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Activated non-neuronal cholinergic system correlates with non-type 2 inflammation and exacerbations in severe asthma

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单位： [1]Department of Respiratory and Critical Care Medicine, Clinical Research Center for Respiratory Disease, West China Hospital, Sichuan University, Chengdu 610041, China [2]The State Key Laboratory of Respiratory Health and Multimorbidity, West China Hospital, Sichuan University, Chengdu 610041, China [3]Division of Internal Medicine, Institute of Integrated Traditional Chinese and Western Medicine, West China Hospital, Sichuan University, Chengdu 610041, China [4]Laboratory of Pulmonary Immunology and inflammation, Frontiers Science Center for Disease-related Molecular Network, Sichuan University, Chengdu 610041, China [5]Department of Respiratory and Critical Care Medicine, The Second Affiliated Hospital of Jilin University, Changchun 130041, Jilin, China [6]Priority Research Center for Healthy Lungs, Hunter Medical Research Institute, The University of Newcastle, Callaghan, Australia [7]School of Life Sciences, Faculty of Science, University of Technology Sydney, Ultimo, NSW, Australia [8]Centre for Inflammation, Centenary Institute, Camperdown, NSW Australia [9]Programme in Emerging Infectious Diseases, Duke-National University of Singapore Medical School, Singapore [10]Department of Pathogen Biology, Basic Medical College, Jilin University, Changchun, 130021, Jilin, China [11]Respiratory Division of Zhongshan Hospital, Shanghai Institute of Respiratory Disease, Fudan University, Shanghai, P.R.China [12]School of Life Sciences, University of Technology Sydney, Ultimo, NSW, Australia [13]Woolcock Institute of Medical Research, The University of Sydney, NSW, Australia [14]Department of Respiratory and Critical Care Medicine, Tongji Hospital, Huazhong University of Science and Technology, Wuhan, P.R.China [15]Department of Respiratory and Critical Care Medicine, Xiangya Hospital, Central South University, Changsha, China [16]Respiratory Microbiome Laboratory, Frontiers Science Center for Disease-related Molecular Network, Sichuan University, Chengdu 610041, China [17]National Health and Medical Research Council Center for Research Excellence in Severe Asthma and Treatable Traits, The University of Newcastle, Newcastle, NSW, Australia [18]Department of Respiratory and Sleep Medicine, John Hunter Hospital, Hunter Medical Research Institute, Newcastle, NSW, Australia

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关键词： Asthma exacerbations non-neuronal cholinergic system non-T2 inflammation severe asthma

摘要：

Non-neuronal cholinergic system (NNCS) contributes to various inflammatory airway diseases. However, the role of NNCS in severe asthma (SA) remains largely unexplored.To explore airway NNCS in SA.In this prospective cohort study based on the Australasian Severe Asthma Network in a real-world setting, patients with SA (n=52) and non-SA (n=104) underwent clinical assessment and sputum induction. The mRNA levels of NNCS components and proinflammatory cytokines in sputum were detected using RT-qPCR, and the concentrations of acetylcholine (Ach)-related metabolites were examined using LC-MS/MS. Asthma exacerbations were prospectively investigated during the following 12 months. The association between NNCS and future asthma exacerbations was also analyzed.Patients with SA were less controlled and had worse airway obstruction, a lower bronchodilator response, higher doses of inhaled corticosteroids, and more add-on treatments. The sputum mRNA levels of NNCS components, such as muscarinic receptors M1R-M5R, OCT3, VACHT, and ACHE; proinflammatory cytokines; and Ach concentration in the SA group were significantly higher than those in the non-SA group. Furthermore, most NNCS components positively correlated with non-type (T) 2 inflammatory profiles, such as sputum neutrophils, IL8, and IL1B. In addition, the mRNA levels of sputum M2R, M3R, M4R, M5R, and VACHT were independently associated with an increased risk of moderate-to-severe asthma exacerbations.This study indicated that the NNCS was significantly activated in SA, leading to elevated Ach and was associated with clinical features, non-T2 inflammation, and future exacerbations of asthma, highlighting the potential role of the NNCS in the pathogenesis of SA.Copyright © 2024. Published by Elsevier Inc.

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出版当年[2023]版：

大类 | 2 区医学

小类 | 2 区免疫学 3 区过敏

最新[2025]版：

大类 | 2 区医学

小类 | 2 区免疫学 3 区过敏

第一作者：

第一作者单位： [1]Department of Respiratory and Critical Care Medicine, Clinical Research Center for Respiratory Disease, West China Hospital, Sichuan University, Chengdu 610041, China [2]The State Key Laboratory of Respiratory Health and Multimorbidity, West China Hospital, Sichuan University, Chengdu 610041, China [3]Division of Internal Medicine, Institute of Integrated Traditional Chinese and Western Medicine, West China Hospital, Sichuan University, Chengdu 610041, China [4]Laboratory of Pulmonary Immunology and inflammation, Frontiers Science Center for Disease-related Molecular Network, Sichuan University, Chengdu 610041, China

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通讯作者：

通讯机构： [1]Department of Respiratory and Critical Care Medicine, Clinical Research Center for Respiratory Disease, West China Hospital, Sichuan University, Chengdu 610041, China [2]The State Key Laboratory of Respiratory Health and Multimorbidity, West China Hospital, Sichuan University, Chengdu 610041, China [4]Laboratory of Pulmonary Immunology and inflammation, Frontiers Science Center for Disease-related Molecular Network, Sichuan University, Chengdu 610041, China [*1]Department of Respiratory and Critical Care Medicine, Clinical Research Center for Respiratory Disease, West China Hospital, Sichuan University, Chengdu 610041, China

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Activated non-neuronal cholinergic system correlates with non-type 2 inflammation and exacerbations in severe asthma

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