Department of Molecular Biosciences, University of California , Davis, California.
Pulmonary Critical Care Medicine, Department of Medicine, Oregon Health & Science University , Portland, Oregon.
Am J Physiol Lung Cell Mol Physiol. 2018 Oct 1;315(4):L485-L501. doi: 10.1152/ajplung.00211.2018. Epub 2018 Jun 28.
Numerous epidemiologic studies have identified an association between occupational exposures to organophosphorus pesticides (OPs) and asthma or asthmatic symptoms in adults. Emerging epidemiologic data suggest that environmentally relevant levels of OPs may also be linked to respiratory dysfunction in the general population and that in utero and/or early life exposures to environmental OPs may increase risk for childhood asthma. In support of a causal link between OPs and asthma, experimental evidence demonstrates that occupationally and environmentally relevant OP exposures induce bronchospasm and airway hyperreactivity in preclinical models. Mechanistic studies have identified blockade of autoinhibitory M2 muscarinic receptors on parasympathetic nerves that innervate airway smooth muscle as one mechanism by which OPs induce airway hyperreactivity, but significant questions remain regarding the mechanism(s) by which OPs cause neuronal M2 receptor dysfunction and, more generally, how OPs cause persistent asthma, especially after developmental exposures. The goals of this review are to 1) summarize current understanding of OPs in asthma; 2) discuss mechanisms of OP neurotoxicity and immunotoxicity that warrant consideration in the context of OP-induced airway hyperreactivity and asthma, specifically, inflammatory responses, oxidative stress, neural plasticity, and neurogenic inflammation; and 3) identify critical data gaps that need to be addressed in order to better protect adults and children against the harmful respiratory effects of low-level OP exposures.
许多流行病学研究已经确定职业性接触有机磷农药（OPs）与成年人哮喘或哮喘症状之间存在关联。新出现的流行病学数据表明，环境相关水平的 OPs 也可能与普通人群的呼吸功能障碍有关，并且在子宫内和/或生命早期接触环境 OPs 可能会增加儿童哮喘的风险。为了支持 OPs 与哮喘之间的因果关系，实验证据表明，职业性和环境相关的 OP 暴露会在临床前模型中引起支气管痉挛和气道高反应性。机制研究已经确定，阻断支配气道平滑肌的副交感神经上的自动抑制性 M2 毒蕈碱受体是 OPs 引起气道高反应性的一种机制，但关于 OPs 引起神经元 M2 受体功能障碍的机制以及更普遍地关于 OPs 如何引起持续性哮喘，尤其是在发育性暴露后，仍存在许多问题。本综述的目的是：1）总结目前对 OPs 在哮喘中的认识；2）讨论 OP 神经毒性和免疫毒性的机制，这些机制在 OPs 引起的气道高反应性和哮喘的背景下值得考虑，具体包括炎症反应、氧化应激、神经可塑性和神经原性炎症；3）确定需要解决的关键数据差距，以便更好地保护成年人和儿童免受低水平 OPs 暴露的有害呼吸影响。
