MECHANISM OF PAF INDUCED LUNG INJURY

拟议中的研究旨在检测血小板活化因子。 (PAF)作为成人肺损伤的介质和致病因素 呼吸窘迫综合征(ARDS)。我们打算研究对以下问题的反应 PAF在慢性肺淋巴瘘清醒动物模型中的作用 左房球囊、离体肺制备及培养 内皮细胞单层。我们的假设是PAF本身是 肺内皮细胞和肺上皮细胞的损伤及其原因 严重的肺部机械和气体交换改变。在总的PAF中 病理生物学某些方面可能通过1)激活来介导或调节 单独或协同作用的血小板和/或白细胞；2)副产品 环氧合酶和脂氧合酶途径或花生四烯酸代谢。 体内和体外实验将被用来研究我们的目标。这个 PAF对血管内皮细胞的损伤作用应表述为 血管内液体和蛋白质流量的变化，并将进行评估 通过1)测量淋巴流量、淋巴和血浆蛋白浓度， 大鼠肺组织蛋白质反射系数和血管外肺含水量 完整动物；2)毛细管过滤系数的测定 (3)~(125)I-白蛋白转运的测定。 培养内皮细胞单层。作为PAF一部分的上皮损伤 在清醒的动物中，通过测量以下指标来评估诱发的肺损伤 雾化技术99mDTPA的清晰度变化肺机械 更改将通过测量静态和动态合规性来确定 可同时记录气管和胸腔的完整动物 压力。功能剩余容量将通过 氮气洗涤法。将监测动脉和混合静脉血液 计算肺泡死腔和分流率。无论是在体内还是体内 将利用体外模型，每个模型都具有独特的优势和 因此是相辅相成的。体内制剂为 非常适合于鉴定和量化细胞(血小板)的作用 和白细胞)以及它们之间的相互作用 PAF损伤以及确定其他的作用和来源 次级因子(AA代谢产物)。有淋巴的完好无损的绵羊 插管将允许确定PAF的作用及其可能的 急性肺损伤中的介质及PAF抑制作用 调节这一反应的物质。

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.