injected into peritoneal cavity on the first day)] and AT group (n = 56) ambroxol 35 mg/kg was injected into peritoneum daily after paraquat intoxication once daily for 7 consecutive days. The arterial gas was determined and the extent of lung injury was assessed by measuring the ratio of wet to dry weight (W/D) and protein content in BALF, the WBC count, the percentage of PMN, the content of malondialdehyde (MDA) and the levels of superoxide dismutase (SOD) in the blood and BALF respectively. Left lung tissue was observed through both light microscope and electron microscope (TEM). The white cell count and the content of protein in the blood and the BALF of PQ group were significantly higher than those of the control group (P ambroxol was administered. Treatment with ambroxol (35 mg/kg) could influence the status of oxidative stress in lung and alleviate lung injury induced by paraquat. Ambroxol has obviously therapeutic effect on paraquat poisoning.

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

    Directory of Open Access Journals (Sweden)

    Yan Wang

    2017-05-01

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

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

    Science.gov (United States)

    Wang, Yan; Xu, Chu-Fan; Liu, Yu-Jian; Mao, Yan-Fei; Lv, Zhou; Li, Si-Yuan; Zhu, Xiao-Yan; Jiang, Lai

    2017-01-01

    Salidroside (SDS) is the main effective ingredient of Rhodiola rosea L with a variety of pharmacologic properties. We aim to investigate the effects of SDS on ventilation induced lung injury (VILI) and explore the possible underlying molecular mechanism. Lung injury was induced in male ICR mice via mechanical ventilation (30 ml/kg) for 4h. The mice were divided in four groups:(1) Control group; (2) Ventilation group; (3) SDS group; (4) Ventilation with SDS group. SDS (50 mg/kg) was injected intraperitoneally 1h before operation. Mouse lung vascular endothelial cells (MLVECs) were subjected to cyclic stretch for 4h. It was found that SDS attenuated VILI as shown in HE staining, cell count and protein content levels in BAL fluid, W/D and Evans blue dye leakage into the lung tissue. SDS treatment inhibited the activation of NLRP3 inflammasome and subsequent caspase-1 cleavage as well as interleukin (IL)-1β secretion both in vivo and in vitro. Moreover, SDS administration up-regulated SIRT1 expression. Importantly, knockdown of SIRT1 reversed the inhibitory effect of SDS on NLRP3 inflammasome activation. Taken together, these findings indicate that SDS may confer protection against ventilation induced lung injury via SIRT1-de-pendent inhibition of NLRP3 inflammasome activation. © 2017 The Author(s). Published by S. Karger AG, Basel.

  17. Lung injury after cigarette smoking is particle-related

    Science.gov (United States)

    That specific component responsible and the mechanistic pathway for increased human morbidity and mortality after cigarette smoking have yet to be delineated. We propose that 1) injury and disease following cigarette smoking are associated with exposure and retention of particles...

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

    NARCIS (Netherlands)

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

    1995-01-01

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

  19. Intraoperative cell salvage during cardiac surgery is associated with reduced postoperative lung injury

    NARCIS (Netherlands)

    Engels, Gerwin E; van Klarenbosch, Jan; Gu, Y John; van Oeveren, Willem; de Vries, Adrianus J

    2016-01-01

    OBJECTIVES: In addition to its blood-sparing effects, intraoperative cell salvage may reduce lung injury following cardiac surgery by removing cytokines, neutrophilic proteases and lipids that are present in cardiotomy suction blood. To test this hypothesis, we performed serial measurements of

  20. Intraoperative cell salvage during cardiac surgery is associated with reduced postoperative lung injury

    NARCIS (Netherlands)

    Engels, Gerwin E.; van Klarenbosch, Jan; Gu, Y. John; van Oeveren, Willem; de Vries, Adrianus J.

    OBJECTIVES: In addition to its blood-sparing effects, intraoperative cell salvage may reduce lung injury following cardiac surgery by removing cytokines, neutrophilic proteases and lipids that are present in cardiotomy suction blood. To test this hypothesis, we performed serial measurements of

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

    NARCIS (Netherlands)

    Bern, R.A.

    2010-01-01

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

  2. Transfusion-related acute lung injury : etiological research and its methodological challenges

    NARCIS (Netherlands)

    Middelburg, Rutger Anton

    2011-01-01

    Transfusion-related acute lung injury (TRALI) is the most common serious side effect of blood transfusion. TRALI could be caused by donor leukocyte antibodies, present primarily in female and transfused donors (Chapters 1 and 2). In The Netherlands this led to the exclusion of female and transfused

  3. The role of selected cytokines and proteins analyzed in bronchoalveolar lavage fluid in lung injury

    Directory of Open Access Journals (Sweden)

    Monika Jedynak

    2014-06-01

    Full Text Available The early organism response to injury or infection involves activation of the innate immune system, in which pattern recognition receptors (PRRs participate. They recognize highly conservative structures that are called pathogen-associated molecular patterns (PAMPs and damage-associated molecular patterns (DAMPs. The interactions between PRRs and PAMPs or DAMPs lead to the activation of transcriptional factors which are responsible for gene expression of inflammatory mediators and synthesis and release of these factors, and result in the development of inflammation. RAGE (receptor for advanced glycation end products and CD163 belonging to PRRs play a significant role in the early immune response in lungs. They are expressed on alveolar epithelial cells and alveolar macrophages, respectively. NK cells are also involved in lung response to injury, though their maturation and the ability to express PRRs depend on the presence of IL-15. Detailed knowledge about these factors enables us to understand the signal pathways that are activated in the course of infectious and noninfectious lung injury. The analysis of these proteins’ concentrations in body fluids creates new possibilities in monitoring lung injury and predicting the results of treatment. In the future, the discussed mediators may become the targets for new forms of treatment in life-threatening respiratory diseases.

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

    Science.gov (United States)

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

  5. Reporting transfusion-related acute lung injury by clinical and preclinical disciplines

    NARCIS (Netherlands)

    Peters, Anna L.; van de Weerdt, Emma K.; Goudswaard, Eline J.; Binnekade, Jan M.; Zwaginga, Jaap J.; Beckers, Erik A. M.; Zeerleder, Sacha S.; van Kraaij, Marian G. J.; Juffermans, Nicole P.; Vlaar, Alexander P. J.

    2017-01-01

    Disciplines involved in diagnosing transfusion-related acute lung injury (TRALI) report according to a "one-hit" theory. However, studies showed that patients with an underlying condition are at increased risk of the development of TRALI. We investigated whether accumulating evidence on the

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

    NARCIS (Netherlands)

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

    2007-01-01

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

  7. Bench to bedside: targeting coagulation and fibrinolysis in acute lung injury

    NARCIS (Netherlands)

    Ware, Lorraine B.; Camerer, Eric; Welty-Wolf, Karen; Schultz, Marcus J.; Matthay, Michael A.

    2006-01-01

    Substantial progress has been made in understanding the contribution of alterations in coagulation and fibrinolysis to the pathogenesis of acute lung injury (ALI). Findings from mouse, rat, baboon, and human studies indicate that alterations in coagulation and fibrinolysis may be of major

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

    Science.gov (United States)

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

    2014-09-01

    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. Copyright © 2014 the American Physiological Society.

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

    DEFF Research Database (Denmark)

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

    1995-01-01

    The role of macrophage inflammatory protein-1 alpha (MIP-1 alpha) in the pathogenesis of acute lung injury in rats after intrapulmonary deposition of IgG immune complexes or intratracheal administration of LPS has been assessed. Critical to these studies was the cloning and functional expression ...

  10. Predictors of Early Acute Lung Injury at a Combat Support Hospital: A Prospective Observational Study

    Science.gov (United States)

    2010-07-01

    FWB) are associated with immunosuppression ,8 transfusion- related acute lung injury (TRALI), and worse outcomes following trauma.9 Of these, TRALI...Trauma. 2003;54:898–907. 9. Marik PE, Raghavan M. Anemia, allogenic blood transfusion, and immunomodulation in the critically ill. Chest. 2005;127:295

  11. Ventilator-induced Lung Injury Is Mediated by the NLRP3 Inflammasome

    NARCIS (Netherlands)

    Kuipers, Maria T.; Aslami, Hamid; Janczy, John R.; van der Sluijs, Koenraad F.; Vlaar, Alexander P. J.; Wolthuis, Esther K.; Choi, Goda; Roelofs, Joris J. T. H.; Flavell, Richard A.; Sutterwala, Fayyaz S.; Bresser, Paul; Leemans, Jaklien C.; van der Poll, Tom; Schultz, Marcus J.; Wieland, Catharina W.

    2012-01-01

    Background: The innate immune response is important in ventilator-induced lung injury (VILI) but the exact pathways involved are not elucidated. The authors studied the role of the intracellular danger sensor NLRP3 inflammasome. Methods: NLRP3 inflammasome gene expression was analyzed in respiratory

  12. Ventilator-induced lung injury is mediated by the NLRP3 inflammasome

    NARCIS (Netherlands)

    Kuipers, Maria T; Aslami, Hamid; Janczy, John R; van der Sluijs, Koenraad F; Vlaar, Alexander P J; Wolthuis, Esther K; Choi, Goda; Roelofs, Joris J T H; Flavell, Richard A; Sutterwala, Fayyaz S; Bresser, Paul; Leemans, Jaklien C; van der Poll, Tom; Schultz, Marcus J; Wieland, Catharina W

    2012-01-01

    BACKGROUND: The innate immune response is important in ventilator-induced lung injury (VILI) but the exact pathways involved are not elucidated. The authors studied the role of the intracellular danger sensor NLRP3 inflammasome. METHODS: NLRP3 inflammasome gene expression was analyzed in respiratory

  13. Transfusion-Related Acute Lung Injury : The role of donor antibodies

    NARCIS (Netherlands)

    D. Mathijssen-van Stein (Danielle)

    2015-01-01

    markdownabstractAbstract Transfusion-related acute lung injury (TRALI) is a serious complication of blood transfusion, which causes serious morbidity and is the leading cause of transfusion-associated mortality according to the FDA. The majority of TRALI cases (up to 89%) are thought to be

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

    Directory of Open Access Journals (Sweden)

    Xianming Zhang

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

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

    Science.gov (United States)

    Zhang, Xianming; Wu, Weiliang; Zhu, Yongcheng; Jiang, Ying; Du, Juan; Chen, Rongchang

    2016-01-01

    Objective It has proved that muscle paralysis was more protective for injured lung in severe acute respiratory distress syndrome (ARDS), but the precise mechanism is not clear. The purpose of this study was to test the hypothesis that abdominal muscle activity during mechanically ventilation increases lung injury in severe ARDS. Methods Eighteen male Beagles were studied under mechanical ventilation with anesthesia. Severe ARDS was induced by repetitive oleic acid infusion. After lung injury, Beagles were randomly assigned into spontaneous breathing group (BIPAPSB) and abdominal muscle paralysis group (BIPAPAP). All groups were ventilated with BIPAP model for 8h, and the high pressure titrated to reached a tidal volume of 6ml/kg, the low pressure was set at 10 cmH2O, with I:E ratio 1:1, and respiratory rate adjusted to a PaCO2 of 35–60 mmHg. Six Beagles without ventilator support comprised the control group. Respiratory variables, end-expiratory volume (EELV) and gas exchange were assessed during mechanical ventilation. The levels of Interleukin (IL)-6, IL-8 in lung tissue and plasma were measured by qRT-PCR and ELISA respectively. Lung injury scores were determined at end of the experiment. Results For the comparable ventilator setting, as compared with BIPAPSB group, the BIPAPAP group presented higher EELV (427±47 vs. 366±38 ml) and oxygenation index (293±36 vs. 226±31 mmHg), lower levels of IL-6(216.6±48.0 vs. 297.5±71.2 pg/ml) and IL-8(246.8±78.2 vs. 357.5±69.3 pg/ml) in plasma, and lower express levels of IL-6 mRNA (15.0±3.8 vs. 21.2±3.7) and IL-8 mRNA (18.9±6.8 vs. 29.5±7.9) in lung tissues. In addition, less lung histopathology injury were revealed in the BIPAPAP group (22.5±2.0 vs. 25.2±2.1). Conclusion Abdominal muscle activity during mechanically ventilation is one of the injurious factors in severe ARDS, so abdominal muscle paralysis might be an effective strategy to minimize ventilator-induce lung injury. PMID:26745868

  16. Electrical impedance tomography compared with thoracic computed tomography during a slow inflation maneuver in experimental models of lung injury.

    Science.gov (United States)

    Wrigge, Hermann; Zinserling, Jörg; Muders, Thomas; Varelmann, Dirk; Günther, Ulf; von der Groeben, Cornelius; Magnusson, Anders; Hedenstierna, Göran; Putensen, Christian

    2008-03-01

    To determine the validity of functional electric impedance tomography to monitor regional ventilation distribution in experimental acute lung injury, and to develop a simple electric impedance tomography index detecting alveolar recruitment. Randomized prospective experimental study. Academic research laboratory. Sixteen anesthetized, tracheotomized, and mechanically ventilated pigs. Acute lung injury was induced either by acid aspiration (direct acute lung injury) or by abdominal hypertension plus oleic acid injection (indirect acute lung injury) in ten pigs. Six pigs with normal lungs were studied as a control group and with endotracheal suction-related atelectasis. After 4 hrs of mechanical ventilation, a slow inflation was performed. During slow inflation, simultaneous measurements of regional ventilation by electric impedance tomography and dynamic computed tomography were highly correlated in quadrants of a transversal thoracic plane (r2 = .63-.88, p Electric impedance tomography indexes to detect alveolar recruitment were determined by mathematical curve analysis of regional impedance time curves. Empirical tests of different methods revealed that regional ventilation delay, that is, time delay of regional impedance time curve to reach a threshold, correlated well with recruited volume as measured by CT (r2 = .63). Correlation coefficients in subgroups were r2 = .71 and r2 = .48 in pigs with normal lungs with and without closed suction related atelectasis and r2 = .79 in pigs subject to indirect acute lung injury, respectively, whereas no significant correlation was found in pigs undergoing direct acute lung injury. Electric impedance tomography allows assessment of regional ventilation distribution and recruitment in experimental models of direct and indirect acute lung injury as well as normal lungs. Except for pigs with direct acute lung injury, regional ventilation delay determined during a slow inflation from impedance time curves appears to be a simple

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

    Science.gov (United States)

    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.

  18. Alleviation of Lipopolysaccharides-Induced Acute Lung Injury by MiR-454

    Directory of Open Access Journals (Sweden)

    Zhengang Tao

    2016-01-01

    Full Text Available Background/Aims: Although acute lung injury (ALI is an important and common disease in humans, its pathogenesis is poorly understood and its therapeutic outcome has not been significantly improved in the past years. Here, we examined whether application of microRNAs might inhibit the ALI-associated lung inflammatory, and subsequently reduce the injury. Methods: In vitro, we performed bioinformatics analyses to identify the miRNAs that target the most important chemo-attractive factor CXCL12, and confirmed that the binding was functional by luciferase reporter assay. We prepared adeno-associated virus (AAV carrying miRNA mimics or null control. We expressed miRNA in mouse lung through i.v. injection of AAV and then we used Lipopolysaccharides (LPS to induce ALI in mice. We analyzed the changes in permeability index and production of inflammatory cytokines in mouse lung, and we also verified the effects of virus-mediated gene expression by examining the levels of miRNAs and CXCL12 in lung by RT-qPCR and ELISA, and by quantifying the recruited inflammatory cells in mouse lung by flow cytometry. Results: We found that miR-454 targeted the 3'-UTR of CXCL12 mRNA to inhibit its protein translation in human lung epithelial cells. Overexpression of miR-454 in mouse lung significantly reduced the LPS-induced increases in permeability index and production of inflammatory cytokines CXCL1, CXCL2, IL6 and TNFα, possibly through suppression of CXCL12/CXCR4-mediated recruitment of inflammatory cells. Conclusion: Overexpression of miR-454 in lung may be a promising therapeutic approach to reduce the severity of ALI.

  19. [Protective effect of synthetic salidroside on acute lung injury in rats].

    Science.gov (United States)

    Huang, Qian; Cai, Yan-Chun; Wei, Xiao-Li; Wu, Jin-Long; Mei, Ru-Huan; Hu, Xiao-Lan

    2017-06-25

    To study the protective effect and mechanism of synthetic salidroside on acute lung injury (ALI) induced by lipopolysaccharide (LPS), male Sprague-Dawley (SD) rats were randomly divided into saline control group, 3 mg/kg LPS model group, different doses of salidroside groups (5, 20 and 80 mg/kg), and 5 mg/kg dexamethasone group. Intratracheal LPS instillation was used to establish the ALI model 0.5 h after intraperitoneal injection of salidroside or dexamethasone, and the rats were sacrificed 6 h later. Lung wet/dry weight ratio (W/D) was calculated. Lung tissue pathology and lung injury score (LIS) were observed and evaluated through hematoxylin and eosin (HE) staining. The centrifugal sediment of bronchoalveolar lavage fluid (BALF) was used to count the polymorphonuclear leukocyte (PMN) number by Wright's staining, and the centrifugal supernatant of BALF was used to determine the contents of protein and inflammatory factors (TNF-α, IL-1β and IL-6). The contents of myeloperoxidase (MPO) and malondialdehyde (MDA) in lung tissue were determined. Western blot was used to detect the expression levels of phosphorylated and total nuclear factor kappa B (NF-κB)/p65 protein in lung tissue. The results showed that, compared with LPS group, the intervention of synthetic salidroside alleviated the pathological damage in lung tissue, decreased the LIS and lung W/D ratio (P salidroside has a protective effect on ALI induced by LPS, and its mechanism is related to inhibiting the phosphorylation of NF-κB and reducing the aggregation of PMN in the lung.

  20. Lung-Protective Ventilation Strategies for Relief from Ventilator-Associated Lung Injury in Patients Undergoing Craniotomy: A Bicenter Randomized, Parallel, and Controlled Trial

    Directory of Open Access Journals (Sweden)

    Chaoliang Tang

    2017-01-01

    Full Text Available Current evidence indicates that conventional mechanical ventilation often leads to lung inflammatory response and oxidative stress, while lung-protective ventilation (LPV minimizes the risk of ventilator-associated lung injury (VALI. This study evaluated the effects of LPV on relief of pulmonary injury, inflammatory response, and oxidative stress among patients undergoing craniotomy. Sixty patients undergoing craniotomy received either conventional mechanical (12 mL/kg tidal volume [VT] and 0 cm H2O positive end-expiratory pressure [PEEP]; CV group or protective lung (6 mL/kg VT and 10 cm H2O PEEP; PV group ventilation. Hemodynamic variables, lung function indexes, and inflammatory and oxidative stress markers were assessed. The PV group exhibited greater dynamic lung compliance and lower respiratory index than the CV group during surgery (P0.05. Patients receiving LPV during craniotomy exhibited low perioperative inflammatory response, oxidative stress, and VALI.

  1. Protective effect of sesquiterpene lactone parthenolide on LPS-induced acute lung injury.

    Science.gov (United States)

    Jang, You Jin; Back, Moon Jung; Fu, Zhicheng; Lee, Joo Hyun; Won, Jong Hoon; Ha, Hae Chan; Lee, Hae Kyung; Jang, Ji Min; Choi, Jong Min; Kim, Dae Kyong

    2016-12-01

    Acute lung injury (ALI) is a respiratory failure disease and the major source of mortality in the critically ill patients. The main pathological changes involved in ALI include the excessive recruitment and activation of neutrophils by increased pro-inflammatory mediators. However, any specific therapy for ALI has not been developed. The objective of this study was to investigate protective effects of parthenolide, a sesquiterpene lactone produced in feverfew, on LPS-induced lung injury. In the present study, parthenolide treatment reduced infiltration of inflammatory cells, airway permeability and production of pro-inflammatory cytokines in LPS-induced ALI mouse model. Further, LPS-stimulated phosphorylation of NF-κB, the key regulatory transcription factor in ALI, was inhibited by parthenolide treatment in lung epithelial BEAS-2B cells and alveolar macrophage MH-S cells. These results suggest that parthenolide may provide a beneficial therapeutic strategy for ALI.

  2. Mesenchymal stem cell derived secretome and extracellular vesicles for acute lung injury and other inflammatory lung diseases.

    Science.gov (United States)

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

    2016-07-01

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

  3. Humidifier disinfectant-associated lung injury in adults: Prognostic factors in predicting short-term outcome

    Energy Technology Data Exchange (ETDEWEB)

    Koo, Hyun Jung; Do, Kyung-Hyun; Chae, Eun Jin [University of Ulsan College of Medicine, Department of Radiology and Research Institute of Radiology, Asan Medical Center, Songpa-gu, Seoul (Korea, Republic of); Kim, Hwa Jung [University of Ulsan College of Medicine, Cancer Center, Department of Clinical Epidemiology and Biostatistics, Asan Medical Center, Seoul (Korea, Republic of); Song, Joon Seon; Jang, Se Jin [University of Ulsan College of Medicine, Department of Pathology, Asan Medical Center, Seoul (Korea, Republic of); Hong, Sang-Bum; Huh, Jin Won [University of Ulsan College of Medicine, Department of Pulmonary and Critical Care Medicine, Asan Medical Center, Seoul (Korea, Republic of); Lee, En [Inje University Haundae Paik Hospital, Department of Pediatrics, Busan (Korea, Republic of); Hong, Soo-Jong [University of Ulsan College of Medicine, Department of Pediatrics, Childhood Asthma and Atopy Center, Environmental Health Center, Asan Medical Center, Seoul (Korea, Republic of)

    2017-01-15

    To identify clinical and radiologic findings that affect disease severity and short-term prognosis of humidifier disinfectant-associated lung injury in adults and to compare computed tomography (CT) findings between the patients with and without death or lung transplantation. Fifty-nine adults (mean age, 34 years; M/F = 12:47) were enrolled in this retrospective study. Medical records and prospective surveillance data were used to assess clinical and radiological factors associated with a poor clinical outcome. Multivariate generalized estimating equation models were used to analyse serial CT findings. Overall cumulative major events including lung transplantation and mortality were assessed using the Kaplan-Meier method. Almost half needed ICU admission (47.5 %) and 17 died (28.8 %). Young age, peripartum and low O{sub 2} saturation were factors associated with ICU admission. On initial chest radiographs, consolidation (P < 0.001) and ground-glass opacity (P = 0.01) were significantly noted in patients who required ICU admission. CT findings including consolidation (odds ratio (OR), 1.02), pneumomediastinum (OR, 1.66) and pulmonary interstitial emphysema (OR, 1.61) were the risk factors for lung transplantation and mortality. Clinical and radiologic findings are related to the risks of lung transplantation and mortality of humidifier disinfectant-associated lung injury. Consolidation, pneumomediastinum and pulmonary interstitial emphysema were short-term prognostic CT findings. (orig.)

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

    Science.gov (United States)

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

    2016-01-05

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

  5. Strategies to improve oxygenation in experimental acute lung injury

    NARCIS (Netherlands)

    A. Hartog (Arthur)

    2000-01-01

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

  6. Paraquat poisoning: Acute lung injury – a missed diagnosis

    African Journals Online (AJOL)

    event were found to have interstitial pulmonary fibrosis with decreased lung capacity. In the same study,[7] patients who developed pneumomediastinum within 7 days all died. Some of these patients had pneumothoraces. The mortality rate for patients who had used paraquat in a suicide attempt was 96% (26/27), while that ...

