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

Otilonium bromide ameliorates pulmonary fibrosis in mice through activating phosphatase PPM1A

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Otilonium bromide ameliorates pulmonary fibrosis in mice through activating phosphatase PPM1A
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 instillation of bleomycin(BLM,5 mg/kg).We showed that the protein level of pulmonary protein phosphatase magnesium-dependent 1A(PPM1A,also known as PP2Cα)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 EC50 value of 4.23 μM.Treatment with OB(2.5,5 mg·kg-1·d-1,i.p.,for 20 days)significantly ameliorated PF-like pathology in mice.We constructed PF mice with PPM1 A-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-κB/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.

pulmonary fibrosisPPM1Aotilonium bromideNLRP3SMAD3

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

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Jiangsu Key Laboratory of Drug Target and Drug for Degenerative Diseases,School of Medicine,Nanjing University of Chinese Medicine,Nanjing 210023,China

School of Pharmacy,Fudan University,Shanghai 201203,China

School of Pharmacy,Nanjing University of Chinese Medicine,Nanjing 210023,China

Immunology and Reproduction Biology Laboratory & State Key Laboratory of Analytical Chemistry for Life Science,Medical School,Nanjing University,Nanjing 210093,China

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pulmonary fibrosis PPM1A otilonium bromide NLRP3 SMAD3

2025

10.1038/s41401-024-01368-8

中国药理学报(英文版)
中科院上海药物研究所

中国药理学报(英文版)

影响因子：0.926
ISSN：1671-4083
年,卷(期)：2025.46(1)