MECHANISMS OF AIRWAY RESPONSES TO ENDOTOXEMIA

这项建议考察了脂质介质(血小板)的作用 激活因子(PAF)和二十烷类化合物，包括环氧合酶， 花生四烯酸脂氧合酶和单加氧酶产物) 内毒素致肺功能障碍。特别注意的是 与肺力学和呼吸道的改变有关 内毒素引起的反应性。具体目标是： 1.测定精制脂质的直接作用和次要作用 体内肺功能和小鼠肺细胞和肺组织中的介质 体外培养。 2.确定释放的数量、时间和方式 体内和体外内毒素暴露后的脂质介体。 3.测定受体拮抗剂和抑制剂的作用 PAF和二十烷基类化合物代谢对内毒素诱导的脂质的影响 慢性阻塞性肺疾病中介质释放与肺功能障碍 有仪表盘的清醒的绵羊。 最先进的分析方法和对 药理探针的特异性被谨慎地用来 确定个别调解人和互动的作用(如果有的话) 内毒素所致肺功能障碍中的脂质介体。 这项提议的长期目标是获得 了解这将有助于制定干预措施 与成人呼吸道疾病的预防或治疗有关的 男性的窘迫综合征(ARDS)和哮喘。

This proposal examines the role of lipid mediators (platelet activating factor (PAF) and eicosanoids including cyclooxygenase, lipoxygenase and monooxygenase products of arachidonic acid) in endotoxin-induced pulmonary dysfunction. Special attention is given to the alterations in lung mechanics and airway responsiveness caused by endotoxin. The Specific Aims are: 1. To determine the direct and secondary effects of purified lipid mediators on lung function in vivo and on cells and lung tissue in vitro. 2. To determine the quantity, timing and pattern of release of lipid mediators following endotoxin exposure in vivo and in vitro. 3. To determine the effects of receptor antagonists and inhibitors of PAF and eicosanoid metabolism on endotoxin-induced lipid mediator release and pulmonary dysfunction in chronically instrumented awake sheep. State-of-the-art analytic methods and a natural skepticism about the specificity of pharmacologic probes are used to carefully define the roles of individual mediators and interactions, if any, among lipid mediators in endotoxin-induced pulmonary dysfunction. It is the long-term objective of this proposal to gain understanding that will assist in the development of interventions relevant to the prevention or treatment of the adult respiratory distress syndrome (ARDS) and asthma in man.