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Query: UMLS:C0034063 (pulmonary edema)
 10,665 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Pulmonary vascular endothelial cells are an important barrier that helps keep lung tissue intact. These cells are exposed to potentially injurious cells and to harmful mediators that are produced in or released into the blood. The endothelial cells may then be stimulated and injured. Stimulated and injured pulmonary vascular endothelial cells can themselves produce and release injury-promoting mediators. Using isolated perfused rat lungs and cultured human pulmonary endothelial cells, we assessed the effect of neutrophil-derived injurious mediators, leukotoxin, and neutrophil elastase on the pulmonary endothelium. Both mediators caused high-permeability pulmonary edema in the isolated lungs and caused dose-dependent and time-dependent damage in the cell cultures. Injury due to leukotoxin was suppressed in the presence of LNMMA or superoxide dismutase and injury due to neutrophil elastase was suppressed by neutrophil elastase inhibitors. These data indicate that these mediators cause lung injury via different mechanisms and that they may synergistically evoke clinical lung injury.
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PMID:[Lung injury and pulmonary vascular endothelial cell injury]. 875 10

We investigated the roles of neutrophil and neutrophil elastase in acute lung injury (ALI) to elucidate the mechanism of ALI. We designed two protocols. Protocol I: Experimental ALI was induced by endotoxin (0.02 mg/kg) and platelet-activating factor (8 microg/kg/4 h) in untreated rabbits (control group I), in neutropenic rabbits pretreated with nitrogen-N-oxide hydrochloride, and in untreated rabbits infused with a neutrophil elastase inhibitor (ONO-5046; 20 mg/kg/4 h). Protocol II: ALI was induced by smaller doses of endotoxin (0.015 mg/kg) and platelet-activating factor (7 microg/kg/4 h) than those used in protocol I in untreated rabbits (control group II), in neutrophilic rabbits pretreated with human recombinant granulocyte colony-stimulating factor, and in neutrophilic rabbits infused with ONO-5046 (as in protocol I). The severity of ALI was assessed by the protein concentration, the elastase activity in the bronchoalveolar lavage fluid, and the histologic pulmonary edema ratio. The degree of pulmonary neutrophil accumulation was assessed by pulmonary myeloperoxidase activity and histological findings. Both ALI and pulmonary neutrophil accumulation were suppressed by neutropenia (protocol I), while they were exacerbated by neutrophilia (protocol II). The neutrophil elastase inhibitor could suppress ALI, but it could not suppress pulmonary neutrophil accumulation in both untreated and neutrophilic rabbits (protocols I and II). These findings indicate that neutrophils play an important role in the pathogenesis of ALI via neutrophil elastase.
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PMID:Neutrophils mediate acute lung injury in rabbits: role of neutrophil elastase. 1118 17

Acute respiratory distress syndrome (ARDS), is characterised by capillary permeability and pulmonary oedema formation and may complicate a variety of medical and surgical illnesses. As a self-perpetuating state of inflammatory derangement, acute lung injury (ALI)/ARDS is manifest clinically as rapid development of radiographic infiltrates, severe hypoxaemia and reduced lung compliance. Over the years, researchers have made significant progress in elucidating the pathophysiology of this complex syndrome. Therapies targeting specific pathophysiologic steps in the development or persistence of this syndrome are in various stages of laboratory and clinical testing. Results to date have shown nitric oxide (NO) to improve oxygenation in the majority of patients but fail to improve mortality. Surfactant replacement has had limited success in adults, but new formulations and delivery methods may prove beneficial. Several inflammatory mediator-targeted therapies have progressed successfully through early clinical evaluation. Among these, neutrophil elastase inhibitors have shown the most promise and are currently undergoing Phase III trials. Other mediator-targeted therapies, such as prostaglandin E1, IL-10 and platelet activating factor antagonists, have not been found efficacious in large clinical trials of ARDS. However, these therapies, along with coagulation modulators, may have a favourable impact on ARDS by improving outcomes in sepsis, the greatest risk factor for developing this condition. In the interim, supportive care through improvements in mechanical ventilation are beneficial, while specific fluid balance and nutrition strategies may prove advantageous.
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PMID:Clinical developments for treating ARDS. 1177 19

