PATHOGENIC MECHANISMS PRODUCING LUNG INJURY

引起肺损伤的致病机制

• 批准号: 3340396
• 负责人: Charles Emory McCall
• 金额: $ 17.77万
• 依托单位: WAKE FOREST UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1982
• 资助国家: 美国
• 起止时间: 1982-09-01 至 1992-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3340396
• 关键词: antimetabolites; arachidonate; cell aggregation; endotoxins; enzyme inhibitors; enzyme mechanism; fatty acid metabolism; human tissue; laboratory rabbit; leukopenia; lung disorder; myristates; neutrophil; phorbols; platelet activating factor; platelets; radioimmunoassay; radiotracer; thrombocytopenia; tissue /cell culture

We perceive that aggregating agents fall into 3 categories: 1) agents which transiently aggregate neutrophils (PMN) (e.g., C5a and synthetic oligopeptides [FMLP]), cause equally transient neutropenia and evanescent mild lung dysfunction; 2) agents which transiently aggregate PMN and platelets (PL) (e.g., platelet activating factor [PAF]) cause equally transient neutropenia and thrombocytopenia and severe lung dysfunction; 3) agents which aggregate PMN and PL irreversibly (e.g., phorbol myristate acetate [PMA]) cause prolonged (greater than 3 hr) neutropenia, thrombocytopenia, and lung dysfunction. We propose that C5a, FMLP, PAF, BUT NOT PMA are active in vivo because they trigger the generation of arachidonate metabolites which mediate cytopenias and lung dysfunction. We will test this hypothesis by measuring blood levels of two arachidonate metabolites (e.g. PGE2 and TXB2), following intravenous administration of the various stimuli; by assessing the effects of arachidonate antimetabolites on the in vivo actions of C5a, FMLP, PAF, and PMA; by determining if PMN of PL obtained from treated rabbits are insensitive (i.e., are desensitized) to stimulation by C5a, FMLP, PAF, LTB4, or PMA; by determining if certain arachidonate metabolites can mimic the actions of the stimuli; and, where possible, by determining if these bioactive arachidonate metabolites circulate in the blood of treated rabbits. In addition, we will explore the role of endogenous C5a, PAF, and arachidonate metabolism on the syndrome of endotoxin shock, a syndrome that also involves neutropenia, thrombocytopenia, and lung dysfunction. In these pursuits our aim is to find evidence supporting the hypothesis that various endogenously formed aggregating agents (e.g., products of arachidonate metabolism or PAF) mediate various syndromes which associate cytopenia with lung dysfunction. Finally, we will examine the effects of these mediators on lung function and structure when administered to animals over prolonged periods (i.e., days to months). These studies may uncover possible etiologies for acute or chronic lung disease and fibrosis.

我们认为汇总代理分为三类：1）代理 瞬时聚集嗜中性粒细胞（PMN）（例如C5A和合成 寡肽[FMLP]），引起同样短暂的中性粒细胞减少和衰老 轻度肺功能障碍； 2）瞬时汇总PMN和 血小板（PL）（例如，血小板激活因子[PAF]）同样引起 短暂性中性粒细胞减少和血小板减少症和严重的肺功能障碍； 3） 汇总PMN和PL不可逆的代理（例如，凤凰肉芽菌 乙酸盐[PMA]）导致延长（大于3小时）中性粒细胞减少症， 血小板减少症和肺功能障碍。 我们建议C5A，FMLP，PAF， 但是PMA在体内没有活跃，因为它们会触发生成 介导细胞质和肺功能障碍的蛛形代谢产物。 我们 将通过测量两种蛛网酸的血液水平来检验这一假设 静脉给药后，代谢物（例如PGE2和TXB2） 各种刺激；通过评估蛛网酸的影响 C5A，FMLP，PAF和PMA的体内作用上的抗代谢物；经过 确定从处理过的兔子获得的PL的PMN是否不敏感 （即，脱敏）通过C5A，FMLP，PAF，LTB4或PMA刺激；经过 确定某些蛛形代谢产物是否可以模仿 刺激；而且，通过确定这些生物活性是否是否 蛛形代谢物在处理过的兔子的血液中循环。 在 此外，我们将探讨内源性C5A，PAF和蛛网酸的作用 内毒素休克综合征的代谢，这也是一种综合征 涉及中性粒细胞减少症，血小板减少症和肺功能障碍。 在这些 追求我们的目的是找到证据，以支持各种假设 内源形成的聚集剂（例如，蛛网酸的产物 代谢或PAF）介导各种综合症，将细胞质与 肺功能障碍。 最后，我们将研究这些调解人的影响 在肺部功能和结构上施用对动物的延长 时期（即天到几个月）。 这些研究可能会发现 急性或慢性肺疾病和纤维化的病因。