Combination of glycopyrronium and indacaterol inhibits carbachol-induced ERK5 signal in fibrotic processes

Respiratory Research

Research

Akira Orimo¹  Miniwan Tulafu²  Kotaro Kadoya²  Kumi Yoneda Nagahama²  Kazuhisa Takahashi²  Shinsaku Togo²  Yukiko Namba²  Naoko Kaga³  Hikari Taka³  Xiangde Liu⁴ 

[1] Departments of Pathology and Oncology, Juntendo University School of Medicine, 2-1-1 Hongo, Bunkyo-ku, 113-8421, Tokyo, Japan;Division of Respiratory Medicine, Juntendo University Faculty of Medicine & Graduate School of Medicine, 2-1-1 Hongo, Bunkyo-ku, 113-8421, Tokyo, Japan;Research Institute for Diseases of Old Ages, Juntendo University Graduate School of Medicine, 2-1-1 Hongo, Bunkyo-ku, 113-8421, Tokyo, Japan;Laboratory of Proteomics and Biomolecular Science, Research Support Center, Juntendo University Graduate School of Medicine, 2-1-1 Hongo, Bunkyo-ku, 113-8421, Tokyo, Japan;Pulmonary Critical Care and Sleep Medicine, University of Nebraska Medical Center, Omaha, NE, USA;

关键词: Acetylcholine;    Extracellular-signal-regulated kinase 5 (ERK5);    Long-acting β2-adrenergic receptor agonist;    Long-acting muscarinic receptor antagonist;    Transforming growth factor-β1;   

DOI  :  10.1186/s12931-017-0529-6

 received in 2016-12-15, accepted in 2017-03-06,  发布年份 2017

来源: Springer

【 摘 要 】

BackgroundAirway fibrosis is one of the pathological features of chronic obstructive pulmonary disease (COPD), and recent studies revealed that acetylcholine plays an important role in the development of airway remodeling by stimulating proliferation and collagen synthesis of lung fibroblasts. This study was designed to examine the effects of a long-acting muscarinic receptor antagonist (LAMA) glycopyrronium and a long-acting β2 adrenergic receptor agonist (LABA) indacaterol on acetylcholine-mediated fibrotic responses in lung fibroblasts.MethodsAfter carbachol (CCh) or transforming growth factor-β1 (TGF-β1) exposure, the response to glycopyrronium and indacaterol was determined in vitro in fibroblasts isolated from mild-to-moderate COPD lung tissue. The ability of fibroblasts to mediate the contraction of collagen gels was assessed. The expression of α-smooth muscle actin (α-SMA) and the phosphorylation of extracellular-signal-regulated kinase 5 (ERK5) were determined by immunoblot. TGF-β1 was quantified by ELISA and acetylcholine was quantified by liquid chromatography tandem-mass spectrometry.ResultsCCh stimulated fibroblast-mediated collagen gel contraction and α-SMA expression and TGF-β1 release by fibroblasts. Blockade of autocrine TGF-β1 attenuated CCh-mediated fibrotic responses, while TGF-β1 did not stimulate acetylcholine release. Glycopyrronium plus indacaterol significantly attenuated CCh- and TGF-β1-mediated fibrotic responses through inhibition of ERK5 phosphorylation. Notably, the magnitudes of CCh- and TGF-β1-stimulated gel contraction, CCh-induced TGF-β1 release, and ERK5 phosphorylation were greater in fibroblasts isolated from COPD subjects than in those from non-smokers.ConclusionsCCh induced TGF-β1 self-sustaining signaling loops by potentiating ERK5 signaling and promoted myofibroblast activity. This autocrine signaling mechanism may be an attractive therapeutic target to block the fibrotic response, which was modulated by the combination of glycopyrronium and indacaterol.

【 授权许可】

CC BY   
© The Author(s). 2017