  7. High tidal volume mechanical ventilation-induced lung injury in rats is greater after acid instillation than after sepsis-induced acute lung injury, but does not increase systemic inflammation: an experimental study

    Directory of Open Access Journals (Sweden)

    Kuiper Jan

    2011-12-01

    Full Text Available Abstract Background To examine whether acute lung injury from direct and indirect origins differ in susceptibility to ventilator-induced lung injury (VILI and resultant systemic inflammatory responses. Methods Rats were challenged by acid instillation or 24 h of sepsis induced by cecal ligation and puncture, followed by mechanical ventilation (MV with either a low tidal volume (Vt of 6 mL/kg and 5 cm H2O positive end-expiratory pressure (PEEP; LVt acid, LVt sepsis or with a high Vt of 15 mL/kg and no PEEP (HVt acid, HVt sepsis. Rats sacrificed immediately after acid instillation and non-ventilated septic animals served as controls. Hemodynamic and respiratory variables were monitored. After 4 h, lung wet to dry (W/D weight ratios, histological lung injury and plasma mediator concentrations were measured. Results Oxygenation and lung compliance decreased after acid instillation as compared to sepsis. Additionally, W/D weight ratios and histological lung injury scores increased after acid instillation as compared to sepsis. MV increased W/D weight ratio and lung injury score, however this effect was mainly attributable to HVt ventilation after acid instillation. Similarly, effects of HVt on oxygenation were only observed after acid instillation. HVt during sepsis did not further affect oxygenation, compliance, W/D weight ratio or lung injury score. Plasma interleukin-6 and tumour necrosis factor-α concentrations were increased after acid instillation as compared to sepsis, but plasma intercellular adhesion molecule-1 concentration increased during sepsis only. In contrast to lung injury parameters, no additional effects of HVt MV after acid instillation on plasma mediator concentrations were observed. Conclusions During MV more severe lung injury develops after acid instillation as compared to sepsis. HVt causes VILI after acid instillation, but not during sepsis. However, this differential effect was not observed in the systemic release of

  8. Effects of FTY720 on Lung Injury Induced by Hindlimb Ischemia Reperfusion in Rats

    Directory of Open Access Journals (Sweden)

    Liangrong Wang

    2017-01-01

    Full Text Available Background. Sphingosine-1-phosphate (S1P is a biologically active lysophospholipid mediator involved in modulating inflammatory process. We investigated the effects of FTY720, a structural analogue of S1P after phosphorylation, on lung injury induced by hindlimb ischemia reperfusion (IR in rats. Methods. Fifty Sprague-Dawley rats were divided into groups SM, IR, F3, F5, and F10. Group SM received sham operation, and bilateral hindlimb IR was established in group IR. The rats in groups F3, F5, and F10 were pretreated with 3, 5, and 10 mg/kg/d FTY720 for 7 days before IR. S1P lyase (S1PL, sphingosine kinase (SphK 1, and SphK2 mRNA expressions, wet/dry weight (W/D, and polymorphonuclear/alveolus (P/A in lung tissues were detected, and the lung injury score was evaluated. Results. W/D, P/A, and mRNA expressions of S1PL, SphK1, and SphK2 were higher in group IR than in group SM, while these were decreased in both groups F5 and F10 as compared to IR (p<0.05. The lung tissue presented severe lesions in group IR, which were attenuated in groups F5 and F10 with lower lung injury scores than in group IR (p<0.05. Conclusions. FTY720 pretreatment could attenuate lung injury induced by hindlimb IR by modulating S1P metabolism and decreasing pulmonary neutrophil infiltration.

  9. Phagocytosis of microparticles by alveolar macrophages during acute lung injury requires MerTK.

    Science.gov (United States)

    Mohning, Michael P; Thomas, Stacey M; Barthel, Lea; Mould, Kara J; McCubbrey, Alexandria L; Frasch, S Courtney; Bratton, Donna L; Henson, Peter M; Janssen, William J

    2018-01-01

    Microparticles are a newly recognized class of mediators in the pathophysiology of lung inflammation and injury, but little is known about the factors that regulate their accumulation and clearance. The primary objective of our study was to determine whether alveolar macrophages engulf microparticles and to elucidate the mechanisms by which this occurs. Alveolar microparticles were quantified in bronchoalveolar fluid of mice with lung injury induced by LPS and hydrochloric acid. Microparticle numbers were greatest at the peak of inflammation and declined as inflammation resolved. Isolated, fluorescently labeled particles were placed in culture with macrophages to evaluate ingestion in the presence of endocytosis inhibitors. Ingestion was blocked with cytochalasin D and wortmannin, consistent with a phagocytic process. In separate experiments, mice were treated intratracheally with labeled microparticles, and their uptake was assessed though microscopy and flow cytometry. Resident alveolar macrophages, not recruited macrophages, were the primary cell-ingesting microparticles in the alveolus during lung injury. In vitro, microparticles promoted inflammatory signaling in LPS primed epithelial cells, signifying the importance of microparticle clearance in resolving lung injury. Microparticles were found to have phosphatidylserine exposed on their surfaces. Accordingly, we measured expression of phosphatidylserine receptors on macrophages and found high expression of MerTK and Axl in the resident macrophage population. Endocytosis of microparticles was markedly reduced in MerTK-deficient macrophages in vitro and in vivo. In conclusion, microparticles are released during acute lung injury and peak in number at the height of inflammation. Resident alveolar macrophages efficiently clear these microparticles through MerTK-mediated phagocytosis.

  10. Role of the urokinase-fibrinolytic system in epithelial-mesenchymal transition during lung injury.

    Science.gov (United States)

    Marudamuthu, Amarnath Satheesh; Bhandary, Yashodhar Prabhakar; Shetty, Shwetha Kumari; Fu, Jian; Sathish, Venkatachalem; Prakash, Ys; Shetty, Sreerama

    2015-01-01

    Alveolar type II epithelial (ATII) cell injury precedes development of pulmonary fibrosis. Mice lacking urokinase-type plasminogen activator (uPA) are highly susceptible, whereas those deficient in plasminogen activator inhibitor (PAI-1) are resistant to lung injury and pulmonary fibrosis. Epithelial-mesenchymal transition (EMT) has been considered, at least in part, as a source of myofibroblast formation during fibrogenesis. However, the contribution of altered expression of major components of the uPA system on ATII cell EMT during lung injury is not well understood. To investigate whether changes in uPA and PAI-1 by ATII cells contribute to EMT, ATII cells from patients with idiopathic pulmonary fibrosis and chronic obstructive pulmonary disease, and mice with bleomycin-, transforming growth factor β-, or passive cigarette smoke-induced lung injury were analyzed for uPA, PAI-1, and EMT markers. We found reduced expression of E-cadherin and zona occludens-1, whereas collagen-I and α-smooth muscle actin were increased in ATII cells isolated from injured lungs. These changes were associated with a parallel increase in PAI-1 and reduced uPA expression. Further, inhibition of Src kinase activity using caveolin-1 scaffolding domain peptide suppressed bleomycin-, transforming growth factor β-, or passive cigarette smoke-induced EMT and restored uPA expression while suppressing PAI-1. These studies show that induction of PAI-1 and inhibition of uPA during fibrosing lung injury lead to EMT in ATII cells. Copyright © 2015 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.

  11. Leukocyte-mediated epithelial injury in ozone-exposed rat lung

    Energy Technology Data Exchange (ETDEWEB)

    Donaldson, K.; Brown, G.M.; Brown, D.M.; Slight, J.; Maclaren, W.M.; Davis, J.M. (Institute of Occupational Medicine, Edinburgh, Scotland (United Kingdon))

    1991-10-01

    Both epithelial injury and inflammation are characteristic findings in the centriacinar regions of the lungs of rats exposed to ozone. In humans such effects could lead to long-term lung damage and disease. In animals, neoplastic change in the lungs after exposure to ozone has been described previously. The possible relationships between inflammatory cell recruitment, epithelial injury, and hyperplasia, with special regard to the important role of repair processes in leading to increased incidence of tumors in some species, have been addressed in the present study. We have previously described that leukocytes from lungs inflamed by different agents can injure epithelial cells in vitro. We have suggested that this leukocyte-mediated epithelial injury could enhance epithelial turnover in ozone-exposed lungs and so enhance the likelihood of tumor development. We, therefore, set out to test the hypothesis that bronchoalveolar leukocytes from ozone-exposed lungs can injure epithelial cells in vitro. PVG rats were exposed to 0.2, 0.4, 0.6, and 0.8 parts per million (ppm) ozone for seven hours per day for up to four days. On the morning following the last exposure, bronchoalveolar lavage was used to sample the bronchoalveolar leukocytes and the following parameters were assessed: total number, differential leukocyte count, production of oxidants, ability to degrade fibronectin, and ability to injure epithelial cells. In addition to these parameters, which were measured at all concentrations and time points in limited experiments, we also assessed macrophage size in short-term culture and inflammation in histological sections of lungs. Total number of lavageable cells was not affected by ozone inhalation. However, the percentage of macrophages decreased with ozone treatment and the percentage of neutrophils increased on days 1 and 2 at 0.6 and 0.8 ppm ozone.

  12. Influenza Virus Infection Induces Platelet-Endothelial Adhesion Which Contributes to Lung Injury.

    Science.gov (United States)

    Sugiyama, Michael G; Gamage, Asela; Zyla, Roman; Armstrong, Susan M; Advani, Suzanne; Advani, Andrew; Wang, Changsen; Lee, Warren L

    2015-12-04

    Lung injury after influenza infection is characterized by increased permeability of the lung microvasculature, culminating in acute respiratory failure. Platelets interact with activated endothelial cells and have been implicated in the pathogenesis of some forms of acute lung injury. Autopsy studies have revealed pulmonary microthrombi after influenza infection, and epidemiological studies suggest that influenza vaccination is protective against pulmonary thromboembolism; however, the effect of influenza infection on platelet-endothelial interactions is unclear. We demonstrate that endothelial infection with both laboratory and clinical strains of influenza virus increased the adhesion of human platelets to primary human lung microvascular endothelial cells. Platelets adhered to infected cells as well as to neighboring cells, suggesting a paracrine effect. Influenza infection caused the upregulation of von Willebrand factor and ICAM-1, but blocking these receptors did not prevent platelet-endothelial adhesion. Instead, platelet adhesion was inhibited by both RGDS peptide and a blocking antibody to platelet integrin α5β1, implicating endothelial fibronectin. Concordantly, lung histology from infected mice revealed viral dose-dependent colocalization of viral nucleoprotein and the endothelial marker PECAM-1, while platelet adhesion and fibronectin deposition also were observed in the lungs of influenza-infected mice. Inhibition of platelets using acetylsalicylic acid significantly improved survival, a finding confirmed using a second antiplatelet agent. Thus, influenza infection induces platelet-lung endothelial adhesion via fibronectin, contributing to mortality from acute lung injury. The inhibition of platelets may constitute a practical adjunctive strategy to the treatment of severe infections with influenza.IMPORTANCE There is growing appreciation of the involvement of the lung endothelium in the pathogenesis of severe infections with influenza virus. We have

  13. COMPLEX CLINICAL AND INSTRUMENTAL EVALUATION OF LUNG INJURY IN PATIENTS WITH RHEUMATOID ARTHRITIS

    Directory of Open Access Journals (Sweden)

    I. I. Nesterovich

    2016-01-01

    Full Text Available The damage of the respiratory system is a quite common  extra-articular manifestation  of rheumatoid  arthritis (RA. It is important  to note that its clinical symptoms occur in only 20–30% of patients; however, subclinical forms identified by active screening are observed in 70–80% of patients.Objective: to compare the significance of pulmonary complaints,  the results of physical examination, and the data of instrumental  studies for the detection  of lung injury in patients with RA.Subjects and methods. The study enrolled 70 RA patients (63 women and 7 men aged 24 to 83 years. Only 10% of them had clinically evident lung injury associated with RA. Patients with other pulmonary diseases, such as asthma, chronic obstructive pulmonary disease, etc., were excluded. Physical examination, radiography/fluoroscopy, high-resolution computed  tomography (HRCT, single-photon emission computed  tomography (SPECT of the lung, and lung function testing (LFT with the determination of lung diffusion capacity.Results and discussion. The data of physical examination  were nonspecific and unconvincing.  Pulmonary  complaints (dyspnea, cough, expectoration were seen in 65% of the patients; an objective assessment revealed changes (vesiculotympanitic resonance,  harsh breathing, and pleural friction rub in 40%. The X-ray films/fluorograms  displayed abnormalities (pulmonary fibrosis, focal changes in only 10% of cases. 92% of the patients had lung HRCT  changes including moderate (bronchial  obstruction (40%, rheumatoid  nodules (10%, ground glass opacities (60%, bronchial thickening (20%, pleural effusion (10%, tree-in-bud opacities (3% and severe (pulmonary hypertension  (10%, bronchiectasis (10%, emphysema (5% and lung tissue fibrotic changes as the honeycomb lung (2% ones. SPECT showed local hypoperfusion in the mantle and mediastinal parts of the lungs in 80% of cases. LFT analysis demonstrated reduced lung diffusion capacity in 41% of

  14. Recurrent recruitment manoeuvres improve lung mechanics and minimize lung injury during mechanical ventilation of healthy mice.

    Directory of Open Access Journals (Sweden)

    Lucy Kathleen Reiss

    Full Text Available INTRODUCTION: Mechanical ventilation (MV of mice is increasingly required in experimental studies, but the conditions that allow stable ventilation of mice over several hours have not yet been fully defined. In addition, most previous studies documented vital parameters and lung mechanics only incompletely. The aim of the present study was to establish experimental conditions that keep these parameters within their physiological range over a period of 6 h. For this purpose, we also examined the effects of frequent short recruitment manoeuvres (RM in healthy mice. METHODS: Mice were ventilated at low tidal volume V(T = 8 mL/kg or high tidal volume V(T = 16 mL/kg and a positive end-expiratory pressure (PEEP of 2 or 6 cm H(2O. RM were performed every 5 min, 60 min or not at all. Lung mechanics were followed by the forced oscillation technique. Blood pressure (BP, electrocardiogram (ECG, heart frequency (HF, oxygen saturation and body temperature were monitored. Blood gases, neutrophil-recruitment, microvascular permeability and pro-inflammatory cytokines in bronchoalveolar lavage (BAL and blood serum as well as histopathology of the lung were examined. RESULTS: MV with repetitive RM every 5 min resulted in stable respiratory mechanics. Ventilation without RM worsened lung mechanics due to alveolar collapse, leading to impaired gas exchange. HF and BP were affected by anaesthesia, but not by ventilation. Microvascular permeability was highest in atelectatic lungs, whereas neutrophil-recruitment and structural changes were strongest in lungs ventilated with high tidal volume. The cytokines IL-6 and KC, but neither TNF nor IP-10, were elevated in the BAL and serum of all ventilated mice and were reduced by recurrent RM. Lung mechanics, oxygenation and pulmonary inflammation were improved by increased PEEP. CONCLUSIONS: Recurrent RM maintain lung mechanics in their physiological range during low tidal volume ventilation of healthy mice by

  15. Recurrent recruitment manoeuvres improve lung mechanics and minimize lung injury during mechanical ventilation of healthy mice.

    Science.gov (United States)

    Reiss, Lucy Kathleen; Kowallik, Anke; Uhlig, Stefan

    2011-01-01

    Mechanical ventilation (MV) of mice is increasingly required in experimental studies, but the conditions that allow stable ventilation of mice over several hours have not yet been fully defined. In addition, most previous studies documented vital parameters and lung mechanics only incompletely. The aim of the present study was to establish experimental conditions that keep these parameters within their physiological range over a period of 6 h. For this purpose, we also examined the effects of frequent short recruitment manoeuvres (RM) in healthy mice. Mice were ventilated at low tidal volume V(T) = 8 mL/kg or high tidal volume V(T) = 16 mL/kg and a positive end-expiratory pressure (PEEP) of 2 or 6 cm H(2)O. RM were performed every 5 min, 60 min or not at all. Lung mechanics were followed by the forced oscillation technique. Blood pressure (BP), electrocardiogram (ECG), heart frequency (HF), oxygen saturation and body temperature were monitored. Blood gases, neutrophil-recruitment, microvascular permeability and pro-inflammatory cytokines in bronchoalveolar lavage (BAL) and blood serum as well as histopathology of the lung were examined. MV with repetitive RM every 5 min resulted in stable respiratory mechanics. Ventilation without RM worsened lung mechanics due to alveolar collapse, leading to impaired gas exchange. HF and BP were affected by anaesthesia, but not by ventilation. Microvascular permeability was highest in atelectatic lungs, whereas neutrophil-recruitment and structural changes were strongest in lungs ventilated with high tidal volume. The cytokines IL-6 and KC, but neither TNF nor IP-10, were elevated in the BAL and serum of all ventilated mice and were reduced by recurrent RM. Lung mechanics, oxygenation and pulmonary inflammation were improved by increased PEEP. Recurrent RM maintain lung mechanics in their physiological range during low tidal volume ventilation of healthy mice by preventing atelectasis and reduce the development of

  16. Recurrent Recruitment Manoeuvres Improve Lung Mechanics and Minimize Lung Injury during Mechanical Ventilation of Healthy Mice

    Science.gov (United States)

    Reiss, Lucy Kathleen; Kowallik, Anke; Uhlig, Stefan

    2011-01-01

    Introduction Mechanical ventilation (MV) of mice is increasingly required in experimental studies, but the conditions that allow stable ventilation of mice over several hours have not yet been fully defined. In addition, most previous studies documented vital parameters and lung mechanics only incompletely. The aim of the present study was to establish experimental conditions that keep these parameters within their physiological range over a period of 6 h. For this purpose, we also examined the effects of frequent short recruitment manoeuvres (RM) in healthy mice. Methods Mice were ventilated at low tidal volume VT = 8 mL/kg or high tidal volume VT = 16 mL/kg and a positive end-expiratory pressure (PEEP) of 2 or 6 cmH2O. RM were performed every 5 min, 60 min or not at all. Lung mechanics were followed by the forced oscillation technique. Blood pressure (BP), electrocardiogram (ECG), heart frequency (HF), oxygen saturation and body temperature were monitored. Blood gases, neutrophil-recruitment, microvascular permeability and pro-inflammatory cytokines in bronchoalveolar lavage (BAL) and blood serum as well as histopathology of the lung were examined. Results MV with repetitive RM every 5 min resulted in stable respiratory mechanics. Ventilation without RM worsened lung mechanics due to alveolar collapse, leading to impaired gas exchange. HF and BP were affected by anaesthesia, but not by ventilation. Microvascular permeability was highest in atelectatic lungs, whereas neutrophil-recruitment and structural changes were strongest in lungs ventilated with high tidal volume. The cytokines IL-6 and KC, but neither TNF nor IP-10, were elevated in the BAL and serum of all ventilated mice and were reduced by recurrent RM. Lung mechanics, oxygenation and pulmonary inflammation were improved by increased PEEP. Conclusions Recurrent RM maintain lung mechanics in their physiological range during low tidal volume ventilation of healthy mice by preventing atelectasis and

  17. C60 Exposure Augments Cardiac Ischemia/Reperfusion Injury and Coronary Artery Contraction in Sprague Dawley Rats

    Science.gov (United States)

    Holland, Nathan A.; Vidanapathirana, Achini K.; Pitzer, Joshua E.; Han, Li; Sumner, Susan J.; Lewin, Anita H.; Fennell, Timothy R.; Lust, Robert M.; Brown, Jared M.; Wingard, Christopher J.

    2014-01-01

    The potential uses of engineered C60 fullerene (C60) have expanded in recent decades to include industrial and biomedical applications. Based on clinical findings associated with particulate matter exposure and our data with multi-walled carbon nanotubes, we hypothesized that ischemia/reperfusion (I/R) injury and pharmacological responses in isolated coronary arteries would depend upon the route of exposure and gender in rats instilled with C60. Male and female Sprague Dawley rats were used to test this hypothesis by surgical induction of cardiac I/R injury in situ 24 h after intratracheal (IT) or intravenous (IV) instillation of 28 μg of C60 formulated in polyvinylpyrrolidone (PVP) or PVP vehicle. Serum was collected for quantification of various cytokines. Coronary artery segments were isolated for assessment of vasoactive pharmacology via wire myography. Both IV and IT exposure to C60 resulted in expansion of myocardial infarction in male and female rats following I/R injury. Serum-collected post-I/R showed elevated concentrations of interleukin-6 and monocyte chemotactic protein-1 in male rats exposed to IV C60. Coronary arteries isolated from male rats exposed to IT C60 demonstrated augmented vasocontraction in response to endothelin-1 that was attenuated with Indomethacin. IV C60 exposure resulted in impaired acetylcholine relaxation in male rats and IT C60 exposure resulted in depressed vasorelaxation in response to sodium nitroprusside in female rats. Based on these data, we conclude that IT and IV exposure to C60 results in unique cardiovascular consequences that may favor heightened coronary resistance and myocardial susceptibility to I/R injury. PMID:24431213

  18. Peroxisome Proliferator-Activated Receptors and Acute Lung Injury

    Directory of Open Access Journals (Sweden)

    Rosanna Di Paola

    2007-01-01

    Full Text Available Peroxisome proliferator-activated receptors are ligand-activated transcription factors belonging to the nuclear hormone receptor superfamily. PPARs regulate several metabolic pathways by binding to sequence-specific PPAR response elements in the promoter region of target genes, including lipid biosynthesis and glucose metabolism. Recently, PPARs and their respective ligands have been implicated as regulators of cellular inflammatory and immune responses. These molecules are thought to exert anti-inflammatory effects by negatively regulating the expression of proinflammatory genes. Several studies have demonstrated that PPAR ligands possess anti-inflammatory properties and that these properties may prove helpful in the treatment of inflammatory diseases of the lung. This review will outline the anti-inflammatory effects of PPARs and PPAR ligands and discuss their potential therapeutic effects in animal models of inflammatory lung disease.

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

    Science.gov (United States)

    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.

  20. Long-Term Ethanol Consumption Leadsto Lung Tissue Oxidative Stress and Injury

    Science.gov (United States)

    Das, Subir Kumar; Mukherjee, Sukhes

    2010-01-01

    Background: 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. Results: Though body weight of rats increased significantly with duration of exposure compared to its initial weight, 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 (GSS G), redox ratio (GSS G/ 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. Methods: 16–18 week-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. Conclusions: Results of this study indicate that long-term ethanol administration aggravates systemic and local oxidative stress, which may be associated with lung tissue injury. PMID:21307643

  1. [Significance of the NLRP3 inflammasome expression in rats with acute lung injury induced by phosgene].

    Science.gov (United States)

    He, D K; Shao, Y R; Shen, J; Zhang, L; Zhang, J; Zhang, F

    2017-07-20

    Objective: To investigate changes of NLRP3 signal transduction pathway of acute lung injury induced by phosgene to analyze NLRP3-mediated IL-1β release inflammatory process in rats. Methods: Rats were randomly divided into two groups, 10 rats in the Air group that consists of the rats with air exposure, 10 rats in the Psg group that consists of the rats with phosgene exposure at 8.33 g/m(3) for 5 min. The specimens of serum, bronchoalveolar lavage fluid (BALF) and lung were collected after 6h. Morphological changes were observed by HE staining. The expression of NLRP3 in the lung of two groups was detected by immunohistochemistry. NLRP3、ASC and caspase-1 expression in the lung tissue was quantified by Western blot. Reverse transcription-polymerase chain reaction (RT-PCR) were used to detect the expression of NLRP3、ASC and caspase-1 mRNA in the lung tissue. The concentrations of IL-1β、IL-18 and IL-33 in the serum and BALF were measured by enzyme-linked immunosorbent assay. RT-PCR were used to detect the expression of IL-1β、IL-18 and IL-33 mRNA in the lung tissue. Results: We successfully replicated the model of phosgene-induced ALI in rats. Morphological of HE staining after phosgene exposure to 6 h observed inflammatory cell infiltration in lung tissue in Phosgene group. Immunohistochemical staining results showed that there were many NLRP3 positive cells in lung tissue in Phosgene group. The levels of NLRP3 and caspase-1 mRNA and protein expression in lung were significantly increased ( P lung ASC mRNA and protein expression ( P >0.05) . Compared with Air group, the serum, BALF and lung tissue of IL-1β、IL-18 and IL-33 mRNA and protein expression were significantly increased ( P NLRP3-mediated inflammatory response probably involved in the process of the phosgene, so it maybe one of the pathogenesis of acute lung injury.

