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PATHOPHYSIOLOGY OF ISCHEMIA-REPERFUSION LUNG INJURY

缺血再灌注肺损伤的病理生理学

基本信息

批准号：
3359848
负责人：
AUBREY E. TAYLOR
金额：
$ 16.44万
依托单位：
UNIVERSITY OF SOUTH ALABAMA
依托单位国家：
美国
项目类别：
财政年份：
1988
资助国家：
美国
起止时间：
1988-09-30 至 1994-07-31
项目状态：
已结题

项目摘要

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.

缺血和再灌注引起的组织损伤很常见临床疾病，如心肌梗塞、急性肾病衰竭、中风和缺血性肠综合征。缺血- 再灌注可能在急性肺损伤中发挥病因作用肺移植、体外循环后清除主要肺动脉的血栓性阻塞，可能是复张性肺水肿和肺水肿的一个因素成人呼吸窘迫综合征，其中较小的血栓形成肺动脉变得再灌注。在肠道模型中缺血再灌注，有证据表明，来自次黄嘌呤-黄嘌呤氧化酶的有毒氧自由基系统，也许来自激活的中性粒细胞受伤。由于缺血再灌注的机制肺损伤尚未明确定义，本次研究的总体目标研究是 1) 确定肺血管通透性和缺血和随后的再灌注后阻力变化在各种条件下，2）将这些结果与生化结果（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酶谷胱甘肽），形态学结果（光学和电子显微镜），和支气管血流量的测量。隔离、灌注来自 3 个物种（狗、兔、大鼠 - 目前所有这些物种）的肺在本实验室使用）将在血管方面进行研究渗透性（通过毛细管过滤测定来评估系数和等重毛细血管压力）和血管阻力变化（分为动脉阻力和静脉阻力）成分）。这项研究的具体目标包括确定正常肺和受到影响的肺中黄嘌呤氧化酶的含量不同形式的缺血再灌注的比较缺血后的渗透性和抵抗力影响再灌注与缺氧-再氧合，测定阻断黄嘌呤氧化酶（别嘌呤醇，或钨- 丰富的饮食）并从灌注液中去除中性粒细胞。还，化合物的保护作用（氧自由基清除剂和其他）与缺血再灌注相关的组织损伤将被评估。在狗的完整肺部中，支气管血流（不存在于孤立的肺中）将研究缺血再灌注肺损伤。经过血管病理生理变化的相关性生化和组织学的渗透性和阻力研究结果，更好地了解肺损伤的机制将获得缺血再灌注后的结果。