At critical points in chronic liver injury the potential for liver repair is lost. Timely surgical and medical treatment however, initiates liver repair interrupting the cycle of inflammation and hepatic fibrosis. The subsequent cellular regulation of matrix protein degradation and resolution of injury dependent fibrosis is unknown. The long-term goals of our studies are to define the molecular mechanisms required for ordered matrix resorption and liver repair without scar. Specific aims have been designed to test the hypothesis that repair, resolution of scar, and the restoration of hepatic architecture depend on coordinated regulatory mechanisms of matrix degradation through matrix metalloproteinase (MMP) and tissue inhibitor of MMP (TIMP) gene expression, cellular localization and most importantly, biologic activity. Further, we propose that Kupffer cells (KC), the resident macrophage population, have a central role in the inflammatory and fibrogenic regulation of liver repair after chronic injury. Specific Aim 1 addresses the molecular and cellular mechanisms of reversible hepatic fibrosis and those of delayed matrix resorption. A unique rat model of reversible biliary obstruction will simulate early, intermediate, and late, near end stage cholestatic liver injury. This model allows biliary decompression to initiate liver repair. [The effect of injury duration on key matrix (collagen I and III, laminin), MMP (1,2,8,9) and TIMP (1,2) mRNA and protein expression will be measured in whole liver and in [individual] cells using new methods of laser capture microdissection. [These data will demonstrate the mechanism and physiology of matrix resorption through measurement of MMP activity by in-gel and in-situ zymography]. Specific Aim 2 tests the hypothesis that KC are in vivo regulators of matrix metabolism. Through strategies of KC depletion/ inactivation by gadolinium or Dexa-Man10-HSA targeted dexamethasone during repair, matrix resorption, regulatory cytokine profiles and MMP-TIMP activity will be localized in cells and measured. In Specific Aim 3 we will establish the effect of progressive injury on the in vitro capacity of isolated hepatic macrophages (MPh) to express specific MMP and fibrogenic/ antifibrogenic cytokine (TGFbeta, IL1, 6, 10) profiles during repair. KC inactivation and MMP stimulation/ suppression strategies will isolate the net collagenolytic activity of MPh. [In addition to the broad clinical implications for the treatment of cholestatic or other chronic liver diseases in infants, children, and adults, these studies may be the first to identify key molecular mechanisms for successful repair after progressive liver injury. They have the unique potential to yield targets for therapy to promote liver repair or rescue patients approaching end stage liver disease