Subendothelial fibrosis is a severe form of liver injury, often associated with markedly impaired hepatocellular function. Our recent studies suggest that this represents pathological alteration of the normal subendothelial matrix comprising type IV collagen, laminin and heparan sulfate proteoglycan. The latter are constituents of epithelial basement membranes generally. Our focus in the present proposal is the mechanism whereby this pathologic process is initiated. We hypothesize that an early stage is breakdown of the normal matrix mediated by locally elaborated proteinases (collagenases as well as enzymes that attack laminin or proteoglycan). The proposed studies will examine proteinase production by defined hepatic parenchymal and individual non-parenchymal cell populations in primary culture. Secreted proteinases will be characterized in terms of their substrate specificity inhibitor sensitivity, molecular size and modulation by agents that activate mesenchymal cells (such as phorbl esters). Cells from normal liver will be compared with those from experimentally fibrotic liver. Finally, the effect of proteinases, defined in this manner, on the structure and biological properties of a model basement membrane will be examined. The findings are expected to shed new light on the initiation of pathologic hepatic fibrosis at the cellular and molecular level.
| Arthur, M J; Stanley, A; Iredale, J P et al. (1992) Secretion of 72 kDa type IV collagenase/gelatinase by cultured human lipocytes. Analysis of gene expression, protein synthesis and proteinase activity. Biochem J 287 ( Pt 3):701-7 |
| Iredale, J P; Murphy, G; Hembry, R M et al. (1992) Human hepatic lipocytes synthesize tissue inhibitor of metalloproteinases-1. Implications for regulation of matrix degradation in liver. J Clin Invest 90:282-7 |