Ischemia-reperfusion injury is a significant problem in lung transplantation. Polymorphonuclear elastase derived from neutrophils plays a major mechanistic role in this process. Hence, we have investigated the effects of ONO-5046, a neutrophil elastase inhibitor, on ischemia-reperfusion injury. Fifteen rabbits were divided into three groups: 2 h of single left-lung perfusion (control group, n=3); 2 h of ischemia followed by 2 h of reperfusion (ischemic group, n=6); and drip intravenous administration of ONO-5046 during the 2 h of ischemia and 2 h of reperfusion (ONO-5046 group, n=6). Hemodynamic parameters were determined and a histopathological examination of the lung was performed. In the ONO-5046 group, arterial oxygen pressure, cardiac output, and tissue blood perfusion were higher and pulmonary vascular resistance was lower than in the ischemic group. The ONO-5046 group also showed large decreases in neutrophil infiltration, pulmonary edema, and intra-alveolar hemorrhage. Treatment with ONO-5046 improves lung function in a rabbit-lung ischemia-reperfusion model.
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PMID:The effects of a specific neutrophil elastase inhibitor (ONO-5046) in pulmonary ischemia-reperfusion injury. 1275 26

Mediators released from polymorphonuclear neutrophils, in particular elastase, are known to induce acute edematous lung injury. In this study we show that the pulmonary edema in isolated perfused rabbit lungs caused by activated neutrophils via release of elastase is significantly decreased by the Kunitz-type Inhibitor BbCI (10(-5) M) from Bauhinia bauhinoides to the same degree as by eglin C (10(-5) M) from Hirudo medicinalis, which was used as a reference. The highly homologous proteinase inhibitor BrPI (10(-5) M) from Bauhinia rufa, however, did not reduce edema formation. The major difference between these inhibitors is the much higher Ki value of BrPI (Ki = 38 nM) for elastase compared to BbCI (Ki = 5.3 nM) and eglin C (Ki = 0.2 nM), respectively. Elastase liberation from activated PMNs was not influenced by the inhibitors. Our results indicate that BbCI can be a useful tool to study the role of neutrophil elastase in pathophysiological processes.
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PMID:Effect of plant Kunitz inhibitors from Bauhinia bauhinioides and Bauhinia rufa on pulmonary edema caused by activated neutrophils. 1288 61

Acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) are acute life-threatening forms of hypoxemic respiratory failure. ALI/ARDS patients require intensive care with prolonged mechanical ventilation. Despite advances in our understanding of the pathophysiology of ALI/ARDS, mortality rates remain > 30% and survivors suffer significant decrements in their quality of life. The evolving understanding of ALI/ARDS and the complex interactions involved in ALI/ARDS open the door for many potential targets for treatment. The condition is characterised by an acute inflammatory state that leads to increased capillary permeability and accumulation of proteinaceous pulmonary oedema. The changes that occur as a result of this inflammation clinically manifest themselves as hypoxemia, infiltrates on chest radiograph and reduced lung compliance. Many years have been dedicated to analysing the complexities involved in ALI/ARDS in order to improve current and future possibilities for treatment, with the aim of improving patient outcomes. Although some therapies have demonstrated benefits of improved oxygenation, such as surfactant and nitric oxide, these benefits have not translated into reductions in the duration of mechanical ventilation or mortality. Inflammatory mediator-targeted therapies were promising early on; however, larger trials have found therapies such as cytokine modulation, platelet-activating factor inhibition and neutrophil elastase inhibitors to be ineffective in the treatment of ALI/ARDS. Preclinical studies with beta2-agonists and granulocyte macrophage colony-stimulating factor have shown promise for restoring alveolar capillary barrier integrity or reducing pulmonary oedema, and further studies are being conducted to test for true clinical benefit. Despite previous therapeutic failures, newer surfactant formulations have shown promise, particularly in patients with direct forms of lung injury, and are currently in Phase III trials. Anticoagulant therapy with activated protein C has been shown to improve survival in sepsis, the most common risk factor for the development of ALI/ARDS, and is now being studied in ALI/ARDS. Until new data emerge, the focus must remain on supportive care, including optimised mechanical ventilation, nutritional support, manipulation of fluid balance and prevention of intervening medical complications.
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PMID:Evolution of treatments for patients with acute lung injury. 1592 69

