Spatial distribution of tissue inhibitor of metalloproteinase-1 mRNA in chronic liver disease

Background/Aims: Tissue inhibitor of metalloproteinase-1, a specific inhibitor of matrix metalloproteinases, plays an important role in the pathogenesis of fibrosis and tumor progression. However, the precise expression of tissue inhibitor of metalloproteinase-1 messenger RNA in human hepatic fibrosis has not yet been defined. We investigated the spatial distribution of tissue inhibitor of metalloproteinase-1 messenger RNA in chronic human liver disease. Methods: Northern and in situ hybridization of probes to tissue inhibitor of metalloproteinase-1 messenger RNA were performed in specimens from 16 surgically resected human livers. Immunohistochemical staining of sections for tissue inhibitor of metalloproteinase-1 and immunoelectron microscopy were also performed. Results: Northern hybridization demonstrated that expression of tissue inhibitor of metalloproteinase-1 messenger RNA was increased 3.9-fold in mild chronic hepatitis, 6.8-fold in moderate chronic hepatitis, and 6.4-fold in cirrhosis, compared with control liver. In situ hybridization showed the expression of tissue inhibitor of metalloproteinase-1 messenger RNA in spindle-shaped cells in the fibrous septa and lobules in chronic hepatitis and cirrhosis; these cells were immunohistochemically positive for alpha-smooth muscle actin. Immunoelectron microscopy revealed localization of tissue inhibitor of metalloproteinase-1 in between fibers, to the rough endoplasmic reticula of stellate cells located in the lobules and periportal areas, and to fibroblasts in the fibrous septa. These results indicate that tissue inhibitor of metalloproteinase-1 was produced mainly by stellate cells in the specimens of chronic liver diseases. Conclusions: Expression of tissue inhibitor of metalloproteinase-1 messenger RNA is increased in hepatic fibrosis and stellate cells are involved primarily in its expression.