Roxithromycin attenuates bleomycin-induced pulmonary fibrosis by targeting senescent cells  

作　　者：Xuan Zhang Ying Dong Wan-chen Li Bi-xi Tang Jia Li Yi Zang 

机构地区：[1]State Key Laboratory of Drug Research,Shanghai Institute of Materia Medica,Chinese Academy of Sciences,Shanghai 201203,China [2]University of Chinese Academy of Sciences,Beijing 100049,China [3]Department of Pharmacology,School of Pharmacy,Fudan University,Shanghai 200000,China [4]Open Studio for Druggability Research of Marine Natural Products,Pilot National Laboratory for Marine Science and Technology(Qingdao),Qingdao 266237,China [5]School of Pharmaceutical Science and Technology,Hangzhou Institute for Advanced Study,UCAS,Hangzhou 310024,China

出　　处：《Acta Pharmacologica Sinica》2021年第12期2058-2068,共11页中国药理学报（英文版）

基　　金：supported by the National Science and Technology Major Project"Key New Drug Creation and Manufacturing Program"(2019ZX09201001-004-010,2019ZX09201001-003-010);the National Natural Science Foundation of China(Grant U1703235,31871414);the National Science Fund for Distinguished Young Scholars(Grant 81125023);the K.C.Wong Education Foundation.

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-β-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.

关 键 词：idiopathic pulmonary fibrosis cellular senescence ROXITHROMYCIN NOX4 senescence-associated secretory phenotype(SASP) 

分 类 号：R339.38[医药卫生—人体生理学]