Esomeprazole alleviates fibrosis in systemic sclerosis by modulating AhR/Smad2/3 signaling

被引:10
|
作者
Liu, Jiani [1 ,2 ]
Pi, Zixin [1 ,2 ]
Xiao, Yangfan [3 ,4 ]
Zeng, Zhuotong [1 ,2 ]
Yu, Jiangfan [1 ,2 ]
Zou, Puyu [1 ,2 ]
Tang, Bingsi [1 ,2 ]
Qiu, Xiangning [1 ,2 ]
Tang, Rui [5 ]
Shi, Yaqian [1 ,2 ]
Xiao, Rong [1 ,2 ]
机构
[1] Cent South Univ, Xiangya Hosp 2, Dept Dermatol, 139 Renmin Middle Rd, Changsha 410011, Hunan, Peoples R China
[2] Cent South Univ, Xiangya Hosp 2, Hunan Key Lab Med Epigenet, Changsha 410011, Hunan, Peoples R China
[3] Cent South Univ, Xiangya Hosp 2, Dept Anesthesiol, Changsha, Peoples R China
[4] Cent South Univ, Xiangya Hosp 2, Clin Nursing Teaching & Res Sect, Changsha, Peoples R China
[5] Cent South Univ, Xiangya Hosp 2, Dept Rheurnatol, Changsha 410000, Peoples R China
基金
中国国家自然科学基金;
关键词
Esomeprazole; Systemic sclerosis; Fibrosis; Aryl hydrocarbon receptor; Smad2/3; ARYL-HYDROCARBON RECEPTOR;
D O I
10.1016/j.phrs.2022.106057
中图分类号
R9 [药学];
学科分类号
1007 ;
摘要
Systemic sclerosis (SSc) is a connective tissue disease with the involvement of complex signaling pathways, such as TGF-beta/Smad2/3. SSc can lead to severe multiple organ fibrosis, but no effective therapy is currently available because of its unclear pathogenesis. Exploring new treatments is the focus of recent research on SSc. Recent studies have implied a potential antifibrotic role of esomeprazole (ESO), but with currently unidentified mechanisms. Signaling of AhR, a ligand-dependent transcription factor, has been described as a key controller of fibrosis, tumorigenesis, and immune balance. Recently, it has been reported that ESO may be an exogenous agonist of AhR signaling, while no previous study has revealed the effects of ESO on SSc and its underlying mechanisms. In this study, we demonstrate that ESO suppresses the migration of SSc dermal fibroblasts, downregulates profibrotic markers, including COLIA1, alpha-SMA CTGF and MMP1, and limits collagen production potentially via the activation of AhR signaling. More importantly, ESO could block Smad2/3 phosphorylation concurrently with the reduction in collagen via AhR signaling. Moreover, our results from the bleomycin (BLM)-induced SSc model in skin and lung shows that ESO ameliorates fibrosis in vivo, which in keeping with our in vitro results. We conclude that ESO is a potential therapeutic drug for SSc fibrosis.
引用
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页数:9
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