INTEGRIN INHIBITOR CYCLORGDN BLUNTS ENHANCED LPS-INDUCED LIVER INJURY CAUSED BY ETHANOL IN MICE Veronica L. Massey 11/15/2012 Background. Progression of alcoholic liver disease (ALD) is associated with an increase in fibrin extracellular matrix (ECM) and inflammation. Previous studies have shown that this accumulation of fibrin in ALD is mediated by impaired fibrinolysis. Additionally, it is known that fibrin(ogen) interacts with the av~3 integrin of endothelial cells. The purpose of this study was to test the hypothesis that hepatic inflammation caused by alcohol is mediated, at least in part, by activation of integrin av~3 by fibrin(ogen). To test this hypothesis, a study was designed to determine the effect of cycloRGDN, a peptide inhibitor of integrin av~3, in a mouse model of lipopolysaccharide (LPS)-induced inflammation enhanced by ethanol pre-exposure. Methods. Accordingly, male C57BLl6J mice were exposed to ethanol (6 g/kg i.g.) or isocaloriclisovolumetric maltose dextrin solution for 3 days and injected with lipopolysaccharide (LPS; 10 mg/kg i.p.) 24 hours after the last dose of ethanol. Some animals received the av~3 integrin inhibitor (cycloRGDN; 3 mg/kg i.p.) 1 hour prior to LPS administration. Animals were sacrificed 8 or 24 hours after LPS administration. Liver damage was assessed by plasma (AL T, AST) and histological indices of liver damage (hematoxylin and eosin; HE CAE). Results. Ethanol pre-exposure enhanced liver injury due to LPS, as indicated by a significant increase in plasma AL T levels. cycloRGDN significantly attenuated the increase in plasma AL T caused by ethanol pre-exposure. These results were supported by histological changes. Animals that received ethanol and LPS had both larger and more numerous necroinflammatory foci compared to animals that received LPS alone. The number