CELLULAR MECHANISMS OF PULMONARY ENDOTHELIAL INJURY

肺血管内皮细胞损伤的一般假设 涉及内皮细胞自身对有毒物质的直接反应 刺激将使用在培养和培养中生长的内皮细胞进行测试 肺动脉内膜的外植体。内皮反应可以包括 细胞内有毒氧自由基的产生和细胞内氧自由基的产生 花生四烯酸的代谢物。这些产品可能都会改变 内皮层并影响其与炎症细胞的相互作用。 补体的激活也可能影响对 内皮细胞对损伤性刺激的反应及其相互作用 炎性细胞。最后，炎性细胞本身可能会增强 血管内皮损伤。为了检验这一假设， 肺动脉内膜内皮层和内皮细胞单层 将通过平衡同位素示踪剂来测量在培养中生长的 通过跨膜和直接测量水力传导性来实现。 干预对两者血管内皮细胞结构的影响 接下来将进行准备工作，并产生脂氧合酶和 血管内皮细胞分泌花生四烯酸的环氧合酶产物 将对诱发伤害的比例进行评估。各种因素的直接影响 二十碳二烯类化合物对内皮结构、代谢和功能的影响 同样被确定的问题是，一个外源的 花生四烯酸导致跨内皮细胞的良性过程 粒细胞迁移损伤内皮细胞。测量结果将是 内毒素和纯化脂质-A对血管内皮细胞的影响 结构、新陈代谢和功能。还将进行测量，以 确定内毒素如何改变内皮细胞与内皮细胞的相互作用 白细胞，以确定抗氧化酶是否传递到细胞内 通过脂质体包裹改变内皮细胞对内毒素的反应 以确定皮质类固醇、非类固醇抗炎药 而自由基清除剂影响内毒素诱导的损伤。 不同细胞系培养的血管内皮细胞的敏感性 将检测几种内毒素和补体在体内的作用 内毒素在存在和不存在时引起的内皮损伤 将对白细胞进行研究。拟议的研究结果是广泛的 整个动物获得结构和功能信息的基础 准备工作和大量的初步数据表明 这些研究的目标是可行的。这些研究将提供新的 肺血管细胞和体液机制的研究进展 并为创新的预防和预防方法提供了理由。 弥漫性肺损伤的治疗。

The general hypothesis that injury of pulmonary vascular endothelium involves direct responses of the endothelial cells themselves to toxic stimuli will be tested using endothelial cells grown in culture and explants of pulmonary artery intima. The endothelial responses may include intracellular generation of toxic oxygen radicals and generation of metabolites of arachidonic acid. These products may both alter the endothelial layer and affect its interaction with inflammatory cells. Activation of complement may also affect both the direct response of the endothelial cells to injurious stimuli and their interactions with inflammatory cells. Finally, inflammatory cells, per se, may potentiate the endothelial injury. To test the hypothesis, the barrier function of the endothelial layer of pulmonary artery intima and endothelial monolayers grown in culture will be measured by equilibration of isotopic tracers across the membrane and by direct measurement of hydraulic conductance. The effects of interventions on the structure of endothelial cells in both preparations will be followed and production of both lipoxygenase and cyclooxygenase products of arachidonic acid by endothelium over the course of the induced injury will be evaluated. The direct effects of various eicosanoids on endothelial structure, metabolism and function will be determined as will the question of whether an exogenous source of arachidonic acid causes the otherwise benign process of transendothelial migration of granulocytes to injure the endothelium. Measurements will be made of the effects of endotoxin and purified lipid-A on endothelial structure, metabolism and function. Measurements will also be made to determine how endotoxin alters the interactions of endothelium with leukocytes, to determine whether antioxidant enzymes delivered into cells by liposome encapsulation alter the endothelial response to endotoxin and to determine whether corticosteroids, nonsteroidal antiinflammatory drugs and free radical scavengers affect the endotoxin-induced injury. Susceptibility of different lines of cultured endothelial cells from several species to endotoxin will be examined and the role of complement in endotoxin-induced endothelial injury in the presence and absence of leukocytes will be studied. The proposed studies result from an extensive base of structural and functional information obtained in whole animal preparations and from a large amount of preliminary data suggesting that the goals of the studies are feasible. The studies will provide new information about cellular and humoral mechanisms of pulmonary vascular injury and provide a rationale for innovative approaches for prevention and therapy of diffuse lung injury.