IL-11 drives the phenotypic transformation of tracheal epithelial cells and fibroblasts to enhance abnormal repair after tracheal injury

作者全名："Xiao, Rui; Gu, Lei; Li, An-mao; Gan, Yi-ling; He, Chun-yan; Liao, Jia-xin; Li, Yi-shi; Xu, Li; Guo, Shu-liang"

作者地址："[Xiao, Rui; Gu, Lei; Li, An-mao; Gan, Yi-ling; He, Chun-yan; Liao, Jia-xin; Li, Yi-shi; Xu, Li; Guo, Shu-liang] Chongqing Med Univ, Affiliated Hosp 1, Dept Resp & Crit Care Med, Chongqing, Peoples R China"

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

来源：BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR CELL RESEARCH

ESI学科分类：MOLECULAR BIOLOGY & GENETICS

WOS号：WOS:000995434100001

JCR分区：Q1

影响因子：4.6

年份：2023

卷号：1870

期号：4

开始页：　

结束页：　

文献类型：Article

关键词：Fibrosis; IL-11; Tracheal stenosis; Phenotypic transformation; Therapy

摘要："Tracheal stenosis (TS) is a multifactorial and heterogeneous disease that can easily lead to respiratory failure and even death. Interleukin-11 (IL-11) has recently received increased attention as a fibrogenic factor, but its function in TS is uncertain. This study aimed to investigate the role of IL-11 in TS regulation based on clinical samples from patients with TS and a rat model of TS produced by nylon brush scraping. Using lentiviral vectors expressing shRNA (lentivirus-shRNA) targeting the IL-11 receptor (IL-11R alpha), we lowered IL-11R alpha levels in the rat trachea. Histological and immunostaining methods were used to evaluate the effects of IL-11R alpha knockdown on tracheal injury, molecular phenotype, and fibrosis in TS rats. We show that IL-11 was significantly elevated in circulating serum and granulation tissue in patients with TS. In vitro, TGF81 dose-dependently stimulated IL-11 secretion from human tracheal epithelial cells (Beas-2b) and primary rat tracheal fibroblasts (PRTF). IL-11 transformed the epithelial cell phenotype to the mesenchymal cell phenotype by activating the 8-catenin pathway. Furthermore, IL-11 activated the atypical ERK signaling pathway, stimulated fibroblasts proliferation, and transformed fibroblasts into alpha-smooth muscle actin (alpha-SMA) positive myofibroblasts. IL-11-neutralizing antibodies (IL-11NAb) or ERK inhibitors (U0126) inhibited IL-11 activity and downregulated fibrotic responses involving TGF8/SMAD signaling. In vivo, IL-11R alpha knockdown rats showed unobstructed tracheal lumen, relatively intact epithelial structure, and significantly reduced granulation tissue proliferation and collagen fiber deposition. Our findings confirm that IL-11 may be a target for future drug prevention and treatment of tracheal stenosis."

基金机构：National Major Science and Technology Projects of China [2018ZX10302302003]; Chongqing talents projects-Famous masters and teachers; Chongqing young and middle-aged medical high-end talent studio-Lung Nodule Studio

基金资助正文：This study was supported by the National Major Science and Technology Projects of China (grant number 2018ZX10302302003) and Chongqing talents projects-Famous masters and teachers (Shuliang Guo) and Chongqing young and middle-aged medical high-end talent studio-Lung Nodule Studio.