Recombinant Slit2 attenuates tracheal fibroblast activation in benign central airway obstruction by inhibiting the TGF-β1/Smad3 signaling pathway

作者全名："He, Chunyan; Gu, Lei; Li, Anmao; Li, Yishi; Xiao, Rui; Liao, Jiaxin; Mu, Junhao; Gan, Yiling; Peng, Mingyu; Mohan, Giri; Liu, Wei; Xu, Li; Guo, Shuliang"

作者地址："[He, Chunyan; Li, Anmao; Li, Yishi; Xiao, Rui; Liao, Jiaxin; Mu, Junhao; Gan, Yiling; Peng, Mingyu; Mohan, Giri; Xu, Li; Guo, Shuliang] Chongqing Med Univ, Dept Pulm & Crit Care Med, Affiliated Hosp 1, Chongqing 400016, Peoples R China; [Gu, Lei] Soochow Univ, Dept Pulm & Crit Care Med, Affiliated Hosp 1, Suzhou 215006, Peoples R China; [Liu, Wei] Fujian Med Univ, Peoples Liberat Army, 900th Hosp Joint Logist Support Force, Dept Resp & Crit Care Med, Fuzhou 350025, Fujian, Peoples R China"

通信作者："Xu, L; Guo, SL (通讯作者)，Chongqing Med Univ, Dept Pulm & Crit Care Med, Affiliated Hosp 1, Chongqing 400016, Peoples R China."

来源：MOLECULAR AND CELLULAR PROBES

ESI学科分类：MOLECULAR BIOLOGY & GENETICS

WOS号：WOS:001147405200001

JCR分区：Q3

影响因子：2.3

年份：2024

卷号：73

期号：　

开始页：　

结束页：　

文献类型：Article; Early Access

关键词：Airway fibrosis; Benign central airway obstruction; Slit2-Robo1; Fibroblast activation; TGF-beta 1/Smad3 pathway

摘要："Airway fibrosis is among the pathological manifestations of benign central airway obstruction noted in the absence of effective treatments and requires new drug targets to be developed. Slit guidance ligand 2-roundabout guidance receptor 1 (Slit2-Robo1) is involved in fibrosis and organ development. However, its significance in airway fibrosis has not yet been reported. The study explored how the recombinant protein Slit2 functions in transforming growth factor-beta 1 (TGF-beta 1)-mediated airway fibrosis in vivo and in vitro. In this study, Slit2 expression initially increased in the tracheal granulation tissues of patients with tracheobronchial stenosis but decreased in the fibrotic tissue. In primary rat tracheal fibroblasts (RTFs), recombinant Slit2 inhibited the expression of extracellular matrices such as Timp1, alpha-SMA, and COL1A2, whereas recombinant TGF-beta 1 promoted the expression of Robo1, alpha-SMA, and COL1A2. Slit2 and TGF-beta 1 played a mutual inhibitory role in RTFs. Slit2 supplementation and Robo1 downregulation inhibited excessive extracellular matrix (ECM) deposition induced by TGF-beta 1 in RTFs via the TGF-beta 1/Smad3 pathway. Ultimately, exogenous Slit2 and Robo1 knockdown-mediated attenuation of airway fibrosis were validated in a trauma-induced rat airway obstruction model. These findings demonstrate that recombinant Slit2 alleviated pathologic tracheobronchial healing by attenuating excessive ECM deposition. Slit2-Robo1 is an attractive target for further exploring the mechanisms and treatment of benign central airway obstruction."

基金机构：National Major Science and Technology Projects of China [2018ZX10302302003]; Natural Science Foundation of Fujian Province [2020J011129]

基金资助正文："This research was funded by the National Major Science and Technology Projects of China (grant number 2018ZX10302302003) , Chongqing talents projects-Famous masters and teachers (Shuliang Guo) and Chongqing young and middle-aged medical high-end talent studio Lung Nodule Studio, and Natural Science Foundation of Fujian Province (General Program: 2020J011129) ."