  2. Mesenchymal stromal cells are more effective than the MSC secretome in diminishing injury and enhancing recovery following ventilator-induced lung injury.

    Science.gov (United States)

    Hayes, Mairead; Curley, Gerard F; Masterson, Claire; Devaney, James; O'Toole, Daniel; Laffey, John G

    2015-12-01

    The potential for mesenchymal stem cells (MSCs) to reduce the severity of experimental lung injury has been established in several pre-clinical studies. We have recently demonstrated that MSCs, and MSC-secreted factors (secretome), enhance lung repair and regeneration at 48 h following ventilation-induced lung injury (VILI). We wished to determine the potential for MSC therapy to exert beneficial effects in the early recovery phase following VILI when ongoing injury coexists with processes of repair, and to compare the efficacy of MSC therapy to the use of the secretome alone. Male Sprague-Dawley rats were anesthetized, oro-tracheally intubated, and subjected to high stretch mechanical ventilation until lung compliance had declined by 50 % of baseline. Animals were then weaned from mechanical ventilation, and anesthesia discontinued. Once awake and spontaneously ventilating, animals received an intravenous injection of either rodent MSCs (10 million/kg), MSC-conditioned medium, fibroblasts (10 million/kg), or vehicle. Thereafter, the animals were allowed to recover and the extent of lung injury/repair was determined after 4 h. Treatment with MSCs diminished injury and enhanced recovery following VILI to a greater extent compared to MSC-conditioned medium, with fibroblasts proving ineffective. MSCs, but not their conditioned medium, attenuated indices of lung injury including oxygenation, respiratory compliance, and lung edema. Total lung water as assessed by wet:dry ratio, bronchoalveolar lavage total inflammatory cell, neutrophil counts, and alveolar IL-6 concentrations were reduced in the animals that received MSC therapy. The immunomodulating and/or reparative effect of MSCs is evident early after VILI in this model. MSC-conditioned medium was not as effective as the cells themselves in diminishing injury and restoring lung structure and function.

  3. Role of cholesterol in the biophysical dysfunction of surfactant in ventilator-induced lung injury.

    Science.gov (United States)

    Vockeroth, Dan; Gunasekara, Lasantha; Amrein, Matthias; Possmayer, Fred; Lewis, James F; Veldhuizen, Ruud A W

    2010-01-01

    Mechanical ventilation may lead to an impairment of the endogenous surfactant system, which is one of the mechanisms by which this intervention contributes to the progression of acute lung injury. The most extensively studied mechanism of surfactant dysfunction is serum protein inhibition. However, recent studies indicate that hydrophobic components of surfactant may also contribute. It was hypothesized that elevated levels of cholesterol significantly contribute to surfactant dysfunction in ventilation-induced lung injury. Sprague-Dawley rats (n = 30) were randomized to either high-tidal volume or low-tidal volume ventilation and monitored for 2 h. Subsequently, the lungs were lavaged, surfactant was isolated, and the biophysical properties of this isolated surfactant were analyzed on a captive bubble surfactometer with and without the removal of cholesterol using methyl-beta-cyclodextrin. The results showed lower oxygenation values in the high-tidal volume group during the last 30 min of ventilation compared with the low-tidal volume group. Surfactant obtained from the high-tidal volume animals had a significant impairment in function compared with material from the low-tidal volume group. Removal of cholesterol from the high-tidal volume group improved the ability of the surfactant to reduce the surface tension to low values. Subsequent reconstitution of high-cholesterol values led to an impairment in surface activity. It is concluded that increased levels of cholesterol associated with endogenous surfactant represent a major contributor to the inhibition of surfactant function in ventilation-induced lung injury.

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

    Directory of Open Access Journals (Sweden)

    Jutaro Fukumoto

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

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

    Energy Technology Data Exchange (ETDEWEB)

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

    2013-07-05

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

  6. Ventilator-Induced Lung Injury (VILI) in Acute Respiratory Distress Syndrome (ARDS): Volutrauma and Molecular Effects

    Science.gov (United States)

    Carrasco Loza, R; Villamizar Rodríguez, G; Medel Fernández, N

    2015-01-01

    Acute Respiratory Distress Syndrome (ARDS) is a clinical condition secondary to a variety of insults leading to a severe acute respiratory failure and high mortality in critically ill patients. Patients with ARDS generally require mechanical ventilation, which is another important factor that may increase the ALI (acute lung injury) by a series of pathophysiological mechanisms, whose common element is the initial volutrauma in the alveolar units, and forming part of an entity known clinically as ventilator-induced lung injury (VILI). Injured lungs can be partially protected by optimal settings and ventilation modes, using low tidal volume (VT) values and high positive-end expiratory pressure (PEEP). The benefits in ARDS outcomes caused by these interventions have been confirmed by several prospective randomized controlled trials (RCTs) and are attributed to reduction in volutrauma. The purpose of this article is to present an approach to VILI pathophysiology focused on the effects of volutrauma that lead to lung injury and the ‘mechanotransduction’ mechanism. A more complete understanding about the molecular effects that physical forces could have, is essential for a better assessment of existing strategies as well as the development of new therapeutic strategies to reduce the damage resulting from VILI, and thereby contribute to reducing mortality in ARDS. PMID:26312103

  7. Ghrelin attenuates acute pancreatitis-induced lung injury and inhibits substance P expression.

    Science.gov (United States)

    Zhou, Xiaolei; Xue, Chengrui

    2010-01-01

    To investigate the effect of ghrelin administration on the severity of acute lung injury and on the production of proinflammatory cytokines and Substance P (SP) in rats with acute pancreatitis (AP). AP was induced in rats by sodium taurocholate injection through pancreaticobiliary duct. Ghrelin 20 nmol/kg was given before and after the treatment. Tumor necrosis factor-alpha, interleukin-1beta, and -6 levels in the serum were measured using the radioimmunoassay method. Morphological signs of lung injury, pulmonary water content, microvascular permeability, and myeloperoxidase activity were measured. Meanwhile, the determination of pulmonary SP mRNA level and its expression were performed by reverse transcriptase polymerase chain reaction and immunohistochemistry. The serum proinflammatory cytokines, pulmonary water content, microvascular permeability, and myeloperoxidase activity were increased, and morphological damages were observed in the lung of AP rats. SP mRNA level and its expression were significantly higher in sham-operated rats (P ghrelin. Pulmonary SP expression was also significantly down-regulated by ghrelin (P Ghrelin attenuates the severity of acute lung injury induced by AP. The reduction of neutrophil sequestration, limitation of proinflammatory cytokines release, and inhibition of pulmonary SP expression may be the mechanisms involved in the therapeutic effect of ghrelin.

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

    Science.gov (United States)

    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.

  9. Preservation solution supplemented with biliverdin prevents lung cold ischaemia/reperfusion injury.

    Science.gov (United States)

    Sugimoto, Ryujiro; Tanaka, Yugo; Noda, Kentaro; Kawamura, Tomohiro; Toyoda, Yoshiya; Billiar, Timothy R; McCurry, Kenneth R; Nakao, Atsunori

    2012-12-01

    Biliverdin (BV), one of the byproducts of heme catalysis through the heme oxygenase system, is a known scavenger of the reactive oxygen species. We hypothesized that adding BV to the perfusate and cold storage solution could protect rat lung grafts from oxidative injuries via its antioxidant efficacies. Orthotopic left lung transplantation was performed in a syngenic Lewis-to-Lewis rat combination under 100% oxygen. Grafts were preserved in low-potassium dextran (LPD; Perfadex) at 4°C for 6 h with or without supplementation of 1 or 10 μM of BV into LPD. Prolonged cold storage and reperfusion resulted in a considerable deterioration of graft functions associated with massive apoptosis in the grafts after reperfusion. The untreated grafts exhibited the early up-regulations of mRNA for inflammatory mediators and an increase in a marker of lipid peroxidation, showing oxidative injuries. Although BV supplementation of LPD at a lower concentration (1 μM) did not improve the graft gas exchange, the grafts treated with BV (10 μM) showed a significant improvement of oxygenation and less inflammatory responses as well as reduced lipid peroxidation and apoptosis. Although the rapid activations of mitogen-activated protein kinases (MAPKs) were seen 30 min after reperfusion in the grafts stored in control LPD, BV treatment significantly reduced phosphorylated-MAPK protein expression. This study demonstrates that the exposure of the lung grafts to BV during cold storage can impart potent cytoprotective effects to lung cold ischaemia/reperfusion injury and significantly improve the lung graft function following extended cold preservation and transplantation by the mechanism of a reduction in oxidative injury and following inflammatory events.

  10. Inflammasome-regulated cytokines are critical mediators of acute lung injury.

    Science.gov (United States)

    Dolinay, Tamás; Kim, Young Sam; Howrylak, Judie; Hunninghake, Gary M; An, Chang Hyeok; Fredenburgh, Laura; Massaro, Anthony F; Rogers, Angela; Gazourian, Lee; Nakahira, Kiichi; Haspel, Jeffrey A; Landazury, Roberto; Eppanapally, Sabitha; Christie, Jason D; Meyer, Nuala J; Ware, Lorraine B; Christiani, David C; Ryter, Stefan W; Baron, Rebecca M; Choi, Augustine M K

    2012-06-01

    Despite advances in clinical management, there are currently no reliable diagnostic and therapeutic targets for acute respiratory distress syndrome (ARDS). The inflammasome/caspase-1 pathway regulates the maturation and secretion of proinflammatory cytokines (e.g., IL-18). IL-18 is associated with injury in animal models of systemic inflammation. We sought to determine the contribution of the inflammasome pathway in experimental acute lung injury and human ARDS. We performed comprehensive gene expression profiling on peripheral blood from patients with critical illness. Gene expression changes were assessed using real-time polymerase chain reaction, and IL-18 levels were measured in the plasma of the critically ill patients. Wild-type mice or mice genetically deficient in IL-18 or caspase-1 were mechanically ventilated using moderate tidal volume (12 ml/kg). Lung injury parameters were assessed in lung tissue, serum, and bronchoalveolar lavage fluid. In mice, mechanical ventilation enhanced IL-18 levels in the lung, serum, and bronchoalveolar lavage fluid. IL-18-neutralizing antibody treatment, or genetic deletion of IL-18 or caspase-1, reduced lung injury in response to mechanical ventilation. In human patients with ARDS, inflammasome-related mRNA transcripts (CASP1, IL1B, and IL18) were increased in peripheral blood. In samples from four clinical centers, IL-18 was elevated in the plasma of patients with ARDS (sepsis or trauma-induced ARDS) and served as a novel biomarker of intensive care unit morbidity and mortality. The inflammasome pathway and its downstream cytokines play critical roles in ARDS development.

  11. Targeted Type 2 Alveolar Cell Depletion. A Dynamic Functional Model for Lung Injury Repair

    Science.gov (United States)

    Garcia, Orquidea; Hiatt, Michael J.; Lundin, Amber; Lee, Jooeun; Reddy, Raghava; Navarro, Sonia; Kikuchi, Alex

    2016-01-01

    Type 2 alveolar epithelial cells (AEC2) are regarded as the progenitor population of the alveolus responsible for injury repair and homeostatic maintenance. Depletion of this population is hypothesized to underlie various lung pathologies. Current models of lung injury rely on either uncontrolled, nonspecific destruction of alveolar epithelia or on targeted, nontitratable levels of fixed AEC2 ablation. We hypothesized that discrete levels of AEC2 ablation would trigger stereotypical and informative patterns of repair. To this end, we created a transgenic mouse model in which the surfactant protein-C promoter drives expression of a mutant SR39TK herpes simplex virus-1 thymidine kinase specifically in AEC2. Because of the sensitivity of SR39TK, low doses of ganciclovir can be administered to these animals to induce dose-dependent AEC2 depletion ranging from mild (50%) to lethal (82%) levels. We demonstrate that specific levels of AEC2 depletion cause altered expression patterns of apoptosis and repair proteins in surviving AEC2 as well as distinct changes in distal lung morphology, pulmonary function, collagen deposition, and expression of remodeling proteins in whole lung that persist for up to 60 days. We believe SPCTK mice demonstrate the utility of cell-specific expression of the SR39TK transgene for exerting fine control of target cell depletion. Our data demonstrate, for the first time, that specific levels of type 2 alveolar epithelial cell depletion produce characteristic injury repair outcomes. Most importantly, use of these mice will contribute to a better understanding of the role of AEC2 in the initiation of, and response to, lung injury. PMID:26203800

  12. Protective effect of U74500A on phorbol myristate acetate-induced acute lung injury.

    Science.gov (United States)

    Chu, Shi-Jye; Chang, Deh-Ming; Wang, David; Lin, Hen-I; Lin, Shih-Hua; Hsu, Kang

    2004-08-01

    1. The present study was designed to determine whether U74500A could ameliorate acute lung injury (ALI) induced by phorbol myristate acetate (PMA) in our rat isolated lung model compared with any amelioration induced by dimethylthiourea (DMTU), superoxide dismutase (SOD) and catalase. 2. Acute lung injury was induced successfully by PMA during 60 min of observation. At 2 microg/kg, PMA elicited a significant increase in microvascular permeability (measured using the capillary filtration coefficient Kfc), lung weight gain, the lung weight/bodyweight ratio, pulmonary arterial pressure and protein concentration of the bronchoalveolar lavage fluid. 3. Pretreatment with 1.5 mg/kg U74500A significantly attenuated ALI; there was no significant increase in any parameters measured, except for pulmonary arterial pressure. The protective effect of U74500A was approximately the same as that of 600 mg/kg DMTU. However, 6000 U/kg SOD, 50,000 U/kg catalase and 6000 U/kg SOD + 50,000 U/kg catalase had no protective effect. 4. These experimental data suggest that U74500A significantly ameliorates ALI induced by PMA in rats.

  13. Inhibition of acid-induced lung injury by hyperosmolar sucrose in rats.

    Science.gov (United States)

    Safdar, Zeenat; Yiming, Maimiti; Grunig, Gabriele; Bhattacharya, Jahar

    2005-10-15

    Acid aspiration causes acute lung injury (ALI). Recently, we showed that a brief intravascular infusion of hyperosmolar sucrose, given concurrently with airway acid instillation, effectively blocks the ensuing ALI. The objective of the present study was to determine the extent to which intravascular infusion of hyperosmolar sucrose might protect against acid-induced ALI when given either before or after acid instillation. Our studies were conducted in anesthetized rats and in isolated, blood-perfused rat lungs. We instilled HCl through the airway, and we quantified lung injury in terms of the extravascular lung water (EVLW) content, filtration coefficient (Kfc), and cell counts and protein concentration in the bronchoalveolar lavage. We infused hyperosmolar sucrose via the femoral vein. In anesthetized rats, airway HCl instillation induced ALI as indicated by a 52% increase of EVLW and a threefold increase in Kfc. However, a 15-min intravenous infusion of hyperosmolar sucrose given up to 1 h before or 30 min after acid instillation markedly blunted the increases in EVLW, as well as the increases in cell count, and in protein concentration in the bronchoalveolar lavage. Hyperosmolar pretreatment also blocked the acid-induced increase of Kfc. Studies in isolated perfused lungs indicated that the protective effect of hyperosmolar sucrose was leukocyte independent. We conclude that a brief period of vascular hyperosmolarity protects against acid-induced ALI when the infusion is administered shortly before, or shortly after, acid instillation in the airway. The potential applicability of hyperosmolar sucrose in therapy for ALI requires consideration.

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

    Science.gov (United States)

    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.

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

    Directory of Open Access Journals (Sweden)

    Zhongchen Zhang

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

  16. Integrative Assessment of Chlorine-Induced Acute Lung Injury in Mice

    Science.gov (United States)

    Pope-Varsalona, Hannah; Concel, Vincent J.; Liu, Pengyuan; Bein, Kiflai; Berndt, Annerose; Martin, Timothy M.; Ganguly, Koustav; Jang, An Soo; Brant, Kelly A.; Dopico, Richard A.; Upadhyay, Swapna; Di, Y. P. Peter; Hu, Zhen; Vuga, Louis J.; Medvedovic, Mario; Kaminski, Naftali; You, Ming; Alexander, Danny C.; McDunn, Jonathan E.; Prows, Daniel R.; Knoell, Daren L.

    2012-01-01

    The genetic basis for the underlying individual susceptibility to chlorine-induced acute lung injury is unknown. To uncover the genetic basis and pathophysiological processes that could provide additional homeostatic capacities during lung injury, 40 inbred murine strains were exposed to chlorine, and haplotype association mapping was performed. The identified single-nucleotide polymorphism (SNP) associations were evaluated through transcriptomic and metabolomic profiling. Using ≥ 10% allelic frequency and ≥ 10% phenotype explained as threshold criteria, promoter SNPs that could eliminate putative transcriptional factor recognition sites in candidate genes were assessed by determining transcript levels through microarray and reverse real-time PCR during chlorine exposure. The mean survival time varied by approximately 5-fold among strains, and SNP associations were identified for 13 candidate genes on chromosomes 1, 4, 5, 9, and 15. Microarrays revealed several differentially enriched pathways, including protein transport (decreased more in the sensitive C57BLKS/J lung) and protein catabolic process (increased more in the resistant C57BL/10J lung). Lung metabolomic profiling revealed 95 of the 280 metabolites measured were altered by chlorine exposure, and included alanine, which decreased more in the C57BLKS/J than in the C57BL/10J strain, and glutamine, which increased more in the C57BL/10J than in the C57BLKS/J strain. Genetic associations from haplotype mapping were strengthened by an integrated assessment using transcriptomic and metabolomic profiling. The leading candidate genes associated with increased susceptibility to acute lung injury in mice included Klf4, Sema7a, Tns1, Aacs, and a gene that encodes an amino acid carrier, Slc38a4. PMID:22447970

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

    Science.gov (United States)

    Liverani, Elisabetta

    2017-03-01

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

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

    Directory of Open Access Journals (Sweden)

    Ye. V Suborov

    2007-01-01

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

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

    Science.gov (United States)

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

    2015-02-01

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

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

    Directory of Open Access Journals (Sweden)

    Basyigit Ilknur

    2010-04-01

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

  1. Microstructural Consequences of Blast Lung Injury Characterized with Digital Volume Correlation

    Directory of Open Access Journals (Sweden)

    Hari Arora

    2017-12-01

    Full Text Available This study focuses on microstructural changes that occur within the mammalian lung when subject to blast and how these changes influence strain distributions within the tissue. Shock tube experiments were performed to generate the blast injured specimens (cadaveric Sprague-Dawley rats. Blast overpressures of 100 and 180 kPa were studied. Synchrotron tomography imaging was used to capture volumetric image data of lungs. Specimens were ventilated using a custom-built system to study multiple inflation pressures during each tomography scan. These data enabled the first digital volume correlation (DVC measurements in lung tissue to be performed. Quantitative analysis was performed to describe the damaged architecture of the lung. No clear changes in the microstructure of the tissue morphology were observed due to controlled low- to moderate-level blast exposure. However, significant focal sites of injury were observed using DVC, which allowed the detection of bias and concentration in the patterns of strain level. Morphological analysis corroborated the findings, illustrating that the focal damage caused by a blast can give rise to diffuse influence across the tissue. It is important to characterize the non-instantly fatal doses of blast, given the transient nature of blast lung in the clinical setting. This research has highlighted the need for better understanding of focal injury and its zone of influence (alveolar interdependency and neighboring tissue burden as a result of focal injury. DVC techniques show great promise as a tool to advance this endeavor, providing a new perspective on lung mechanics after blast.

  2. Augmented inhibition from cannabinoid sensitive interneurons diminishes CA1 output after traumatic brain injury

    Directory of Open Access Journals (Sweden)

    Brian Neal Johnson

    2014-12-01

    Full Text Available The neurological impairments associated with traumatic brain injury include learning and memory deficits and increased risk of seizures. The hippocampus is critically involved in both of these phenomena and highly susceptible to damage by traumatic brain injury. To examine network activity in the hippocampal CA1 region after lateral fluid percussion injury, we used a combination of voltage sensitive dye, field potential and patch clamp recording in mouse hippocampal brain slices. When the stratum radiatum was stimulated in slices from injured mice we found decreased depolarization in stratum radiatum and increased hyperpolarization in stratum oriens, together with a decrease in the percentage of pyramidal neurons firing stimulus-evoked action potentials. Increased hyperpolarization in stratum oriens persisted when glutamatergic transmission was blocked. However, we found no changes in stratum oriens responses when the alveus was stimulated to directly activate stratum oriens. These results suggest that the increased stratum oriens hyperpolarization evoked by stratum radiatum stimulation was mediated by interneurons that have cell bodies and/or axons in stratum radiatum, and form synapses in stratum pyramidale and stratum oriens. A low concentration (100 nM of the synthetic cannabinoid WIN55,212-2,restored CA1 output in slices from injured animals. These findings support the hypothesis that increased GABAergic signaling by cannabinoid sensitive interneurons contributes to the reduced CA1 output following traumatic brain injury.

  3. Plasminogen Activator Inhibitor-1 Is Critical in Alcohol-Enhanced Acute Lung Injury in Mice.

    Science.gov (United States)

    Poole, Lauren G; Massey, Veronica L; Siow, Deanna L; Torres-Gonzáles, Edilson; Warner, Nikole L; Luyendyk, James P; Ritzenthaler, Jeffrey D; Roman, Jesse; Arteel, Gavin E

    2017-09-01

    Chronic alcohol exposure is a clinically important risk factor for the development of acute respiratory distress syndrome, the most severe form of acute lung injury (ALI). However, the mechanisms by which alcohol sensitizes the lung to development of this disease are poorly understood. We determined the role of the antifibrinolytic protein plasminogen activator inhibitor-1 (PAI-1) in alcohol enhancement of experimental endotoxin-induced ALI. Wild-type, PAI-1-/-, and integrin β3-/- mice were fed ethanol-containing Lieber-DeCarli liquid or a control diet for 6 weeks, followed by systemic LPS challenge. LPS administration triggered coagulation cascade activation as evidenced by increased plasma thrombin-antithrombin levels and pulmonary fibrin deposition. Ethanol-exposed animals showed enhanced PAI-1 expression and pulmonary fibrin deposition with coincident exaggeration of pulmonary inflammatory edematous injury. PAI-1 deficiency markedly reduced pulmonary fibrin deposition and greatly reduced inflammation and injury without impacting upstream coagulation. Interestingly, pulmonary platelet accumulation was effectively abolished by PAI-1 deficiency in ethanol/LPS-challenged mice. Moreover, mice lacking integrin αIIBβ3, the primary platelet receptor for fibrinogen, displayed a dramatic reduction in early inflammatory changes after ethanol/LPS challenge. These results indicate that the mechanism whereby alcohol exaggerates LPS-induced lung injury requires PAI-1-mediated pulmonary fibrin accumulation, and suggest a novel mechanism whereby alcohol contributes to inflammatory ALI by enhancing fibrinogen-platelet engagement.

