| Abstrak/Abstract |
Fibrosis is a pathophysiological state characterized by the excessive formation/deposition of ?brous extracellularmatrix. Transforming growth factor-beta (TGF-?) is a central pro?brotic mediator, and targeting TGF-? is apromising strategy in the development of drugs for the treatment of ?brosis. Therefore, the e?ect of LY2109761,a small molecule inhibitor against TGF-? with targets beyond TGF-? signaling, on ?brogenesis was elucidated invitro (HepG2 cells and LX-2 cells) and ex vivo (human and rat precision-cut liver slices). Our results displayed ananti-?brotic e?ect of LY2109761, as it markedly down-regulated gene and protein expression of collagen type 1,as well as gene expression of the inhibitor of metalloproteinases 1. This e?ect on ?brosis markers was partiallymediated by targeting TGF-? signaling, seeing that LY2109761 inhibited TGF-?1 gene expression and SMAD2protein phosphorylation. Interestingly, particularly at a high concentration, LY2109761 decreased SMAD1protein phosphorylation and gene expression of the inhibitor of DNA binding 1, which appeared to be TGF-?-independent e?ects. In conclusion, LY2109761 exhibited preclinical anti-?brotic e?ects via both TGF-?-de-pendent and -independent pathways. These results illustrate that small molecule inhibitors directed against TGF-? could possibly in?uence numerous signaling pathways and thereby mitigate ?brogenesis. |
