This research involves the development and use of a small animal model to study acute and chronic hepatic radiation injury. Such hepatic injury can be a dose limiting, life threatening complication in patients undergoing treatment of metastatic and primary liver cancers and other neoplasms in the upper abdomen of lower thorax, or after total body or abdominal irradiation prior to bone marrow transplantation. Hepatic radiation injury is a particular problem in patients who have compromised livers due to partial liver resection, administration of hepatotoxic chemotherapeutic agents, or preexisting liver abnormalities at the time of irradiation. The consequences of these co-existing risk factors at the time of liver irradiation will be addressed in this research. Experiments with male Sprague-Dawley rats will be conducted to characterize and quantitate the pathophysiological changes that are produced by localized whole-liver irradiation. This will be studied in intact livers and in livers subjected to partial hepatectomy. At various times after irradiation, liver function, necrosis, steatosis, fibrosis, edema, cholestasis, sepsis, and endotoxemia will be measured using standard histological, microbiological, biochemical, and clinical chemistry procedures. The cellular basis for these pathophysiological changes will be investigated by quantitative isolation of hepatocytes, Kupffer and endothelial cells, followed by study of these individual cell types with respect to number, viability and functional integrity as a function of dose and time after irradiation. The influence of cell proliferation on radiation-induced hepatic injury will be investigated by comparing the rate of injury development in unstimulated intact livers, in livers stimulated to proliferate by partial hepatectomy and in partially hepatectomized livers where proliferation has been inhibited. Radiation dose fractionation studies will be performed to measure time dependent recovery processes (e.g., slow repair), repair capacity and kinetics in the liver.
