neutrophils in the pathogenesis of liver damage. 1 Conse-Alcoholic hepatitis is characterized by parenchymal quently, attention has been focused on factors determining neutrophil infiltration. Hepatic synthesis of the neutroneutrophil recruitment and activation as potentially pivotal phil chemokine interleukin-8 (IL-8) is highly elevated in in the pathogenesis of alcoholic liver disease. alcoholic hepatitis and levels correlate with the degree
We have previously found hepatic and plasma levels of the of neutrophil infiltration. The aim of this study was to cytokine interleukin-8 (IL-8), a potent neutrophil chemoatfurther determine the spectrum of synthesis of chemotractant, are markedly increased in patients with alcoholic kines in liver tissue from patients with alcoholic liver hepatitis and correlate with mortality and the biochemical disease and a range of disease control subjects. Subjects markers of disease severity. 2 In contrast, only modest elevawere composed of 24 patients with alcoholic liver distions of circulating IL-8 were seen in alcoholic cirrhosis, in ease of whom 15 had histopathological evidence of alcoalcoholic patients without significant liver disease, and in holic hepatitis (10 cirrhotic) and 9 no evidence of alcoinflammatory liver disease when compared with normals. holic hepatitis (5 cirrhotic); other controls included;
The relative specificity of hepatic IL-8 expression to alcoholnormal liver (n Å 6), viral hepatitis (n Å 16), primary induced hepatitis suggests that this finding is not merely an biliary cirrhosis (n Å 5), acute liver failure (n Å 4), and epi-phenomenon reflecting nonspecific hepatic inflammation miscellaneous liver disease (n Å 13). Levels of the C-X-C and that the cytokine may be playing a significant role in neutrophil chemokine GRO alpha and the mononuclear coordinating the inflammatory response. To examine the cell C-C chemokines: macrophage inflammatory protein specificity of this association in terms of the superfamily of 1 alpha, macrophage chemotactic protein 1 and chemoattractant proteins we have quantitatively assayed he-RANTES, were determined by ELISA in liver homogepatic levels of a range of chemokines exerting their effects nates. Levels of the neutrophil chemokine GRO alpha on different leukocyte subsets. were specifically elevated (mean 46 pg/mg, compared
The chemokines are a family of small chemoattractant prowith normal liver 11 pg/mg) in patients with alcoholic teins with varying specificity of chemoattractant and other hepatitis. GRO alpha levels correlated with IL-8 levels activities upon different leukocytes. 3 They may be classified and were higher in patients with alcoholic liver disease into three groups C-X-C, C-C, and C dependent upon the and parenchymal neutrophil infiltration. Hepatic number and position of cysteine residues which form internal RANTES was elevated in diseased liver, with the highest disulphide bonds. The C-X-C group includes IL-8, GRO alpha, levels found in viral hepatitis (mean 117 pg/mg, combeta and gamma, platelet factor 4, neutrophil activating peppared with 24 pg/mg in normal liver). No significant tide 2, interferon inducible protein 10, and epithelial derived changes in hepatic levels of macrophage inflammatory neutrophil activating peptide 78 and act predominantly but protein 1 alpha (MIP-1 alpha) or macrophage chemotacnot exclusively on neutrophils. Whereas the C-C and C tic protein 1 (MCP-1) were found. These data provide groups include macrophage chemotactic protein 1, 2, and 3 further supportive evidence that parenchymal neutro-(macrophage chemotactic protein-1 [MCP-1], MCP-2, and phil infiltration in alcoholic hepatitis may be deter-MCP-3); macrophage inflammatory proteins 1 alpha and beta mined by selective upregulation of C-X-C chemokine (macrophage inflammatory protein-1 alpha [MIP-1 alpha] synthesis. (HEPATOLOGY 1996;24:1156-1160.) and MIP-1 beta); regulated upon activation, normal T-cell expressed, and presumably secreted (RANTES); eotaxin; 1-Parenchymal neutrophil infiltration is a highly character-309; and lymphotactin, and act predominantly on macroistic feature of acute alcoholic hepatitis, and is unusual in phages, lymphocytes, or eosinophils. 4 Having previously exother forms of acute liver injury. Severe cases may have an amined hepatic levels of IL-8, we contrast these results with associated peripheral neutrophilia in the absence of detecthepatic levels of another C-X-C chemokine, GRO alpha, and able bacterial or fungal sepsis and studies have implicated with three representative C-C chemokines: MCP-1, MIP-1 alpha, and RANTES.
PATIENTS AND METHODS
Abbreviations: IL, interleukin; MCP, macrophage chemotactic protein; MIP, macrophage Samples of liver were taken from 24 inpatients with a diagnosis inflammatory protein; RANTES, regulated upon activation, normal T-cell expressed, and of alcoholic liver disease and a history of alcohol intake exceeding presumably secreted; PBC, primary biliary cirrhosis; CI, confidence interval.