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.
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