INFLAMMATION OF THE LUNG AND CHRONIC PULMONARY HYPERTENSION

肺部炎症和慢性肺动脉高压

• 批准号: 3879653
• 负责人: BARBARA O MEYRICK
• 金额: --
• 依托单位: VANDERBILT UNIVERSITY
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/3879653
• 关键词: acetylcysteine; air embolism; allopurinol; antioxidants; disease /disorder model; eicosanoid metabolism; endotoxins; free radicals; indomethacin; inflammation; leukocyte depletion therapy; lipid peroxides; lipoxygenase; neutrophil; platelet activating factor; prostaglandin inhibitors; pulmonary circulation; pulmonary circulation obstruction; pulmonary edema; pulmonary hypertension; radiobiology; radioimmunoassay; respiratory function; sheep; transforming growth factors; vascular endothelium; vasoconstriction

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.

在这个项目中，我们将检验持久性的假设， 肺动脉高压的发生与 肺部的炎症。 这一发展是由于 产生和释放有毒的氧代谢产物， 中性粒细胞在肺部隔离，导致释放 血管收缩脂质介质（类花生酸或血小板 激活因子）。 我们将联合收割机结合生理学， 形态学和生化技术来表征 肺循环对胸部照射的反应， 慢性空气栓塞和反复静脉输注 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 有效的血管收缩剂PGH 2-A（9-亚甲基环 PGH 2的醚类似物）。 将进行形态学研究 在基线和每周或两次采集的肺活检组织 每次干预开始后每周一次; 此外，还将对心脏和肺进行死后研究。 生化测量将包括肺组织 抗氧化酶的浓度在基线和超过 实验过程;以及肺淋巴和 类花生酸代谢物的血浆浓度，血小板 活化因子和共轭二烯。 氧代谢物 假设将通过确定免费的影响进行测试 自由基清除剂、N-乙酰半胱氨酸和黄嘌呤氧化酶 抑制剂别嘌呤醇对肺循环对 慢性炎症 还将对动物进行以下研究： 粒细胞耗竭，以确定中性粒细胞是否 对肺动脉高压反应和 确定中性粒细胞是否负责生成 脂质介质在模型中进行研究。 影响5- 脂氧合酶抑制剂（例如，L-651，39.2- 00 N10）和白三烯 受体拮抗剂（例如，FLP 55712）将被研究， 确定脂氧合酶产品是否参与 反应的发病机制。 这些研究将阐明 慢性肺结核的病理生理和发病机制 由弥漫性肺部炎症引起的高血压， 提供了药理学干预的依据， 预防或逆转慢性炎症对 肺循环