Division of Pulmonary and Critical Care Medicine, Department of Medicine, Oregon Health and Science University, Portland, Oregon.
Am J Respir Cell Mol Biol. 2020 Apr;62(4):493-502. doi: 10.1165/rcmb.2019-0214OC.
Asthma is characterized by airway hyperreactivity and inflammation. In the lungs, parasympathetic and sensory nerves control airway tone and induce bronchoconstriction. Dysregulation of these nerves results in airway hyperreactivity. Humans with eosinophilic asthma have significantly increased sensory nerve density in airway epithelium, suggesting that type 2 cytokines and inflammatory cells promote nerve growth. Similarly, mice with congenital airway eosinophilia also have airway hyperreactivity and increased airway sensory nerve density. Here, we tested whether this occurs during development. We show that transgenic mice that overexpress IL-5, a cytokine required for eosinophil hematopoiesis, give birth to wild-type offspring that have significantly increased airway epithelial nerve density and airway hyperreactivity that persists into adulthood. These effects are caused by exposure to maternal IL-5 and resulting fetal eosinophilia. Allergen exposure of these adult wild-type offspring results in severe airway hyperreactivity, leading to fatal reflex bronchoconstriction. Our results demonstrate that fetal exposure to IL-5 is a developmental origin of airway hyperreactivity, mediated by hyperinnervation of airway epithelium.
哮喘的特征是气道高反应性和炎症。在肺部，副交感神经和感觉神经控制气道张力并引起支气管收缩。这些神经的失调导致气道高反应性。嗜酸粒细胞性哮喘患者的气道上皮中感觉神经密度显著增加，这表明 2 型细胞因子和炎症细胞促进神经生长。同样，先天性气道嗜酸粒细胞增多的小鼠也具有气道高反应性和增加的气道感觉神经密度。在这里，我们测试了这种情况是否发生在发育过程中。我们发现，过表达细胞因子 IL-5 的转基因小鼠会生出野生型后代，这些后代的气道上皮神经密度显著增加，气道高反应性持续到成年。这些效应是由 暴露于母体 IL-5 和导致胎儿嗜酸粒细胞增多引起的。这些成年野生型后代的过敏原暴露会导致严重的气道高反应性，导致致命的反射性支气管收缩。我们的结果表明，胎儿暴露于 IL-5 是气道高反应性的发育起源，由气道上皮的过度神经支配介导。