  4. Inhibition of Chlorine-Induced Lung Injury by the Type 4 Phosphodiesterase Inhibitor Rolipram

    Science.gov (United States)

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

    2012-01-01

    Chlorine is a highly toxic respiratory irritant that when inhaled causes epithelial cell injury, alveolar-capillary barrier disruption, airway hyperreactivity, inflammation, and pulmonary edema. Chlorine is considered a chemical threat agent, and its release through accidental or intentional means has the potential to result in mass casualties from acute lung injury. The type 4 phosphodiesterase inhibitor rolipram was investigated as a rescue treatment for chlorine-induced lung injury. Rolipram inhibits degradation of the intracellular signaling molecule cyclic AMP. Potential beneficial effects of increased cyclic AMP levels include inhibition of pulmonary edema, inflammation, and airway hyperreactivity. Mice were exposed to chlorine (whole body exposure, 228–270 ppm for 1 h) and were treated with rolipram by intraperitoneal, intranasal, or intramuscular (either aqueous or nanoemulsion formulation) delivery starting 1 h after exposure. Rolipram administered intraperitoneally or intranasally inhibited chlorine-induced pulmonary edema. Minor or no effects were observed on lavage fluid IgM (indicative of plasma protein leakage), KC (Cxcl1, neutrophil chemoattractant), and neutrophils. All routes of administration inhibited chlorine-induced airway hyperreactivity assessed 1 day after exposure. The results of the study suggest that rolipram may be an effective rescue treatment for chlorine-induced lung injury and that both systemic and targeted administration to the respiratory tract were effective routes of delivery. PMID:22763362

  5. Pycnogenol, a compound isolated from the bark of pinus maritime mill, attenuates ventilator-induced lung injury through inhibiting NF-κB-mediated inflammatory response

    OpenAIRE

    Xia, YF; Zhang, JH; Xu, ZF; Deng, XM

    2015-01-01

    Background: During mechanical ventilation, high end-inspiratory lung volume results in a permeability type pulmonary oedema, called ventilator-induced lung injury (VILI). The pathophysiology of ventilator-induced lung injury involves multiple mechanisms, such as excessive inflammation. And pycnogenol is a mixture of flavonoid compounds extracted from pine tree bark that have anti-inflammatory activity. Objective: We investigated the effects of pyncogenol on ventilator-induced lung injury in r...

  6. Protective Effects of Infliximab on Lung Injury Induced by Methotrexate.

    Science.gov (United States)

    Kurt, Aysel; Tumkaya, Levent; Turut, Hasan; Cure, Medine Cumhur; Cure, Erkan; Kalkan, Yildiray; Sehitoglu, Ibrahim; Acipayam, Ahmet

    2015-11-01

    Methotrexate (MTX) is used to treat cancers, several forms of arthritis and other rheumatic conditions, although MTX may cause pulmonary toxicity related to the production of free oxygen radicals, various cytokines. Infliximab (IB) with its potent effect on tumor necrosis factor-alpha (TNF-α) inhibition also inhibits the release of endothelin-1 (ET-1). We aimed to investigate whether IB reduces pulmonary damage induced by an overdose of MTX. The rats were divided into 3 groups of 8 animals. The control group was given only saline. One dose of 20mg/kg MTX intraperitoneal was administered in the MTX group. IB 7 mg/kg was given to the MTX+IB (MI) group. Three days after IB was administered, 20mg/kg MTX was given. Five days after MTX was administered, all rats were sacrificed. The TNF-α, ET-1, malondialdehyde (MDA), myeloperoxidase (MPO) and caspase-3 levels in MTX group were significantly higher than in control groups of TNF-α (P=.001), ET-1 (P=.001), MDA (P=.001), MPO (P=.001) and caspase-3 levels (P=.001) and MI groups of TNF-α (P=.009), ET-1 (P=.001), MDA (P=.047), MPO (P=.007) and caspase-3 levels (P=.003). The MI group had less histopathological damage in lung tissue than the MTX group. Overdose of MTX leads to cytokine release and the formation of reactive oxygen species in addition to increased ET-1 secretion release that causes lung damage. IB, as a potent proinflammatory agent, TNF-α blocker, can decrease ET-1 release and oxidative stress, it may show significant protective effects in lung tissue against damage caused by MTX overdose. Copyright © 2014 SEPAR. Published by Elsevier Espana. All rights reserved.

  7. Adrenaline stimulates the proliferation and migration of mesenchymal stem cells towards the LPS-induced lung injury

    Science.gov (United States)

    Wu, Xiaodan; Wang, Zhiming; Qian, Mengjia; Wang, Lingyan; Bai, Chunxue; Wang, Xiangdong

    2014-01-01

    Bone marrow-derived mesenchymal stem cells (BMSCs) could modulate inflammation in experimental lung injury. On the other hand, adrenergic receptor agonists could increase DNA synthesis of stem cells. Therefore, we investigated the therapeutic role of adrenaline-stimulated BMSCs on lipopolysaccharide (LPS)-induced lung injury. BMSCs were cultured with adrenergic receptor agonists or antagonists. Suspensions of lung cells or sliced lung tissue from animals with or without LPS-induced injury were co-cultured with BMSCs. LPS-stimulated alveolar macrophages were co-cultured with BMSCs (with adrenaline stimulation or not) in Transwell for 6 hrs. A preliminary animal experiment was conducted to validate the findings in ex vivo study. We found that adrenaline at 10 μM enhanced proliferation of BMSCs through both α- and β-adrenergic receptors. Adrenaline promoted the migration of BMSCs towards LPS-injured lung cells or lung tissue. Adrenaline-stimulated BMSCs decreased the inflammation of LPS-stimulated macrophages, probably through the expression and secretion of several paracrine factors. Adrenaline reduced the extent of injury in LPS-injured rats. Our data indicate that adrenaline-stimulated BMSCs might contribute to the prevention from acute lung injury through the activation of adrenergic receptors, promotion of proliferation and migration towards injured lung, and modulation of inflammation. PMID:24684532

  8. Adrenaline stimulates the proliferation and migration of mesenchymal stem cells towards the LPS-induced lung injury.

    Science.gov (United States)

    Wu, Xiaodan; Wang, Zhiming; Qian, Mengjia; Wang, Lingyan; Bai, Chunxue; Wang, Xiangdong

    2014-08-01

    Bone marrow-derived mesenchymal stem cells (BMSCs) could modulate inflammation in experimental lung injury. On the other hand, adrenergic receptor agonists could increase DNA synthesis of stem cells. Therefore, we investigated the therapeutic role of adrenaline-stimulated BMSCs on lipopolysaccharide (LPS)-induced lung injury. BMSCs were cultured with adrenergic receptor agonists or antagonists. Suspensions of lung cells or sliced lung tissue from animals with or without LPS-induced injury were co-cultured with BMSCs. LPS-stimulated alveolar macrophages were co-cultured with BMSCs (with adrenaline stimulation or not) in Transwell for 6 hrs. A preliminary animal experiment was conducted to validate the findings in ex vivo study. We found that adrenaline at 10 μM enhanced proliferation of BMSCs through both α- and β-adrenergic receptors. Adrenaline promoted the migration of BMSCs towards LPS-injured lung cells or lung tissue. Adrenaline-stimulated BMSCs decreased the inflammation of LPS-stimulated macrophages, probably through the expression and secretion of several paracrine factors. Adrenaline reduced the extent of injury in LPS-injured rats. Our data indicate that adrenaline-stimulated BMSCs might contribute to the prevention from acute lung injury through the activation of adrenergic receptors, promotion of proliferation and migration towards injured lung, and modulation of inflammation. © 2014 The Authors. Journal of Cellular and Molecular Medicine published by John Wiley & Sons Ltd and Foundation for Cellular and Molecular Medicine.

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

    Science.gov (United States)

    Slutsky, Arthur S

    2015-05-15

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

  10. Oxidative Lung Injury in Virus-Induced Wheezing

    Science.gov (United States)

    2014-05-01

    in other disease models, such as cardiac hypertrophy and ischemia-reperfusion injury, as well as rheumathoid arthritis (20, 43). HDAC1 and 2 activity...model we will determine by established clinical-like parameters and pathophysiologic endpoints of airway dysfunction the effect of such pharmacologic...synthesis.  There are no studies investigating the role of H2S generation in pathophysiology of viral infections or the use of H2S donors as

  11. Overexpression of Brg1 Alleviates Hepatic Ischemia/Reperfusion-Induced Acute Lung Injury through Antioxidative Stress Effects

    Directory of Open Access Journals (Sweden)

    Mian Ge

    2017-01-01

    Full Text Available Aim. To investigate whether overexpression of Brahma-related gene-1 (Brg1 can alleviate lung injury induced by hepatic ischemia/reperfusion (HIR and its precise mechanism. Methods. Cytomegalovirus-transgenic Brg1-overexpressing (CMV-Brg1 mice and wild-type (WT C57BL/6 mice underwent HIR. Lung histology, oxidative injury markers, and antioxidant enzyme concentrations in the lung were assessed. The protein expression levels of Brg1, nuclear factor erythroid 2-related factor 2 (Nrf2, heme oxygenase-1 (HO-1, and NAD(PH:quinone oxidoreductase 1 (NQO1 in the lung were analyzed by Western blotting. Results. In the WT group, histopathological analysis revealed that lung damage peaked at 6 h after HIR. Meanwhile, the lung reactive oxygen species (ROS and 8-isoprostane levels were significantly increased. The protein expression of Brg1 in lung tissue decreased to a minimum at 6 h. Overexpression of Brg1 alleviated lung injury and decreased the amounts of oxidative products, including the levels of 8-isoprostane and ROS, as well as the percentage of positive cells for 4-hydroxynonenal (4-HNE and 8-oxo-2′-deoxyguanosine (8-OHdG. Brg1 overexpression increased the expression and nuclear translocation of Nrf2 as well as activated the antioxidases. In addition, it decreased the expression of inflammatory factors. Conclusion. Overexpression of Brg1 alleviates oxidative lung injury induced by HIR, likely through the Nrf2 pathway.

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

    Directory of Open Access Journals (Sweden)

    Crimi Nunzio

    2005-06-01

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

  13. ACE2 Antagonizes VEGFa to Reduce Vascular Permeability During Acute Lung Injury

    Directory of Open Access Journals (Sweden)

    Xiaobo Yu

    2016-03-01

    Full Text Available Background/Aims: Angiotensin converting enzyme 2 (ACE2 treatment suppresses the severity of acute lung injury (ALI, through antagonizing hydrolyzing angiotensin II (AngII and the ALI-induced apoptosis of pulmonary endothelial cells. Nevertheless, the effects of ACE2 on vessel permeability and its relationship with vascular endothelial growth factor a (VEGFa remain ill-defined. In the current study, we examined the relationship between ACE2 and VEGFa in ALI model in mice. Methods: Here, we used a previously published bleomycin method to induce ALI in mice, and treated the mice with ACE2. We analyzed the levels of VEGFa in these mice. The mouse lung vessel permeability was determined by a fluorescence pharmacokinetic assay following i.v. injection of 62.5µg/kg Visudyne. VEGFa pump or SU5416 pump was given to increase or decrease VEGFa effects, respectively. The long-term effects on lung function were determined by measurement of lung resistance using methacholine. Results: ACE2 treatment did not alter VEGFa levels in lung, but antagonized the effects of VEGFa on increases of lung vessel permeability. Ectogenic VEGFa abolished the antagonizing effects of ACE2 on the vessel permeability against VEGFa. On the other hand, suppression of VEGF signaling mimicked the effects of ACE2 on the vessel permeability against VEGFa. The suppression of vessel permeability resulted in improvement of lung function after ALI. Conclusion: ACE2 may antagonize the VEGFa-mediated increases in lung vessel permeability during ALI, resulting in improvement of lung function after ALI.

  14. Ozone Therapy and Hyperbaric Oxygen Treatment in Lung Injury in Septic Rats

    Science.gov (United States)

    Yamanel, Levent; Kaldirim, Umit; Oztas, Yesim; Coskun, Omer; Poyrazoglu, Yavuz; Durusu, Murat; Cayci, Tuncer; Ozturk, Ahmet; Demirbas, Seref; Yasar, Mehmet; Cinar, Orhan; Tuncer, Salim Kemal; Eyi, Yusuf Emrah; Uysal, Bulent; Topal, Turgut; Oter, Sukru; Korkmaz, Ahmet

    2011-01-01

    Various therapeutic protocols were used for the management of sepsis including hyperbaric oxygen (HBO) therapy. It has been shown that ozone therapy (OT) reduced inflammation in several entities and exhibits some similarity with HBO in regard to mechanisms of action. We designed a study to evaluate the efficacy of OT in an experimental rat model of sepsis to compare with HBO. Male Wistar rats were divided into sham, sepsis+cefepime, sepsis+cefepime+HBO, and sepsis+cefepime+OT groups. Sepsis was induced by an intraperitoneal injection of Escherichia coli; HBO was administered twice daily; OT was set as intraperitoneal injections once a day. The treatments were continued for 5 days after the induction of sepsis. At the end of experiment, the lung tissues and blood samples were harvested for biochemical and histological analysis. Myeloperoxidase activities and oxidative stress parameters, and serum proinflammatory cytokine levels, IL-1β and TNF-α, were found to be ameliorated by the adjuvant use of HBO and OT in the lung tissue when compared with the antibiotherapy only group. Histologic evaluation of the lung tissue samples confirmed the biochemical outcome. Our data presented that both HBO and OT reduced inflammation and injury in the septic rats' lungs; a greater benefit was obtained for OT. The current study demonstrated that the administration of OT as well as HBO as adjuvant therapy may support antibiotherapy in protecting the lung against septic injury. HBO and OT reduced tissue oxidative stress, regulated the systemic inflammatory response, and abated cellular infiltration to the lung demonstrated by findings of MPO activity and histopathologic examination. These findings indicated that OT tended to be more effective than HBO, in particular regarding serum IL-1β, lung GSH-Px and histologic outcome. PMID:21234269

  15. Intratracheal synthetic CpG oligodeoxynucleotide causes acute lung injury with systemic inflammatory response

    Directory of Open Access Journals (Sweden)

    Hasegawa Naoki

    2009-09-01

    Full Text Available Abstract Bacterial genome is characterized by frequent unmethylated cytosine-phosphate-guanine (CpG motifs. Deleterious effects can occur when synthetic oligodeoxynucleotides (ODN with unmethylated CpG dinucleotides (CpG-ODN are administered in a systemic fashion. We aimed to evaluate the effect of intratracheal CpG-ODN on lung inflammation and systemic inflammatory response. C57BL/6J mice received intratracheal administration of CpG-ODN (0.01, 0.1, 1.0, 10, or 100 μM or control ODN without CpG motif. Bronchoalveolar lavage (BAL fluid was obtained 3 or 6 h or 1, 2, 7, or 14 days after the instillation and subjected to a differential cell count and cytokine measurement. Lung permeability was evaluated as the BAL fluid-to-plasma ratio of the concentration of human serum albumin that was injected 1 h before euthanasia. Nuclear factor (NF-κB DNA binding activity was also evaluated in lung homogenates. Intratracheal administration of 10 μM or higher concentration of CpG-ODN induced significant inflammatory cell accumulation into the airspace. The peak accumulation of neutrophils and lymphocytes occurred 1 and 2 days after the CpG-ODN administration, respectively. Lung permeability was increased 1 day after the 10 μM CpG-ODN challenge. CpG-ODN also induced nuclear translocation of NF-κB and upregulation of various inflammatory cytokines in BAL fluid and plasma. Histopathology of the lungs and liver revealed acute lung injury and liver damage with necrosis, respectively. Control ODN without CpG motif did not induce any inflammatory change. Since intratracheal CpG-ODN induced acute lung injury as well as systemic inflammatory response, therapeutic strategies to neutralize bacterial DNA that is released after administration of bactericidal agents should be considered.

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

    Science.gov (United States)

    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. Copyright © 2016 Elsevier Masson SAS. All rights reserved.

  17. Usefulness of polyetheretherketone (PEEK) cage with plate augmentation for anterior arthrodesis in traumatic cervical spine injury.

    Science.gov (United States)

    Song, Kyung-Jin; Choi, Byung-Wan; Kim, Gyu-Hyung; Song, Ji-Hun

    2010-01-01

    Even though many clinical reports about cages have been documented in patients with degenerative disorders, reports were scarce for traumatic injury cases, and those cases using metal cages were restricted to only one-level injury. To evaluate the usefulness of polyetheretherketone (PEEK) cage and plate construction in anterior interbody fusions (AIF) for traumatic cervical spine injuries by analyzing radiographic changes and clinical outcomes. Retrospective study. Fifty-eight patients (91 levels) underwent cage and plate construction for treatment of traumatic cervical spine injury. The fusion rate, fusion time, changes of Cobb angle, subsidence rate, and adjacent level changes were assessed as a radiographic outcome. Clinical analysis includes the recovery rate on the American Spinal Injury Association (ASIA) impairment scale and the presence of the complications. We evaluated 58 patients (91 levels) who underwent surgery and had at least 24 months in follow-up study. Radiographic evaluation included the assessment of interbody fusion rate, fusion time, changes of Cobb angle, subsidence rate, and adjacent level changes. Clinical assessment was done by analyzing recovery state of ASIA impairment scale from preoperative period to the last follow-up and by evaluating complications. Fifty-four cases showed bony fusion within 3 months after the surgery. The mean Cobb angle between the vertebral bodies was 2.54 degrees before operation, 9.13 degrees after operation, and 8.39 degrees at the latest follow-up. The mean intervertebral disc height was increased by 3.01 mm after the operation, but the mean height was 2.17 mm shorter at the last follow-up than after postoperation. In terms of clinical results, five Grade A cases and one Grade B case as assessed by the ASIA impairment scale were unchanged until the last follow-up. Twenty-three cases of Grade C, 16 cases of Grade D, and 13 cases of Grade E improved to seven cases, 26 cases, and 19 cases, respectively. Three

  18. Mast cells protect against Pseudomonas aeruginosa-induced lung injury.

    Science.gov (United States)

    Junkins, Robert D; Carrigan, Svetlana O; Wu, Zhengli; Stadnyk, Andrew W; Cowley, Elizabeth; Issekutz, Thomas; Berman, Jason; Lin, Tong-Jun

    2014-08-01

    Pseudomonas aeruginosa, an opportunistic pathogen, is the leading cause of morbidity and mortality in immune-compromised individuals. Maintaining the integrity of the respiratory epithelium is critical for an effective host response to P. aeruginosa. Given the close spatial relationship between mast cells and the respiratory epithelium, and the importance of tightly regulated epithelial permeability during lung infections, we examined whether mast cells influence airway epithelial integrity during P. aeruginosa lung infection in a mouse model. We found that mast cell-deficient Kit(W-sh)/Kit(W-sh) mice displayed greatly increased epithelial permeability, bacterial dissemination, and neutrophil accumulation compared with wild-type animals after P. aeruginosa infection; these defects were corrected on reconstitution with mast cells. An in vitro Transwell co-culture model further demonstrated that a secreted mast cell factor decreased epithelial cell apoptosis and tumor necrosis factor production after P. aeruginosa infection. Together, our data demonstrate a previously unrecognized role for mast cells in the maintenance of epithelial integrity during P. aeruginosa infection, through a mechanism that likely involves prevention of epithelial apoptosis and tumor necrosis factor production. Our understanding of mechanisms of the host response to P. aeruginosa will open new avenues for the development of successful preventative and treatment strategies. Copyright © 2014 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.

  19. Combined anticoagulants ameliorate acute lung injury in sheep after burn and smoke inhalation.

    Science.gov (United States)

    Enkhbaatar, Perenlei; Esechie, Aimalohi; Wang, Jianpu; Cox, Robert A; Nakano, Yoshimitsu; Hamahata, Atsumori; Lange, Matthias; Traber, Lillian D; Prough, Donald S; Herndon, David N; Traber, Daniel L

    2008-02-01

    Burn and smoke inhalation-related multiple organ dysfunction is associated with a severe fall in the plasma concentration of antithrombin. Therefore the aim of the present study was to test the hypothesis that intravenous administration of recombinant human antithrombin in combination with aerosolized heparin will ameliorate acute lung injury in sheep exposed to cutaneous burn and smoke inhalation. Sheep were prepared operatively for study and, 7 days post-surgery, sheep were given a cutaneous burn (40% of total body surface area, third-degree burn) and insufflated with cotton smoke (48 breaths, injury, sheep were placed on a ventilator and resuscitated with Ringer's lactate solution. The animals were divided into three groups: sham group (non-injured and non-treated; n=6), saline group (injured and received saline; n=6) and rhAT.iv.+Hep group [injured and treated with rhAT (recombinant human antithrombin) and heparin; n=6]. In the rhAT.iv.+Hep group, rhAT was infused continuously for 48 h starting 1 h post-injury with a dose of 0.34 mg.h(-1).kg(-1) of body weight and heparin (10000 units) was aerosolized every 4 h starting at 1 h post-injury. The experiment lasted 48 h. Haemodynamics were stable in sham group, whereas the saline-treated sheep developed multiple signs of acute lung injury, including decreased pulmonary gas exchange, increased inspiratory pressures, extensive airway obstruction and increased pulmonary oedema. These pathological changes were associated with a severe fall in plasma antithrombin concentration, lung tissue accumulation of leucocytes and excessive production of NO. Treatment of injured sheep with anticoagulants attenuated all of the pulmonary pathophysiology observed. In conclusion, the results provide definitive evidence that anticoagulant therapy may be a novel and effective treatment tool in the management of burn patients with concomitant smoke inhalation injury.

  20. Hemocompatibility of a miniaturized extracorporeal membrane oxygenation and a pumpless interventional lung assist in experimental lung injury.

    Science.gov (United States)

    Kopp, Ruedger; Bensberg, Ralf; Henzler, Dietrich; Niewels, Anja; Randerath, Simone; Rossaint, Rolf; Kuhlen, Ralf

    2010-01-01

    Extracorporeal membrane oxygenation (ECMO) is used for most severe acute respiratory distress syndrome cases in specialized centers. Hemocompatibility of devices depends on the size and modification of blood contacting surfaces as well as blood flow rates. An interventional lung assist using arteriovenous perfusion of a low-resistance oxygenator without a blood pump (Novalung, Hechingen, Germany) or a miniaturized ECMO with reduced filling volume and a diagonal blood pump (Deltastream, Medos AG, Stolberg, Germany) could optimize hemocompatibility. The aim of the study was to compare hemocompatibility with conventional ECMO. Female pigs were connected to extracorporeal circulation for 24 h after lavage induced lung injury (eight per group). Activation of coagulation and immune system as well as blood cell damage was measured. A P value Plasmatic coagulation was slightly activated in all groups demonstrated by increased thrombin-anti-thrombin III-complex. No clinical signs of bleeding or thromboembolism occurred. Thrombelastography revealed decreased clotting capacities after miniaturized ECMO, probably due to significantly reduced platelet count. These resulted in reduced dosage of intravenous heparin. Scanning electron microscopy of oxygenator fibers showed significantly increased binding and shape change of platelets after interventional lung assist. In all groups, hemolysis remained negligible, indicated by low plasma hemoglobin concentration. Interleukin 8 and tumor necrosis factor-alpha concentration as well as leukocyte count remained unchanged. Both devices demonstrated adequate hemocompatibility for safe clinical application, although a missing blood pump did not increase hemocompatibility. Further studies seem necessary to analyze the influence of different blood pumps on platelet drop systematically.

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

    Science.gov (United States)

    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.

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

    Science.gov (United States)

    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.