Reexpansion of a collapsed lung increases the microvascular permeability and causes reexpansion pulmonary edema. Neutrophils and their products have been implicated in the development of this phenomenon. The small GTP-binding proteins Rho and its target Rho-kinase (ROCK) regulate endothelial permeability, although their roles in reexpansion pulmonary edema remain unclear. We studied the contribution of ROCK to pulmonary endothelial and epithelial permeability in a rabbit model of this disorder. Endothelial and epithelial permeability was assessed by measuring the tissue-to-plasma (T/P) and bronchoalveolar lavage (BAL) fluid-to-plasma (B/P) ratios with (125)I-labeled albumin. After intratracheal instillation of (125)I-albumin, epithelial permeability was also assessed from the plasma leak (PL) index, the ratio of (125)I-albumin in plasma/total amount of instilled (125)I-albumin. T/P, B/P, and PL index were significantly increased in the reexpanded lung. These increases were attenuated by pretreatment with Y-27632, a specific ROCK inhibitor. However, neutrophil influx, neutrophil elastase activity, and malondialdehyde concentrations in BAL fluid collected from the reexpanded lung were not changed by Y-27632. In endothelial monolayers, Y-27632 significantly attenuated the H(2)O(2)-induced increase in permeability and mitigated the morphological changes in the actin microfilament cytoskeleton of endothelial cells. These in vivo and in vitro observations suggest that the Rho/ROCK pathway contributes to the increase in alveolar barrier permeability associated with reexpansion pulmonary edema.
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PMID:Role of Rho-kinase in reexpansion pulmonary edema in rabbits. 1600 83

Hemorrhagic shock followed by resuscitation (HSR) causes neutrophil sequestration in the lung which leads to acute lung injury (ALI). Neutrophil elastase (NE) is thought to play a pivotal role in the pathogenesis of ALI. This study investigated whether sivelestat, a specific NE inhibitor, can attenuate ALI induced by HSR in rats. Male Sprague-Dawley rats were subjected to hemorrhagic shock by withdrawing blood so as to maintain a mean arterial blood pressure of 30+/-5 mm Hg for 60 min followed by resuscitation with the shed blood. HSR-treated animals received a bolus injection of sivelestat (10 mg/kg) intravenously at the start of resuscitation followed by continuous infusion for 60 min (10 mg/kg/h) during the resuscitation phase, or the vehicle. Lung injury was assessed by pulmonary histology, lung wet-weight to dry-weight (W/D) ratio, myeloperoxidase (MPO) activity, gene expression of tumor necrosis factor (TNF)-alpha and inducible nitric oxide synthase (iNOS), DNA binding activity of nuclear factor (NF)-kappaB, and immunohistochemical analysis of intercellular adhesion molecule (ICAM)-1. HSR treatment induced lung injury, as demonstrated by pulmonary edema with infiltration of neutrophils, the increase in lung W/D ratio, MPO activity, gene expression of TNF-alpha and iNOS, and DNA-binding activity of NF-kappaB, and enhanced expression of ICAM-1. In contrast, sivelestat treatment significantly ameliorated the HSR-induced lung injury, as judged by the marked improvement in all these indices. These results indicate that sivelestat attenuated HSR-induced lung injury at least in part through an inhibition of the inflammatory signaling pathway, in addition to the direct inhibitory effect on NE.
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PMID:A neutrophil elastase inhibitor, sivelestat, ameliorates lung injury after hemorrhagic shock in rats. 1720 97

