Abstract：
BACKGROUND: Non-neuronal cholinergic system (NNCS) contributes to various inflammatory airway diseases. However, the role of NNCS in severe asthma (SA) remains largely unexplored.
OBJECTIVE: To explore airway NNCS in SA.
METHODS: 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 messenger RNA (mRNA) levels of NNCS components and proinflammatory cytokines in the sputum were detected using real-time quantitative polymerase chain reaction, and the concentrations of acetylcholine (Ach)-related metabolites were evaluated using liquid chromatography coupled with tandem mass spectrometry. Asthma exacerbations were prospectively investigated during the next 12 months. The association between NNCS and future asthma exacerbations was also analyzed.
RESULTS: 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.
CONCLUSIONS: 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.
BACKGROUND: ChiCTR-OOC-16009529 (http://www.chictr.org.cn).
OBJECTIVE: To explore airway NNCS in SA.
METHODS: 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 messenger RNA (mRNA) levels of NNCS components and proinflammatory cytokines in the sputum were detected using real-time quantitative polymerase chain reaction, and the concentrations of acetylcholine (Ach)-related metabolites were evaluated using liquid chromatography coupled with tandem mass spectrometry. Asthma exacerbations were prospectively investigated during the next 12 months. The association between NNCS and future asthma exacerbations was also analyzed.
RESULTS: 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.
CONCLUSIONS: 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.
BACKGROUND: ChiCTR-OOC-16009529 (http://www.chictr.org.cn).
摘要：
背景：非神经元胆碱能系统（NNCS）有助于各种炎性气道疾病。然而,NNCS在重度哮喘(SA)中的作用在很大程度上仍未被研究.
目的：探索SA的气道NNCS。
方法：在这项基于现实世界背景下的澳大利亚重度哮喘网络的前瞻性队列研究中，SA(n=52)和非SA(n=104)患者接受了临床评估和痰诱导.采用RT-qPCR检测痰液中NNCS组分和促炎细胞因子的mRNA水平,使用LC-MS/MS检查乙酰胆碱（Ach）相关代谢物的浓度。在接下来的12个月中对哮喘恶化进行了前瞻性调查。还分析了NNCS与未来哮喘加重之间的关联。
结果：SA患者控制较差，气道阻塞更差，较低的支气管扩张剂反应，更高剂量的吸入性皮质类固醇，和更多的附加治疗。NNCS组分的痰mRNA水平，如毒蕈碱受体M1R-M5R，OCT3,VACHT,和ACHE;促炎细胞因子;和Ach浓度SA组显著高于非SA组。此外，大多数NNCS组分与非型（T）2炎症谱呈正相关，如痰中嗜中性粒细胞，IL8和IL1B。此外,痰M2R的mRNA水平，M3R,M4R,M5R,和VACHT与中度至重度哮喘加重的风险增加独立相关.
结论：这项研究表明NNCS在SA中被显著激活，导致Ach升高，并与临床特征相关，非T2炎症，以及未来哮喘的恶化，强调NNCS在SA发病机制中的潜在作用。
目的：探索SA的气道NNCS。
方法：在这项基于现实世界背景下的澳大利亚重度哮喘网络的前瞻性队列研究中，SA(n=52)和非SA(n=104)患者接受了临床评估和痰诱导.采用RT-qPCR检测痰液中NNCS组分和促炎细胞因子的mRNA水平,使用LC-MS/MS检查乙酰胆碱（Ach）相关代谢物的浓度。在接下来的12个月中对哮喘恶化进行了前瞻性调查。还分析了NNCS与未来哮喘加重之间的关联。
结果：SA患者控制较差，气道阻塞更差，较低的支气管扩张剂反应，更高剂量的吸入性皮质类固醇，和更多的附加治疗。NNCS组分的痰mRNA水平，如毒蕈碱受体M1R-M5R，OCT3,VACHT,和ACHE;促炎细胞因子;和Ach浓度SA组显著高于非SA组。此外，大多数NNCS组分与非型（T）2炎症谱呈正相关，如痰中嗜中性粒细胞，IL8和IL1B。此外,痰M2R的mRNA水平，M3R,M4R,M5R,和VACHT与中度至重度哮喘加重的风险增加独立相关.
结论：这项研究表明NNCS在SA中被显著激活，导致Ach升高，并与临床特征相关，非T2炎症，以及未来哮喘的恶化，强调NNCS在SA发病机制中的潜在作用。
