ENDOTOXIN INDUCED LUNG INJURY

内毒素引起的肺损伤

• 批准号: 3780007
• 负责人: KENNETH L BRIGHAM
• 金额: --
• 依托单位: VANDERBILT UNIVERSITY
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/3780007
• 关键词: adult respiratory distress syndrome; alveolar macrophages; antioxidants; bioassay; biopsy; bronchoscopy; cytokine; diagnostic respiratory lavage; disease /disorder model; endothelin; endotoxins; enzyme linked immunosorbent assay; gene expression; in situ hybridization; lung injury; nonhuman therapy evaluation; northern blottings; pathologic process; prostacyclins; prostaglandin endoperoxide synthase; prostaglandins; radioimmunoassay; sheep; tissue /cell culture; tumor necrosis factor alpha; vascular endothelium permeability

In an animal model of endotoxin induced diffuse lung injury, we propose to investigate the hypotheses that the pathogenesis of the injury involves oxidant injury to the lungs, an endotoxin induced proteinase/antiproteinase imbalance and alterations in cyclic nucleotide metabolism. Further, we propose that eicosanoids and platelet activating factor (PAF) released as part of the inflammatory response to endotoxemia mediate alterations in lung function and interactions of inflammatory cells with the lungs. To test these hypotheses, we propose studies which will measure lipid peroxidation products in blood and lung lymph and antioxidant enzymes in lung tissue after endotoxin and determine effects of exogenous antioxidants and induction of endogenous antioxidants on the endotoxin response. We will measure a panel of proteinases and antiproteinases in bronchoalveolar lavage (BAL) fluid, blood and lung lymph and determine effects of depletion (chloramine-T) or enhancement (alpha-1-antitrypsin) of antiproteinase activity on the responses of the lungs to endotoxemia. We will measure effects of endotoxin on release of eicosanoids and platelet activating factor in the lungs and determine effects of drugs which inhibit such release on the endotoxin reaction. We will collect lymphocytes and alveolar macrophages from sheep given endotoxin for in vitro measurements of chemotaxin, eicosanoid and PAF production. We will define the trafficking of neutrophils, lymphocytes (including subsets) and macrophages in blood, lung lymph, BAL fluid and lung tissue during the response to endotoxin and determine effects of interventions which alter the pathophysiology of the response on inflammatory cell traffic. We will determine the mechanism of suppression of the lungs' response to endotoxemia by prostaglandin E2. Finally, we will determine whether pharmacologic manipulation of cyclic nucleotide metabolism will prevent or reverse the increase in lung vascular permeability caused by endotoxemia. These studies, combined with others in this proposal, will permit a definition of the pathogenesis of endotoxin induced lung injury and demonstrate rational approaches for therapy and prevention which may be useful in humans.

在内毒素诱导的弥漫性肺损伤的动物模型中，我们 建议调查以下假说： 这种损伤包括对肺部的氧化性损伤，一种内毒素 诱导性蛋白水解酶/抗蛋白水解酶失衡及其变化 环核苷酸代谢。此外，我们建议 二十烷基类化合物和血小板激活因子(PAF)部分释放 炎症反应对内毒素血症的调节作用 肺功能改变与炎性反应的相互作用 肺的细胞。为了检验这些假设，我们建议 将测量血液中脂质过氧化产物的研究 以及肺淋巴和肺组织中的抗氧化酶 内毒素和测定外源抗氧化剂和 内源性抗氧化剂对内毒素反应的诱导。 我们将测量一组蛋白水解酶和抗蛋白酶 支气管肺泡灌洗(BAL)液、血和肺淋巴及 确定消耗(氯胺-T)或增强的效果 (α-1-抗胰蛋白酶)对抗蛋白酶活性的影响 对内毒素血症的影响。我们将衡量以下方面的影响 内毒素对二十烷类化合物释放和血小板活化的影响 肺中的因子和确定抑制的药物的效果 这样就释放了内毒素反应。我们会收集 绵羊淋巴细胞和肺泡巨噬细胞 内毒素用于趋化素类二十烷类化合物的体外检测 和PAF生产。我们将定义贩运 中性粒细胞、淋巴细胞(包括亚群)和巨噬细胞 反应过程中的血液、肺淋巴、BAL液和肺组织 内毒素和确定干预措施的效果 炎性细胞运输反应的病理生理学。 我们将确定抑制肺的机制 前列腺素E_2对内毒素血症的反应最后，我们会 确定环磷酰胺的药理作用是否 核苷酸新陈代谢将防止或逆转 内毒素血症引起的肺血管通透性。这些 与本提案中的其他研究相结合，将允许 内毒素性肺损伤发病机制的界定 并展示合理的治疗和预防方法 这可能对人类有用。