Acute respiratory distress syndrome (ARDS) is the most devastating form of acute lung injury (ALI) or pulmonary edema (PE). We presented the experimental studies and clinical investigations of two serious forms of ALI. Drastic and severe PE could be induced by intracranial hypertension or cerebral compression (CC). The CC-induced PE was attributed to overactivation of the medullary sympathetic mechanism. Sympathetic vasoconstriction of the systemic and pulmonary resistance and capacitance vessels caused shift of blood volume from the splanchnic vascular beds to the lung. The hemodynamic changes led to systemic and pulmonary hypertension. Consequently, left ventricular failure as evidenced by dramatic decline in aortic flow with a slow decrease in pulmonary flow resulted in pressure and volume loading in the pulmonary circulation. These changes finally produced severe alveolar flooding and sudden death. Vasodilators such as sodium nitroprusside or nitroglycerin were capable of reducing the CC-induced pulmonary pathology and hemodynamic alterations. Fat embolism syndrome (FES) is a serious clinical problem in patients suffering from long bone fractures. ARDS may develop and cause mortality. Our laboratory reported a total of 14 subjects associated with FES and died of ARDS. We also developed a simple technique to produce FES. Corn oil was mixed with distilled water to form fatty micelles. Intravenous administration of or introduction of fatty micelles in anesthetized rats or isolated perfused lungs caused severe alveolar damage. Our clinical observation and animal experimentation revealed that infusion of fatty acids caused physical phase, resulting in microvascular obstruction accompanied by pulmonary hypertension and increased capillary permeability. Thereafter, the lipases in the lung hydrolyzed the neutral fat and released free fatty acids and biochemical mediators which were toxic to the lung. Our data have suggested that nitric oxide (NO), inducible NO synthase (iNOS), phospholipase A2, free radical and inflammatory cytokines (tumor necrosis factor alpha, interleukin-1beta and interleukin-6) are involved in the biochemical phase of FES with ARDS. The alveolar macrophages are the major source of iNOS. Later study also found that neutrophil elastase and myeloperoxidase were elevated following fat embolism. N-acetylcysteine (an antioxidant), and NOS inhibitors such as Nomega nitro-L-arginine methyl ester (L-NAME), S-methylisothiourea (SMT) or L-N6 (1-iminoethyl)-lysine (L-Nil) were able to abrogate the FES or the fat embolism-induced changes.
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PMID:From neurogenic pulmonary edema to fat embolism syndrome: a brief review of experimental and clinical investigations of acute lung injury and acute respiratory distress syndrome. 2035 24

Acute respiratory distress syndrome (ARDS) is a noncardiogenic pulmonary edema resulting from increased capillary permeability. Numerous pharmacologic therapies have been studied for prevention and treatment of ARDS. Although several pharmacological therapies could improve patient's respiratory function, there have been no controlled studies which clearly demonstrated the clinical benefit for ARDS-related mortality. The role of corticosteroids in ARDS remains controversial. Available evidence is against early administration of high-dose corticosteroids (methylprednisolon 120 mg x kg-1 x day - 1). In contrast, low-dose corticosteroid therapy (methylprednisolon 0.5-2.5mgg kg-1 xday-1)remains controversial. With regard to sivelestat sodium, a specific inhibitor of neutrophil elastase, although the effectiveness in decreasing mortality was not clarified, increases in lung oxygenation and ventilator-free days have consistently been revealed. Other probable pharmacologic therapies for ARDS include continuous infusion of cisatracurium. In conclusion, there are not established drugs for ARDS, and further studies are necessary to reveal the clinical effectiveness of the above mentioned and novel pharmacologic therapies.
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PMID:[Pharmacological therapies for ARDS]. 2377 27


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