Regulation of hepatic repair responses by metabolites of the uric acid pathway

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DESCRIPTION (provided by applicant): Hepatocyte apoptosis results in repair responses including hepatic stellate cell (HSC) chemotaxis, contraction and matrix remodeling. The signals from apoptotic hepatocytes which modulate these responses are poorly identified. The uric acid pathway (UAP) mediates the breakdown of purines to uric acid. Flux through this pathway is greatly increased in tissues .undergoing cellular death by necrosis or apoptosis, and UAP metabolites regulate cellular responses to injury in many organs. We show that in primary mouse HSC adenosine i) results in inhibition of PDGF induced Ca++ mobilization and chemotaxis in HSC ii) induces actin reorganization and contraction of HSC via the A2a receptor iii) upregulates TGF beta and collagen 1 mRNA. A number of other UAP metabolites including uric acid also induce HSC contraction, and in addition upregulate TGF beta and collagen 1 mRNA. Distal inhibition of the UAP results in greater fibrosis in two models of liver injury. The hypothesis for this proposal is that metabolites of the UAP regulate HSC differentiation in response to tissue injury in the liver. Specific Aim 1: a) Determine the intracellular signaling pathways responsible for adenosine mediated actin reorganization and HSC contraction b) Determine the role of the cAMP, PKA pathway in adenosine mediated inhibition of PDGF induced cytosolic Ca++ increase. Specific Aim 2: a) Determine if UAP metabolites downstream of adenosine inhibit ATP and PDGF mediated Ca++ mobilization and chemotaxis of primary HSC b) Establish the requirement for adenosine receptors in the effect of UAP metabolites downstream of adenosine with the exception of uric acid c) Determine the intracellular signaling pathways responsible for uric acid induced HSC differentiation. Specific Aim 3: a) Determine the role of the immune system in adenosine mediated regulation of liver fibrosis in-vivo. b) Determine the ability of adenosine to regulate intrahepatic vascular resistance in cirrhotic livers. We have identified a new role for the UAP in HSC differentiation and regulation. This identifies a new set of molecules with a role in hepatic repair, and has implications for new therapies in liver fibrosis.