Reversibility of hepatic fibrosis: from the first report of collagenase in the liver to the possibility of gene therapy for recovery.

Since the authors reported the presence of collagenase in the liver as well as its increased activity in the early stage of hepatic fibrosis and its reduced activity in advanced fibrosis in rats induced by chronic CCl4 intoxication, in baboons fed alcohol chronically and in patients with alcoholic fibrosis, other investigators have demonstrated the same tendency of collagenase activity biologically and histochemically. Very recently, the authors demonstrated definite gene expression of collagenase during the recovery from experimental hepatic fibrosis using Northern blotting and in situ hybridization. The findings of in situ hybridization not only demonstrated the cells expressing collagenase, but also suggested much information on the mechanism of the recovery from fibrosis. Hepatic stellate cells play a key role not only in fibrogenesis but also in fibrolysis. The authors' recent observation revealed that collagenase (matrix metalloproteinase-13 (MMP-13)) gene expression appears very early in the process of recovery from liver fibrosis, and that both stellate cells and hepatocytes express MMP-13. Recovery from liver cirrhosis requires the gene expression of collagenase, increased production of the collagenase enzyme, and activation of the enzyme balanced with the specific inhibitors of collagenase. The understanding of molecular mechanisms of MMP-1 gene expression which is under investigation in our laboratory may provide us a new strategy for the treatment of liver fibrosis including the possibility of gene therapy.