合并功能性消化不良反映了 IL-33 介导的哮喘气道神经元功能障碍
2024/07/30
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。本研究旨在阐明哮喘合并功能性消化不良的临床意义，并通过关注气道神经元功能障碍探索哮喘和功能性消化不良之间的统一途径。
方法：比较有 FD 和无 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是根据能引起至少两次（C2）或五次（C5）咳嗽的辣椒素浓度确定的。此外，还在 2 型气道炎症小鼠模型中评估了气道炎症与气道神经支配和胃肠道运动的关系。
结果：与无 FD 的哮喘患者相比，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和哮喘控制不佳是哮喘患者C-CS升高（定义为C5≤2.44 μM）的预测因素。木瓜蛋白酶诱发气道炎症的小鼠模型会出现气道神经过度支配和胃肠道运动障碍，而抗白细胞介素（IL）-33 抗体可改善这两种病理现象。此外，使用钠通道阻滞剂 QX-314 沉默气道感觉神经元后，木瓜蛋白酶诱导的胃肠道运动障碍也得到了缓解。此外，与同类哮喘患者相比，伴有 FD 或 C-CS 增高的哮喘患者痰中 IL-33 水平明显升高。
结论：FD与哮喘患者气道神经元功能障碍密切相关。IL-33 介导的气道神经元功能障碍可能是哮喘与 FD 相互影响的原因之一。
Comorbid functional dyspepsia reflects IL-33-mediated airway neuronal dysfunction in asthma
Ito K, Kanemitsu Y, Ueda T, Kamiya T, Kubota E, Mori Y, Fukumitsu K, Tajiri T, Fukuda S, Uemura T, Ohkubo H, Ito Y, Shibata Y, Kumamoto N, Ugawa S, Niimi A.
Abstract
Background:Neuronal dysfunction is implicated in the pathophysiology of asthma and functional dyspepsia (FD). However, the relationship between these diseases remains unclear. 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。本研究旨在阐明哮喘合并功能性消化不良的临床意义，并通过关注气道神经元功能障碍探索哮喘和功能性消化不良之间的统一途径。
方法：比较有 FD 和无 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是根据能引起至少两次（C2）或五次（C5）咳嗽的辣椒素浓度确定的。此外，还在 2 型气道炎症小鼠模型中评估了气道炎症与气道神经支配和胃肠道运动的关系。
结果：与无 FD 的哮喘患者相比，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和哮喘控制不佳是哮喘患者C-CS升高（定义为C5≤2.44 μM）的预测因素。木瓜蛋白酶诱发气道炎症的小鼠模型会出现气道神经过度支配和胃肠道运动障碍，而抗白细胞介素（IL）-33 抗体可改善这两种病理现象。此外，使用钠通道阻滞剂 QX-314 沉默气道感觉神经元后，木瓜蛋白酶诱导的胃肠道运动障碍也得到了缓解。此外，与同类哮喘患者相比，伴有 FD 或 C-CS 增高的哮喘患者痰中 IL-33 水平明显升高。
结论：FD与哮喘患者气道神经元功能障碍密切相关。IL-33 介导的气道神经元功能障碍可能是哮喘与 FD 相互影响的原因之一。
(中日友好医院呼吸与危重症医学科 沈焜路 摘译 林江涛 审校)
(J Allergy Clin Immunol. 2024 Jun 21; DOI: 10.1016/j.jaci.2024.06.008)
(J Allergy Clin Immunol. 2024 Jun 21; DOI: 10.1016/j.jaci.2024.06.008)
Comorbid functional dyspepsia reflects IL-33-mediated airway neuronal dysfunction in asthma
Ito K, Kanemitsu Y, Ueda T, Kamiya T, Kubota E, Mori Y, Fukumitsu K, Tajiri T, Fukuda S, Uemura T, Ohkubo H, Ito Y, Shibata Y, Kumamoto N, Ugawa S, Niimi A.
Abstract
Background:Neuronal dysfunction is implicated in the pathophysiology of asthma and functional dyspepsia (FD). However, the relationship between these diseases remains unclear. 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.
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哮喘多基因风险评分的表观基因组划分揭示不同基因驱动疾病的通路
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