Endothelin 1 contributes to the effect of transforming growth factor β1 on wound repair and skin fibrosis

摘要: Objective To characterize the pathways induced by transforming growth factor beta1 (TGFbeta1) that lead to expression of endothelin 1 (ET-1) in human dermal fibroblasts, and study effects TGFbeta1 ET-1 on acquisition a profibrotic phenotype assess contribution TGFbeta1/ET-1 axis skin wound healing fibrosis vivo. Methods The mechanism induction its effect alpha-smooth muscle actin type I collagen were studied experiments involving TGFbeta receptor inhibitor GW788388 ET antagonist bosentan, real-time reverse transcription-polymerase chain reaction (RT-PCR), enzyme-linked immunosorbent assay, immunofluorescence, Western blotting, promoter/reporter transient transfection analyses. Experiments assessing mice performed with adenovirus-driven overexpression active ET-1, or without treatment bosentan. contributions fibrotic response also assessed mouse model bleomycin-induced fibrosis, histologic, immunohistochemical, RT-PCR, protein Results fibroblasts through Smad- activator 1/JNK-dependent signaling. ability induce genes was dependent ET-1. Adenovirus-mediated associated accelerated closure, increased fibrogenesis, excessive scarring. Treatment bosentan prevented TGFbeta1. In model, response. Conclusion Our results strongly support notion has role repair fibrosis. antagonists, such as may represent useful therapeutic tool scarring fibrosis-related diseases.