南京中医药大学Xu Shen等研究人员合作发现，奥替溴铵通过激活磷酸酶PPM1A改善小鼠肺纤维化。该研究于2024年8月19日在线发表于国际学术期刊《中国药理学报》。

研究人员探讨了肺纤维化（PF）的分子发病机制和潜在的治疗靶点，并发现了PF治疗的药物先导化合物。通过气管内注射博来霉素（BLM，5 mg/kg），研究人员建立了小鼠PF模型。研究显示，肺部蛋白磷酸酶镁依赖性1A（PPM1A，也称为PP2Cα）的蛋白水平在PF患者和BLM诱导的PF小鼠中显著下调。研究人员证明了TRIM47促进了PPM1A的泛素化并减少了PPM1A蛋白在PF进展中的表达。

通过筛选实验室内部化合物库，研究人员发现了用于治疗肠易激综合症的药物奥替溴铵（OB），其作为PPM1A酶激活剂的EC₅₀值为4.23 μM。使用OB（2.5、5 mg/kg每天，腹腔注射，持续20天）治疗小鼠显著改善了PF样病理。

研究人员构建了肺组织中特异性沉默PPM1A的小鼠模型，发现通过靶向PPM1A，OB治疗通过TGF-β/SMAD3通路抑制了纤维母细胞中的细胞外基质（ECM）沉积，通过NF-κB/NLRP3通路抑制了肺泡上皮细胞中的炎症反应，并减弱了肺泡上皮细胞炎症与纤维母细胞中ECM沉积之间的相互作用。综合来看，这些结果表明激活肺部PPM1A是治疗PF的有前景的策略，并突出了OB在治疗该疾病中的潜力。

据介绍，PF是一种慢性、进行性且不可逆的间质性肺病，其特征为持续的肺肌成纤维细胞激活、ECM沉积和炎症招募。目前尚无治愈药物。

附：英文原文

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

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

Issue&Volume: 2024-08-19

Abstract: 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, 5mg/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 4.23μM. Treatment with OB (2.5, 5mg·kg1·d1, i.p., 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-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.

DOI: 10.1038/s41401-024-01368-8

Source: https://www.nature.com/articles/s41401-024-01368-8