| Popis: |
BackgroundSystemic sclerosis (SSc) is a collagen disease that exhibits intractable fibrosis and vascular injury of the skin and internal organs. Transforming growth factor-β (TGF-β)/Smad signaling plays a central role in extracellular matrix (ECM) production by myofibroblasts. Myofibroblasts may be derived from epithelial and endothelial precursor cells in addition to resident fibroblasts. Recently, our high-throughput in vitro screening discovered a small compound, LG283, that can disrupt the differentiation of dermal fibroblasts into myofibroblasts. This compound was originally generated as a curcumin derivative. MethodsIn this study, we investigated the effect of LG283 on inhibiting fibrosis and vascular injury. The action of LG283 on TGF-β-dependent fibrogenic activity, epithelial mesenchymal transition (EMT), and endothelial cell mesenchymal transition (EndoMT) was analyzed in vitro. The effects of LG283 were also examined in a bleomycin-induced skin fibrosis mouse model.ResultsLG283 suppressed TGF-β-induced ECM expression, Smad3 phosphorylation, and expression of transcription factors responsible for the mesenchymal transition, Snail 1 and 2, in cultured human dermal fibroblasts. LG283 was also found to block EMT and EndoMT in cultured human epithelial cells and endothelial cells, respectively. During these processes, Smad3 phosphorylation and/or expression of Snail 1 and 2 were inhibited by LG283 treatment. In the bleomycin-induced skin fibrosis model, oral administration of LG283 efficiently protected against the development of fibrosis and vascular injury without affecting cell infiltration or cytokine concentrations in the skin. No apparent adverse effects of LG283 were found. LG283 treatment remarkably inhibited the enhanced expression of phosphorylated Smad3 in the bleomycin-injected skin. Increased expression of Snail 1 and 2 were reduced by LG283 treatment in the mouse model. ConclusionsThe LG283 compound exhibits antagonistic activity on fibrosis and vascular injury through inhibition of TGF-β/Smad/Snail mesenchymal transition pathways and thus, may be a candidate therapeutic for treatment of SSc. Furthermore, the screening of EMT and/or EndoMT regulatory compounds may be an attractive approach for SSc therapy. |
