Alcoholic liver disease is characterised by infiltration of the liver with leucocytes; alcoholic hepatitis is characterised by a neutrophil infiltrate whilst both hepatitis and cirrhosis are characterised by monocytic and lymphocytic infiltration. Chemokines are chemoattractant molecules that regulate leueocyte adhesion and migration at sites of tissue damage. In this thesis I studied the hypothesis that chemokines regulate the leucocyte infiltration and tissue damage characteristic of alcoholic liver disease and thereby determine the nature of the liver damage. Immunohistochemical and in situ hybridisation demonstrated increased expression of several chemokines in alcoholic liver disease. The neutrophil chemokine IL-8 and the lymphoeyte and monocyte ehemokines MCP-1, MIP-1α and MIP-1β were present throughout the hepatic acinus in patterns corresponding to the severity of infiltration with these leucocytes. Chemokine mRNA was mainly localised to non-parenchymal eells including sinusoidal cells, fibroblasts and infiltrating leueocytes. In patients with alcoholic liver disease, circulating serum levels of the ehemokine MCP-1 were raised compared to healthy controls and in proportion to histological severity of liver disease. Peripheral mononuclear cell secretion of both MCP-1 and MIP-1α were raised in alcoholic hepatitis with evidence for both liver-derived and circulating monocyte-derived synthesis. In vitro studies with radiolabelled chemokine protein demonstrated uptake of chemokines into isolated hepatocytes from surrounding culture medium, with uptake increased by the addition of alcohol or the pro-inflammatory cytokine TNF-α. Uptake was predominantly by low-affinity receptors but immunohistochemical studies suggest that specific receptors may nevertheless be up-regulated in alcoholic liver disease. Secretion of the chemokine MCP-1 from peripheral mononuclear cells and hepatocytes in vitro was diminished by alcohol or acetaldehyde with a dose-dependent effect. However, an ex vivo study in healthy volunteers showed that mononuclear cell secretion of MCP-1 may be increased when alcohol is ingested together with a balanced meal. An uncontrolled pilot study of the xanthine-derivative pentoxifylline in subjects with severe alcoholic hepatitis, together with in vitro studies of its effect upon chemokine seeretion, showed that this agent may have a role in the treatment of the disease. In a controlled study examining genetic predisposition to symptomatic alcoholic liver disease, we examined two TNF-α promoter polymorphisms and HLA haplotypes DR3 and DQ2; however we failed to show any associations between these markers and the disease
