ADENOVIRUS-MEDIATED EXPRESSION OF CYTOKINE-INDUCED NEUTROPHIL CHEMOATTRACTANT IN RAT-LIVER INDUCES A NEUTROPHILIC HEPATITIS

C-X-C chemokines are potent chemoattractants that are believed to medi ate neutrophilic inflammation in several organs. Recent studies sugges t a role for C-X-C chemokines in the pathogenesis of neutrophilic hepa titis but do not prove causation. We investigated the biological conse quences of hepatic chemokine production in vivo by transiently overexp ressing cytokine-induced neutrophil chemoattractant (CINC), a member o f the C-X-C chemokine family, in intact rats. Rats were injected intra portally with a replication-defective recombinant adenovirus containin g the CINC complementary DNA (cDNA). Within 4 days, treated animals ha d high levels of CINC in both liver tissue and plasma. Rats overexpres sing CINC exhibited an eightfold increase in circulating neutrophils; they also developed severe hepatic injury, characterized by a 6- to 25 -fold increase in plasma transaminases and marked hepatic inflammation on biopsy. Liver disease in CINC-producing rats correlated positively with the number of neutrophils sequestered in the hepatic parenchyma. Tissue injury was attributed directly to chemokine overproduction, be cause control rats infected with adenoviruses lacking the CINC cDNA di d not produce CINC and developed only minor hepatic abnormalities. The se experiments provide direct evidence that C-X-C chemokines, when exp ressed in sufficient quantity in the liver in vivo, induce neutrophil recruitment and tissue invasion and provoke severe liver injury. The d ata suggest that C-X-C chemokines have important pathogenic potential in both clinical and experimental liver disease.