PATHOPHYSIOLOGY OF ISCHEMIA-REPERFUSION LUNG INJURY

缺血再灌注肺损伤的病理生理学

• 批准号: 3359847
• 负责人: AUBREY E. TAYLOR
• 金额: $ 15.88万
• 依托单位: UNIVERSITY OF SOUTH ALABAMA
• 依托单位国家: 美国
• 财政年份: 1988
• 资助国家: 美国
• 起止时间: 1988-09-30 至 1993-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3359847
• 关键词: allopurinol; bronchus circulation; catalase; dietary trace element; dogs; electron microscopy; enzyme mechanism; free radicals; glutathione; glutathione peroxidase; histopathology; hydrogen peroxide; hydroxyl group; laboratory rabbit; laboratory rat; lung; lung ischemia /hypoxia; myeloperoxidase; neutrophil; nutrition related tag; oxidoreductase inhibitor; perfusion; pulmonary edema; reperfusion; respiratory disorder epidemiology; respiratory oxygenation; singlet oxygen; superoxide dismutase; superoxides; tungsten; vascular endothelium permeability; vascular resistance; xanthine dehydrogenase; xanthine oxidase

Tissue injury due to ischemia and reperfusion occurs in common clinical disorders such as myocardial infarction, acute renal failure, stroke, and ischemic bowel syndromes. Ischemia- reperfusion may play an etiological role in acute lung injury following lung transplantation, cardiopulmonary bypass, and removal of thrombotic obstruction of major pulmonary arteries, and may be a factor in re-expansion pulmonary edema and in the adult respiratory distress syndrome in which smaller thrombosed pulmonary arteries become reperfused. In the intestinal model of ischemia-reperfusion, evidence suggests that the production of toxic oxygen radicals from the hypoxanthine-xanthine oxidase system and perhaps from activated neurtrophils accounts for the injury. Since the mechanisms involved in ischemia-reperfusion lung injury have not been well defined, the overall goals of this research are 1) to determine lung vascular permeability and resistance changes following ischemia and subsequent reperfusion under various conditions and 2) to correlate these results with biochemical findings (xanthine oxidase, superoxide dismutase, catalase, glutathione peroxidase, myeloperoxidase, and reduced glutathione), morphologic findings (light and electron microscopy), and measurements of bronchial blood flow. Isolated, perfused lungs from 3 species (dog, rabbit, rat - all of which are currently in use in this laboratory) will be studied in terms of vascular permeability (assessed by determinations of capillary filtration coefficient and the isogravimetric capillary pressure) and vascular resistance changes (which are partitioned into arterial and venous components). Specific aims of this reseach include determination of xanthine oxidase in normal lungs and lungs subjected to the various forms of ischemia-reperfusion, comparison of the permeability and resistance effects following ischemia- reperfusion versus hypoxia-reoxygenation, determination of the effect of blocking xanthine oxidase (allopurinol, or a tungsten- enriched diet) and removing neutrophils from the perfusate. Also, the protective effects of compounds (oxygen radical scavengers and others) in tissue damage associated with ischemia-reperfusion will be evaluated. In intact lungs of dogs, the effect that the bronchial blood flow (not present in isolated lungs) has in ischemia-reperfusion lung injury will be investigated. By correlating the pathophysiological changes in vascular permeability and resistances with biochemical and histologic findings, a better understanding of the mechanisms of lung injury following ischemia-reperfusion will be obtained.

由于缺血和再灌注引起的组织损伤是常见的 临床疾病，如心肌梗死、急性肾功能衰竭、 衰竭、中风和缺血性肠综合征。 局部缺血- 再灌注可能在急性肺损伤中起病因作用 肺移植、心肺转流术后， 去除主要肺动脉的血栓性阻塞， 并且可能是再扩张性肺水肿的因素， 成人呼吸窘迫综合征，其中血栓较小 肺动脉再灌注。 在肠道模型中， 缺血再灌注，证据表明，生产的 次黄嘌呤-黄嘌呤氧化酶产生的有毒氧自由基 系统，也许从激活的嗜神经细胞帐户， 损伤 由于缺血再灌注的机制 肺损伤尚未得到很好的定义，这一总体目标 研究是1）确定肺血管渗透性， 缺血再灌注后的阻力变化 在各种条件下，2）将这些结果与 生化检查结果（黄嘌呤氧化酶，超氧化物歧化酶， 过氧化氢酶、谷胱甘肽过氧化物酶、髓过氧化物酶和还原型 谷胱甘肽），形态学发现（光学和电子显微镜）， 以及支气管血流的测量。 隔离，灌注 来自3个物种的肺（狗、兔、大鼠-所有这些目前都是 在本实验室中使用）将在血管方面进行研究 渗透性（通过测定毛细管过滤来评估 系数和等重毛细血管压力）和血管 阻力变化（分为动脉和静脉 组件）。 本研究的具体目标包括确定 黄嘌呤氧化酶在正常肺和肺受到 不同形式的缺血再灌注， 局部缺血后的渗透性和阻力作用- 再灌注与缺氧-复氧的比较， 阻断黄嘌呤氧化酶（别嘌呤醇，或钨- 强化饮食）和从灌注液中除去嗜中性粒细胞。 还有， 化合物（氧自由基清除剂）的保护作用 和其他）在与缺血再灌注相关的组织损伤中的作用 将被评估。 在狗的完整肺中， 支气管血流（不存在于孤立的肺中） 将研究局部缺血-再灌注肺损伤。 通过 与血管病变的病理生理变化相关， 渗透性和阻力与生化和组织学 研究结果，更好地了解肺损伤的机制 将获得缺血-再灌注后的细胞。