Methacholine induces extracellular matrix production by human airway smooth muscle cells through β-catenin signaling

Yating Huo; Jiawen Xu; Lili Guan; Weiliang Wu; Bingpeng Guo; Yuqiong Yang; Lin Lin; Yonger Ou; Fangfang Jiang; Luqian Zhou; Rongchang Chen

doi:10.1016/j.resp.2018.04.010

Methacholine induces extracellular matrix production by human airway smooth muscle cells through β-catenin signaling

Respir Physiol Neurobiol. 2018 Aug:254:55-63. doi: 10.1016/j.resp.2018.04.010. Epub 2018 Apr 30.

Authors

Yating Huo¹, Jiawen Xu², Lili Guan³, Weiliang Wu⁴, Bingpeng Guo⁵, Yuqiong Yang⁶, Lin Lin⁷, Yonger Ou⁸, Fangfang Jiang⁹, Luqian Zhou¹⁰, Rongchang Chen¹¹

Affiliations

¹ State Key Laboratory of Respiratory Disease, Guangzhou Institute of Respiratory Health, The First Affiliated Hospital of Guangzhou Medical University, 151 Yan Jiang Rd., Guangzhou 510120, China. Electronic address: [email protected].
² State Key Laboratory of Respiratory Disease, Guangzhou Institute of Respiratory Health, The First Affiliated Hospital of Guangzhou Medical University, 151 Yan Jiang Rd., Guangzhou 510120, China. Electronic address: [email protected].
³ State Key Laboratory of Respiratory Disease, Guangzhou Institute of Respiratory Health, The First Affiliated Hospital of Guangzhou Medical University, 151 Yan Jiang Rd., Guangzhou 510120, China. Electronic address: [email protected].
⁴ State Key Laboratory of Respiratory Disease, Guangzhou Institute of Respiratory Health, The First Affiliated Hospital of Guangzhou Medical University, 151 Yan Jiang Rd., Guangzhou 510120, China. Electronic address: [email protected].
⁵ State Key Laboratory of Respiratory Disease, Guangzhou Institute of Respiratory Health, The First Affiliated Hospital of Guangzhou Medical University, 151 Yan Jiang Rd., Guangzhou 510120, China. Electronic address: [email protected].
⁶ State Key Laboratory of Respiratory Disease, Guangzhou Institute of Respiratory Health, The First Affiliated Hospital of Guangzhou Medical University, 151 Yan Jiang Rd., Guangzhou 510120, China. Electronic address: [email protected].
⁷ State Key Laboratory of Respiratory Disease, Guangzhou Institute of Respiratory Health, The First Affiliated Hospital of Guangzhou Medical University, 151 Yan Jiang Rd., Guangzhou 510120, China. Electronic address: [email protected].
⁸ State Key Laboratory of Respiratory Disease, Guangzhou Institute of Respiratory Health, The First Affiliated Hospital of Guangzhou Medical University, 151 Yan Jiang Rd., Guangzhou 510120, China. Electronic address: [email protected].
⁹ State Key Laboratory of Respiratory Disease, Guangzhou Institute of Respiratory Health, The First Affiliated Hospital of Guangzhou Medical University, 151 Yan Jiang Rd., Guangzhou 510120, China. Electronic address: [email protected].
¹⁰ State Key Laboratory of Respiratory Disease, Guangzhou Institute of Respiratory Health, The First Affiliated Hospital of Guangzhou Medical University, 151 Yan Jiang Rd., Guangzhou 510120, China. Electronic address: [email protected].
¹¹ State Key Laboratory of Respiratory Disease, Guangzhou Institute of Respiratory Health, The First Affiliated Hospital of Guangzhou Medical University, 151 Yan Jiang Rd., Guangzhou 510120, China. Electronic address: [email protected].

PMID: 29715518
DOI: 10.1016/j.resp.2018.04.010

Abstract

Altered extracellular matrix (ECM) production by airway smooth muscle cells (ASMCs) is an important feature of airway remodeling. Muscarinic receptor agonists contribute to ECM production in vivo, but the mechanisms involved remain unclear. This study attempted to investigate the role of methacholine in promoting ECM production by human ASMCs (HASMCs) and the underlying mechanism. We found that methacholine induced the expression of collagen I protein and multiple ECM genes. β-catenin signaling was activated in this process upon GSK3β phosphorylation, leading to upregulation of total and active β-catenin. Silencing β-catenin by specific small interfering RNA (siRNA) or with the β-catenin inhibitor, PKF115-584, decreased collagen I expression. Conversely, overexpression of active β-catenin by adenoviruses carrying the S33Y-β-catenin mutant increased the methacholine-induced collagen I expression. Furthermore, methacholine induced TGF-β expression in HASMCs, while pan-TGF-β-neutralizing antibody only partially decreased collagen I expression. These findings suggest that methacholine induced ECM production through β-catenin signaling and partially through TGF-β.

Keywords: Collagen I; GSK3β; Human airway smooth muscle cells; Methacholine; TGF-β; β-catenin.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Bronchoconstrictor Agents / pharmacology*
Cell Line
Collagen / metabolism
Extracellular Matrix / metabolism*
Glycogen Synthase Kinase 3 beta / metabolism
Humans
Methacholine Chloride / pharmacology*
Myocytes, Smooth Muscle / cytology
Myocytes, Smooth Muscle / drug effects*
Myocytes, Smooth Muscle / metabolism*
RNA, Messenger / metabolism
Signal Transduction / drug effects
Time Factors
Transforming Growth Factor beta / antagonists & inhibitors
Transforming Growth Factor beta / metabolism
beta Catenin / antagonists & inhibitors
beta Catenin / metabolism

Substances

Bronchoconstrictor Agents
CTNNB1 protein, human
RNA, Messenger
Transforming Growth Factor beta
beta Catenin
Methacholine Chloride
Collagen
GSK3B protein, human
Glycogen Synthase Kinase 3 beta