ACCELERATED DEVELOPMENT OF LIVER FIBROSIS IN CCL4-TREATED RATS BY THEWEEKLY INDUCTION OF ACUTE-PHASE RESPONSE EPISODES - UP-REGULATION OF ALPHA-1(I) PROCOLLAGEN AND TISSUE INHIBITOR OF METALLOPROTEINASE-1 MESSENGER-RNAS

Patients with alcoholic hepatitis have several manifestations of the a cute phase response (APR) and have elevated blood levels of interleuki n-1, interleukin-6 and tumor necrosis factor-alpha. We have previously shown that liver stellate cells express interleukin-6 mRNA and protei n and respond to this cytokine with increased expression of alpha 1(I) procollagen mRNA. We further showed that the production of an APR epi sode stimulates a transient expression of alpha 1(I) procollagen mRNA in the Liver. In this communication we demonstrate that the concomitan t induction of a weekly APR episode in rats with a schedule of CCl4 to produce cirrhosis, accelerates the development of liver fibrosis. We show that the enhancement of Liver fibrosis is due, in part, to furthe r upregulation in the expression of alpha 1(I) procollagen and tissue inhibitor of metalloproteinases-1 mRNAs above values observed in contr ol rats receiving only CCl4. The effect of the APR appears to have spe cificity since not all the mRNAs measured were equally affected. Altog ether, these results suggest that increased blood or liver levels of A PR cytokines, whether induced by APR episodes, endotoxin or other unre lated causes, may contribute to the development of liver fibrosis by e nhancing the expression of type I collagen and of tissue inhibitor of metalloproteinases-1 mRNAs. (C) 1997 Elsevier Science B.V.