PATHOPHYSIOLOGY OF ISCHEMIA-REPERFUSION LUNG INJURY

缺血和再灌流引起的组织损伤是常见的 临床疾病，如心肌梗死、急性肾脏 衰竭、中风和缺血性肠综合征。缺血症- 再灌注可能在急性肺损伤中起病因学作用 肺移植，体外循环，以及 清除主要肺动脉的血栓阻塞， 可能是再扩张性肺水肿的一个因素 成人呼吸窘迫综合征，血栓较小 肺动脉会变得再灌流。在小鼠肠道模型中 缺血-再灌注，有证据表明， 次黄嘌呤-黄嘌呤氧化酶产生的有毒氧自由基 系统和可能来自激活的神经中性粒细胞 受伤。由于缺血-再灌流的机制 肺损伤还没有得到很好的定义，这一总体目标 研究包括：1)测定肺血管通透性和 缺血再灌流后阻力的变化 在不同条件下，以及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 谷胱甘肽)，形态发现(光镜和电子显微镜)， 以及测量支气管血流量。孤立的，灌流的 来自3个物种(狗、兔、鼠)的肺--所有这些都是目前 在这个实验室中使用)将从血管的角度进行研究 渗透性(通过测定毛细管过滤进行评估 系数和等压毛细管压力)和血管 阻力改变(分为动脉和静脉 组件)。这项研究的具体目标包括确定 黄嘌呤氧化酶在正常肺和肺中的表达 不同形式的缺血-再灌流的比较 缺血后的通透性和阻力效应 再灌流与缺氧-复氧，测定 阻断黄嘌呤氧化酶的作用(别嘌醇或钨- 强化饮食)和从灌流液中去除中性粒细胞。另外， 化合物(氧自由基清除剂)的保护作用 和其他)与缺血-再灌流相关的组织损伤 将会被评估。在完好无损的狗的肺中， 支气管血流(在离体肺中不存在) 将对缺血-再灌注肺损伤进行调查。通过 血管病理生理变化的相关性研究 通透性和抵抗力与生化和组织学 发现，更好地理解肺损伤的机制 缺血再灌注后即可达到再灌流。

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.