Previous studies have provided evidence that lung tissue subjected to period of decreased perfusion undergoes increased damage during reperfusion (ischemia-reperfusion injury). The hypothesis is that injury results from an increased rate of generation of oxidizaing free radicals associated with reoxygenation of tissue. This study will utilize the isolated perfused rat lung to develop a model for ischemia-reperfusion injury. Injury will be assessed by measurments of lipid peroxidation, protein oxidation, energy and redox state, and cellular ionic composition. Sp.
Aim 1 is the development of the model which emphasis on the roles of hypoxia, pH, and substrate in the genesis of injury. The lung is especially amenable to manipulation of these variables since the perfusate and alveolar gas composition can be varied independently. We will also evaluate the role of alveolar O2 tension during the reperfusion period. Our preliminary studies with this model have indicated lipid peroxidation during ischemia/reperfusion. Sp.
Aim 2 will evaluate the role of oxidants in generation of the injury. We will study Fe chelators, an inhibitor of xanthine oxidase, and vit. E and selenium (glutathione peroxidase) deficiencies. Sp.
Aim 3 will separately evaluate epithelial and endothelial components for ischemia-reperfusion injury. Ion composition (Na, K, Cl, Ca, Mg) in cytoplasm and mitochondria will be evaluated with electron probe microanalysis. Function of epithelium and endothelium will be evaluated through B-agonsit stimulated surfactant secretion and serotonin clearance, respectively. Sp.
Aim 4 will attempt to modify ischemia-reperfusion injury through delivery of liposome encapsulated antioxidant enzymes (SOD, catalase) by endotracheal or perfusate administration. These studies will establish the basic parameters for production of ischemia-reperfusion injury and will provide insights into possible prevention of this form of injury in lungs subjected to ischemia as, for example, after a pulmonary embolism.
Showing the most recent 10 out of 31 publications