Otilonium bromide ameliorates pulmonary fibrosis in mice through activating phosphatase Otilonium bromide ameliorates pulmonary fibrosis in mice through activating phosphatase PPM1A  

作　　者：Tong Zhao Zhi-ruo Zhou Hui-qi Wan Tian Feng Xu-hui Hu Xiao-qian Li Shi-mei Zhao Hong-lin Li Ji-wei Houl Wei Li Da-yun Lu Min-yi Qian Xu Shen 

机构地区：[1]Jiangsu Key Laboratory of Drug Target and Drug for Degenerative Diseases,School of Medicine,Nanjing University of Chinese Medicine,Nanjing 210023,China [2]School of Pharmacy,Fudan University,Shanghai 201203,China [3]School of Pharmacy,Nanjing University of Chinese Medicine,Nanjing 210023,China [4]Immunology and Reproduction Biology Laboratory&State Key Laboratory of Analytical Chemistry for Life Science,Medical School,Nanjing University,Nanjing 210093,China

出　　处：《Acta Pharmacologica Sinica》2025年第1期107-121,共15页中国药理学报(英文版)

基　　金：This work was supported by the National Natural Science Foundation of China(82273930);the Jiangsu Provincial Natural Science Foundation Project(BK20240747);the National Natural Science Foundation for Young Scientists of China(82204486,82304468 and 82304494);the Natural Science Foundation for Young Scientists of Nanjing University of Chinese Medicine(XPT82204486 and XPT82304468);Major Programof the Natural Science Foundation of the Jiangsu Higher Education Institutions of China(24KJA310006,23KJA350002);Jiangsu Key Discipline Construction Fund of the 14th Five-Year Plan(Biology)and"Qing Lan"project.Graph abstract was drawn by Figdraw.

摘　　要：Pulmonary fibrosis(PF)is a chronic,progressive and irreversible interstitial lung disease characterized by unremitting pulmonary myofibroblasts activation,extracellular matrix(ECM)deposition and inflammatory recruitment.PF has no curable medication yet.In this study we investigated the molecular pathogenesis and potential therapeutic targets of PF and discovered drug lead compounds for PF therapy.A murine PF model was established in mice by intratracheal instilation of bleomycin(BLM,5 mg/kg).We showed that the protein level of pulmonary protein phosphatase magnesium-dependent 1A(PPM1A,also known as PP2Ca)was significantly downregulated in PF patients and BLM-induced PF mice.We demonstrated that TRIM47 promoted ubiquitination and decreased PPM1A protein in PF progression.By screening the lab in-house compound library,we discovered otilonium bromide(OB,clinically used for treating irritable bowel syndrome)as a PPM1A enzymatic activator with an EC_(50) value of 4.23μM.Treatment with OB(2.5,5 mg-kg^(-l).d^(-1),ip,for 20 days)significantly ameliorated PF-like pathology in mice.We constructed PF mice with PPM1A-specific knockdown in the lung tissues,and determined that by targeting PPM1A,OB treatment suppressed ECM deposition through TGF-β/SMAD3 pathway in fibroblasts,repressed inflammatory responses through NF-kB/NLRP3 pathway in alveolar epithelial cells,and blunted the crosstalk between inflammation in alveolar epithelial cells and ECM deposition in fibroblasts.Together,our results demonstrate that pulmonary PPM1A activation is a promising therapeutic strategy for PF and highlighted the potential of OB in the treatment of the disease.

关 键 词：pulmonary fibrosis PPM1A otilonium bromide NLRP3 SMAD3 

分 类 号：R73[医药卫生—肿瘤]