This work was supported by grants from the Wellcome Trust (Grants 038712/Z/93 and 050443/2/97). John Iredale is an MRC Clinician Scientist.
Tissue Inhibitors of Metalloproteinases: Role in Liver Fibrosis and Alcoholic Liver Disease
Article first published online: 30 MAY 2006
Alcoholism: Clinical and Experimental Research
Volume 23, Issue 5, pages 940–943, May 1999
How to Cite
Arthur, M. J. P., Iredale, J. P. and Mann, D. A. (1999), Tissue Inhibitors of Metalloproteinases: Role in Liver Fibrosis and Alcoholic Liver Disease. Alcoholism: Clinical and Experimental Research, 23: 940–943. doi: 10.1111/j.1530-0277.1999.tb04208.x
- Issue published online: 30 MAY 2006
- Article first published online: 30 MAY 2006
- Matrix Degradation;
- Matrix Metalloproteinase;
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.