Tissue inhibitors of metalloproteinases: Role in liver fibrosis and alcoholic liver disease

In liver fibrosis, activated hepatic stellate cells (HSC) play a major role in the deposition of excess extracellular matrix including fibrillar colla gens type I and type III. In addition to matrix protein synthesis, HSC regu late matrix degradation in the liver. This is mediated via a combination of synthesis of matrix (pro)metalloproteinases, which activate these zymogens via specific mechanisms and by inhibiting the active matrix-degrading enzy mes via expression of tissue inhibitors of metalloproteinases (TIMPs). Ther e are currently four members of the TIMP family described and of these, bot h TIMP-1 and TIMP-2 are synthesised by HSC. These observations have led to the suggestion that inhibition of matrix degradation mediated by a change i n HSC-expression of TIMPs relative to metalloproteinases, such as interstit ial collagenase, may contribute to progression of liver fibrosis. This hypo thesis is supported by studies of human liver disease in which TIMP-1 expre ssion is upregulated 5-fold in cirrhotic compared with normal liver. TIMP-1 and TIMP-2 expression is also upregulated in animal models of progressive fibrosis, whereas expression of collagenase is unchanged. In a model which is characterized by natural resolution of liver fibrosis, degradation of th e deposited fibrillar liver matrix is accompanied by rapid down-regulation of TIMP-1 expression. In alcoholic liver disease, the role of TIMPs has not been studied exhausti vely, but the evidence currently available supports a role for inhibition o f matrix degradation by TIMPs in this progressive fibrotic liver disease.