Department of Physiology & Pharmacology, Oregon Health & Science Univ., Portland, OR 97239, USA.
Am J Physiol Lung Cell Mol Physiol. 2011 Feb;300(2):L176-84. doi: 10.1152/ajplung.00060.2010. Epub 2010 Nov 5.
Ozone causes persistent airway hyperreactivity in humans and animals. One day after ozone exposure, airway hyperreactivity is mediated by release of eosinophil major basic protein that inhibits neuronal M(2) muscarinic receptors, resulting in increased acetylcholine release and increased smooth muscle contraction in guinea pigs. Three days after ozone, IL-1β, not eosinophils, mediates ozone-induced airway hyperreactivity, but the mechanism at this time point is largely unknown. IL-1β increases NGF and the tachykinin substance P, both of which are involved in neural plasticity. These experiments were designed to test whether there is a role for NGF and tachykinins in sustained airway hyperreactivity following a single ozone exposure. Guinea pigs were exposed to filtered air or ozone (2 parts per million, 4 h). In anesthetized and vagotomized animals, ozone potentiated vagally mediated airway hyperreactivity 24 h later, an effect that was sustained over 3 days. Pretreatment with antibody to NGF completely prevented ozone-induced airway hyperreactivity 3 days, but not 1 day, after ozone and significantly reduced the number of substance P-positive airway nerve bundles. Three days after ozone, NK(1) and NK(2) receptor antagonists also blocked this sustained hyperreactivity. Although the effect of inhibiting NK(2) receptors was independent of ozone, the NK(1) receptor antagonist selectively blocked vagal hyperreactivity 3 days after ozone. These data confirm mechanisms of ozone-induced airway hyperreactivity change over time and demonstrate 3 days after ozone that there is an NGF-mediated role for substance P, or another NK(1) receptor agonist, that enhances acetylcholine release and was not present 1 day after ozone.
臭氧可导致人类和动物的持续性气道高反应性。臭氧暴露 1 天后，气道高反应性是由嗜酸性粒细胞主要碱性蛋白的释放介导的，该蛋白抑制神经元 M2 毒蕈碱受体，导致豚鼠乙酰胆碱释放增加和平滑肌收缩增加。臭氧暴露 3 天后，白细胞介素-1β（IL-1β）而非嗜酸性粒细胞介导了臭氧引起的气道高反应性，但此时的机制在很大程度上尚不清楚。IL-1β增加了神经生长因子（NGF）和速激肽物质 P，两者都参与神经可塑性。这些实验旨在测试在单次臭氧暴露后，NGF 和速激肽是否在持续气道高反应性中发挥作用。豚鼠暴露于过滤空气或臭氧（2 ppm，4 h）。在麻醉和迷走神经切断的动物中，臭氧增强了 24 小时后迷走神经介导的气道高反应性，这种效应持续 3 天。NGF 抗体预处理完全阻止了臭氧 3 天后引起的气道高反应性，但不能阻止臭氧 1 天后引起的气道高反应性，并显著减少了物质 P 阳性气道神经束的数量。臭氧 3 天后，NK1 和 NK2 受体拮抗剂也阻断了这种持续性高反应性。尽管抑制 NK2 受体的作用不依赖于臭氧，但 NK1 受体拮抗剂选择性地阻断了臭氧 3 天后的迷走神经高反应性。这些数据证实了臭氧诱导的气道高反应性随时间变化的机制，并表明臭氧 3 天后存在一种 NGF 介导的物质 P 作用，或另一种 NK1 受体激动剂，增强乙酰胆碱释放，而在臭氧 1 天后不存在。