  3. Immunohistochemical detection of CCR2 and CX3CR1 in sepsis-induced lung injury.

    Science.gov (United States)

    An, Jun-Ling; Ishida, Yuko; Kimura, Akihiko; Tsokos, Michael; Kondo, Toshikazu

    2009-11-20

    Sepsis is a systemic inflammatory disease with high mortality. In the present study, we immunohistochemically examined CCR2 and CX3CR1 expression in sepsis-induced lung injury, and discussed its availability for the postmortem diagnosis of sepsis. Lung samples were obtained from different lung lobes of nine sepsis and eight control cases with postmortem intervals between 12 and 48h. Immunohistochemically, mononuclear cells recruited into the lungs expressed CCR2 and CX3CR1 in both sepsis and non-septic groups. In double-color immunofluorescence analysis, CCR2- or CX3CR1-positive cells could be identified as CD68-positive macrophages. Moreover, most of CD68-positive macrophages expressed both CCR2 and CX3CR1. Morphometrically, the average of CCR2- and CX3CR1-positive macrophages was significantly increased in sepsis group, compared with control group (sepsis vs. control: 41.6+/-1.3% vs. 8.0+/-0.4% in CCR2; 36.2+/-1.3% vs. 9.2+/-0.4% in CX3CR1). These observations implied that CCR2- or CX3CR1-positive macrophages were recruited into the lungs under several pathological conditions. In particular, their recruitment might be more evident in sepsis. Moreover, from the forensic aspects, immunohistochemical detection of CCR2 and CX3CR1 expression in the lungs can be considered as valuable diagnostic tools for the postmortem diagnosis of sepsis.

  4. Therapeutic Effect of the Tuber of Alisma orientale on Lipopolysaccharide-Induced Acute Lung Injury

    Directory of Open Access Journals (Sweden)

    Kyun Ha Kim

    2013-01-01

    Full Text Available Although Alisma orientale, an ethnic herb, has been prescribed for treating various diseases in Asian traditional medicine, experimental evidence to support its therapeutic effects is lacking. Here, we sought to determine whether A. orientale has a therapeutic effect on acute lung injury (ALI. Ethanol extract of the tuber of A. orientale (EEAO was prepared and fingerprinted by HPLC for its constituents. Mice received an intraperitoneal (i.p. injection of lipopolysaccharide (LPS for the induction of ALI. At 2 h after LPS treatment, mice received an intratracheal (i.t. spraying of various amounts of EEAO to the lung. Bioluminescence imaging of transgenic NF-κB/luciferase reporter mice shows that i.t. EEAO posttreatment suppressed lung inflammation. In similar experiments with C57BL/6 mice, EEAO posttreatment significantly improved lung inflammation, as assessed by H&E staining of lung sections, counting of neutrophils in bronchoalveolar lavage fluid, and semiquantitative RT-PCR analyses of proinflammatory cytokines and Nrf2-dependent genes in the inflamed lungs. Furthermore, EEAO posttreatment enhanced the survival of mice that received a lethal dose of LPS. Together, our results provide evidence that A. orientale has a therapeutic effect on ALI induced by sepsis.

  5. Contributions of high mobility group box protein in experimental and clinical acute lung injury.

    Science.gov (United States)

    Ueno, Hiroshi; Matsuda, Tomoyuki; Hashimoto, Satoru; Amaya, Fumimasa; Kitamura, Yoshihiro; Tanaka, Masaki; Kobayashi, Atsuko; Maruyama, Ikuro; Yamada, Shingo; Hasegawa, Naoki; Soejima, Junko; Koh, Hidefumi; Ishizaka, Akitoshi

    2004-12-15

    This study was performed to examine the putative role of high mobility group box (HMGB) protein in the pathogenesis of acute lung injury (ALI). Observations were made (1) in 21 patients who were septic with ALI and 15 patients with normal lung function and (2) in a mouse model 24 hours after intratracheal instillation of lipopolysaccharide (LPS). The concentrations of HMGB1 were increased in plasma and lung epithelial lining fluid of patients with ALI and mice instilled with LPS. LPS-induced ALI was mitigated by anti-HMGB1 antibody. Although this protein was not detected in the plasma of control humans or mice, the concentrations of HMGB1 in lung epithelial lining fluid or in bronchoalveolar lavage fluid were unexpectedly high. The nuclear expression of HMGB1 was apparent in epithelial cells surrounding terminal bronchioles in normal mice, whereas its nuclear and cytoplasmic expression was observed in alveolar macrophages in LPS-instilled mice. Lung instillation of HMGB2 did not cause as much inflammation as HMGB1. Extracellular HMGB1 may play a key role in the pathogenesis of clinical and experimental ALI. However, its expression in normal airways is noteworthy and suggests that it also plays a physiologic role in the lung.

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

    Science.gov (United States)

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

    2007-09-01

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

  7. Respiratory impact of paracentesis in cirrhotic patients with acute lung injury.

    Science.gov (United States)

    Levesque, Eric; Hoti, Emir; Jiabin, Jin; Dellamonica, Jean; Ichai, Philippe; Saliba, Faouzi; Azoulay, Daniel; Samuel, Didier

    2011-06-01

    Ascites may contribute to the loss of lung volume and alter the gas exchange in cirrhotic patients with acute lung injury (ALI). The aim of the study was to evaluate the effects of paracentesis on respiratory parameters in ventilated cirrhotic patients with ALI. This was a prospective trial in an intensive care unit of a university hospital. Thirty-one cirrhotic patients on mechanical ventilation (with ALI) requiring paracentesis were included in this study. Arterial blood gases, intraabdominal pressures, ventilator parameters, and lung volumes were measured before and after the ascitic drainage. Following paracentesis, the intraabdominal pressure decreased (24.1 ± 7.0 vs 12.3 ± 8.9 mm Hg, P < .0001) and the Pao(2)/Fio(2) improved significantly (190.0 ± 65.2 vs 284.9 ± 76.1 mm Hg, P < .0001), without hemodynamic disturbances. End-expiratory lung volume, markedly reduced before drainage, increased significantly following paracentesis (Δ end-expiratory lung volume: +463 ± 249 mL, P = .0009). No adverse effects related to the paracentesis were encountered. In contrast to ventilatory recruitment maneuvers, paracentesis is a simple and well-tolerated technique able to improve oxygenation and alveolar recruitment without the risk of the lung overdistension in severely hypoxemic cirrhotic patients. Copyright © 2011 Elsevier Inc. All rights reserved.

  8. [Total hepatic ischemia-reperfusion-induced lung injury in rats and protective effects of melatonin].

    Science.gov (United States)

    Jiang, Chun Ling; Yang, Ba Xian; Zhao, Dong; Jia, Ruo

    2008-06-18

    To explore total hepatic ischemia-reperfusion(I/R)-induced lung injury in rats,its related mechanism and the protective effects of melatonin on lungs. This study was divided into 2 parts. In the first part, 72 healthy male SD rats weighing 250-300 g were randomly divided into 2 groups: I/R group(ischemia-reperfusion,n=36) and sham-operation group(n=36). Total hepatic I/R was produced by occlusion of hepatic helium for 30 minutes, and the occlusion was then released for reperfusion. The animals were killed at 5 minutes prior to ischemia and 0 h, 0.5 h, 1 h, 3 h and 6 h after reperfusion in sham-operation group and I/R group (n=6 at each time point), and the lung tissue was taken. Through comparisons of these two groups, we observed the dynamic changes of lung tissue after total hepatic I/R. In the second part, 12 healthy male SD rats weighing 250-300 g were randomly divided into 2 groups: melatonin group(n=6) and vehicle group(n=6). Melatonin (0.5%,10 mg/kg)or vehicle of the same volume was injected via femoral vein 15 min before ischemia and 10 min before reperfusion, the animals were killed at 1 h after reperfusion, and the lung tissue was taken. Through comparisons of these two groups, we observed the effects of melatonin. (1)Total hepatic I/R led to severe histological injury in lungs. Compared with those in sham-operation group, the MDA content and apoptotic index were increased, the SOD activity was decreased, the p-ERK/ERK ratio and PCNA-positive index were decreased respectively 0 h and 0.5 h after reperfusion, and then were increased gradually. Histological examination revealed that the alveolar architecture was destroyed with interstitial thickening and neutrophil infiltration in I/R group. Correlate analysis revealed that p-ERK/ERK ratio showed a positive correlation with PCNA-positive index(r=0.56, P<0.05) and apoptotic index (r=0.62, P<0.05) in I/R group. (2)Melatonin treatment alleviated total hepatic I/R-induced lung injury. In melatonin group, the

  9. Major concerns regarding lung injury and related health conditions caused by the use of humidifier disinfectant

    Directory of Open Access Journals (Sweden)

    Donguk Park

    2016-07-01

    Full Text Available A total of 221 patients were evaluated to be humidifier disinfectant associated with lung injury (HDLI through two rounds of programs through April 2015. The humidifier disinfectant (HD brands most often associated with HDLI were found to be Oxy (n=151, 68 % and Cefu (n=26, 17 %. Polyhexamethylene guanidine used for disinfectant for four types of HD brands including Oxy was found to be associated with the highest number of HDLI cases (n=188. Further programs are operating to identify various health effects including lung injury which may be associated with the use of HD. Not only national agencies, but also pertinent environmental health societies should cooperate in the necessary investigations so that this tragedy can be properly addressed and future incidents concerning chemicals and chemical-containing products can be prevented.

  10. Protective effects of oligosaccharides in P-selectin-dependent lung injury.

    Science.gov (United States)

    Mulligan, M S; Paulson, J C; De Frees, S; Zheng, Z L; Lowe, J B; Ward, P A

    1993-07-08

    Neutrophil recruitment into tissues is a multistep process involving sequential engagement of adhesion molecules, including selectins (E,P,L), which are reactive with oligosaccharides, and the family of beta 2 integrins which are reactive with endothelial intercellular adhesion molecules. These processes result in the initial rolling of leukocytes along the endothelial surfaces, followed by the firm attachment of leukocytes to the endothelium. The intravenous infusion of cobra venom factor into rats results in acute lung injury that is neutrophil-dependent, oxygen radical mediated and P-selectin-dependent. Here we report that infusion of sialyl-Lewis X, a ligand for P-selectin, dramatically reduced lung injury and diminished the tissue accumulation of neutrophils, whereas irrelevant oligosaccharides had no such effects. These results suggest that sialyl-Lewis X carbohydrates may be used as a new strategy for anti-inflammatory therapy.

  11. Cardiogenic Shock and Lung Injury as a Complication of Defibrillation

    Directory of Open Access Journals (Sweden)

    Hasan Serdar Kıhtır

    2017-12-01

    Full Text Available Local burns, embolism, and arrhythmia are the most common side effects observed after electrical shock treatments. However, systolic function may be rarely affected and pulmonary edema may develop. The cases of pulmonary edema after electrical shock treatments have been reported since 1960s and the proposed mechanism is the inadequacy of the left atrium cuff and ventricle. It was learned that a 7-year-old-girl without any known disease except vesicoureteral reflux had a ventricular fibrillation during general anesthesia induction and defibrillation at 2 joule/kg was attempted. It was also learned that the procedure was delayed and the patient was diagnosed with a long QT (QTc: 0.47 ms and had respiratory distress and circulatory disturbances after four hours. Pulmonary edema and heart failure was determined, and due to hipoxemia (SpO2 <88% not getting any better with non-invasive ventilation, the patient was intubated and followed with mechanical ventilation. A thermodilution catheter was inserted into the femoral artery and a low cardiac index (CI: 1.58 L/min/m2, elevated extravascular lung water index (EVLWI: 18 mL/kg and high pulmonary vascular permeability index (PVPI: 7.6 were determined. The patient was treated by mechanical ventilation and vasoactive/inotropic management and discharged at the fifth day of hospitalization without any sequela. Having high EVLWI with high PVPI suggest that the pulmonary edema mechanism may also be caused by alveolocapillary membrane damage, which is not accompanied by heart failure alone. This case is presented to show that it is the first child in the literature and that the results of transpulmonary thermodilution can also give information about lung function as well as cardiac function.

  12. The effects of airway pressure release ventilation on respiratory mechanics in extrapulmonary lung injury.

    Science.gov (United States)

    Kollisch-Singule, Michaela; Emr, Bryanna; Jain, Sumeet V; Andrews, Penny; Satalin, Joshua; Liu, Jiao; Porcellio, Elizabeth; Kenyon, Van; Wang, Guirong; Marx, William; Gatto, Louis A; Nieman, Gary F; Habashi, Nader M

    2015-12-01

    Lung injury is often studied without consideration for pathologic changes in the chest wall. In order to reduce the incidence of lung injury using preemptive mechanical ventilation, it is important to recognize the influence of altered chest wall mechanics on disease pathogenesis. In this study, we hypothesize that airway pressure release ventilation (APRV) may be able to reduce the chest wall elastance associated with an extrapulmonary lung injury model as compared with low tidal volume (LVt) ventilation. Female Yorkshire pigs were anesthetized and instrumented. Fecal peritonitis was established, and the superior mesenteric artery was clamped for 30 min to induce an ischemia/reperfusion injury. Immediately following injury, pigs were randomized into (1) LVt (n = 3), positive end-expiratory pressure (PEEP) 5 cmH2O, V t 6 cc kg(-1), FiO2 21 %, and guided by the ARDSnet protocol or (2) APRV (n = 3), P High 16-22 cmH2O, P Low 0 cmH2O, T High 4.5 s, T Low set to terminate the peak expiratory flow at 75 %, and FiO2 21 %. Pigs were monitored continuously for 48 h. Lung samples and bronchoalveolar lavage fluid were collected at necropsy. LVt resulted in mild acute respiratory distress syndrome (ARDS) (PaO2/FiO2 = 226.2 ± 17.1 mmHg) whereas APRV prevented ARDS (PaO2/FiO2 = 465.7 ± 66.5 mmHg; p  0.05). This was because the pleural pressure was significantly lower in LVt (7.6 ± 0.5 cmH2O) as compared with APRV (17.4 ± 3.5 cmH2O; p ventilated lung without increasing lung stress.

  13. Immune-Replacement Therapy in the Complex Treatment of Acute Lung Injury in Patients with Severe Sepsis

    OpenAIRE

    K. B. Grigoryev; S. I. Apevalov; A. E. Matyukov; L. V. Okhinko

    2007-01-01

    Objective: to improve the results of intensive care in patients with acute lung injury in the presence of severe sepsis. Subjects and methods. Complex intensive therapy was analyzed in 87 patients with severe sepsis and acute lung injury. The patients were divided into 2 groups: 1) 43 patients treated without immune-replacement therapy; 2) 44 were additionally given the intravenous immunoglobulin G Gamimun H. The laboratory parameters, mortality, and intensive care duration in an intensive ca...

  14. [Protective effect of rupatadine against oleic acid-induced acute lung injury in rabbits].

    Science.gov (United States)

    Zhang, Lin-Li; Lu, Jing; Yu, Shu-Qin; He, Jian-Lin; Zhou, Min; Xu, Guang-Lin

    2007-03-01

    Acute lung injury (ALI) makes up a spectrum of disease that is commonly defined as "acute non-cardiogenic edematous lung injury". It may contribute to morbidity and mortality in the critically ill patient in the intensive care unit. ALI was induced by oleic acid in rabbits. During the experiment, blood samples were taken from cervical artery and subjected to blood-gas analysis at different time points after oleic acid injection. Shortly after the rabbits were killed at 3 hour after iv OA injection, bronchoalveolar lavage fluid (BALF) was colleted, and the concentrations of protein, platelet-activating factor (PAF), intercellular adhesion molecule-1 (ICAM-1), interleukin 8 (IL-8) in BALF were then measured by ELISA. The ratio of wet to dry weight (W/D) of left lung was calculated to assess alveolar edema. Lung tissue was fixed in formaldehyde and stained with HE, and examined under a light microscope. The OA-induced elevation of arterial blood oxygen pressure was inhibited, as well as PAF, ICAM-1, IL-8 in BALF in rupatadine group. Furthermore, rupatadine also decreased the concentration of protein in BALF and inhibited the increase of the W/D weight ratio significantly. Light microscopic findings showed that the damage in rupatadine groups was far less severe than that in OA model group. Pretreatment with rupatadine has a beneficial effect on acute lung injury induced by oleic acid in rabbits. The ultimate reduction of inflammatory factors was involved, at least in part, in the mechanism of action of rupatadine effects.

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

    Directory of Open Access Journals (Sweden)

    Poursaleh Zohreh

    2012-09-01

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

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

    Directory of Open Access Journals (Sweden)

    Zohreh Poursaleh

    2012-09-01

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

  17. Roles for C-X-C chemokines and C5a in lung injury after hindlimb ischemia-reperfusion

    DEFF Research Database (Denmark)

    Bless, N M; Warner, R L; Padgaonkar, V A

    1999-01-01

    We evaluated the roles of the C-X-C chemokines cytokine-induced neutrophil chemoattractant (CINC) and macrophage inflammatory protein-2 (MIP-2) as well as the complement activation product C5a in development of lung injury after hindlimb ischemia-reperfusion in rats. During reperfusion, CD11b...... permeability and decreased lung myeloperoxidase content by 93 and 68%, respectively (P C5a-related neutrophil chemotactic activity. Treatment with anti-C5a decreased lung vascular permeability, lung myeloperoxidase, and BAL CINC by 51......, 58, and 23%, respectively (P C5a are required for lung neutrophil recruitment and full induction of lung injury after hindlimb ischemia-reperfusion in rats....

  18. Risk Factors for Mortality and Outcomes in Pediatric Acute Lung Injury/Acute Respiratory Distress Syndrome.

    Science.gov (United States)

    Panico, Flávia F; Troster, Eduardo J; Oliveira, Cindy S; Faria, Aline; Lucena, Michelle; João, Paulo R D; Saad, Everardo D; Foronda, Flávia A K; Delgado, Artur F; de Carvalho, Werther Brunow

    2015-09-01

    Children admitted to PICUs often present with or develop respiratory failure that requires mechanical ventilation. We prospectively identified children admitted to three general PICUs, with the goal of identifying risk factors for mortality. Prospective multicenter observational study. Three general PICUs, two in São Paulo and one in Curitiba, Brazil. Children aged between 1 month and 15 years, consecutively admitted between August 2008 and July 2010, with acute lung injury or acute respiratory distress syndrome that developed at least 12 hours after invasive or noninvasive mechanical ventilation. None. We used logistic regression models to explore the relationship between death and independent variables. Of 3,046 patients admitted to the three PICUs, 1,658 patients underwent mechanical ventilation, and 84 fulfilled the acute lung injury/acute respiratory distress syndrome inclusion criteria and were analyzed. Nearly 60% were boys, and the median age was 31 months. Pressure control/assist control was the initial mode of mechanical ventilation in 86% of cases, and the median durations of mechanical ventilation and PICU stay were 12 and 15 days, respectively. None of the eight patients with acute lung injury died, whereas 33 of 76 of the remaining patients with acute respiratory distress syndrome died, for an overall mortality rate of 39.3% (95% CI, 28.8-50.6%). In different multivariate logistic regression model, the number of organ dysfunctions at admission, peak inspiratory pressure, airway pressure gradient on day 1, and the mean airway pressure gradient over the first 7 days of mechanical ventilation were significantly associated with mortality. Mortality is high in pediatric acute lung injury/acute respiratory distress syndrome. Mechanical ventilation-associated risk factors for death among such patients are potential targets for intervention.

  19. Treatment of intractable interstitial lung injury with alemtuzumab after lung transplantation

    DEFF Research Database (Denmark)

    Kohno, M; Perch, M; Andersen, E

    2011-01-01

    A 44-year-old woman underwent left single-lung transplantation for end-stage emphysema due to a1-antitrypsin deficiency in January 2010. Cyclosporine, azathioprine, and prednisolone were administered for immunosuppression and antithymocyte globulin for induction therapy at the time of transplanta......A 44-year-old woman underwent left single-lung transplantation for end-stage emphysema due to a1-antitrypsin deficiency in January 2010. Cyclosporine, azathioprine, and prednisolone were administered for immunosuppression and antithymocyte globulin for induction therapy at the time...... of acute rejection, worsened within 2 weeks, despite high-dose steroids, change of calcineurin inhibitor, and plasmapheresis. Within a few days after a single, 10-mg, intravenous dose of alemtuzumab, the patient's health improved markedly. She has remained stable for 4 months on a standard, ambulatory...

  20. Noninvasive In Vivo Quantification of Neutrophil Elastase Activity in Acute Experimental Mouse Lung Injury

    Directory of Open Access Journals (Sweden)

    Sylvie Kossodo

    2011-01-01

    Full Text Available We developed a neutrophil elastase-specific near-infrared fluorescence imaging agent, which, combined with fluorescence molecular tomographic imaging, allowed us to detect and quantify neutrophil elastase activity in vivo, in real time, and noninvasively in an acute model of lung injury (ALI. Significantly higher fluorescent signal was quantified in mice with LPS/fMLP-induced ALI as compared to healthy controls, correlating with increases in the number of bronchoalveolar lavage cells, neutrophils, and elastase activity. The agent was significantly activated ex vivo in lung sections from ALI but not from control mice, and this activation was ablated by the specific inhibitor sivelestat. Treatment with the specific inhibitor sivelestat significantly reduced lung signal in mice with ALI. These results underscore the unique ability of fluorescence molecular imaging to quantify specific molecular processes in vivo, crucial for understanding the mechanisms underlying disease progression and for assessing and monitoring novel pharmacological interventions.

  1. Glomerular type 1 angiotensin receptors augment kidney injury and inflammation in murine autoimmune nephritis.

    Science.gov (United States)

    Crowley, Steven D; Vasievich, Matthew P; Ruiz, Phillip; Gould, Samantha K; Parsons, Kelly K; Pazmino, A Kathy; Facemire, Carie; Chen, Benny J; Kim, Hyung-Suk; Tran, Trinh T; Pisetsky, David S; Barisoni, Laura; Prieto-Carrasquero, Minolfa C; Jeansson, Marie; Foster, Mary H; Coffman, Thomas M

    2009-04-01

    Studies in humans and animal models indicate a key contribution of angiotensin II to the pathogenesis of glomerular diseases. To examine the role of type 1 angiotensin (AT1) receptors in glomerular inflammation associated with autoimmune disease, we generated MRL-Faslpr/lpr (lpr) mice lacking the major murine type 1 angiotensin receptor (AT1A); lpr mice develop a generalized autoimmune disease with glomerulonephritis that resembles SLE. Surprisingly, AT1A deficiency was not protective against disease but instead substantially accelerated mortality, proteinuria, and kidney pathology. Increased disease severity was not a direct effect of immune cells, since transplantation of AT1A-deficient bone marrow did not affect survival. Moreover, autoimmune injury in extrarenal tissues, including skin, heart, and joints, was unaffected by AT1A deficiency. In murine systems, there is a second type 1 angiotensin receptor isoform, AT1B, and its expression is especially prominent in the renal glomerulus within podocytes. Further, expression of renin was enhanced in kidneys of AT1A-deficient lpr mice, and they showed evidence of exaggerated AT1B receptor activation, including substantially increased podocyte injury and expression of inflammatory mediators. Administration of losartan, which blocks all type 1 angiotensin receptors, reduced markers of kidney disease, including proteinuria, glomerular pathology, and cytokine mRNA expression. Since AT1A-deficient lpr mice had low blood pressure, these findings suggest that activation of type 1 angiotensin receptors in the glomerulus is sufficient to accelerate renal injury and inflammation in the absence of hypertension.

