title: Tissue inhibitors of metalloproteinases: role in liver fibrosis and alcoholic liver disease.
abstract: In liver fibrosis, activated hepatic stellate cells (HSC) play a major role in the deposition of excess extracellular matrix, including fibrillar collagens type I and type III. In addition to matrix protein synthesis, HSC regulate 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 enzymes via expression of tissue inhibitors of metalloproteinases (TIMPs). There are currently four members of the TIMP family described and of these, both 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 in HSC-expression of TIMPs relative to metalloproteinases, such as interstitial collagenase, may contribute to progression of liver fibrosis. This hypothesis is supported by studies of human liver disease in which TIMP-1 expression 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 the 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 exhaustively, but the evidence currently available supports a role for inhibition of matrix degradation by TIMPs in this progressive fibrotic liver disease.
authors.affiliation: University Medicine, University of Southampton, Hampshire, United Kingdom. mja1@soton.ac.uk
authors.forename: M J
authors.initials: MJ
authors.lastname: Arthur
authors.forename: J P
authors.initials: JP
authors.lastname: Iredale
authors.forename: D A
authors.initials: DA
authors.lastname: Mann
mesh_terms: D006801:Humans; D008103:Liver Cirrhosis / Q000503:physiopathology*; D008666:Metalloendopeptidases / Q000037:antagonists & inhibitors*
chemical_list: D008666:Metalloendopeptidases