哮喘合并功能性消化不良表现出IL-33介导的气道神经功能障碍
2024/07/31
摘要
背景：神经功能障碍与哮喘和功能性消化不良（functional dyspepsia, FD）的病理生理有关。然而，这些疾病之间的关系仍不明确。
目的：本研究旨在阐明哮喘合并FD的临床意义，并通过关注气道神经功能障碍探索哮喘与FD之间的共同通路。
方法：比较伴有和不伴有FD的哮喘患者的临床指标和生物标志物，包括辣椒素咳嗽敏感性（C-CS）。C-CS是根据引起至少两次（C2）或五次咳嗽（C5）的辣椒素浓度来确定的。此外，在2型气道炎症小鼠模型中评估了气道炎症与气道神经分布和胃肠运动的关系。
结果：哮喘合并FD的患者哮喘控制更差、咳嗽严重程度更高，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和哮喘控制不佳是哮喘C-CS升高（定义为 C5 ≤ 2.44 μM）的预测因素。木瓜蛋白酶诱导的气道炎症小鼠模型出现了气道神经分布增加和胃肠道运动障碍，而抗白细胞介素（IL）-33 抗体可改善这两种病理状况。此外，使用 QX-314（一种钠通道阻滞剂）沉默气道感觉神经，可以减轻木瓜蛋白酶引起的胃肠道运动障碍。与对照组相比，伴有FD或C-CS升高的哮喘患者的痰液 IL-33水平显著升高。
结论：在哮喘中，FD与气道神经功能障碍显著相关。IL-33介导的气道神经功能障碍可能导致哮喘与FD之间的相互作用。
Comorbid functional dyspepsia reflects IL-33-mediated airway neuronal dysfunction in asthma
Keima Ito, Yoshihiro Kanemitsu, Takashi Ueda, Takeshi Kamiya, Eiji Kubota, Yuta Mori, Kensuke Fukumitsu, Tomoko Tajiri, Satoshi Fukuda, Takehiro Uemura, Hirotsugu Ohkubo, Yutaka Ito, Yasuhiro Shibata, Natsuko Kumamoto, Shinya Ugawa, Akio Niimi
J Allergy Clin Immunol. 2024 Jun 21:S0091-6749(24)00632-8. doi: 10.1016/j.jaci.2024.06.008
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.
Conclusion: 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.
背景：神经功能障碍与哮喘和功能性消化不良（functional dyspepsia, FD）的病理生理有关。然而，这些疾病之间的关系仍不明确。
目的：本研究旨在阐明哮喘合并FD的临床意义，并通过关注气道神经功能障碍探索哮喘与FD之间的共同通路。
方法：比较伴有和不伴有FD的哮喘患者的临床指标和生物标志物，包括辣椒素咳嗽敏感性（C-CS）。C-CS是根据引起至少两次（C2）或五次咳嗽（C5）的辣椒素浓度来确定的。此外，在2型气道炎症小鼠模型中评估了气道炎症与气道神经分布和胃肠运动的关系。
结果：哮喘合并FD的患者哮喘控制更差、咳嗽严重程度更高，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和哮喘控制不佳是哮喘C-CS升高（定义为 C5 ≤ 2.44 μM）的预测因素。木瓜蛋白酶诱导的气道炎症小鼠模型出现了气道神经分布增加和胃肠道运动障碍，而抗白细胞介素（IL）-33 抗体可改善这两种病理状况。此外，使用 QX-314（一种钠通道阻滞剂）沉默气道感觉神经，可以减轻木瓜蛋白酶引起的胃肠道运动障碍。与对照组相比，伴有FD或C-CS升高的哮喘患者的痰液 IL-33水平显著升高。
结论：在哮喘中，FD与气道神经功能障碍显著相关。IL-33介导的气道神经功能障碍可能导致哮喘与FD之间的相互作用。
(四川大学华西医院呼吸与危重症医学科 王霁1 王刚1 译)
(J Allergy Clin Immunol. 2024 Jun 21:S0091-6749(24)00632-8. doi: 10.1016/j.jaci.2024.06.008)
(J Allergy Clin Immunol. 2024 Jun 21:S0091-6749(24)00632-8. doi: 10.1016/j.jaci.2024.06.008)
Comorbid functional dyspepsia reflects IL-33-mediated airway neuronal dysfunction in asthma
Keima Ito, Yoshihiro Kanemitsu, Takashi Ueda, Takeshi Kamiya, Eiji Kubota, Yuta Mori, Kensuke Fukumitsu, Tomoko Tajiri, Satoshi Fukuda, Takehiro Uemura, Hirotsugu Ohkubo, Yutaka Ito, Yasuhiro Shibata, Natsuko Kumamoto, Shinya Ugawa, Akio Niimi
J Allergy Clin Immunol. 2024 Jun 21:S0091-6749(24)00632-8. doi: 10.1016/j.jaci.2024.06.008
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.
Conclusion: 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.
