Abstract：
BACKGROUND: Neuronal dysfunction is implicated in the pathophysiology of asthma and functional dyspepsia (FD). However, the relationship between these diseases remains unclear.
OBJECTIVE: This study aimed to clarify the clinical implications of comorbid FD in asthma and to explore the unified pathway between asthma and FD by focusing on airway neuronal dysfunction.
METHODS: Clinical indices and biomarkers, including capsaicin cough sensitivity (C-CS), were compared between patients with asthma with and without FD. C-CS was determined based on the capsaicin concentration that induced at least two (C2) or five coughs (C5). Additionally, the associations of airway inflammation with airway innervation and gastrointestinal motility were evaluated in mouse models of type 2 airway inflammation.
RESULTS: Patients with asthma with FD had worse asthma control and cough severity and lower C2 and C5 thresholds than those without FD. The severity of FD symptoms was negatively correlated with C2 and C5 thresholds. FD and poor asthma control were predictors of heightened C-CS (defined as C5 of ≤ 2.44 μM) in asthma. A mouse model of papain-induced airway inflammation developed airway hyperinnervation and gastrointestinal dysmotility, and both pathologies were ameliorated by an anti-interleukin (IL)-33 antibody. Moreover, papain-induced gastrointestinal dysmotility was mitigated by silencing the airway sensory neurons using QX-314, a sodium channel blocker. Furthermore, sputum IL-33 levels were significantly elevated in patients with asthma with FD or heightened C-CS compared with those in their counterparts.
CONCLUSIONS: FD is significantly associated with airway neuronal dysfunction in asthma. IL-33-mediated airway neuronal dysfunction may contribute to the interaction between asthma and FD.
OBJECTIVE: This study aimed to clarify the clinical implications of comorbid FD in asthma and to explore the unified pathway between asthma and FD by focusing on airway neuronal dysfunction.
METHODS: Clinical indices and biomarkers, including capsaicin cough sensitivity (C-CS), were compared between patients with asthma with and without FD. C-CS was determined based on the capsaicin concentration that induced at least two (C2) or five coughs (C5). Additionally, the associations of airway inflammation with airway innervation and gastrointestinal motility were evaluated in mouse models of type 2 airway inflammation.
RESULTS: Patients with asthma with FD had worse asthma control and cough severity and lower C2 and C5 thresholds than those without FD. The severity of FD symptoms was negatively correlated with C2 and C5 thresholds. FD and poor asthma control were predictors of heightened C-CS (defined as C5 of ≤ 2.44 μM) in asthma. A mouse model of papain-induced airway inflammation developed airway hyperinnervation and gastrointestinal dysmotility, and both pathologies were ameliorated by an anti-interleukin (IL)-33 antibody. Moreover, papain-induced gastrointestinal dysmotility was mitigated by silencing the airway sensory neurons using QX-314, a sodium channel blocker. Furthermore, sputum IL-33 levels were significantly elevated in patients with asthma with FD or heightened C-CS compared with those in their counterparts.
CONCLUSIONS: FD is significantly associated with airway neuronal dysfunction in asthma. IL-33-mediated airway neuronal dysfunction may contribute to the interaction between asthma and FD.
摘要：
背景：神经元功能障碍与哮喘和功能性消化不良（FD）的病理生理学有关。然而,这些疾病之间的关系仍不清楚。
目的：本研究旨在阐明哮喘并发FD的临床意义，并通过关注气道神经元功能障碍来探索哮喘和FD之间的统一通路。
方法：临床指标和生物标志物，包括辣椒素咳嗽敏感性（C-CS），比较有和没有FD的哮喘患者。基于诱导至少2次(C2)或5次咳嗽(C5)的辣椒素浓度测定C-CS。此外,在2型气道炎症小鼠模型中评价了气道炎症与气道神经支配和胃肠动力的关系.
结果：与没有FD的患者相比，患有FD的哮喘患者的哮喘控制和咳嗽严重程度更差，C2和C5阈值更低。FD症状的严重程度与C2和C5阈值呈负相关。FD和哮喘控制不良是哮喘C-CS升高（定义为C5≤2.44μM）的预测因子。木瓜蛋白酶诱导的气道炎症的小鼠模型出现了气道神经支配过度和胃肠动力障碍，抗白细胞介素（IL）-33抗体改善了两种病理。此外，通过使用钠通道阻滞剂QX-314沉默气道感觉神经元,木瓜蛋白酶诱导的胃肠动力障碍得到缓解.此外，哮喘合并FD或C-CS升高患者的痰液IL-33水平显著升高。
结论：FD与哮喘的气道神经元功能障碍显著相关。IL-33介导的气道神经元功能障碍可能与哮喘和FD之间的相互作用有关。
目的：本研究旨在阐明哮喘并发FD的临床意义，并通过关注气道神经元功能障碍来探索哮喘和FD之间的统一通路。
方法：临床指标和生物标志物，包括辣椒素咳嗽敏感性（C-CS），比较有和没有FD的哮喘患者。基于诱导至少2次(C2)或5次咳嗽(C5)的辣椒素浓度测定C-CS。此外,在2型气道炎症小鼠模型中评价了气道炎症与气道神经支配和胃肠动力的关系.
结果：与没有FD的患者相比，患有FD的哮喘患者的哮喘控制和咳嗽严重程度更差，C2和C5阈值更低。FD症状的严重程度与C2和C5阈值呈负相关。FD和哮喘控制不良是哮喘C-CS升高（定义为C5≤2.44μM）的预测因子。木瓜蛋白酶诱导的气道炎症的小鼠模型出现了气道神经支配过度和胃肠动力障碍，抗白细胞介素（IL）-33抗体改善了两种病理。此外，通过使用钠通道阻滞剂QX-314沉默气道感觉神经元,木瓜蛋白酶诱导的胃肠动力障碍得到缓解.此外，哮喘合并FD或C-CS升高患者的痰液IL-33水平显著升高。
结论：FD与哮喘的气道神经元功能障碍显著相关。IL-33介导的气道神经元功能障碍可能与哮喘和FD之间的相互作用有关。
