MOLECULAR PATHOGENESIS OF RADIATION ENTEROPATHY

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DESCRIPTION: (Adapted from the applicant's abstract): Abdominal radiation therapy is often dose-limited by the risk of intestinal toxicity (radiation enteropathy). Radiation enteropathy is associated with consistent and sustained transforming growth factor b (TGF-b) overexpression in areas that display structural injury. This project tests the hypotheses that 1) TGF-b overexpression is an independent predictor of radiation enteropathy, 2) Modulation of post-radiation TGF-b levels affects development of chronic radiation-induced lesions and complications, 3) TGF-b plays a more significant role in consequential radiation enteropathy (chronic injury secondary to mucosal break-down) than in primary radiation enteropathy (chronic injury without mucosal disruption), and 4) interactions between mast cells and TGF-b are important in the mechanism of chronicity. A loop of small bowel is surgically attached in the scrotum of male rats. The intestine in the "scrotal hernia" is subsequently irradiated, producing intestinal complications and morphologic lesions similar to those seen clinically. TGF-b expression and histopathologic, cellular, morphometric, and functional changes are assessed up to 26 weeks after irradiation. Specific aims are to 1) assess quantitative associations between TGF-b expression, radiation dose, observation time, and parameters of intestinal toxicity, 2) determine if adding TGF-b during the acute phase of injury increases the severity of subsequent radiation enteropathy, 3) determine if neutralization of TGF-b during the acute phase of injury ameliorates subsequent chronic radiation enteropathy, 4) compare TGF-b expression in consequential versus primary radiation enteropathy, and 5) assess TGF-b expression and severity of radiation enteropathy in mast cell-deficient rats compared to mast cell-competent litter-mates. Results from these experiments will provide significant new information regarding the molecular pathogenesis of radiation enteropathy. An improved understanding of these mechanisms will facilitate development of treatment protocols and interventions to minimize intestinal toxicity, and thus has potential to improve the therapeutic ratio of radiation therapy in patients with abdominal tumors.