Mechanisms of organophosphate insecticide-induced airway hyperreactivity
Mechanisms of organophosphate insecticide-induced airway hyperreactivity
复制标题
DOI：
10.1152/ajplung.00343.2003
复制
发表时间：
2004-05-01
影响因子：
4.9
通讯作者：
Jett, DA
中科院分区：
文献类型：
--
作者：
Fryer, AD;Lein, PJ;Jett, DA
有人认为，接触农药可能是美国和其他工业化国家哮喘发病率增加的一个因素。为了检验这一假设，对接触毒死蜱（一种广泛使用的有机磷农药）的豚鼠进行了气道高反应性测量。迷走神经的电刺激引起频率依赖性支气管收缩，在动物单次皮下注射 390 mg/kg 或 70 mg/kg 毒死蜱后 24 小时或 7 天，这种收缩显着增强。毒死蜱引起气道高反应性的机制包括抑制乙酰胆碱酯酶 (AChE) 或气道平滑肌上的 M3 毒蕈碱受体功能障碍或肺副交感神经上的自抑制性 M2 毒蕈碱受体功能障碍。 390mg/kg毒死蜱处理后24小时，肺内AChE活性显着受到抑制，但注射70mg/kg毒死蜱后7天则不显着抑制。急性暴露于 eserine（250 微克/毫升）也能显着抑制肺 AChE，但不会增强迷走神经诱导的支气管收缩。使用 M2 激动剂毛果芸香碱测试神经元 M2 受体功能，毛果芸香碱可抑制对照动物中迷走神经诱导的支气管收缩。在毒死蜱治疗的动物中，毛果芸香碱剂量反应曲线显着向右移动，表明神经元 M2 受体的反应性降低。相反，毒死蜱治疗不会改变醋甲胆碱诱导的支气管收缩，表明毒死蜱不会改变气道平滑肌上的M3毒蕈碱受体功能。这些数据表明，有机磷杀虫剂可以通过降低神经元 M2 受体功能，在缺乏 AChE 抑制的情况下引起气道高反应性。
It has been suggested that pesticide exposure may be a contributing factor underlying the increased incidence of asthma in the United States and other industrialized nations. To test this hypothesis, airway hyperreactivity was measured in guinea pigs exposed to chlorpyrifos, a widely used organophosphate pesticide. Electrical stimulation of the vagus nerves caused frequency-dependent bronchoconstriction that was significantly potentiated in animals 24 h or 7 days after a single subcutaneous injection of either 390 mg/kg or 70 mg/kg of chlorpyrifos, respectively. Mechanisms by which chlorpyrifos may cause airway hyperreactivity include inhibition of acetylcholinesterase (AChE) or dysfunction of M3 muscarinic receptors on airway smooth muscle or of autoinhibitory M2 muscarinic receptors on parasympathetic nerves in the lung. AChE activity in the lung was significantly inhibited 24 h after treatment with 390 mg/kg of chlorpyrifos, but not 7 days after injection of 70 mg/kg of chlorpyrifos. Acute exposure to eserine ( 250 mug/ml) also significantly inhibited lung AChE but did not potentiate vagally induced bronchoconstriction. Neuronal M2 receptor function was tested using the M2 agonist pilocarpine, which inhibits vagally induced bronchoconstriction in control animals. In chlorpyrifostreated animals, pilocarpine dose-response curves were shifted significantly to the right, demonstrating decreased responsiveness of neuronal M2 receptors. In contrast, chlorpyrifos treatment did not alter methacholine-induced bronchoconstriction, suggesting that chlorpyrifos does not alter M3 muscarinic receptor function on airway smooth muscle. These data demonstrate that organophosphate insecticides can cause airway hyperreactivity in the absence of AChE inhibition by decreasing neuronal M2 receptor function.