MECHANISM OF PAF INDUCED LUNG INJURY

拟议的研究旨在检查血小板活化因子 (PAF)作为肺损伤的介质和成人中的致病因素， 呼吸窘迫综合征（ARDS）。 我们打算研究对以下问题的反应： 慢性肺淋巴瘘清醒动物的PAF激发， 左心房球囊、离体肺标本和培养的 内皮细胞单层（CEM）。 我们的假设是PAF本身是 损伤肺内皮和肺上皮， 严重的肺机械和气体交换改变。 在总PAF中 病理生物学某些方面可以通过以下方式介导或调节：1）激活 血小板和/或白细胞单独或协同作用; 2）副产物 环加氧酶和脂加氧酶途径或花生四烯酸代谢。 体内和体外实验将用于研究我们的目标。 的 PAF对内皮的损伤作用应表示为 改变经血管液体和蛋白质通量，并将评估 通过1）测量淋巴流量、淋巴和血浆蛋白浓度， 蛋白质反射系数和血管外肺含水量 完整动物; 2）测量毛细血管滤过系数， 离体兔肺;和3）测量125I白蛋白转运， 培养的内皮细胞单层。 作为PAF一部分的上皮损伤 通过测量在清醒动物中诱导的肺损伤， 99m DTPA气雾剂清除率变化。 肺部机械 将通过测量静态和动态顺应性来确定变化， 同时记录气管和胸膜内的完整动物 压力 功能剩余容量将根据 氮洗法 将监测动脉血和混合静脉血 并计算肺泡死腔和分流分数。 体内和 将使用体外模型，每种模型都具有独特的优势， 因此是互补的。 体内制剂是 非常适合于鉴定和定量细胞（血小板）的作用 和白细胞）及其相互作用，以确定 PAF损伤以及用于确定其他PAF损伤的作用和来源。 次要因素（AA代谢产物）。 带淋巴液的完整绵羊 插管将允许确定PAF的作用及其可能的 急性肺损伤的介质及PAF抑制剂的疗效 调节这种反应的物质。

The proposed studies are designed to examine the platelet activating factor (PAF) as a mediator of lung injury and as a causative factor in the adult respiratory distress syndrome (ARDS). We intend to study the responses to PAF challenge in the awake animal with a chronic lung lymph fistula and left atrial balloon, the isolated lung preparation and the cultured endothelial cell monolayer (CEM). Our hypothesis is that PAF per se is injurious to the lung endothelium as well as lung epithelium and causes severe lung mechanical and gas exchange alterations. In the total PAF pathobiology certain facets may be mediated or modulated by 1) activated platelets and/or leukocytes singularly or synergistically; 2) by products of the cyclo- and lipo-oxygenase pathway or arachidonic acid metabolism. In vivo and in vitro experiments will be used to study our objectives. The injurious effect of PAF on the endothelium should be expressed as alterations in transvascular fluid and protein fluxes and will be assessed by 1) measurement of lymph flow, lymph and plasma protein concentrations, the protein reflection coefficient and extravascular lung water content in intact animals; 2) measurement of the capillary filtration coefficient in isolated rabbit lungs; and 3) measurement of 125I albumin transport in cultured endothelial cell monolayers. Epithelial damage as part of the PAF induced lung injury will be assessed in the awake animal by measuring clearance changes of aerosolized technicium 99m DTPA. Lung mechanical changes will be determined by measuring static and dynamic compliance in intact animals with simultaneous recordings of tracheal and intrapleural pressure. Functional residual capacity will be determined with the nitrogen washout method. Arterial and mixed venous blood will be monitored and alveolar dead space and shunt fraction calculated. Both in vivo and in vitro models will be utilized, each offering distinct advantages and therefore are complimentary to each other. The in vivo preparations are very suitable for identifying and quantifying the role of cells (platelets and leukocytes) and their interactions in determining the magnitude of the PAF injury as well as for determining the role and source of other secondary factors (products of AA metabolism). The intact sheep with lymph cannula will allow for determination of the role of PAF and its possible mediators in the acute lung injury and the efficacy of PAF inhibitory substances to modulate this response.