  2. Molecular and cellular mechanisms of the inhibitory effects of ACE-2/ANG1-7/Mas axis on lung injury.

    Science.gov (United States)

    Gopallawa, Indiwari; Uhal, Bruce D

    2014-01-01

    An established body of recent literature has demonstrated potent inhibitory effects of the angiotensin converting enzyme-2 (ACE-2)/ANG1-7/ Mas axis on acute lung injury and lung fibrogenesis. One of the mechanisms of this inhibition is the enzymatic action of ACE-2 to degrade its main substrate angiotensin (ANG) II, thereby reducing the injurious and profibrotic activities of this octapeptide. Another, potentially more important mechanism is the production by ACE-2 of the heptapeptide ANG1-7, which inhibits the actions of ANGII through its own receptor Mas, the product of the oncogene of the same name. Very recent efforts to define the molecular and cellular mechanisms of ANG1-7/Mas action have revealed a number of similar, but mechanistically distinct, pathways by which ANG1-7 and Mas act on various lung cell types to inhibit lung injury and fibrosis. In this review we summarize the beneficial actions of the ANG1-7/Mas pathway, specifically on lung cells in non-neoplastic lung injury. We also review the currently known downstream signaling mechanisms of the ANG1-7/Mas pathway in various lung cell types known to be key in acute injury and fibrogenesis.

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

    NARCIS (Netherlands)

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

    1999-01-01

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

  4. Risk factors and outcome of transfusion-related acute lung injury in the critically ill: A nested case-control study

    NARCIS (Netherlands)

    Vlaar, Alexander P. J.; Binnekade, Jan M.; Prins, David; van Stein, Danielle; Hofstra, Jorrit J.; Schultz, Marcus J.; Juffermans, Nicole P.

    2010-01-01

    Objectives: To determine the incidence, risk factors, and outcome of transfusion-related acute lung injury in a cohort of critically ill patients. Design: In a retrospective cohort study, patients with transfusion-related acute lung injury were identified using the consensus criteria of acute lung

  5. Chest wall restriction limits high airway pressure-induced lung injury in young rabbits.

    Science.gov (United States)

    Hernandez, L A; Peevy, K J; Moise, A A; Parker, J C

    1989-05-01

    High peak inspiratory pressures (PIP) during mechanical ventilation can induce lung injury. In the present study we compare the respective roles of high tidal volume with high PIP in intact immature rabbits to determine whether the increase in capillary permeability is the result of overdistension of the lung or direct pressure effects. New Zealand White rabbits were assigned to one of three protocols, which produced different degrees of inspiratory volume limitation: intact closed-chest animals (CC), closed-chest animals with a full-body plaster cast (C), and isolated excised lungs (IL). The intact animals were ventilated at 15, 30, or 45 cmH2O PIP for 1 h, and the lungs of the CC and C groups were placed in an isolated lung perfusion system. Microvascular permeability was evaluated using the capillary filtration coefficient (Kfc). Base-line Kfc for isolated lungs before ventilation was 0.33 +/- 0.31 ml.min-1.cmH2O-1.100g-1 and was not different from the Kfc in the CC group ventilated with 15 cmH2O PIP. Kfc increased by 850% after ventilation with only 15 cmH2O PIP in the unrestricted IL group, and in the CC group Kfc increased by 31% after 30 cmH2O PIP and 430% after 45 cmH2O PIP. Inspiratory volume limitation by the plaster cast in the C group prevented any significant increase in Kfc at the PIP values used. These data indicate that volume distension of the lung rather than high PIP per se produces microvascular damage in the immature rabbit lung.

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

    Science.gov (United States)

    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.

  7. Exogenous surfactant attenuation of ischemia-reperfusion injury in the lung through alteration of inflammatory and apoptotic factors

    NARCIS (Netherlands)

    van Putte, Bart P.; Cobelens, Pieter M.; van der Kaaij, Niels; Lachmann, Burkhard; Kavelaars, Annemieke; Heijnen, Cobi J.; Kesecioglu, Jozef

    Objective: Lung ischemia-reperfusion injury is associated with impaired gas exchange from increased edema formation and surfactant inactivation. Surfactant replacement therapy is believed to improve gas exchange and lung function, but its effect on inflammation is less well understood. We therefore

  8. Nebulized anticoagulants in lung injury in critically ill patients-an updated systematic review of preclinical and clinical studies

    NARCIS (Netherlands)

    Juschten, Jenny; Tuinman, Pieter R.; Juffermans, Nicole P.; Dixon, Barry; Levi, Marcel; Schultz, Marcus J.

    2017-01-01

    Pneumonia, inhalation trauma and acute respiratory distress syndrome (ARDS), typical causes of lung injury in critically ill patients, are all three characterized by dysregulated inflammation and coagulation in the lungs. Nebulized anticoagulants are thought to have beneficial effects as they could

  9. Pre-Treatment with Allopurinol or Uricase Attenuates Barrier Dysfunction but Not Inflammation during Murine Ventilator-Induced Lung Injury

    NARCIS (Netherlands)

    Kuipers, Maria T.; Aslami, Hamid; Vlaar, Alexander P. J.; Juffermans, Nicole P.; Tuip-de Boer, Anita M.; Hegeman, Maria A.; Jongsma, Geartsje; Roelofs, Joris J. T. H.; van der Poll, Tom; Schultz, Marcus J.; Wieland, Catharina W.

    2012-01-01

    Introduction: Uric acid released from injured tissue is considered a major endogenous danger signal and local instillation of uric acid crystals induces acute lung inflammation via activation of the NLRP3 inflammasome. Ventilator-induced lung injury (VILI) is mediated by the NLRP3 inflammasome and

  10. Citral inhibits lipopolysaccharide-induced acute lung injury by activating PPAR-γ.

    Science.gov (United States)

    Shen, Yongbin; Sun, Zhanfeng; Guo, Xiaotong

    2015-01-15

    Citral, a component of lemongrass oil, has been reported to have many pharmacological activities such as anti-bacterial and anti-inflammatory effects. However, the effects of citral on acute lung injury (ALI) and the molecular mechanisms have not been reported. The aim of this study was to detect the effects of citral on lipopolysaccharide (LPS)-induced acute lung injury and investigate the molecular mechanisms. LPS-induced acute lung injury model was used to detect the anti-inflammatory effect of citral in vivo. The alveolar macrophages were used to investigate the molecular mechanism of citral in vitro. The results showed that pretreatment with citral remarkably attenuated pulmonary edema, histological severities, TNF-α, IL-6 and IL-1β production in LPS-induced ALI in vivo. In vitro, citral inhibited LPS-induced TNF-α, IL-6 and IL-1β production in alveolar macrophages. LPS-induced NF-κB activation was also inhibited by citral. Furthermore, we found that citral activated PPAR-γ and the anti-inflammatory effects of citral can be reversed by PPAR-γ antagonist GW9662. In conclusion, this is the first to demonstrate that citral protects LPS-induced ALI in mice. The anti-inflammatory mechanism of citral is associated with activating PPAR-γ, thereby inhibiting LPS-induced inflammatory response. Copyright © 2014 Elsevier B.V. All rights reserved.

  11. CD73+ regulatory T cells contribute to adenosine-mediated resolution of acute lung injury.

    Science.gov (United States)

    Ehrentraut, Heidi; Clambey, Eric T; McNamee, Eoin N; Brodsky, Kelley S; Ehrentraut, Stefan F; Poth, Jens M; Riegel, Ann K; Westrich, Joseph A; Colgan, Sean P; Eltzschig, Holger K

    2013-06-01

    Acute lung injury (ALI) is characterized by alveolar injury and uncontrolled inflammation. Since most cases of ALI resolve spontaneously, understanding the endogenous mechanisms that promote ALI resolution is important to developing effective therapies. Previous studies have implicated extracellular adenosine signaling in tissue adaptation and wound healing. Therefore, we hypothesized a functional contribution for the endogenous production of adenosine during ALI resolution. As a model, we administered intratracheal LPS and observed peak lung injury at 3 d, with resolution by d 14. Treatment with pegylated adenosine-deaminase to enhance extracellular adenosine breakdown revealed impaired ALI resolution. Similarly, genetic deletion of cd73, the pacemaker for extracellular adenosine generation, was associated with increased mortality (0% wild-type and 40% in cd73(-/-) mice; P<0.05) and failure to resolve ALI adequately. Studies of inflammatory cell trafficking into the lungs during ALI resolution revealed that regulatory T cells (Tregs) express the highest levels of CD73. While Treg numbers in cd73(-/-) mice were similar to controls, cd73-deficient Tregs had attenuated immunosuppressive functions. Moreover, adoptive transfer of cd73-deficient Tregs into Rag(-/-) mice emulated the observed phenotype in cd73(-/-) mice, while transfer of wild-type Tregs was associated with normal ALI resolution. Together, these studies implicate CD73-dependent adenosine generation in Tregs in promoting ALI resolution.

  12. Lung ischemia reperfusion injury: the therapeutic role of dipeptidyl peptidase 4 inhibition.

    Science.gov (United States)

    Beckers, Paul A J; Gielis, Jan F; Van Schil, Paul E; Adriaensen, Dirk

    2017-03-01

    Dipeptidyl peptidase 4 (DPP4) is a cell surface protease that has been reported to play a role in glucose homeostasis, cancer, HIV, autoimmunity, immunology and inflammation. A role for DPP4 in ischemia-reperfusion injury (IRI) in the heart has been established. Dipeptidyl peptidase 4 inhibition (DPP4i) appeared to decrease infarct size, improves cardiac function and promotes myocardial regeneration. Lung ischemia reperfusion injury is caused by a complex mechanism in which macrophages and neutrophils play an important role. Generation of reactive oxygen species (ROS), uncoupling of nitric oxide synthase (NOS), activation of nuclear factor-κB (NF-κB), activation of nicotinamide adenine dinucleotide phosphate metabolism, and generation of pro-inflammatory cytokines lead to acute lung injury (ALI). In this review we present the current knowledge on DPP4 as a target to treat IRI in the lung. We also provide evidence of the roles of the DPP4 substrates glucagon-like peptide 1 (GLP-1), vasoactive intestinal peptide (VIP) and stromal cell-derived factor-1α (SDF-1α) in protection against oxidative stress through activation of the mitogen-activated protein kinase (MAPK) 1/2 and phosphatidylinositol 3'-kinase (PI3K)/Akt signal transduction pathways.

  13. The treatment of acidosis in acute lung injury with tris-hydroxymethyl aminomethane (THAM).

    Science.gov (United States)

    Kallet, R H; Jasmer, R M; Luce, J M; Lin, L H; Marks, J D

    2000-04-01

    Mechanical hyperventilation of acidemic patients with acute lung injury (ALI) requires the use of high volumes and pressures that may worsen lung injury. However, permissive hypercapnia in the presence of shock, metabolic acidosis, and multi-organ system dysfunction may compromise normal cellular function. Tris-hydroxymethyl aminomethane (THAM) may be an effective method to control acidosis in this circumstance. Protonated THAM is excreted by the kidneys, so that carbon dioxide production is not raised. In an uncontrolled study, we administered THAM to 10 patients with acidosis (mean pH = 7.14) and ALI (mean lung injury score = 3.28) in whom adequate control of arterial pH could not be maintained during either eucapnic ventilation or permissive hypercapnia ventilation. THAM was given at a mean dose of 0.55 mmol/kg/h. Administration of THAM was associated with significant improvements in arterial pH and base deficit, and a decrease in arterial carbon dioxide tension that could not be fully accounted for by ventilation. Although further studies are needed to confirm these observations, THAM appears to be an effective alternative to sodium bicarbonate for treating acidosis during ALI.

  14. Recombinant human soluble thrombomodulin prevents acute lung injury in a rat cardiopulmonary bypass model.

    Science.gov (United States)

    Hirao, Shingo; Minakata, Kenji; Masumoto, Hidetoshi; Yamazaki, Kazuhiro; Ikeda, Tadashi; Minatoya, Kenji; Sakata, Ryuzo

    2017-12-01

    Cardiopulmonary bypass (CPB) may induce systemic inflammatory responses causing acute lung injury. Recombinant human soluble thrombomodulin (rTM) is reported to attenuate the secretion of inflammatory cytokines and the high-mobility group box 1 (HMGB1) protein, which is critical in controlling systemic inflammation and apoptosis. We investigated the protective effects of rTM on CPB-induced lung injury in a rat model. Eighteen male Sprague-Dawley rats were divided into 3 groups: sham, control (CPB alone), and rTM (CPB + rTM). CPB was conducted in the control group and the rTM group. A bolus of rTM (3 mg/kg) was administered to the rTM group rats before CPB establishment. The ratio of partial pressure of arterial oxygen to the fraction of inspired oxygen only dropped markedly from before CPB in the control group (P rTM group. The number of apoptotic cells and the protein of cleaved Caspase-3 were reduced in the rTM group. These results suggest that rTM prevents acute lung injury through attenuating inflammation and apoptosis during and after CPB in a rat model. Copyright © 2017 The American Association for Thoracic Surgery. Published by Elsevier Inc. All rights reserved.

  15. Hyaluronan reduces surfactant inhibition and improves rat lung function after meconium injury.

    Science.gov (United States)

    Lu, Karen W; Goerke, Jon; Clements, John A; Taeusch, H William

    2005-08-01

    Hyaluronan (HA), an ionic polymer, is normally present in the alveolar subphase and is known to decrease lung surfactant inactivation caused by serum in vitro. In this study, we examined whether HA can ameliorate the inactivating effects of meconium in vitro and in vivo. Surface activities of various mixtures of Survanta, HA, and meconium were measured using a modified pulsating bubble surfactometer. With meconium, almost all surface activity measures were improved by the addition of HA of several molecular weights at a concentration of 0.25%. Anesthetized, paralyzed rats were maintained on positive-pressure ventilation. After lung injury by instillation of meconium, they were treated with Survanta, Survanta with HA, or control mixtures. Serial measures of blood gases and peak inspiratory pressure were recorded for the duration of the experiment. When the Survanta plus HA group was compared with the Survanta alone group, arterial oxygen tension averaged 117% higher, peak inspiratory pressure was 27% lower at the end of the experiment, and lung compliance also showed significant improvement. These results indicate that HA added to Survanta decreases inactivation caused by meconium in vitro and improves gas exchange and pulmonary mechanics of animals with meconium-induced acute lung injury.

  16. Impact of ventilation-induced lung injury on the structure and function of lamellar bodies.

    Science.gov (United States)

    Milos, Scott; Khazaee, Reza; McCaig, Lynda A; Nygard, Karen; Gardiner, Richard B; Zuo, Yi Y; Yamashita, Cory; Veldhuizen, Ruud

    2017-09-01

    Alterations to the pulmonary surfactant system have been observed consistently in ventilation-induced lung injury (VILI) including composition changes and impairments in the surface tension reducing ability of the isolated extracellular surfactant. However, there is limited information about the effects of VILI on the intracellular form of surfactant, the lamellar body. It is hypothesized that VILI leads to alterations of lamellar body numbers and function. To test this hypothesis, rats were randomized to one of three groups, nonventilated controls, control ventilation, and high tidal volume ventilation (VILI). Following physiological assessment to confirm lung injury, isolated lamellar bodies were tested for surfactant function on a constrained sessile drop surfactometer. A separate cohort of animals was used to fix the lungs followed by examination of lamellar body numbers and morphology using transmission electron microscopy. The results showed an impaired ability of reducing surface tension for the lamellar bodies isolated from the VILI group as compared with the two other groups. The morphological assessment revealed that the number, and the relative area covered by, lamellar bodies were significantly decreased in animals with VILI animals as compared with the other groups. It is concluded that VILI causes significant alterations to lamellar bodies. It is speculated that increased secretion causes a depletion of lamellar bodies that cannot be compensated by de novo synthesis of surfactant in these injured lungs. Copyright © 2017 the American Physiological Society.

  17. Targeted Metabolomics Identifies Pharmacodynamic Biomarkers for BIO 300 Mitigation of Radiation-Induced Lung Injury.

    Science.gov (United States)

    Jones, Jace W; Jackson, Isabel L; Vujaskovic, Zeljko; Kaytor, Michael D; Kane, Maureen A

    2017-10-02

    Biomarkers serve a number of purposes during drug development including defining the natural history of injury/disease, serving as a secondary endpoint or trigger for intervention, and/or aiding in the selection of an effective dose in humans. BIO 300 is a patent-protected pharmaceutical formulation of nanoparticles of synthetic genistein being developed by Humanetics Corporation. The primary goal of this metabolomic discovery experiment was to identify biomarkers that correlate with radiation-induced lung injury and BIO 300 efficacy for mitigating tissue damage based upon the primary endpoint of survival. High-throughput targeted metabolomics of lung tissue from male C57L/J mice exposed to 12.5 Gy whole thorax lung irradiation, treated daily with 400 mg/kg BIO 300 for either 2 weeks or 6 weeks starting 24 h post radiation exposure, were assayed at 180 d post-radiation to identify potential biomarkers. A panel of lung metabolites that are responsive to radiation and able to distinguish an efficacious treatment schedule of BIO 300 from a non-efficacious treatment schedule in terms of 180 d survival were identified. These metabolites represent potential biomarkers that could be further validated for use in drug development of BIO 300 and in the translation of dose from animal to human.

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

    Science.gov (United States)

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

    2012-08-15

    The regional distribution of inflammation during acute lung injury (ALI) is not well known. In an ovine ALI model we studied regional alveolar inflammation, surfactant composition, and CT-derived regional specific volume change (sVol) and specific compliance (sC). 18 ventilated adult sheep received IV lipopolysaccharide (LPS) until severe ALI was achieved. Blood and bronchoalveolar lavage (BAL) samples from apical and basal lung regions were obtained at baseline and injury time points, for analysis of cytokines (IL-6, IL-1β), BAL protein and surfactant composition. Whole lung CT images were obtained in 4 additional sheep. BAL protein and IL-1β were significantly higher in injured apical vs. basal regions. No significant regional surfactant composition changes were observed. Baseline sVol and sC were lower in apex vs. base; ALI enhanced this cranio-caudal difference, reaching statistical significance only for sC. This study suggests that apical lung regions show greater inflammation than basal ones during IV LPS-induced ALI which may relate to differences in regional mechanical events. Copyright © 2012 Elsevier B.V. All rights reserved.

  19. Augmented exercise in the treatment of deconditioning from major burn injury.

    Science.gov (United States)

    de Lateur, Barbara J; Magyar-Russell, Gina; Bresnick, Melissa G; Bernier, Faedra A; Ober, Michelle S; Krabak, Brian J; Ware, Linda; Hayes, Michael P; Fauerbach, James A

    2007-12-01

    To investigate the efficacy of a 12-week exercise program in producing greater improvement in aerobic capacity in adult burn survivors, relative to usual care. Randomized, controlled, double-blinded trial. Burn center. A population-based sample of 35 adult patients admitted to a burn center for treatment of a serious burn injury. A 12-week, 36-session, aerobic treadmill exercise program where work to quota (WTQ) participants intensified their exercise according to preset quotas and work to tolerance (WTT) participants continued to their tolerance. Participants completed a maximal stress test at baseline and 12 weeks to measure physical fitness. Maximal aerobic capacity. The WTT and the WTQ exercise groups both made significant improvements in aerobic capacity from baseline to 12 weeks (t=-3.60, P< or =.01; t=-3.17, P< or =.01, respectively). The control group did not (t=-1.39, P=.19). WTT and WTQ participants demonstrated significantly greater improvements in aerobic capacity in comparison to the control group members (F=4.6, P< or =.05). The WTT and WTQ groups did not differ significantly from each other with regard to their respective improvements in aerobic capacity (F=.014, P=.907). The aerobic capacity of adult burn survivors can be improved with participation in a structured, 12-week exercise program after injury.

  20. Aerosolized anticoagulants ameliorate acute lung injury in sheep after exposure to burn and smoke inhalation.

    Science.gov (United States)

    Enkhbaatar, Perenlei; Cox, Robert A; Traber, Lillian D; Westphal, Martin; Aimalohi, Esechie; Morita, Naoki; Prough, Donald S; Herndon, David N; Traber, Daniel L

    2007-12-01

    Acute lung injury is a detrimental complication for victims of burn accidents. Airway obstruction plays an important role in pulmonary dysfunction in these patients. In this study, we tested the hypothesis that aerosolized anticoagulants will reduce the degree of airway obstruction and improve pulmonary function in sheep with severe combined burn and smoke inhalation injury by preventing the formation of airway fibrin clots. Prospective, randomized, controlled, experimental animal study. Investigational intensive care unit at a university hospital. Adult female sheep. After 7 days of surgical recovery, sheep were given a cutaneous burn (40% of total body surface, third degree) and insufflated with cotton smoke (48 breaths, injury, sheep were placed on ventilators and resuscitated with lactated Ringer's solution. Sheep were randomly divided into five groups: sham, noninjured and nontreated (n = 6); control, injured and aerosolized with saline (n = 6); recombinant human antithrombin (rhAT) + heparin, injured and aerosolized with rhAT (290 units for each) and heparin (10,000 units for each) (n = 6); rhAT, injured and aerosolized with rhAT alone (290 units for each; n = 5); and heparin, injured and aerosolized with heparin alone (10,000 units for each; n = 5). rhAT and heparin were aerosolized every 4 hrs, starting at 2 hrs postinjury. Cardiopulmonary hemodynamics were monitored during a 48-hr experimental time period. Control sheep developed multiple signs of acute lung injury. This pathophysiology included decreased pulmonary gas exchange and lung compliance, increased pulmonary edema, and extensive airway obstruction. These variables were stable in sham animals. The aerosolization of rhAT or heparin alone did not significantly improve deteriorated pulmonary gas exchange. However, aerosolization of these anticoagulants in combination significantly attenuated all the observed pulmonary pathophysiology. The results provide definitive evidence that aerosolized rhAT and

  1. Increased claudin-3, -4 and -18 levels in bronchoalveolar lavage fluid reflect severity of acute lung injury.

    Science.gov (United States)

    Jin, Wenting; Rong, Linyi; Liu, Yinkun; Song, Yuanlin; Li, Yan; Pan, Jue

    2013-05-01

    Acute lung injury (ALI) is characterized by disruption of lung epithelial and endothelial cells, leading to increased membrane permeability and loss of barrier function. Claudins are key components of tight junctions (TJ) that regulate paracellular permeability, and play an important role in alveolar epithelial barrier function and fluid clearance. However, whether claudin-3, -4, -18 or -5 expression changes in Pseudomonas aeruginosa (PA)-induced ALI and the clinical significance of such change is unknown. Rats underwent intratracheal instillation of PA, and samples were collected prior to and 3, 9 and 24 h after instillation. Lung injury was evaluated by bronchoalveolar lavage fluid (BALF) total protein, arterial blood gas analysis, lung injury score, and expression of surfactant protein and von Willebrand factor. Claudin expression in lung was measured with quantitative real-time polymerase chain reaction and western blotting, and in BALF by enzyme-linked immunosorbent assay. The relationship between claudins in BALF and lung injury grade were analysed with Spearman's rank correlation. Alveolar epithelium, endothelium and TJ ultrastructure were observed with electron microscopy. Claudin-4, -18 and -5 mRNA levels increased significantly 24 h after PA instillation in the most severe lung injury cases, whereas there was no significant change in protein levels. Claudin-3, -4 and -18 levels in BALF increased most 24 h after PA instillation; this paralleled alveolar epithelial disruption and lung injury severity. Claudin-3, -4 and -18 released into the alveolar compartment is highly associated with barrier function loss caused by alveolar epithelial injury. © 2012 The Authors. Respirology © 2012 Asian Pacific Society of Respirology.

  2. Review of Epidural Spinal Cord Stimulation for Augmenting Cough after Spinal Cord Injury.

    Science.gov (United States)

    Hachmann, Jan T; Calvert, Jonathan S; Grahn, Peter J; Drubach, Dina I; Lee, Kendall H; Lavrov, Igor A

    2017-01-01

    Spinal cord injury (SCI) remains a debilitating condition for which there is no cure. In addition to loss of somatic sensorimotor functions, SCI is also commonly associated with impairment of autonomic function. Importantly, cough dysfunction due to paralysis of expiratory muscles in combination with respiratory insufficiency can render affected individuals vulnerable to respiratory morbidity. Failure to clear sputum can aggravate both risk for and severity of respiratory infections, accounting for frequent hospitalizations and even mortality. Recently, epidural stimulation of the lower thoracic spinal cord has been investigated as novel means for restoring cough by evoking expiratory muscle contraction to generate large positive airway pressures and expulsive air flow. This review article discusses available preclinical and clinical evidence, current challenges and clinical potential of lower thoracic spinal cord stimulation (SCS) for restoring cough in individuals with SCI.

