ENDOTHELIAL DYSFUNCTION IN INTESTIAL RADIATION TOXICITY

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Intestinal radiation toxicity (radiation enteropathy) is characterized by progressive fibrosis of the intestinal wall and over-expression of inflammatory and fibrogenic cytokines, particularly transforming growth factor b 1 (TGF-b 1). Microvascular injury is believed to be important in the mechanisms of chronic radiation enteropathy. However, direct molecular links among endothelial injury, vascular sclerosis, and delayed radiation toxicity have not been established in vivo. Clinical experimental studies from the PI's laboratory have shown a striking down-regulation of thrombomodulin in irradiated intestine. TM is an endothelial cell glycoprotein that acts as a "natural anticoagulant" by regulating thrombin function. Thrombin, in addition to its key role in coagulation, is an important regulator of inflammation and tissue remodeling. Many of these functions are mediated through protease activated receptors (PAR), most notably PAR-1, which is upregulated in experimental radiation enteropathy. After irradiation, deficient levels of TM enhance fibrin deposition and upregulate TGF-b 1. The fibrotic stimulus may thus be sustained by TGF-b 1 in concert with procoagulant, pro-inflammatory, and mitogenic effects of thrombin, mediated through PAR-1. The proposed research examines the relative significance of these processes in the mechanisms of radiation enteropathy. Using in vivo rat and mouse models along with quantitative molecular methods, the project will systematically examine the roles and interrelationships of TM, PAR-1, and TGF-b 1. The project will 1) assess temporal and spatial associations among endothelial cell TM, PAR-1, TGF- b 1, and structural intestinal radiation injury, 2) use mutant and knockout animal models to examine specific interrelationships and the relative significance of TM, PAR-1, and TGF-b 1 in radiation enteropathy, and 3) test whether specific inhibitors of platelet aggregation and thrombin will abrogate the structural, cellular, and molecular changes induced by radiation. These experiments will provide significant new information regarding the molecular pathogenesis and mechanisms of chronicity of radiation enteropathy. A comprehensive understanding of these underlying mechanisms may identify clinically relevant targets for intervention and facilitate development of therapeutic and prophylactic strategies to minimize intestinal radiation toxicity.