神经生长因子通过TrkA 和 TRPV1受体依赖机制增强咳嗽和气道阻塞
2009/10/15
背景：神经生长因子（NGF）是气道高反应性和痛觉过敏的重要介质，但其在咳嗽中的作用尚不清楚。
目的：本实验在豚鼠模型中研究NGF对咳嗽反射和气道管径的影响。同时评价任何NGF诱导的原肌球蛋白非相关性激酶A（TrkA）、瞬时受体电位香草素-1（TRPV1）受体及p38丝裂原活化蛋白激酶（MAPK）依赖途径对咳嗽及气道阻塞中的作用。
方法：将豚鼠置于透明的全身体描箱内。通过视觉、听觉和气流信号分析对咳嗽进行评价。采用enhanced pause（Penh ）测定值作为气道阻塞的检测指标。
结果：将豚鼠暴露于NGF不能诱发咳嗽反射，也不能诱导发生明显的气道阻塞。然而，与溶媒治疗组相比，在吸入柠檬酸之前立即将豚鼠暴露于NGF能显著增强由柠檬酸诱发的咳嗽和气道阻塞。使用TrkA拮抗剂（K252a）或TRPV1受体拮抗剂（巨大戟萜醇）预处理能明显抑制NGF诱导的咳嗽和气道阻力的增加。NGF暴露也能增加p38 MAPK的磷酸化，但使用p38 MAPK抑制剂（SB203580）预处理虽然能抑制NGF诱导的p38 MAPK磷酸化增强效应，但不会影响NGF增强咳嗽和气道阻塞的作用。
结论：研究数据显示，NGF能通过激活TrkA和TRPV1受体增加咳嗽和气道阻塞，而非通过p38 MAPK途径。
（刘国梁 审校）
El-Hashim AZ, et al. Thorax. 2009 Jun 3. [Epub ahead of print]
Nerve growth factor enhances cough and airway obstruction via TrkA and TRPV1 receptor - dependent mechanisms.
El-Hashim AZ, Jaffal SM.
Kuwait University, Kuwait.
BACKGROUND: Nerve growth factor (NGF) is an important mediator of airway hyperresponsiveness and hyperalgesia but its role in cough is unknown.
OBJECTIVES: In this study we investigated the effects of NGF on the cough reflex and airway caliber in guinea pigs. We also assessed the involvement of the tropomyosin not-related kinase A (TrkA) and transient receptor potential vanilloid-1 (TRPV1) receptors, and p38 mitogen activated protein kinase (MAPK) dependent pathway on any NGF-induced effects on cough and airway obstruction.
METHODS: Guinea pigs were placed in a transparent whole body plethysmograph box. Cough was assessed visually, acoustically and by analysis of the flow signal. Airway obstruction was measured using enhanced pause (Penh) as an index.
RESULTS: Exposure of guinea pigs to NGF did not induce a cough response nor a significant airway obstruction. However, exposure of guinea pigs to NGF immediately before citric acid inhalation resulted in a significant increase in the citric acid-induced cough and airway obstruction compared to vehicle treated animals. Pre-treatment with the TrkA antagonist, K252a, or the TRPV1 receptor antagonist, iodoresiniferatoxin, significantly inhibited the NGF enhanced cough and airway obstruction. Exposure to NGF also increased p38 MAPK phosphorylation, but pretreatment with the p38 MAPK inhibitor, SB203580, did not affect either the NGF enhanced cough or airway obstruction despite preventing the NGF-induced elevation in p38 MAPK phosphorylation.
CONCLUSIONS: The data show that NGF can enhance both cough and airway obstruction via a mechanism that involves the activation of TrkA and TRPV1 receptors but not the p38 MAPK pathway.
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