  3. Isoliquiritigenin protects against sepsis-induced lung and liver injury by reducing inflammatory responses.

    Science.gov (United States)

    Chen, Xiong; Cai, Xueding; Le, Rongrong; Zhang, Man; Gu, Xuemei; Shen, Feixia; Hong, Guangliang; Chen, Zimiao

    2018-02-05

    Sepsis, one of the most fatal diseases worldwide, often leads to multiple organ failure, mainly due to uncontrolled inflammatory responses. Despite accumulating knowledge obtained in recent years, effective drugs to treat sepsis in the clinic are still urgently needed. Isoliquiritigenin (ISL), a chalcone compound, has been reported to exert anti-inflammatory properties. However, little is known about the effects of ISL on sepsis and its related complications. In this study, we investigated the potential protective effects of ISL on lipopolysaccharide (LPS)-induced injuries and identified the mechanisms underlying these effects. ISL inhibited inflammatory cytokine expression in mouse primary peritoneal macrophages (MPMs) exposed to LPS. In an acute lung injury (ALI) mouse model, ISL prevented LPS-induced structural damage and inflammatory cell infiltration. Additionally, pretreatment with ISL attenuated sepsis-induced lung and liver injury, accompanied by a reduction in inflammatory responses. Moreover, these protective effects were mediated by the nuclear factor kappa B (NF-κB) pathway-mediated inhibition of inflammatory responses in vitro and in vivo. Our study suggests that ISL may be a potential therapeutic agent for sepsis-induced injuries. Copyright © 2017. Published by Elsevier Inc.

  4. Early biomarkers and potential mediators of ventilation-induced lung injury in very preterm lambs

    Directory of Open Access Journals (Sweden)

    Davis Peter G

    2009-03-01

    Full Text Available Abstract Background Bronchopulmonary dysplasia (BPD is closely associated with ventilator-induced lung injury (VILI in very preterm infants. The greatest risk of VILI may be in the immediate period after birth, when the lungs are surfactant deficient, still partially filled with liquid and not uniformly aerated. However, there have been very few studies that have examined this immediate post-birth period and identified the initial injury-related pathways that are activated. We aimed to determine if the early response genes; connective tissue growth factor (CTGF, cysteine rich-61 (CYR61 and early growth response 1 (EGR1, were rapidly induced by VILI in preterm lambs and whether ventilation with different tidal volumes caused different inflammatory cytokine and early response gene expression. Methods To identify early markers of VILI, preterm lambs (132 d gestational age; GA, term ~147 d were resuscitated with an injurious ventilation strategy (VT 20 mL/kg for 15 min then gently ventilated (5 mL/kg for 15, 30, 60 or 120 min (n = 4 in each. To determine if early response genes and inflammatory cytokines were differentially regulated by different ventilation strategies, separate groups of preterm lambs (125 d GA; n = 5 in each were ventilated from birth with a VT of 5 (VG5 or 10 mL/kg (VG10 for 135 minutes. Lung gene expression levels were compared to levels prior to ventilation in age-matched control fetuses. Results CTGF, CYR61 and EGR1 lung mRNA levels were increased ~25, 50 and 120-fold respectively (p CTGF, CYR61, EGR1, IL1-β, IL-6 and IL-8 mRNA levels compared to control levels. CTGF, CYR61, IL-6 and IL-8 expression levels were higher in VG10 than VG5 lambs; although only the IL-6 and CYR61 mRNA levels reached significance. Conclusion CTGF, CYR61 and EGR1 may be novel early markers of lung injury and mechanical ventilation from birth using relatively low tidal volumes may be less injurious than using higher tidal volumes.

  5. Treatment of intractable interstitial lung injury with alemtuzumab after lung transplantation

    DEFF Research Database (Denmark)

    Kohno, M; Perch, M; Andersen, E

    2011-01-01

    A 44-year-old woman underwent left single-lung transplantation for end-stage emphysema due to α1-antitrypsin deficiency in January 2010. Cyclosporine, azathioprine, and prednisolone were administered for immunosuppression and antithymocyte globulin for induction therapy at the time...... of acute rejection, worsened within 2 weeks, despite high-dose steroids, change of calcineurin inhibitor, and plasmapheresis. Within a few days after a single, 10-mg, intravenous dose of alemtuzumab, the patient's health improved markedly. She has remained stable for 4 months on a standard, ambulatory...

  6. Protective Effects of Myrtol Standardized Against Radiation-Induced Lung Injury.

    Science.gov (United States)

    Zhao, De-yun; Qu, Hong-jin; Guo, Jia-ming; Zhao, Hai-nan; Yang, Yan-yong; Zhang, Pei; Cao, Kun; Lei, Xiao; Cui, Jian-guo; Liu, Cong; Cai, Jian-ming; Gao, Fu; Li, Bai-long

    2016-01-01

    As a major complication after thoracic radiotherapy, radiation-induced lung injury (RILI) has great impact on long term quality of life and could result in fatal respiratory insufficiency The present study was aimed to evaluate the effects of Myrtol standardized on RILI, and to investigate the underlying mechanism. A mouse model of radiation-induced lung injury was generated by using thoracic irradiation with a single dose of 16Gy. Mice were orally administrated with Myrtol (25 mg/kg/day) for 4 weeks after irradiation, while prednisone (5 mg/kg/day) was used as a positive control. After then, the body weight and lung coefficient were calculated. The severity of fibrosis was evaluated by observing pulmonary sections after radiation and collagen content in lung tissues was calculated following the hydroxyproline (HYP) assay. Pathological changes were observed in all the groups by using HE staining and Masson staining. The serum levels of TGF-β1, TNF-α, IL-1β, IL-6, and PGE2 were also measured with an ELISA assay. Western blot assay was used to measure the impact of Myrtol on AKT and its downstream signaling pathway, including MMP-2 and MMP-9. The levels of Vimentin and α-SMA were evaluated with an immunofluorescence assay. Treatment with Myrtol standardized, but not prednisone, reduced lung coefficient and collagen deposition in lung tissues, while attenuated histological damages induced by irradiation. Myrtol standardized also reduced the production of MDA, while increased the level of SOD. It was also observed that Myrtol standardized inhibited TGF-β1 and a series of pro-inflammatory cytokines including TNF-α, IL-1β, IL-6, PGE2. While in prednisone group, even though the early pneumonitis was ameliorated, the collagen disposition remained unchanged in latter times. Immunofluorescence analysis also revealed elevation of vimentin and α-SMA in the alveoli after a single dose of 16Gy. The present results suggest Myrtol standardized as an effective agent for

  7. Protective Effects of Myrtol Standardized Against Radiation-Induced Lung Injury

    Directory of Open Access Journals (Sweden)

    De-yun Zhao

    2016-02-01

    Full Text Available Background/Aims: As a major complication after thoracic radiotherapy, radiation-induced lung injury (RILI has great impact on long term quality of life and could result in fatal respiratory insufficiency The present study was aimed to evaluate the effects of Myrtol standardized on RILI, and to investigate the underlying mechanism. Methods: A mouse model of radiation-induced lung injury was generated by using thoracic irradiation with a single dose of 16Gy. Mice were orally administrated with Myrtol (25 mg/kg/day for 4 weeks after irradiation, while prednisone (5 mg/kg/day was used as a positive control. After then, the body weight and lung coefficient were calculated. The severity of fibrosis was evaluated by observing pulmonary sections after radiation and collagen content in lung tissues was calculated following the hydroxyproline (HYP assay. Pathological changes were observed in all the groups by using HE staining and Masson staining. The serum levels of TGF-β1, TNF-α, IL-1β, IL-6, and PGE2 were also measured with an ELISA assay. Western blot assay was used to measure the impact of Myrtol on AKT and its downstream signaling pathway, including MMP-2 and MMP-9. The levels of Vimentin and α-SMA were evaluated with an immunofluorescence assay. Results: Treatment with Myrtol standardized, but not prednisone, reduced lung coefficient and collagen deposition in lung tissues, while attenuated histological damages induced by irradiation. Myrtol standardized also reduced the production of MDA, while increased the level of SOD. It was also observed that Myrtol standardized inhibited TGF-β1 and a series of pro-inflammatory cytokines including TNF-α, IL-1β, IL-6, PGE2. While in prednisone group, even though the early pneumonitis was ameliorated, the collagen disposition remained unchanged in latter times. Immunofluorescence analysis also revealed elevation of vimentin and α-SMA in the alveoli after a single dose of 16Gy. Conclusion: The present

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

    Science.gov (United States)

    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.

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

    Directory of Open Access Journals (Sweden)

    M.F.R. Silva

    1998-03-01

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

  10. Lung capillary injury and repair in left heart disease: a new target for therapy?

    Science.gov (United States)

    Azarbar, Sayena; Dupuis, Jocelyn

    2014-07-01

    The lungs are the primary organs affected in LHD (left heart disease). Increased left atrial pressure leads to pulmonary alveolar-capillary stress failure, resulting in cycles of alveolar wall injury and repair. The reparative process causes the proliferation of MYFs (myofibroblasts) with fibrosis and extracellular matrix deposition, resulting in thickening of the alveolar wall. Although the resultant reduction in vascular permeability is initially protective against pulmonary oedema, the process becomes maladaptive causing a restrictive lung syndrome with impaired gas exchange. This pathological process may also contribute to PH (pulmonary hypertension) due to LHD. Few clinical trials have specifically evaluated lung structural remodelling and the effect of related therapies in LHD. Currently approved treatment for chronic HF (heart failure) may have direct beneficial effects on lung structural remodelling. In the future, novel therapies specifically targeting the remodelling processes may potentially be utilized. In the present review, we summarize data supporting the clinical importance and pathophysiological mechanisms of lung structural remodelling in LHD and propose that this pathophysiological process should be explored further in pre-clinical studies and future therapeutic trials.

  11. Activation of Akt protects alveoli from neonatal oxygen-induced lung injury.

    Science.gov (United States)

    Alphonse, Rajesh S; Vadivel, Arul; Coltan, Lavinia; Eaton, Farah; Barr, Amy J; Dyck, Jason R B; Thébaud, Bernard

    2011-02-01

    Bronchopulmonary dysplasia (BPD) is the main complication of extreme prematurity, resulting in part from mechanical ventilation and oxygen therapy. Currently, no specific treatment exists for BPD. BPD is characterized by an arrest in alveolar development and increased apoptosis of alveolar epithelial cells (AECs). Type 2 AECs are putative distal lung progenitor cells, capable of regenerating alveolar homeostasis after injury. We hypothesized that the protection of AEC2 death via the activation of the prosurvival Akt pathway prevents arrested alveolar development in experimental BPD. We show that the pharmacologic inhibition of the prosurvival factor Akt pathway with wortmannin during the critical period of alveolar development impairs alveolar development in newborn rats, resulting in larger and fewer alveoli, reminiscent of BPD. Conversely, in an experimental model of BPD induced by oxygen exposure of newborn rats, alveolar simplification is associated with a decreased activation of lung Akt. In vitro studies with rat lung epithelial (RLE) cells cultured in hyperoxia (95% O(2)) showed decreased apoptosis and improved cell survival after the forced expression of active Akt by adenovirus-mediated gene transfer. In vivo, adenovirus-mediated Akt gene transfer preserves alveolar architecture in the newborn rat model of hyperoxia-induced BPD. We conclude that inhibition of the prosurvival factor Akt disrupts normal lung development, whereas the expression of active Akt in experimental BPD preserves alveolar development. We speculate that the modulation of apoptosis may have therapeutic potential in lung diseases characterized by alveolar damage.

  12. Humidifier disinfectant lung injury, how do we approach the issues?

    Directory of Open Access Journals (Sweden)

    Jihyun Emma Choi

    2016-08-01

    Full Text Available A large portion of the Korean population has been exposed to toxic humidifier disinfectants (HDs, and considering that the majority of the victims are infants, the magnitude of the damage is expected to be considerably larger than what has currently been revealed. The current victims are voicing problems caused by various diseases, including but not limited to lung, upper respiratory tract, cardiovascular, kidney, musculoskeletal, eye, and skin diseases, etc. However, there has been difficulty in gaining validation for these health problems and identifying causal relationships due to lack of evidence proving that toxic HD is the specific causes of extrapulmonary diseases such as allergic rhinitis. Furthermore, the victims and bereaved families of the HD case have not received any support for psychological distress such as post-traumatic stress disorder, depression, feelings of injustice, and anger caused by the trauma. In addition, because the underlying mechanisms of the toxic materials within the HDs such as polyhexamethylene guanidine phosphate, poly(oxyalkylene guanidine hydrochloride, chloromethylisothiazolinone/methylisothiazolinone have yet to be determined, the demand for information regarding the HD issue is growing. The victims of the HD cases require support that goes beyond financial aid for medical costs and living expenses. There is a desperate need for government-led integrated support centers that provide individualized support through health screenings; in other words, we need an integrated facility that provides the appropriate social support to allow the victims to recover their physical and mental health, so as to well prepare them to return to a normal life. The implementation of such a plan requires not only the close cooperation between those departments already directly involved such as the Ministry of Environment and the Ministry of Health and Welfare, but also active support on a national scale from pan

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

    Science.gov (United States)

    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 ...

  14. [Effects and mechanisms of high-volume hemofiltration on endotoxin-induced acute lung injury of piglets].

    Science.gov (United States)

    Chen, W M; Yan, G F; Lu, Z J; Lu, G P

    2017-05-04

    Objective: To compare the effects of high-volume hemofiltration (HVHF) and continuous veno-venous hemofiltration (CVVH) on cardiopulmonary functions, lung fluid balance, lung damage and cytokine expression in endotoxin-induced acute lung injury piglet model, and to further evaluate the value of high-volume hemofiltration in acute lung injury. Method: Eighteen piglets were randomly divided into the control group (6 piglets), the CVVH group (6 piglets) and the HVHF group (6 piglets). By general anesthesia, the intravenous infusion of 0.15 mg/kg endotoxin were received in all the animals and induced acute lung injury.High-volume hemofiltration and continuous veno-venous hemofiltration were addressed to different groups.Subsequently, hemodynamic parameters (heart rate, mean arterial blood pressure, central venous pressure, pulse contour cardiac index, systemic venous resistance index and extravascular lung water index) as well as gas exchange and lung mechanics parameters (respiratory rate, partial pressure of carbon dioxide, partial pressure of oxygen/fraction of inspired oxygen, dynamic lung compliance and airway resistance) were intermittently measured.Lung tissues were collected for further analysis (the lung wet-to-dry weight ratio, lung injury scoring). The plasma protein levels of cytokines (interleukin(IL) -6, 10 and tumor necrosis factors alpha(TNF-α)) were also assessed.Two-way analysis of variance (ANOVA) and Bonferroni post-test were conducted to identify significant differences among the control, CVVH and HVHF group. Result: Compared with CVVH, HVHF had the capacity to improve significantly the index of Cdyn(HVHF (2.3±0.5) vs. CVVH (1.5±0.5) ml/(cmH(2)O·kg), 1 cmH(2)O=0.098 kPa, Plung water accumulation(index of EVLWI in HVHF (22.7±2.1) vs.CVVH (39.5±2.6) ml/m(2,) Plung injury scoring of HVHF group was significantly lower than those of CVVH group((7.8±1.9) vs. (11.3±2.2) scores, Pvolume hemofiltration can improve respiratory function of piglets

  15. HIF1A reduces acute lung injury by optimizing carbohydrate metabolism in the alveolar epithelium.

    Directory of Open Access Journals (Sweden)

    Tobias Eckle

    2013-09-01

    Full Text Available While acute lung injury (ALI contributes significantly to critical illness, it resolves spontaneously in many instances. The majority of patients experiencing ALI require mechanical ventilation. Therefore, we hypothesized that mechanical ventilation and concomitant stretch-exposure of pulmonary epithelia could activate endogenous pathways important in lung protection.To examine transcriptional responses during ALI, we exposed pulmonary epithelia to cyclic mechanical stretch conditions--an in vitro model resembling mechanical ventilation. A genome-wide screen revealed a transcriptional response similar to hypoxia signaling. Surprisingly, we found that stabilization of hypoxia-inducible factor 1A (HIF1A during stretch conditions in vitro or during ventilator-induced ALI in vivo occurs under normoxic conditions. Extension of these findings identified a functional role for stretch-induced inhibition of succinate dehydrogenase (SDH in mediating normoxic HIF1A stabilization, concomitant increases in glycolytic capacity, and improved tricarboxylic acid (TCA cycle function. Pharmacologic studies with HIF activator or inhibitor treatment implicated HIF1A-stabilization in attenuating pulmonary edema and lung inflammation during ALI in vivo. Systematic deletion of HIF1A in the lungs, endothelia, myeloid cells, or pulmonary epithelia linked these findings to alveolar-epithelial HIF1A. In vivo analysis of ¹³C-glucose metabolites utilizing liquid-chromatography tandem mass-spectrometry demonstrated that increases in glycolytic capacity, improvement of mitochondrial respiration, and concomitant attenuation of lung inflammation during ALI were specific for alveolar-epithelial expressed HIF1A.These studies reveal a surprising role for HIF1A in lung protection during ALI, where normoxic HIF1A stabilization and HIF-dependent control of alveolar-epithelial glucose metabolism function as an endogenous feedback loop to dampen lung inflammation.

  16. Characterization of inflammation in a rat model of acute lung injury after repeated pulmonary lavage.

    Science.gov (United States)

    Menk, Mario; Graw, Jan Adriaan; Steinkraus, Henrik; Haefen, Clarissa von; Sifringer, Marco; Spies, Claudia D; Lachmann, Burkhard; Schwaiberger, David

    2015-01-01

    Repeated pulmonary lavage allows to reliably reproduce failure of gas exchange and major histological findings of acute lung injury (ALI). However, because the capacity of pulmonary lavage to induce pulmonary inflammation is not well established in rodents, this study aims to characterize the induction of pulmonary inflammation in a rat model of ALI. Male adult rats were divided into a treatment group (n = 9) that received pulmonary lavage with consecutive mechanical ventilation, and a control group that received mechanical ventilation only (n = 9). Arterial blood gas analyses were performed every 30 min throughout the study. Pressure-volume curves, and lung tissue and plasma samples, were obtained at 240 min after the start of mechanical ventilation. Protein content and surface activity of bronchoalveolar lavage fluid was assessed. Transcriptional and translational regulation of pro- and anti-inflammatory cytokines IL-1β, TNF-α, IL-6, and IL-10 was determined in lungs and plasma. Markers of cellular stress were measured in lung tissue. Pulmonary lavage significantly decreased lung compliance, induced hypoxia and hypercapnia, and mediated respiratory acidosis. Protein content of lavage fluid was significantly increased and contained washed out surfactant. Expression of IL-1β, TNF-α, and IL-6 mRNA and protein expression of IL-1β and TNF-α was significantly induced in lavaged lungs, without spillover into the systemic circulation. Markers of cellular stress were significantly upregulated in lavaged lungs. This model of ALI applied in rats can induce pulmonary inflammation. The model might be used to develop therapeutic strategies that target pulmonary inflammation in ALI.

  17. Acute ozone-induced lung injury in rats: Structural-functional relationships of developing alveolar edema

    Energy Technology Data Exchange (ETDEWEB)

    Paterson, J.F.; Hammond, M.D.; Montgomery, M.R.; Sharp, J.T.; Farrier, S.E.; Balis, J.U. (James A. Haley Veterans Hospital Research Service, Tampa, FL (United States))

    1992-11-01

    As part of a study on the effects of acute ozone stress on the lung surfactant system, we correlated morphometric, biochemical, and functional indices of lung injury using male rats exposed to 3 ppm ozone for 1, 2, 4, and 8 hr. Evaluation of lung mechanics, using the Pulmonary Evaluation and Diagnostic Laboratory System, revealed a significant decrease in dynamic lung compliance (ml/cmH[sub 2]O/kg) from a control value of 0.84 [plus minus] 0.02 (SEM) to 0.72 [plus minus] 0.04 and 0.57 [plus minus] 0.06 at 4 and 8 hr, respectively. At 2 hr there was a transient increase in PaO[sub 2] to 116 torr (control = 92 torr) followed by a decrease at 4 hr (65 torr) and 8 hr (55 torr). Morphometry of lung tissue, fixed by perfusion of fixative via the pulmonary artery at 12 cm H[sub 2]O airway distending pressure, demonstrated an increase in the area of the intravascular compartment at 8 hr, in association with a 65 and 39% replacement of the alveolar area by fluid in ventral and dorsal lung regions, respectively. There was a positive correlation (r = 0.966) between alveolar edema and transudated proteins in lavage fluid. A stepwise multiple regression model, with edema as the dependent variable, suggested that pulmonary vasodilatation, hypoxemia, and depletion of surfactant tubular myelin in lavage fluid were indices for predicting alveolar edema. In a second model, with lavage protein concentration as the dependent variable, decreasing dynamic compliance and hypoxemia were predictors of progressive, intraalveolar transudation of plasma proteins. The above structural-functional relationships support the concept that ozone-induced high-protein alveolar edema is pathogenetically linked to pulmonary hyperemia, deficiency of surfactant tubular myelin, and associated lung dysfunctions.

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

    Science.gov (United States)

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

    2016-12-01

    Induction of oxidative stress and inflammation are considered the primary mechanism of cadmium (Cd) toxicity. Nigella sativa (NS) seeds and their oil (NSO) have been reported to possess antioxidant and anti-inflammatory potential. This study was conducted to assess the protective effect of NSO on Cd-induced lung damage in rat. Forty adult male Wistar rats were divided equally into 4 groups. Animals in groups I, II, and III received 1 ml of isotonic saline intraperitoneally (IP), 2 mg/kg of cadmium chloride (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.

  19. Heme Attenuation Ameliorates Irritant Gas Inhalation-Induced Acute Lung Injury.

    Science.gov (United States)

    Aggarwal, Saurabh; Lam, Adam; Bolisetty, Subhashini; Carlisle, Matthew A; Traylor, Amie; Agarwal, Anupam; Matalon, Sadis

    2016-01-10

    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. 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. This is the first study delineating the role of heme in ALI caused by Br2. The data suggest that attenuating heme may prove to be a useful adjuvant therapy to treat patients with ALI.

  20. Intravenous infusion of mesenteric lymph from severe intraperitoneal infection rats causes lung injury in healthy rats.

    Science.gov (United States)

    Zhang, Yan-Min; Zhang, Shu-Kun; Cui, Nai-Qiang

    2014-04-28

    To investigate whether mesenteric lymph from rats with severe intraperitoneal infection (SII) induces lung injury in healthy rats. Twenty adult male specific pathogen-free Wistar rats were divided into two groups. Animals in the SII group received intraperitoneal injection of Escherichia coli (E. coli) at a dose of 0.3 mL/100 g. Control rats underwent the same procedure, but were injected with normal saline rather than E. coli. We ligated and drained the mesenteric lymphatic vessels and collected the mesenteric lymph. Mesenteric lymph collected from SII or control rats was infused intravenously into male healthy rats at a rate of 1 mL/h for 4 h. At the end of the infusion, all rats were sacrificed. Lungs were removed and examined histologically, and wet-to-dry weight (W/D) ratio and myeloperoxidase (MPO) activity were determined. Enzyme-linked immunosorbent assay (ELISA) was performed to determine the levels of the proinflammatory cytokines tumor necrosis factor (TNF)-α and interleukin (IL)-6. We performed Western blot to investigate the activation of Toll-like receptor (TLR)-4, and nuclear factor (NF)-κB p65. Compared with the control infusion group, there were obvious pathological changes in the SII group. The W/D ratio was significantly increased in the SII compared to control infusion group (5.86 ± 0.06 vs 5.37 ± 0.06, P lung injury. The results indicate that SII lymph is sufficient to induce acute lung injury.

