哮喘联盟

    摘要
    背景：气道组织嗜酸性粒细胞增多是肥胖相关2型（T2）哮喘可能出现的特征，但介导这种炎症的具体机制尚不清楚。

    目标：探讨在T2哮喘中，瘦素（一种在肥胖中升高的脂肪因子）增强肺嗜酸性粒细胞增多和气道成纤维细胞产生嗜酸性粒细胞趋化因子的作用机制。

    方法：本研究评估了82例哮喘患者（其中37例患有肥胖）的体重指数与气道嗜酸性粒细胞增多以及瘦素和嗜酸性粒细胞趋化因子生成之间的关联。通过培养人类气道成纤维细胞和慢性过敏性气道疾病的小鼠模型，研究瘦素对嗜酸性粒细胞趋化因子生成和肺嗜酸性粒细胞增多的影响。通过在体外试验中使用特异性中和性抗体，研究IL-13受体α2（IL-13Rα2）在介导这些过程中的作用。

    结果：在T2哮喘合并肥胖的患者中，气道组织嗜酸性粒细胞增多与传统的T2炎症指标无关，比如外周血和/或支气管肺泡灌洗液嗜酸性粒细胞计数或呼出气一氧化氮。相反，我们观察到支气管肺泡灌洗液中瘦素和嗜酸性粒细胞趋化因子-1（eotaxin-1）水平升高。哮喘患者的气道成纤维细胞中，瘦素可增强IL-13诱导的eotaxin-1和eotaxin-3的生成以及IL13RA2的表达。在小鼠实验中，慢性屋尘螨过敏原暴露后，瘦素升高可促进气道IL-13Rα2表达和肺成纤维细胞中eotaxin产生与肺组织嗜酸性粒细胞增多。抑制IL-13Rα2会减少瘦素和IL-13联合刺激下的人类气道成纤维细胞中eotaxin的分泌。

    结论：本研究揭示了肥胖相关T2哮喘中气道组织嗜酸性粒细胞增多的潜在机制：瘦素通过增强IL-13诱导的气道成纤维细胞嗜酸性粒细胞趋化因子生成发挥作用，并且这个过程依赖IL-13Rα2。

（四川大学华西医院全科医学科 杨芸芸¹ 四川大学华西医院呼吸与危重症医学科 王霁² 王刚² 译）

（J Allergy Clin Immunol. 2025 Vol. 155 Issue 3, DOI: 10.1016/j.jaci.2024.10.039）

Leptin augments IL-13–induced airway eotaxins and submucosal eosinophilia in obesity-associated asthma 
J. L. Ingram, V. L. McQuade, J. Weiss, J. T. Womble, M. D. Ihrie, K. Zhao, et al.
J Allergy Clin Immunol. 2025 Vol. 155 Issue 3, DOI: 10.1016/j.jaci.2024.10.039
Abstract
Background: Airway tissue eosinophilia can be an observed feature of obesity-associated type 2 (T2) asthma, but the processes mediating this inflammation are unknown.
Objective: To investigate a process whereby leptin, an adipokine elevated in obesity, potentiates pulmonary eosinophilia and eotaxin production by airway fibroblasts in T2 asthma.
Methods: We assessed associations between body mass index and airway eosinophilia as well as leptin and eotaxin production in 82 participants with asthma, 37 of whom exhibited obesity. Cultured human airway fibroblasts and mouse models of chronic allergic airway disease were used to evaluate leptin’s effect on eotaxin production and lung eosinophilia. The role of IL-13 receptor alpha 2 (IL-13Ra2) in mediating these processes was examined using specific neutralizing antibodies in vitro.
Results: In participants with T2 asthma and obesity, we observed that airway tissue eosinophilia did not associate with traditional T2 inflammation metrics such as peripheral and/or bronchoalveolar lavage fluid eosinophil counts or with fractional exhaled nitric oxide. Alternatively, we observed elevated bronchoalveolar lavage fluid leptin and eotaxin-1 levels. In airway fibroblasts from participants with asthma, leptin augmented IL-13–induced eotaxin-1 and eotaxin-3 production and IL13RA2 expression. In mice, elevated leptin promoted airway IL-13Ra2 and eotaxin production by lung fibroblasts and lung tissue eosinophilia following chronic house dust mite allergen exposure. Inhibition of IL-13Ra2 reduced combined leptin and IL-13–stimulated eotaxin secretion by human airway fibroblasts.
Conclusions: We identified a potential association explaining airway tissue eosinophil retention in obesity-associated T2 asthma through leptin-mediated enhancement of IL-13–induced eosinophil chemokine production by airway fibroblasts, a process requiring IL-13Ra2.