Roxithromycin attenuates bleomycin-induced pulmonary fibrosis by targeting senescent cells

doi:10.1038/s41401-021-00618-3

	Roxithromycin attenuates bleomycin-induced pulmonary fibrosis by targeting senescent cells
	Zhang, Xuan 1,5; Dong, Ying 1,5; Li, Wan-chen 1,5; Tang, Bi-xi 1,2; Li, Jia 1,3,4,5; Zang, Yi 1,4,5
刊名	ACTA PHARMACOLOGICA SINICA
	2021-03-02
页码	11
关键词	idiopathic pulmonary fibrosis cellular senescence roxithromycin NOX4 senescence-associated secretory phenotype (SASP)
ISSN号	1671-4083
DOI	10.1038/s41401-021-00618-3
通讯作者	Li, Jia(Jli@simm.ac.cn) ; Zang, Yi(Yzang@simm.ac.cn)
英文摘要	Idiopathic pulmonary fibrosis (IPF) is an aging-associated disease with a poor prognosis. Emerging evidence has revealed that targeting senescent cells may be a potential treatment for IPF. In this study, we aimed to explore whether roxithromycin (RXM) can improve lung fibrosis by targeting senescent cells. First, we confirmed the ability of RXM to selectively kill senescent cells by inducing apoptosis and inhibiting the expression of senescence-associated secretory phenotype (SASP) factors, suggesting the potential role of RXM as a "senolytic" and "senomorphic" drug. Next, we observed that TGF-beta- and senescent cell-induced lung fibroblast activation was inhibited by RXM treatment, which prompted us to further investigate its effect in vivo. In a mouse model of bleomycin (BLM)-induced pulmonary fibrosis, RXM was shown to attenuate lung injury, inflammation, and fibrosis. Furthermore, the senescent phenotype of lung tissues induced by BLM was significantly diminished after RXM administration, indicating the potential of RXM as an antifibrotic and antisenescent agent. Interestingly, NADPH oxidase 4 (NOX4), implicated in lung fibrosis and cell senescence, was shown to be inhibited by RXM treatments. The antifibroblast activation and antisenescent effects of RXM were abolished in NOX4 knockdown cells, demonstrating that RXM may ameliorate BLM-induced pulmonary fibrosis by targeting senescent cells mediated by the NOX4 pathway. Collectively, these data demonstrated that RXM may be a potential clinical agent for IPF and further supported the notion that targeting cellular senescence is a promising treatment for progressive age-related disease.
资助项目	National Science and Technology Major Project Key New Drug Creation and Manufacturing Program[2019ZX09201001-004-010] ; National Science and Technology Major Project Key New Drug Creation and Manufacturing Program[2019ZX09201001-003-010] ; National Natural Science Foundation of China[U1703235] ; National Natural Science Foundation of China[31871414] ; National Science Fund for Distinguished Young Scholars[81125023] ; K. C. Wong Education Foundation
WOS研究方向	Chemistry ; Pharmacology & Pharmacy
语种	英语
出版者	NATURE PUBLISHING GROUP
WOS记录号	WOS:000624397300003
内容类型	期刊论文
源URL	[http://119.78.100.183/handle/2S10ELR8/295497]
专题	中国科学院上海药物研究所
通讯作者	Li, Jia; Zang, Yi
作者单位	1.Chinese Acad Sci, Shanghai Inst Mat Med, State Key Lab Drug Res, Shanghai 201203, Peoples R China 2.Fudan Univ, Sch Pharm, Dept Pharmacol, Shanghai 200000, Peoples R China 3.Pilot Natl Lab Marine Sci & Technol Qingdao, Open Studio Druggabil Res Marine Nat Prod, Qingdao 266237, Peoples R China 4.UCAS, Hangzhou Inst Adv Study, Sch Pharmaceut Sci & Technol, Hangzhou 310024, Peoples R China 5.Univ Chinese Acad Sci, Beijing 100049, Peoples R China
推荐引用方式 GB/T 7714	Zhang, Xuan,Dong, Ying,Li, Wan-chen,et al. Roxithromycin attenuates bleomycin-induced pulmonary fibrosis by targeting senescent cells[J]. ACTA PHARMACOLOGICA SINICA,2021:11.
APA	Zhang, Xuan,Dong, Ying,Li, Wan-chen,Tang, Bi-xi,Li, Jia,&Zang, Yi.(2021).Roxithromycin attenuates bleomycin-induced pulmonary fibrosis by targeting senescent cells.ACTA PHARMACOLOGICA SINICA,11.
MLA	Zhang, Xuan,et al."Roxithromycin attenuates bleomycin-induced pulmonary fibrosis by targeting senescent cells".ACTA PHARMACOLOGICA SINICA (2021):11.