Department of Molecular and Environmental Pathology, Institute of Health Biosciences, University of Tokushima Graduate School, Tokushima, Japan.
Clin Exp Allergy. 2012 Mar;42(3):460-70. doi: 10.1111/j.1365-2222.2011.03918.x. Epub 2011 Dec 14.
Bronchial asthma is a chronic allergic airway inflammatory disease. Neurotrophins, including nerve growth factor (NGF), play an important role in the pathogenesis of asthma. However, the effects of NGF derived from epithelium on airway hyperresponsiveness (AHR) after antigen sensitization/exposure remain uncertain.
In this study, we examined the role of NGF on AHR after chronic antigen exposure and the effect of inhibiting NGF by in vivo siRNA on AHR exacerbation.
We generated chronic mouse models of bronchial asthma using house-dust mite antigen (Dermatophagoides pteronyssinus; Dp). NGF concentrations in bronchoalveolar lavage fluid (BALF), lung histopathology, hyperresponsiveness, and related neuronal peptides and cytokines in supernatants of lung homogenates were determined.
NGF in BALF was increased in a dose- and time-dependent manner, and was expressed primarily in bronchial epithelium. Nerve fibres and substance P-positive fibres were detected in subepithelium of Dp-sensitized and challenged mice over 4 weeks of mite antigen exposure. AHR was positively correlated with NGF concentration and nerve fibre innervation. AHR, modulation of innervation, and increased substance P were inhibited by in vivo administration of siRNA that targeted NGF, although the inhibition of NGF did not affect allergic inflammation and subepithelial fibrosis.
These findings suggest that NGF derived from bronchial and alveolar epithelium plays an important role in AHR after chronic exposure to mite antigen. NGF inhibition could potentially manage bronchial asthma, including AHR.
支气管哮喘是一种慢性过敏性气道炎症性疾病。神经生长因子（NGF）等神经递质在哮喘发病机制中发挥重要作用。然而，上皮细胞来源的 NGF 对变应原致敏/暴露后气道高反应性（AHR）的影响尚不确定。
本研究旨在探讨慢性抗原暴露后 NGF 对 AHR 的作用，以及体内 siRNA 抑制 NGF 对 AHR 加重的影响。
我们采用屋尘螨抗原（Dermatophagoides pteronyssinus；Dp）建立了慢性哮喘小鼠模型。检测支气管肺泡灌洗液（BALF）中 NGF 浓度、肺组织病理学、气道高反应性以及肺匀浆上清液中相关神经肽和细胞因子。
BALF 中的 NGF 呈剂量和时间依赖性增加，主要表达于支气管上皮细胞。在屋尘螨抗原暴露 4 周的 Dp 致敏和 challenged 小鼠的支气管上皮下，可检测到神经纤维和 P 物质阳性纤维。AHR 与 NGF 浓度和神经纤维支配呈正相关。体内给予 NGF 靶向 siRNA 可抑制 AHR、神经支配的调节和 P 物质的增加，尽管抑制 NGF 并不影响过敏炎症和上皮下纤维化。
这些发现表明，支气管和肺泡上皮来源的 NGF 在慢性螨抗原暴露后 AHR 中发挥重要作用。NGF 抑制可能有助于管理哮喘，包括 AHR。
