The activation of M3 mAChR in airway epithelial cells promotes IL-8 and TGF-β1 secretion and airway smooth muscle cell migration

被引：11

作者：

Lu, Juan-Juan ^{[1
]}

Xu, Guang-Ni ^{[2
]}

Yu, Ping ^{[1
]}

Song, Yun ^{[1
]}

Wang, Xiao-Lin ^{[1
]}

Zhu, Liang ^{[1
]}

Chen, Hong-Zhuan ^{[1
]}

Cui, Yong-Yao ^{[1
]}

机构：

[1] Shanghai Jiao Tong Univ, Sch Med, Dept Pharmacol, 280 South Chongqing Rd, Shanghai 200025, Peoples R China

[2] Shanghai Jiao Tong Univ, Sch Med, Dept Anat Histol & Embryol, Shanghai 200025, Peoples R China

来源：

RESPIRATORY RESEARCH | 2016年 / 17卷

基金：

中国国家自然科学基金;

关键词：

ASM cell migration; Chemokines; Human epithelial cells; Non-neuronal cholinergic system; Signaling pathways; NONNEURONAL CHOLINERGIC SYSTEM; OBSTRUCTIVE PULMONARY-DISEASE; GROWTH-FACTOR-BETA; CIGARETTE-SMOKE; RECEPTOR SUBTYPES; ASTHMA; EXPRESSION; RELEASE; COPD; A549;

D O I：

10.1186/s12931-016-0344-5

中图分类号：

R56 [呼吸系及胸部疾病];

学科分类号：

摘要：

Background: Muscarinic acetylcholine receptors (mAChRs) have been identified in airway epithelium, and epithelium-derived chemokines can initiate the migration of airway smooth muscle (ASM) cells. However, the mAChRs that are expressed in airway epithelium and the mechanism underlying the regulation of ASM cell migration are not clear. The aim of this study was to test whether the effects of the epithelium-derived chemokines on ASM cell migration could be modulated by mAChRs. Method: Human epithelial cells (A549 cells) were stimulated with cigarette smoke extract (CSE) or the mAChRs agonist carbachol. IL-8 and TGF-beta 1 production were measured by ELISA, and human ASM cell migration was measured using the transwell migration assay and scratch assay. The mRNA levels of the mAChRs subtypes and the acetylcholine concentrations were measured using RT-PCR and LC-MS/MS, respectively. Results: ASM cell migration toward CSE-stimulated A549 cells was markedly reduced by Ac-RRWWCR-NH2 (IL-8 inhibitor) and SB431542 (TGF-beta 1 inhibitor). CSE-induced ASM cell migration was also suppressed by the mAChRs antagonist tiotropium. Interestingly, carbachol-stimulated A549 cells also induced ASM cell migration; this migration event was suppressed by tiotropium, Ac-RRWWCR-NH2 and SB431542. In addition, the effects of CSE on ASM cell migration were significantly and cooperatively enhanced by carbachol compared to CSE alone. Carbachol-induced ASM cell migration was reduced by selective inhibitors of PI3K/Akt (LY294002) and p38 (SB203580), suggesting that it occurred through p38 and Akt phosphorylation, which was inhibited by the M3 mAChR antagonist 4-DAMP. Conclusions: These findings indicate that M3 mAChR may be important therapeutic target for obstructive airway diseases, as it regulates the effects of the epithelial-derived chemokines on ASM cell migration, which results in lung remodeling.

引用

页数：11

共 42 条

[31] Acetylcholine mediates the release of IL-8 in human bronchial epithelial cells by a NFκB/ERK-dependent mechanism [J].

Profita, Mirella ;

Bonanno, Anna ;

Siena, Liboria ;

Ferraro, Maria ;

Montalbano, Angela M. ;

Pompeo, Flora ;

Riccobono, Loredana ;

Pieper, Michael P. ;

Gjornarkaj, Mark .

EUROPEAN JOURNAL OF PHARMACOLOGY, 2008, 582 (1-3) :145-153

[32] Cigarette smoke extract activates human bronchial epithelial cells affecting non-neuronal cholinergic system signalling in vitro [J].

Profita, Mirella ;

Bonanno, Anna ;

Montalbano, Angela Marina ;

Ferraro, Maria ;

Siena, Liboria ;

Bruno, Andreina ;

Girbino, Stefania ;

Albano, Giusy Daniela ;

Casarosa, Paola ;

Pieper, Michael Paul ;

Gjomarkaj, Mark .

LIFE SCIENCES, 2011, 89 (1-2) :36-43

[33] The airway cholinergic system:: physiology and pharmacology [J].

Racké, K ;

Mattheisen, S .

PULMONARY PHARMACOLOGY & THERAPEUTICS, 2004, 17 (04) :181-198

[34] Factors controlling airway smooth muscle proliferation in asthma [J].

Stewart, AG ;

Bonacci, JV ;

Quan, L .

CURRENT ALLERGY AND ASTHMA REPORTS, 2004, 4 (02) :109-115

[35] Epithelium-derived chemokines induce airway smooth muscle cell migration [J].

Takeda, N. ;

Sumi, Y. ;

Prefontaine, D. ;

Al Abri, J. ;

Al Heialy, N. ;

Al-Ramli, W. ;

Michoud, M-C ;

Martin, J. G. ;

Hamid, Q. .

CLINICAL AND EXPERIMENTAL ALLERGY, 2009, 39 (07) :1018-1026

[36] Increased expression of transforming growth factor-β1 in small airway epithelium from tobacco smokers and patients with chronic obstructive pulmonary disease (COPD) [J].

Takizawa, H ;

Tanaka, M ;

Takami, K ;

Ohtoshi, T ;

Ito, K ;

Satoh, M ;

Okada, Y ;

Yamasawa, F ;

Nakahara, K ;

Umeda, A .

AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE, 2001, 163 (06) :1476-1483

[37] Transforming growth factor-beta expression in mucosal biopsies in asthma and chronic bronchitis [J].

Vignola, AM ;

Chanez, P ;

Chiappara, G ;

Merendino, A ;

Pace, E ;

Rizzo, A ;

laRocca, AM ;

Bellia, V ;

Bonsignore, G ;

Bousquet, J .

AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE, 1997, 156 (02) :591-599

[38] The non-neuronal cholinergic system in humans: Expression, function and pathophysiology [J].

Wessler, I ;

Kilbinger, H ;

Bittinger, F ;

Unger, R ;

Kirkpatrick, CJ .

LIFE SCIENCES, 2003, 72 (18-19) :2055-2061

[39] Protective effects of anisodamine on cigarette smoke extract-induced airway smooth muscle cell proliferation and tracheal contractility [J].

Xu, Guang-Ni ;

Yang, Kai ;

Xu, Zu-Peng ;

Zhu, Liang ;

Hou, Li-Na ;

Qi, Hong ;

Chen, Hong-Zhuan ;

Cui, Yong-Yao .

TOXICOLOGY AND APPLIED PHARMACOLOGY, 2012, 262 (01) :70-79

[40] TNF-α-induced CXCL8 production by A549 cells: Involvement of the non-neuronal cholinergic system [J].

Xu, Z. -P. ;

Devillier, P. ;

Xu, G. -N. ;

Qi, H. ;

Zhu, L. ;

Zhou, W. ;

Hou, L. -N. ;

Tang, Y. -B. ;

Yang, K. ;

Yu, Z. -H. ;

Chen, H. -Z. ;

Cui, Y. -Y. .

PHARMACOLOGICAL RESEARCH, 2013, 68 (01) :16-23

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