Relaxin inhibits eVective collagen deposition by cultured hepatic stellate cells and decreases rat liver fibrosis in vivo

Background—Following liver injury, hepatic stellate cells (HSC) transform into myofibroblast-like cells (activation) and are the major source of type I collagen and the potent collagenase inhibitors tissue inhibitors of metalloproteinases 1 and 2 (TIMP-1 and TIMP-2) in the fibrotic liver. The reproductive hormone relaxin has been reported to reduce collagen and TIMP-1 expression by dermal and lung fibroblasts and thus has potential antifibrotic activity in liver fibrosis. Aims—To determine the eVects of relaxin on activated HSC. Methods—Following isolation, HSC were activated by culture on plastic and exposed to relaxin (1–100 ng/ml). Collagen deposition was determined by Sirius red dye binding and radiolabelled proline incorporation. Matrix metalloproteinase (MMP) and TIMP expression were assessed by zymography and northern analysis. Transforming growth factor â1 (TGF-â1) mRNA and protein levels were quantified by northern analysis and ELISA, respectively. Results—Exposure of activated HSC to relaxin resulted in a concentration dependent decrease in both collagen synthesis and deposition. There was a parallel decrease in TIMP-1 and TIMP-2 secretion into the HSC conditioned media but no change in gelatinase expression was observed. Northern analysis demonstrated that primary HSC, continuously exposed to relaxin, had decreased TIMP-1 mRNA expression but unaltered type I collagen, collagenase (MMP-13), alpha smooth muscle actin, and TGF-â1 mRNA expression. Conclusion—These data demonstrate that relaxin modulates eVective collagen deposition by HSC, at least in part, due to changes in the pattern of matrix degradation. (Gut 2001;49:577–583)