单位：[a]Department of Infectious Disease, Beijing Friendship Hospital, Capital Medical University, Beijing, 100050, China临床科室急危重症及感染医学中心感染内科首都医科大学附属北京友谊医院[b]Experimental Center, Liver Research Center, Beijing Friendship Hospital, Capital Medical University, National Clinical Research Center for Digestive Disease, Beijing 100050, PR China临床科室国家中心肝病分中心医技科室北京市临床医学研究所实验中心首都医科大学附属北京友谊医院[c]Department of Respiratory Medicine, Beijing Friendship Hospital, Capital Medical University, Beijing, 100050, China临床科室呼吸内科呼吸内科首都医科大学附属北京友谊医院[d]Laboratory Affiliated with the Institute Pasteur Italy - Cenci Bolognetti Foundation, Department of Drug Chemistry and Technologies, Sapienza University of Rome, Piazzale Aldo Moro 5, I-00185, Roma, Italy
Background: Idiopathic pulmonary fibrosis (IPF) is a progressive disease resulting in respiratory failure with no efficient treatment options. We investigated the protective effect of RS4651 on pulmonary fibrosis in mice and the mechanism. Methods: Intratracheal injection of bleomycin (BLM) was used to induce pulmonary fibrosis in mice. RS4561 was administered intraperitoneally at different doses. Histopathological changes were observed. The level of alphasmooth muscle actin (alpha-SMA) were also tested. In vitro, the proliferation and migratory effects of RS4651 treatment on MRC-5 cells pre-treated with transforming growth factor (TGF-beta 1) were examined. RNA-sequencing was used to detect differentially expressed target genes. Then, the expression of alpha-SMA, pSMAD2 and SMAD7 were analysed during RS4651 treatment of MRC-5 cells with or without silencing by SMAD7 siRNA. Results: Histopathological staining results showed decreased collagen deposition in RS4651 administered mice. Additionally, a lower level of alpha-SMA was also observed compared to the BLM group. The results of in vitro studies confirmed that RS4651 can inhibit the proliferation and migration, as well as alpha-SMA and pSMAD2 expression in MRC-5 cells treated with TGF-beta 1. RNA-sequencing data identified the target gene SMAD7. We found that RS4651 could upregulate SMAD7 expression and inhibit the proliferation and migration of MRC-5 cells via SMAD7, and RS4651 inhibition of alpha-SMA and pSMAD2 expression was blocked in SMAD7-siRNA MRC-5 cells. In vivo studies further confirmed that RS4651 could upregulate SMAD7 expression in BLM-induced lung fibrosis in mice. Conclusions: Our data suggest that RS4651 alleviates BLM-induced pulmonary fibrosis in mice by inhibiting the TGF-beta 1/SMAD signalling pathway.
基金：
Capital Health Research and Development of Special [2020-2-2027]; Research Foundation of Beijing Friendship Hospital, Capital Medical University [2015-13]; Funding Support for Key Clinical Projects in Beijing
