Dakhama Azzeddine, Kanehiro Arihiko, Mäkelä Mika J, Loader Joan E, Larsen Gary L, Gelfand Erwin W
Division of Cell Biology and Pulmonary Medicine, Department of Pediatrics, National Jewish Medical and Research Center, Denver, Colorado 80206, USA.
Am J Respir Crit Care Med. 2002 Apr 15;165(8):1137-44. doi: 10.1164/ajrccm.165.8.2109058.
Sensory neuropeptides are localized to airway nerves and endocrine cells in both human and animal species and may participate in the development of airway inflammation and hyperresponsiveness (AHR). We used a mouse model to identify the changes that occur in calcitonin gene-related peptide (CGRP) expression in the airways during development of allergic inflammation and to investigate the potential role of this neuropeptide in modulating AHR. In sensitized mice, allergen challenge induced eosinophilic airway inflammation and AHR and resulted in considerable depletion of CGRP in neuroepithelial bodies and submucosal nerve plexuses without altering the overall density of airway nerve fibers. This depletion was subsequent to the development of airway inflammation and was prevented by anti-very late antigen-4 and anti-interleukin-5 treatments, which blocked airway eosinophilia and abolished AHR. Administration of CGRP to sensitized and challenged mice resulted in the normalization of airway responsiveness to inhaled methacholine, an effect that was neutralized by the receptor antagonist CGRP(8-37). These data demonstrate that replacement of CGRP following its depletion in allergic mice can reverse the changes in airway responsiveness and suggest that CGRP may have potential for the treatment of allergic AHR.
感觉神经肽在人类和动物的气道神经及内分泌细胞中均有分布，可能参与气道炎症和高反应性（AHR）的发生发展。我们使用小鼠模型来确定变应性炎症发展过程中气道中降钙素基因相关肽（CGRP）表达的变化，并研究这种神经肽在调节AHR中的潜在作用。在致敏小鼠中，变应原激发可诱发嗜酸性气道炎症和AHR，并导致神经上皮小体和黏膜下神经丛中CGRP大量减少，而气道神经纤维的总体密度未发生改变。这种减少发生在气道炎症发展之后，抗极迟抗原-4和抗白细胞介素-5治疗可阻止气道嗜酸性粒细胞增多并消除AHR，从而预防这种减少。给致敏并激发的小鼠注射CGRP可使气道对吸入乙酰甲胆碱的反应性恢复正常，这一作用可被受体拮抗剂CGRP(8-37)中和。这些数据表明，变应性小鼠中CGRP耗竭后进行补充可逆转气道反应性的变化，并提示CGRP可能具有治疗变应性AHR的潜力。
