Pincus Alexandra B, Pierce Aubrey B, Kappel Nicole, Lebold Katie M, Drake Matthew G, Fryer Allison D, Jacoby David B
Department of Pediatrics, University of California San Francisco, San Francisco, California; and.
Division of Pulmonary, Allergy, and Critical Care, Oregon Health & Science University, Portland, Oregon.
Am J Respir Cell Mol Biol. 2025 Jun;72(6):698-707. doi: 10.1165/rcmb.2024-0360OC.
Airway hyperreactivity in asthma is mediated by airway nerves, including sensory nerves in airway epithelium and parasympathetic nerves innervating airway smooth muscle. Isolating the function of these two nerve populations , to distinguish how each is affected by inflammatory processes and contributes to hyperreactivity in asthma, has been challenging. In this study, we used optogenetic activation of airway nerves to study parasympathetic contributions to airway hyperreactivity in two mouse models of asthma: ) acute challenge with house dust mite antigen; and ) chronic airway hypereosinophilia due to genetic IL-5 overexpression in airways. Overall airway hyperreactivity, as measured by bronchoconstriction to an inhaled agonist, was increased in both models. In contrast, optogenetic stimulation of isolated efferent parasympathetic nerves induced bronchoconstriction only in the acute house dust mite antigen challenge group. Using whole-mount tissue immunofluorescence and modeling software, we then measured, in three dimensions, the interactions between eosinophils and parasympathetic nerves in both models and found that eosinophils were more numerous and more proximal to airway parasympathetic nerves in antigen-challenged and IL-5-transgenic mice than in their respective controls but were not significantly different between the two asthma models. Thus, even though eosinophils were increased around nerves in both models, parasympathetic nerves only mediated airway hyperreactivity in the antigen-challenged mice. This study demonstrates divergent effects of acute versus chronic eosinophilia on parasympathetic airway nerve activity and points to eosinophil-nerve interactions as a key regulator of airway hyperreactivity in antigen challenged mice.
哮喘中的气道高反应性由气道神经介导，包括气道上皮中的感觉神经和支配气道平滑肌的副交感神经。区分这两类神经群体的功能，以辨别它们各自如何受到炎症过程的影响以及对哮喘中的高反应性产生何种作用，一直具有挑战性。在本研究中，我们利用气道神经的光遗传学激活来研究副交感神经在两种哮喘小鼠模型中对气道高反应性的作用：（1）用屋尘螨抗原进行急性激发；（2）由于气道中基因IL-5过表达导致的慢性气道嗜酸性粒细胞增多。通过对吸入激动剂的支气管收缩反应来衡量，两个模型中的整体气道高反应性均有所增加。相比之下，光遗传学刺激分离出的传出副交感神经仅在急性屋尘螨抗原激发组中诱导了支气管收缩。然后，我们使用全组织免疫荧光和建模软件，在三维空间中测量了两种模型中嗜酸性粒细胞与副交感神经之间的相互作用，发现与各自的对照组相比，在抗原激发小鼠和IL-5转基因小鼠中，嗜酸性粒细胞数量更多且更靠近气道副交感神经，但两个哮喘模型之间无显著差异。因此，尽管在两个模型中神经周围的嗜酸性粒细胞均增多，但副交感神经仅在抗原激发的小鼠中介导了气道高反应性。本研究证明了急性与慢性嗜酸性粒细胞增多对副交感气道神经活动的不同影响，并指出嗜酸性粒细胞与神经的相互作用是抗原激发小鼠气道高反应性的关键调节因素。
