单位：[1]Department of Infectious Diseases, Peking University First Hospital, No.8 Xishiku Street, Xicheng District, Beijing 100034, China[2]Peking University Ditan Teaching Hospital, Beijing 100015, China Beijing Key Laboratory of Emerging Infectious Diseases, Beijing 100015, China[3]Department of Infectious Disease, China-Japan Friendship Hospital, Beijing 100029, China.[4]Department of Infectious Disease, First Hospital of Shanxi Medical University, Taiyuan 030001, China[5]Laboratory Animal Center, Peking University First Hospital, Beijing 100034, China[6]Department of Infectious Diseases, Beijing Ditan Hospital, Capital Medical University, No.8 East Jingshun Street, Chaoyang District, Beijing 100015, China.
BackgroundPulmonary fibrosis is a progressive and irreversible disease for which therapeutic options are currently limited. A recent in vivo study showed that tenofovir, a nucleotide analogue reverse transcriptase inhibitor, had direct antifibrotic effects on skin and liver fibrosis. Another study in vitro revealed that NS5ATP9 inhibited the activation of human hepatic stellate cells. Because of the similarity of fibrotic diseases, we hypothesized that tenofovir alafenamide fumarate (TAF), the prodrug of tenofovir, and NS5ATP9, is related to and plays a role in the suppression of pulmonary fibrosis.MethodsWe investigated the influence of NS5ATP9 on fibrosis in vitro. Human lung fibroblasts (HFL1) were transfected with short interfering RNAs or overexpression plasmids of NS5ATP9 before stimulation by human recombinant transforming growth factor-beta 1. The effect of TAF was evaluated in a bleomycin-induced fibrosis murine model. Male C57BL/6 mice were treated with bleomycin on day 0 by intratracheal injection and intragastrically administered TAF or vehicle. Left lung sections were fixed for histological analysis, while homogenates of the right lung sections and HFL1 cells were analyzed by western blotting and quantitative reverse transcription polymerase chain reaction.ResultsNS5ATP9 suppressed the activation of lung fibroblasts. Upregulation of collagen type 3 (alpha 1 chain) and alpha-smooth muscle actin was observed in HFL1 cells when NS5ATP9 was silenced, and vice-versa. TAF also showed anti-fibrotic effects in mice, as demonstrated by histological analysis of fibrosis and expression of extracellular matrix components in the lung sections. Additionally, TAF inhibited transforming growth factor-beta 1 and phosphorylated-Smad3 synthesis in HFL1 cells and the murine model, which was accompanied by upregulation of NS5ATP9.ConclusionsOur results suggest that NS5ATP9 forms a negative feedback pathway in pulmonary fibrosis and TAF has anti-fibrotic properties as it upregulates the expression level of NS5ATP9. As TAF has been shown to be safe and well-tolerated in humans, TAF and NS5ATP9 may be useful for developing novel therapeutics for pulmonary fibrosis.
基金：
Beijing Municipal Administration of Hospitals' Ascent Plan [DFL20151701]; National Natural Science Foundation of ChinaNational Natural Science Foundation of China (NSFC) [81470863]; Beijng Advanced Innovation Center for Biomedical Engineering Beihang University [100191]
第一作者单位：[1]Department of Infectious Diseases, Peking University First Hospital, No.8 Xishiku Street, Xicheng District, Beijing 100034, China[2]Peking University Ditan Teaching Hospital, Beijing 100015, China Beijing Key Laboratory of Emerging Infectious Diseases, Beijing 100015, China
通讯作者：
通讯机构：[2]Peking University Ditan Teaching Hospital, Beijing 100015, China Beijing Key Laboratory of Emerging Infectious Diseases, Beijing 100015, China[6]Department of Infectious Diseases, Beijing Ditan Hospital, Capital Medical University, No.8 East Jingshun Street, Chaoyang District, Beijing 100015, China.
推荐引用方式(GB/T 7714)：
Li Lingxia,Zhao Jing,Zhou Li,et al.Tenofovir alafenamide fumarate attenuates bleomycin-induced pulmonary fibrosis by upregulating the NS5ATP9 and TGF-beta 1/Smad3 signaling pathway[J].RESPIRATORY RESEARCH.2019,20:doi:10.1186/s12931-019-1102-2.
APA：
Li, Lingxia,Zhao, Jing,Zhou, Li,Chen, Jie,Ma, Yuanyuan...&Cheng, Jun.(2019).Tenofovir alafenamide fumarate attenuates bleomycin-induced pulmonary fibrosis by upregulating the NS5ATP9 and TGF-beta 1/Smad3 signaling pathway.RESPIRATORY RESEARCH,20,
MLA：
Li, Lingxia,et al."Tenofovir alafenamide fumarate attenuates bleomycin-induced pulmonary fibrosis by upregulating the NS5ATP9 and TGF-beta 1/Smad3 signaling pathway".RESPIRATORY RESEARCH 20.(2019)
