MECHANISMS OF AIRWAY RESPONSES TO ENDOTOXEMIA

本提案探讨了脂质介质（血小板）的作用 活化因子（PAF）和类花生酸包括环氧合酶， 脂氧合酶和花生四烯酸的单加氧酶产物）， 内毒素引起的肺功能障碍 特别注意 考虑到肺力学和气道的改变 由内毒素引起的反应性。 具体目标是： 1. 确定纯化脂质的直接和次要影响 介质对体内肺功能以及对体内细胞和肺组织的影响。 体外 2. 确定释放的数量、时间和模式， 体内和体外内毒素暴露后的脂质介质。 3. 确定受体拮抗剂和抑制剂的作用 PAF和类花生酸代谢对内毒素诱导的脂质代谢的影响 慢性肺功能不全患者介质释放与肺功能 清醒的绵羊 最先进的分析方法和自然的怀疑， 药理学探针特异性被仔细地用于 确定个别调解人的作用和相互作用，如果有的话， 内毒素诱导的肺功能障碍中的脂质介质。 这项建议的长远目标是， 有助于制定干预措施的理解 与成人呼吸道疾病的预防或治疗相关 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.