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Midkine-Notch2 Pathway Mediates Excessive Proliferation of Airway Smooth Muscle Cells in Chronic Obstructive Lung Disease

Inflammation-induced proliferation of airway smooth muscle cells (ASMCs) and subsequent airway remodeling is a hallmark of chronic obstructive lung disease (COPD). The role of midkine (MK) in COPD is unclear. In this work, we explored the role of MK-Notch2 signaling in COPD by inhibiting the express...

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Autores principales: Deng, Tang, Huang, Qifeng, Lin, Kaiwen, Qian, Jin, Li, Qi, Li, Lihua, Xu, Shuangqin, Yun, Hongfang, Wang, Hangfei, Wu, Xinxin, Liu, Heng, Jin, Guiyun, Liu, Xiaoran
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9239375/
https://www.ncbi.nlm.nih.gov/pubmed/35774607
http://dx.doi.org/10.3389/fphar.2022.794952
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author Deng, Tang
Huang, Qifeng
Lin, Kaiwen
Qian, Jin
Li, Qi
Li, Lihua
Xu, Shuangqin
Yun, Hongfang
Wang, Hangfei
Wu, Xinxin
Liu, Heng
Jin, Guiyun
Liu, Xiaoran
author_facet Deng, Tang
Huang, Qifeng
Lin, Kaiwen
Qian, Jin
Li, Qi
Li, Lihua
Xu, Shuangqin
Yun, Hongfang
Wang, Hangfei
Wu, Xinxin
Liu, Heng
Jin, Guiyun
Liu, Xiaoran
author_sort Deng, Tang
collection PubMed
description Inflammation-induced proliferation of airway smooth muscle cells (ASMCs) and subsequent airway remodeling is a hallmark of chronic obstructive lung disease (COPD). The role of midkine (MK) in COPD is unclear. In this work, we explored the role of MK-Notch2 signaling in COPD by inhibiting the expression of MK using lentivirus shRNA in ASMCs in vitro and instillation of AAV9-MK in the airway of a COPD rat model in vivo. The results demonstrated that LPS decreased ASMC migration and proliferation, increased apoptosis and induced the expression of MK and Notch2 signaling molecules. Inhibition of MK exacerbated the changes in migration and proliferation but decreased the expression of MK and Notch2 signaling molecules. Rats treated with smoke fumigation and LPS showed features of COPD. The small airways of COPD rats were remodeled and lung function was significantly reduced. The expressions of TGF-β, ICAM-1, HA, MMP-9, PC-III, and LN in BALF and the expression of MK and Notch2 signaling molecules were significantly increased in the COPD rats compared with controls. Inhibition of MK reversed these changes. In conclusion, the MK-Notch2 pathway plays a key role in airway remodeling induced by ASMC proliferation. Targeting the MK-Notch2 pathway may be a new strategy for improving airway remodeling and preventing progressive decline of pulmonary function in COPD.
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spelling pubmed-92393752022-06-29 Midkine-Notch2 Pathway Mediates Excessive Proliferation of Airway Smooth Muscle Cells in Chronic Obstructive Lung Disease Deng, Tang Huang, Qifeng Lin, Kaiwen Qian, Jin Li, Qi Li, Lihua Xu, Shuangqin Yun, Hongfang Wang, Hangfei Wu, Xinxin Liu, Heng Jin, Guiyun Liu, Xiaoran Front Pharmacol Pharmacology Inflammation-induced proliferation of airway smooth muscle cells (ASMCs) and subsequent airway remodeling is a hallmark of chronic obstructive lung disease (COPD). The role of midkine (MK) in COPD is unclear. In this work, we explored the role of MK-Notch2 signaling in COPD by inhibiting the expression of MK using lentivirus shRNA in ASMCs in vitro and instillation of AAV9-MK in the airway of a COPD rat model in vivo. The results demonstrated that LPS decreased ASMC migration and proliferation, increased apoptosis and induced the expression of MK and Notch2 signaling molecules. Inhibition of MK exacerbated the changes in migration and proliferation but decreased the expression of MK and Notch2 signaling molecules. Rats treated with smoke fumigation and LPS showed features of COPD. The small airways of COPD rats were remodeled and lung function was significantly reduced. The expressions of TGF-β, ICAM-1, HA, MMP-9, PC-III, and LN in BALF and the expression of MK and Notch2 signaling molecules were significantly increased in the COPD rats compared with controls. Inhibition of MK reversed these changes. In conclusion, the MK-Notch2 pathway plays a key role in airway remodeling induced by ASMC proliferation. Targeting the MK-Notch2 pathway may be a new strategy for improving airway remodeling and preventing progressive decline of pulmonary function in COPD. Frontiers Media S.A. 2022-06-14 /pmc/articles/PMC9239375/ /pubmed/35774607 http://dx.doi.org/10.3389/fphar.2022.794952 Text en Copyright © 2022 Deng, Huang, Lin, Qian, Li, Li, Xu, Yun, Wang, Wu, Liu, Jin and Liu. https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Pharmacology
Deng, Tang
Huang, Qifeng
Lin, Kaiwen
Qian, Jin
Li, Qi
Li, Lihua
Xu, Shuangqin
Yun, Hongfang
Wang, Hangfei
Wu, Xinxin
Liu, Heng
Jin, Guiyun
Liu, Xiaoran
Midkine-Notch2 Pathway Mediates Excessive Proliferation of Airway Smooth Muscle Cells in Chronic Obstructive Lung Disease
title Midkine-Notch2 Pathway Mediates Excessive Proliferation of Airway Smooth Muscle Cells in Chronic Obstructive Lung Disease
title_full Midkine-Notch2 Pathway Mediates Excessive Proliferation of Airway Smooth Muscle Cells in Chronic Obstructive Lung Disease
title_fullStr Midkine-Notch2 Pathway Mediates Excessive Proliferation of Airway Smooth Muscle Cells in Chronic Obstructive Lung Disease
title_full_unstemmed Midkine-Notch2 Pathway Mediates Excessive Proliferation of Airway Smooth Muscle Cells in Chronic Obstructive Lung Disease
title_short Midkine-Notch2 Pathway Mediates Excessive Proliferation of Airway Smooth Muscle Cells in Chronic Obstructive Lung Disease
title_sort midkine-notch2 pathway mediates excessive proliferation of airway smooth muscle cells in chronic obstructive lung disease
topic Pharmacology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9239375/
https://www.ncbi.nlm.nih.gov/pubmed/35774607
http://dx.doi.org/10.3389/fphar.2022.794952
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