RELAXIN INDUCES AN EXTRACELLULAR MATRIX-DEGRADING PHENOTYPE IN HUMAN LUNG FIBROBLASTS IN-VITRO AND INHIBITS LUNG FIBROSIS IN A MURINE MODELIN-VIVO

Pulmonary fibrosis is the common end stage of a number of pneumopathie s. In this study, we examined the ability of the human cytokine, relax in, to block extracellular matrix deposition by human lung fibroblasts in vitro, and to inhibit lung fibrosis in a bleomycin-induced murine model, In vitro, relaxin (1-100 ng/ml) inhibited the transforming grow th factor-beta-mediated over-expression of interstitial collagen types I and III by human lung fibroblasts by up to 45% in a dose-dependent manner. Relaxin did not affect basal levels of collagen expression in the absence of TGF-beta-induced stimulation, Relaxin also blocked tran sforming growth factor-beta-induced upregulation of fibronectin by 80% at the highest relaxin dose tested (100 ng/ml), The expression of mat rix metalloproteinase-1, or procollagenase, was stimulated in a biphas ic, dose-dependent manner by relaxin. In vivo, relaxin, at a steady st ate circulating concentration of similar to 50 ng/ml, inhibited bleomy cin-mediated alveolar thickening compared with the vehicle only contro l group (P < 0.05), Relaxin also restored bleomycin-induced collagen a ccumulation, as measured by lung hydroxyproline content, to normal lev els (P < 0.05). In summary, relaxin induced a matrix degradative pheno type in human lung fibroblasts in vitro and inhibited bleomycin-induce d fibrosis in a murine model in vivo. These data indicate that relaxin may be efficacious in the treatment of pathologies characterized by l ung fibrosis.