INFLAMMATION OF THE LUNG AND CHRONIC PULMONARY HYPERTENSION

在这个项目中，我们将检验持久化的假设 肺动脉高压的发生与 肺部发炎。这一发展是由于 被激活的有毒氧代谢产物的产生和释放 中性粒细胞隔离在肺中，导致释放 血管收缩类脂质介质(二十烷基类或血小板 激活因子)。我们将结合生理学、 形态和生化技术来表征 肺循环对胸部照射的反应， 慢性空气栓塞术和反复静脉滴注术 内毒素。生理测量将包括肺 血流动力学和气体交换以及评估 肺循环对高氧、低氧和低氧的反应 强大的血管收缩因子PGH2-A(9-亚甲基环状 PGH2的乙醚类似物)。将进行形态研究 在基线和每周一到两次的肺活检组织上 每一次干预开始后的每周期间； 此外，心脏和肺将在尸检后进行研究。 生化测量将包括肺组织 抗氧化酶在基线及以上的浓度 实验过程中；肺淋巴和肺组织的测量 二十烷基类代谢物、血小板的血浆浓度 活化因子和共轭双烯。氧代谢产物 假设将通过确定免费的影响来检验 自由基清除剂N-乙酰半胱氨酸和黄嘌呤氧化酶 拮抗剂别嘌醇对肺循环的影响 慢性炎症。接下来还将对动物进行研究 粒细胞耗竭以确定中性粒细胞是否 对肺动脉高压反应和对 确定中性粒细胞是否负责生成 脂类介质在模型中的作用有待研究。5- 脂氧合酶抑制剂(如L-651、39.2-00N10)和白三烯 受体拮抗剂(如FLP 55712)将被研究以 确定脂氧合酶产物是否参与 反应的发病机制。这些研究将阐明 慢性肺病的病理生理及发病机制 弥漫性肺部炎症和意志引起的高血压 为药物干预提供理论基础，药物干预可能 预防或逆转慢性炎症对机体的影响 肺循环。

In this project, we will examine the hypothesis that persistent pulmonary hypertension develops in association with inflammation of the lungs. This development is due to generation and release of toxic oxygen metabolites by activated neutrophils sequestered in the lungs resulting in release of vasoconstrictor lipid mediators (eicosanoids or platelet activating factor). We will combine physiological , morphological and biochemical techniques to characterize responses of the pulmonary circulation to thoracic irradiation, chronic air embolization and repeated intravenous infusions of endotoxin. Physiologic measurements will include pulmonary hemodynamics and gas exchange as well as assessment of the response of the pulmonary circulation to hyperoxia, hypoxia and the potent vasoconstrictor, PGH2-A (the 9-methylene cyclic ether analog of PGH2). Morphological studies will be conducted on lung biopsy tissue taken at baseline and at weekly or two weekly periods following the beginning of each intervention; in addition, the heart and lungs will be studied postmortem. Biochemical measurements will include lung tissue concentrations of antioxidant enzymes at baseline and over the course of the experiment; and measurement of lung lymph and blood plasma concentrations of eicosanoid metabolites, platelet activating factor and conjugated dienes. The oxygen metabolite hypothesis will be tested by determining the effects of the free radical scavenger, N-acetyl cysteine, and the xanthine oxidase inhibitor, allopurinol, on the responses of the lungs' circulation to chronic inflammation. Animals will also be studied following granulocyte depletion to determine whether neutrophils are essential to the pulmonary hypertensive response and to determine whether neutrophils are responsible for generation lipid mediators in the models to be studied. Effects of 5- lipoxygenase inhibitors (e.g., L-651, 39.2-00N10) and leukotriene receptor antagonists (e.g., FLP 55712) will be studied to determine whether lipoxygenase products participate in the pathogenesis of the response. These studies will elucidate the pathophysiology and pathogenesis of chronic pulmonary hypertension resulting from diffuse lung inflammation and will provide rationales for pharmacologic interventions which may prevent or reverse the effects of chronic inflammation on the lung circulation.