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

    Directory of Open Access Journals (Sweden)

    Yuben Moodley

    2016-07-01

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

  2. Gene expression profiles characterize inflammation stages in the acute lung injury in mice.

    Directory of Open Access Journals (Sweden)

    Isabelle Lesur

    Full Text Available Acute Lung Injury (ALI carries about 50 percent mortality and is frequently associated with an infection (sepsis. Life-support treatment with mechanical ventilation rescues many patients, although superimposed infection or multiple organ failure can result in death. The outcome of a patient developing sepsis depends on two factors: the infection and the pre-existing inflammation. In this study, we described each stage of the inflammation process using a transcriptional approach and an animal model. Female C57BL6/J mice received an intravenous oleic acid injection to induce an acute lung injury (ALI. Lung expression patterns were analyzed using a 9900 cDNA mouse microarray (MUSV29K. Our gene-expression analysis revealed marked changes in the immune and inflammatory response metabolic pathways, notably lipid metabolism and transcription. The early stage (1 hour-1.5 hours is characterized by a pro-inflammatory immune response. Later (3 hours-4 hours, the immune cells migrate into inflamed tissues through interaction with vascular endothelial cells. Finally, at late stages of lung inflammation (18 hours-24 hours, metabolism is deeply disturbed. Highly expressed pro-inflammatory cytokines activate transcription of many genes and lipid metabolism. In this study, we described a global overview of critical events occurring during lung inflammation which is essential to understand infectious pathologies such as sepsis where inflammation and infection are intertwined. Based on these data, it becomes possible to isolate the impact of a pathogen at the transcriptional level from the global gene expression modifications resulting from the infection associated with the inflammation.

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

    Science.gov (United States)

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

    2014-01-01

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

  4. Action mechanism of apoptosis in the development of acute lung injury after severe acute pancreatitis

    Directory of Open Access Journals (Sweden)

    Zhan-li SHI

    2017-11-01

    Full Text Available Objective To explore the role of apoptosis in the development of acute lung injury (ALI after severe acute pancreatitis (SAP and its mechanism via Notch/Hes signal transduction pathway in the pathologic process. Methods Fifty healthy male Sprague Dawley rats were randomly divided into, sham group (n=8 and model group (n=42. Tissue samples of model group were collected randomly at 3 (n=10, 6 (n=10, 12 (n=10 and 24h (n=12 after model establishment. Tissue collection of Sham group was conducted at 3h. Left lung wet/dry weight ratio (W/D was calculated; Histological scores of pancreatic and lung tissues were assessed under microscope; myeloperoxidase (MPO and tumor necrosis factor-α (TNF-α of lung tissues were determined by enzymatic-chemical method and radioimmunoassay method respectively. Apoptosis of lung cells was evaluated by TUNEL assay followed by calculation of apoptosis index. Protein levels of Notch-1, Hes-1 and Hes-5 were also detected semi-quantitatively by Western blotting. Results The lung tissue W/D of model rats exhibited a gradual increment at the prior 12 hours, and the ratio was significantly higher than that of sham group at each time point (P<0.01 while it reached the peak at 12h time point. Pancreatic and lung pathological scores of model groups were increased at all time points and significantly higher than sham group (P<0.01. Lung pathological scores of model groups achieved a peak at 12h. Meanwhile, lung MPO and TNF-α of model groups showed the same increment trend at each time points. The apoptosis index (AI of lung cells in model groups were higher than that in sham group (P<0.01. Compared with sham group, the model groups showed lower protein expression levels of Notch-1, especially at 3, 6 and 12h (P<0.05. Notch-1 protein expression level of 12h group was lower than that of 3, 6 and 24h groups (P<0.01. Correlation analysis found that apoptosis of lung cells was significantly negatively related to histopathological

  5. Human mesenchymal stromal cells reduce influenza A H5N1-associated acute lung injury in vitro and in vivo

    OpenAIRE

    Chan, Michael C. W.; Kuok, Denise I. T.; Leung, Connie Y. H.; Hui, Kenrie P. Y.; Valkenburg, Sophie A.; Lau, Eric H. Y.; Nicholls, John M.; Fang, Xiaohui; Guan, Yi; Lee, Jae W.; Chan, Renee W. Y.; Webster, Robert G.; Matthay, Michael A.; Peiris, J. S. Malik

    2016-01-01

    Influenza can cause acute lung injury. Because immune responses often play a role, antivirals may not ensure a successful outcome. To identify pathogenic mechanisms and potential adjunctive therapeutic options, we compared the extent to which avian influenza A/H5N1 virus and seasonal influenza A/H1N1 virus impair alveolar fluid clearance and protein permeability in an in vitro model of acute lung injury, defined the role of virus-induced soluble mediators in these injury effects, and demonstr...

  6. Intravenous alpha-1 antitrypsin augmentation therapy for treating patients with alpha-1 antitrypsin deficiency and lung disease

    DEFF Research Database (Denmark)

    Gøtzsche, Peter C; Johansen, Helle Krogh

    2010-01-01

    Alpha-1 antitrypsin deficiency is an inherited disorder that can cause lung disease. People who smoke are more seriously affected and have a greater risk of dying from the disease.......Alpha-1 antitrypsin deficiency is an inherited disorder that can cause lung disease. People who smoke are more seriously affected and have a greater risk of dying from the disease....

  7. Efficacy of a Low-Tidal Volume Ventilation Strategy to Prevent Reperfusion Lung Injury after Pulmonary Thromboendarterectomy.

    Science.gov (United States)

    Bates, Dina M; Fernandes, Timothy M; Duwe, Beau V; King, Bryan O; Banks, Dalia A; Test, Victor J; Fedullo, Peter F; Kim, Nick H; Madani, Michael M; Jamieson, Stuart W; Auger, William R; Kerr, Kim M

    2015-10-01

    Reperfusion lung injury is a postoperative complication of pulmonary thromboendarterectomy that can significantly affect morbidity and mortality. Studies in other postoperative patient populations have demonstrated a reduction in acute lung injury with the use of a low-tidal volume (Vt) ventilation strategy. Whether this approach benefits patients undergoing thromboendarterectomy is unknown. We sought to determine if low-Vt ventilation reduces reperfusion lung injury in patients with chronic thromboembolic pulmonary hypertension undergoing thromboendarterectomy. Patients undergoing thromboendarterectomy at one center were randomized to receive either low (6 ml/kg predicted body weight) or usual care Vts (10 ml/kg) from the initiation of mechanical ventilation in the operating room through Postoperative Day 3. The primary endpoint was the onset of reperfusion lung injury. Secondary outcomes included severity of hypoxemia, days on mechanical ventilation, and intensive care unit and hospital lengths of stay. A total of 128 patients were enrolled and included in the analysis; 63 were randomized to the low-Vt group and 65 were randomized to the usual care group. There was no statistically significant difference in the incidence of reperfusion lung injury between groups (32%, n=20 in the low-Vt group vs. 23%, n=15 in the usual care group; P=0.367). Although differences were noted in plateau pressures (17.9 cm H2O vs. 20.1 cm H2O, Plung injury or improve clinical outcomes. Clinical trial registered with www.clinicaltrials.gov (NCT00747045).

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

    Science.gov (United States)

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

    2016-12-01

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

  9. Apneic oxygenation combined with extracorporeal arteriovenous carbon dioxide removal provides sufficient gas exchange in experimental lung injury

    DEFF Research Database (Denmark)

    Nielsen, Niels Dalsgaard; Kjærgaard, Benedict; Nielsen, Jakob Koefoed

    Background and aim of study We hypothesized that continuous high airway pressure without ventilatory movements (apneic oxygenation), using an open lung approach, combined with extracorporeal, pumpless, arterio-venous, carbon dioxide (CO2) removal would provide adequate gas exchange in acute lung...... In this porcine lung injury model, apneic oxygenation with arteriovenous CO2 removal provided sufficient gas exchange and stable hemodynamics, indicating that the method might have a potential in the treatment of severe ARDS.   Acknowledgements The membrane lungs were kindly provided by Novalung GmbH, Germany....

  10. Lung surgery

    Science.gov (United States)

    ... cavity, particularly after trauma Surgery to remove small balloon-like tissues (blebs) that cause lung collapse ( pneumothorax ) ... this surgery include: Failure of the lung to expand Injury to the lungs or blood vessels Need ...

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

    Directory of Open Access Journals (Sweden)

    Torii Y

    2011-09-01

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

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

    Science.gov (United States)

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

    2016-05-01

    Acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) are clinically severe respiratory disorders, and there are currently no Food and Drug Administration-approved drug therapies. Melatonin is a well-known anti-inflammatory molecule, which has proven to be effective in ALI induced by many conditions. Emerging studies suggest that the NLRP3 inflammasome plays a critical role during ALI. How melatonin directly blocks activation of the NLRP3 inflammasome in ALI remains unclear. In this study, using an LPS-induced ALI mouse model, we found intratracheal (i.t.) administration of melatonin markedly reduced the pulmonary injury and decreased the infiltration of macrophages and neutrophils into lung. During ALI, the NLRP3 inflammasome is significantly activated with a large amount of IL-1β and the activated caspase-1 occurring in the lung. Melatonin inhibits the activation of the NLRP3 inflammasome by both suppressing the release of extracellular histones and directly blocking histone-induced NLRP3 inflammasome activation. Notably, i.t. route of melatonin administration opens a more efficient therapeutic approach for treating ALI. © 2016 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

  13. Role of the Nrf2/HO-1 axis in bronchopulmonary dysplasia and hyperoxic lung injuries.

    Science.gov (United States)

    Amata, Emanuele; Pittalà, Valeria; Marrazzo, Agostino; Parenti, Carmela; Prezzavento, Orazio; Arena, Emanuela; Nabavi, Seyed Mohammad; Salerno, Loredana

    2017-07-15

    Bronchopulmonary dysplasia (BPD) is a chronic illness that usually originates in preterm newborns. Generally, BPD is a consequence of respiratory distress syndrome (RDS) which, in turn, comes from the early arrest of lung development and the lack of pulmonary surfactant. The need of oxygen therapy to overcome premature newborns' compromised respiratory function generates an increasing amount of reactive oxygen species (ROS), the onset of sustained oxidative stress (OS) status, and inflammation in the pulmonary alveoli deputies to respiratory exchanges. BPD is a severe and potentially life-threatening disorder that in the most serious cases, can open the way to neurodevelopmental delay. More importantly, there is no adequate intervention to hamper or treat BPD. This perspective article seeks to review the most recent and relevant literature describing the very early stages of BPD and hyperoxic lung injuries focussing on nuclear factor erythroid derived 2 (Nrf2)/heme oxygenase-1 (HO-1) axis. Indeed, Nrf2/HO1 activation in response to OS induced lung injury in preterm concurs to the induction of certain number of antioxidant, anti-inflammatory, and detoxification pathways that seem to be more powerful than the activation of one single antioxidant gene. These elicited protective effects are able to counteract/mitigate all multifaceted aspects of the disease and may support novel approaches for the management of BPD. © 2017 The Author(s). Published by Portland Press Limited on behalf of the Biochemical Society.

  14. Loss of the intestinal mucus layer in the normal rat causes gut injury but not toxic mesenteric lymph nor lung injury.

    Science.gov (United States)

    Sharpe, Susan M; Qin, Xiaofa; Lu, Qi; Feketeova, Eleonora; Palange, David C; Dong, Wei; Sheth, Sharvil U; Lee, Marlon A; Reino, Diego; Xu, Da-Zhong; Deitch, Edwin A

    2010-11-01

    There is substantial evidence that gut barrier failure is associated with distant organ injury and systemic inflammation. After major trauma or stress, the factors and mechanisms involved in gut injury are unknown. Our primary hypothesis is that loss of the intestinal mucus layer will result in injury of the normal gut that is exacerbated by the presence of luminal pancreatic proteases. Our secondary hypothesis is that the injury produced in the gut will result in the production of biologically active mesenteric lymph and consequently distant organ (i.e., lung) injury. To test this hypothesis, five groups of rats were studied: 1) uninstrumented naive rats; 2) control rats in which a ligated segment of distal ileum was filled with saline; 3) rats with pancreatic proteases placed in their distal ileal segments; 4) rats with the mucolytic N-acetylcysteine (NAC) placed in their distal ileal segments; and 5) rats exposed to NAC and pancreatic proteases in their ileal segments. The potential systemic consequences of gut injury induced by NAC and proteases were assessed by measuring the biological activity of mesenteric lymph as well as gut-induced lung injury. Exposure of the normal intestine to NAC, but not saline or proteases, led to increased gut permeability, loss of mucus hydrophobicity, a decrease in the mucus layer, as well as morphological evidence of villous injury. Although proteases themselves did not cause gut injury, the combination of pancreatic proteases with NAC caused more severe injury than NAC alone, suggesting that once the mucus barrier is impaired, luminal proteases can injure the now vulnerable gut. Because comparable levels of gut injury caused by systemic insults are associated with gut-induced lung injury, which is mediated by biologically active factors in mesenteric lymph, we next tested whether this local model of gut injury would produce active mesenteric lymph or lead to lung injury. It did not, suggesting that gut injury by itself may not

  15. Lung injury following thoracic aortic occlusion: comparison of sevoflurane and propofol anaesthesia.

    Science.gov (United States)

    Annecke, T; Kubitz, J C; Langer, K; Hilberath, J M; Kahr, S; Krombach, F; Bittmann, I; Rehm, M; Kemming, G I; Conzen, P F

    2008-08-01

    Halogenated anaesthetics have been shown to reduce ischaemia-reperfusion injuries in various organs due to pre- and post-conditioning mechanisms. We compared volatile and total intravenous anaesthesia with regard to their effect on remote pulmonary injury after thoracic aortic occlusion and reperfusion. Eighteen pigs were randomized after sternotomy and laparotomy (fentanyl-midazolam anaesthesia) to receive either sevoflurane or propofol in an investigator-blinded fashion. Ninety minutes of thoracic aortic occlusion was induced by a balloon catheter. During reperfusion, a goal-directed resuscitation protocol was performed. After 120 min of reperfusion, the anaesthetic regimen was changed to fentanyl-midazolam again for another 180 min. The oxygenation index and intra-pulmonary shunt fractions were calculated. After 5 h of reperfusion, a bronchoalveolar lavage was performed. The total protein content and lactate dehydrogenase activity were measured in epithelial lining fluid (ELF). Alveolar macrophage oxidative burst was analysed. The wet to dry ratio was calculated and tissue injury was graded using a semi-quantitative score. Ten animals (n=5 for each anaesthetic) without aortic occlusion served as time controls. The oxygenation index decreased and the intra-pulmonary shunt fraction increased significantly in both occlusion groups. There were no significant differences between sevoflurane and propofol with respect to the oxygenation index, ELF composition, morphologic lung damage, wet to dry ratio and alveolar macrophage burst activity. Differences were, however, seen in terms of systemic haemodynamic stability, where catecholamine requirements were less pronounced with sevoflurane. We conclude that the severity of remote lung injury was not different between sevoflurane and propofol anaesthesia in this porcine model of severe lower-body ischaemia and reperfusion injury.

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

    Directory of Open Access Journals (Sweden)

    V. A. Tumanskiy

    2013-08-01

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

  17. Heme Oxygenase-1/Carbon Monoxide-regulated Mitochondrial Dynamic Equilibrium Contributes to the Attenuation of Endotoxin-induced Acute Lung Injury in Rats and in Lipopolysaccharide-activated Macrophages.

    Science.gov (United States)

    Yu, Jianbo; Shi, Jia; Wang, Dan; Dong, Shuan; Zhang, Yuan; Wang, Man; Gong, Lirong; Fu, Qiang; Liu, Daquan

    2016-12-01

    Sepsis-associated acute lung injury remains the major cause of mortality in critically ill patients and is characterized by marked oxidative stress and mitochondrial dysfunction. Mitochondrial dynamics are indispensable for functional integrity. Additionally, heme oxygenase (HO)-1/carbon monoxide conferred cytoprotection against end-organ damage during endotoxic shock. Herein, we tested the hypothesis that HO-1/carbon monoxide played a critical role in maintaining the dynamic process of mitochondrial fusion/fission to mitigate lung injury in Sprague-Dawley rats or RAW 264.7 macrophages exposed to endotoxin. The production of reactive oxygen species, the respiratory control ratio (RCR), and the expressions of HO-1 and mitochondrial dynamic markers were determined in macrophages. Concurrently, alterations in the pathology of lung tissue, lipid peroxidation, and the expressions of the crucial dynamic proteins were detected in rats. Endotoxin caused a 31% increase in reactive oxygen species and a 41% decrease in RCR levels (n = 5 per group). In parallel, the increased expression of HO-1 was observed in lipopolysaccharide-stimulated macrophages, concomitantly with excessive mitochondrial fission. Furthermore, carbon monoxide-releasing molecule-2 or hemin normalized mitochondrial dynamics, which were abrogated by zinc protoporphyrin IX. Additionally, impaired mitochondrial dynamic balance was shown in Sprague-Dawley rats that received lipopolysaccharide, accompanied by pathologic injury, elevated malondialdehyde contents, decreased manganese superoxide dismutase activities, and lowered RCR levels in rat lung mitochondria. However, the above parameters were augmented by zinc protoporphyrin IX and were in turn reversed by hemin. The HO-1/carbon monoxide system modulated the imbalance of the dynamic mitochondrial fusion/fission process evoked by lipopolysaccharide and efficiently ameliorated endotoxin-induced lung injury in vivo and in vitro.

  18. Low tidal volume protects pulmonary vasomotor function from “second-hit” injury in acute lung injury rats

    Directory of Open Access Journals (Sweden)

    Pan Chun

    2012-09-01

    Full Text Available Abstract Background Sepsis could induce indirect acute lung injury(ALI, and pulmonary vasomotor dysfunction. While low tidal volume is advocated for treatment of ALI patients. However, there is no evidence for low tidal volume that it could mitigate pulmonary vasomotor dysfunction in indirect ALI. Our study is to evaluate whether low tidal volume ventilation could protect the pulmonary vascular function in indirect lipopolysaccharide (LPS induced acute lung injury rats. Methods An indirect ALI rat model was induced by intravenous infusion of LPS. Thirty rats (n = 6 in each group were randomly divided into (1Control group; (2 ALI group; (3 LV group (tidal volume of 6mL/kg; (4 MV group (tidal volume of 12mL/kg; (5VLV group (tidal volume of 3mL/kg. Mean arterial pressure and blood gas analysis were monitored every 2 hours throughout the experiment. Lung tissues and pulmonary artery rings were immediately harvested after the rats were bled to be killed to detect the contents of endothelin-1 (ET-1, endothelial nitric oxide synthase (eNOS and TNF-α. Acetylcholine (Ache-induced endothelium-dependent and sodium nitroprusside (SNP-induced endothelium-independent relaxation of isolated pulmonary artery rings were measured by tensiometry. Results There was no difference within groups concerning blood pressure, PaCO2 and SNP-induced endothelium-independent relaxation of pulmonary artery rings. Compared with MV group, LV group significantly reduced LPS-induced expression of ET-1 level (113.79 ± 7.33pg/mL vs. 152.52 ± 12.75pg/mL, P P P -7mol/L-10-4mol/L-induced vasodilatation was ameliorated 30% more in LV group than in MV group. Conclusions Low tidal volume could protect the pulmonary vasodilative function during indirect ALI by decreasing vasoconstrictor factors, increasing expressions of vasodilator factors in pulmonary endothelial cells, and inhibiting inflammation injuries.

  19. Deficiency of the two-pore-domain potassium channel TREK-1 promotes hyperoxia-induced lung injury.

    Science.gov (United States)

    Schwingshackl, Andreas; Teng, Bin; Makena, Patrudu; Ghosh, Manik; Sinclair, Scott E; Luellen, Charlean; Balasz, Louisa; Rovnaghi, Cynthia; Bryan, Robert M; Lloyd, Eric E; Fitzpatrick, Elizabeth; Saravia, Jordy S; Cormier, Stephania A; Waters, Christopher M

    2014-11-01

    We previously reported the expression of the two-pore-domain K channel TREK-1 in lung epithelial cells and proposed a role for this channel in the regulation of alveolar epithelial cytokine secretion. In this study, we focused on investigating the role of TREK-1 in vivo in the development of hyperoxia-induced lung injury. Laboratory animal experiments. University research laboratory. Wild-type and TREK-1-deficient mice. Mice were anesthetized and exposed to 1) room air, no mechanical ventilation, 2) 95% hyperoxia for 24 hours, and 3) 95% hyperoxia for 24 hours followed by mechanical ventilation for 4 hours. Hyperoxia exposure accentuated lung injury in TREK-1-deficient mice but not controls, resulting in increase in lung injury scores, bronchoalveolar lavage fluid cell numbers, and cellular apoptosis and a decrease in quasi-static lung compliance. Exposure to a combination of hyperoxia and injurious mechanical ventilation resulted in further morphological lung damage and increased lung injury scores and bronchoalveolar lavage fluid cell numbers in control but not TREK-1-deficient mice. At baseline and after hyperoxia exposure, bronchoalveolar lavage cytokine levels were unchanged in TREK-1-deficient mice compared with controls. Exposure to hyperoxia and mechanical ventilation resulted in an increase in bronchoalveolar lavage interleukin-6, monocyte chemotactic protein-1, and tumor necrosis factor-α levels in both mouse types, but the increase in interleukin-6 and monocyte chemotactic protein-1 levels was less prominent in TREK-1-deficient mice than in controls. Lung tissue macrophage inflammatory protein-2, keratinocyte-derived cytokine, and interleukin-1β gene expression was not altered by hyperoxia in TREK-1-deficient mice compared with controls. Furthermore, we show for the first time TREK-1 expression on alveolar macrophages and unimpaired tumor necrosis factor-α secretion from TREK-1-deficient macrophages. TREK-1 deficiency resulted in increased sensitivity

  20. Bayesian network analysis of multi-compartmentalized immune responses in a murine model of sepsis and direct lung injury.

    Science.gov (United States)

    Nemzek, Jean A; Hodges, Andrew P; He, Yongqun

    2015-09-30

    Inflammatory disease processes involve complex and interrelated systems of mediators. Determining the causal relationships among these mediators becomes more complicated when two, concurrent inflammatory conditions occur. In those cases, the outcome may also be dependent upon the timing, severity and compartmentalization of the insults. Unfortunately, standard methods of experimentation and analysis of data sets may investigate a single scenario without uncovering many potential associations among mediators. However, Bayesian network analysis is able to model linear, nonlinear, combinatorial, and stochastic relationships among variables to explore complex inflammatory disease systems. In these studies, we modeled the development of acute lung injury from an indirect insult (sepsis induced by cecal ligation and puncture) complicated by a direct lung insult (aspiration). To replicate multiple clinical situations, the aspiration injury was delivered at different severities and at different time intervals relative to the septic insult. For each scenario, we measured numerous inflammatory cell types and cytokines in samples from the local compartments (peritoneal and bronchoalveolar lavage fluids) and the systemic compartment (plasma). We then analyzed these data by Bayesian networks and standard methods. Standard data analysis demonstrated that the lung injury was actually reduced when two insults were involved as compared to one lung injury alone. Bayesian network analysis determined that both the severity of lung insult and presence of sepsis influenced neutrophil recru