Nifuroxazide ameliorates pulmonary fibrosis by blocking myofibroblast genesis: a drug repurposing study

被引：23

作者：

Gan, Cailing ^{[1
]}

Zhang, Qianyu ^{[2
]}

Liu, Hongyao ^{[1
]}

Wang, Guan ^{[1
,3
,4
]}

Wang, Liqun ^{[2
]}

Li, Yali ^{[2
]}

Tan, Zui ^{[1
]}

Yin, Wenya ^{[2
]}

Yao, Yuqin ^{[2
]}

Xie, Yongmei ^{[1
]}

Ouyang, Liang ^{[1
]}

Yu, Luoting ^{[1
]}

Ye, Tinghong ^{[1
]}

机构：

[1] Sichuan Univ, Sichuan Univ Oxford Univ Huaxi Gastrointestinal C, West China Hosp, State Key Lab Biotherapy, 17 3rd Sect,Ren Min South Rd, Chengdu 610041, Peoples R China

[2] Sichuan Univ, Sch Publ Hlth, West China Med Sch, Dept Nutr & Food Hyg, Chengdu 610041, Peoples R China

[3] Sichuan Univ, West China Hosp, Innovat Ctr Nursing Res, Chengdu 610041, Peoples R China

[4] Sichuan Univ, Nursing Key Lab Sichuan Prov, Chengdu 610041, Peoples R China

来源：

RESPIRATORY RESEARCH | 2022年 / 23卷 / 01期

基金：

中国国家自然科学基金;

关键词：

Nifuroxazide; IPF; TGF-beta; 1/Smad; Stat3; EMT; TGF-BETA; EPITHELIAL-CELLS; IMMUNE-RESPONSE; LUNG FIBROSIS; PATHOGENESIS; DISEASE; ACTIVATION; MECHANISMS; SURVIVAL; TARGET;

D O I：

10.1186/s12931-022-01946-6

中图分类号：

R56 [呼吸系及胸部疾病];

学科分类号：

摘要：

Background: Idiopathic pulmonary fibrosis (IPF) is a serious interstitial lung disease with a complex pathogenesis and high mortality. The development of new drugs is time-consuming and laborious; therefore, research on the new use of old drugs can save time and clinical costs and even avoid serious side effects. Nifuroxazide (NIF) was originally used to treat diarrhoea, but more recently, it has been found to have additional pharmacological effects, such as anti-tumour effects and inhibition of inflammatory diseases related to diabetic nephropathy. However, there are no reports regarding its role in pulmonary fibrosis. Methods: The therapeutic effect of NIF on pulmonary fibrosis in vivo was measured by ELISA, hydroxyproline content, H&E and Masson staining, immunohistochemistry (INC) and western blot. Immune cell content in lung tissue was also analysed by flow cytometry. NIF cytotoxicity was evaluated in NIH/3T3 cells, human pulmonary fibroblasts (HPFs), A549 cells and rat primary lung fibroblasts (RPLFs) using the MTT assay. Finally, an in vitro cell model created by transforming growth factor-beta 1 (TGF-beta 1) stimulation was assessed using different experiments (immunofluorescence, western blot and wound migration assay) to evaluate the effects of NIF on the activation of NIH/3T3 and HPF cells and the epithelial-mesenchymal transition (EMT) and migration of A549 cells. Results: In vivo, intraperitoneal injection of NIF relieved and reversed pulmonary fibrosis caused by bleomycin (BLM) bronchial instillation. In addition, NIF inhibited the expression of a variety of cellular inflammatory factors and immune cells. Furthermore, NIF suppressed the activation of fibroblasts and EMT of epithelial cells induced by TGF-beta 1. Most importantly, we used an analytical docking experiment and thermal shift assay to further verify that NIF functions in conjunction with signal transducer and activator of transcription 3 (Stat3). Moreover, NIF inhibited the TGF-beta/Smad pathway in vitro and decreased the expression of phosphorylated Stat3 in vitro and in vivo. Conclusion: Taken together, we conclude that NIF inhibits and reverses pulmonary fibrosis, and these results support NIF as a viable therapeutic option for IPF treatment.

引用

页数：15

共 57 条

[11]

[何爱明 He Aiming], 2015, [中国老年学杂志, Chinese Journal of Gerontology], V35, P1887

[12] The myofibroblast - One function, multiple origins [J].