PULMONARY EDEMA, LUNG VASCULAR INJURY AND LUNG FUNCTION

本项目旨在研究急性呼吸衰竭的发病机制。 在肺血管损伤后。我们假设急性呼吸道疾病 血管损伤导致的衰竭(ARDS；非心源性肺水肿) 由于肺水肿，缺氧性肺血管收缩丧失和 呼吸道功能异常。我们假设所有这些变化， 无论病因如何，都是由阿昔多酸的代谢物介导的 (或许还有其他相关的脂肪酸)和粒细胞。我们建议 通过1)花生四烯酸作用的详细研究来检验这些假设 (及相关脂肪酸)及其代谢物对肺功能的影响，2 粒细胞与肺相互作用的详细研究 循环，肺白质淤积的病理生理效应和 这些影响的机理，3)理论和实验研究 通过血管的传输将定义压力的贡献， 流动、交换血管表面积和血管对肺的通透性 液体平衡，4)肺异常发病机制的研究 人类疾病的动物模型--革兰氏阴性内毒素血症、肺氧 毒性、神经源性肺水肿和急性心肌梗死，以及 5)人类肺脏异常的发病机制研究 心源性与非心源性肺水肿及其治疗效果 大剂量甲基强的松龙在成人呼吸道疾病患者中的应用 窘迫综合症。大多数动物研究将长期进行。 未麻醉的仪器化绵羊，准备采集肺淋巴； 多指示剂稀释法测定肺水和通透性 将在人类和动物身上使用。前列腺素的测量， 血栓烷、花生四烯酸脂氧合酶产物与体外趋化作用 肺力学的化验和人体体积描记术测量， 对研究来说也是很重要的。医学研究人员， 生物工程、药理学、外科和儿科将参加 这个项目。这些研究将有助于明确肺的发病机制。 血管损伤后的失败，提高我们对物理的认识 血管损伤后影响肺液的因素，增强我们的 了解影响肺液平衡的物理因素，提供 肺水肿患者治疗方案设计的合理依据 (心源性或ARDS)，并严格评估 甲泼尼龙在患有ARDS的人类中的应用。

This program proposes to stdy the pathogenesis of acute respiratory failure following pulmonary vascular injury. We hypothesize that acute respiratory failure due to vascular injury (ARDS; non-cardiac pulmonary edema) occurs because of lung edema, loss of hypoxic pulmonary vasoconstriction and abnormal airway function. We hyupothesize that all of those changes, regardless of the etiology, are mediated by metabolites of archidonic acid (and perhaps other related fatty acids) and granulocytes. We propose to test these hypotheses by 1) detailed stdies of effects of arachidonic acid (and related fatty acids) and their metabolites on lung function, 2) detailed studies of the interaction of granulocytes with the lung circulation, the pathophysiological effects of pulmonary leukostasis and themechanisms of those effects, 3) theoretical and experimental studies of transvascular transport which will define the contributions of pressures, flows, exchanging vessel surface area and vascular permeability to lung fluid balance, 4) studies of the pathogenesis of lung abnormalities in four animal models of human disease-gram negative endotoxemia, pulmonary oxygen toxicity, neurogenic pulmonary edema, and acute myocardial infarction, and 5) studies of the pathogenesis of lung abnormalities in humans with cardiogenic and noncardiogenic pulmonary edema and the therapeutic effects of high dose methylprednisolone in patients with the adult respiratory distress syndrome. Most of the animal studies will be done in chronically instrumented unanesthetized sheep prepared for collection of lung lymph; multiple indicator dilution measurements of lung water and permeability will be used in humans and animals. Measurements of prostaglandins, thromboxanes, arachidonate lipoxygenase products and in vitro chemotaxis assays as well as body plethysmographic measurements of lung mechanics, will also be important to the studies. Investigators in Medicine, Bioengineering, Pharmacology, Surgery and Pediatrics will participate in the program. The studies will help to define the pathogenesis of lung failure following vascular injury, enhance our understanding of physical factors affecting lung fluid following vascular injury, enhance our understanding of physical factors affecting lung fluid balance, provide a rational basis for designing therapies for patients with pulmonary edema (cardiogenic or ARDS) and critically evaluate the effects of methylprednisolone in humans with ARDS.