MECHANISMS OF HYPERREACTIVITY IN ATOPIC HOSTS

正常情况下，呼吸道副交感神经的乙酰胆碱释放受到M2受体抑制的限制。在一些哮喘患者和哮喘动物模型中，这些受体通常提供的负反馈会减少或消失，从而导致高反应性。在抗原攻击的豚鼠中，我们已经证明嗜酸性粒细胞通过释放M2受体上的变构拮抗剂主要碱性蛋白而导致M2受体功能障碍。高反应性可被主要碱性蛋白的抗体阻断，并可由呼吸道嗜酸性粒细胞增多症明显表征。臭氧暴露后2天和3天的高反应性不会被嗜酸性粒细胞耗尽所阻断，也不会被肝素逆转，除非动物事先对某种抗原致敏。最近已经证明，肺部的炎症反应可能会因宿主的特应性状态而有所不同。我们的假设是，肺对损伤的炎症反应，以及炎症导致呼吸道高反应和抑制M2受体功能障碍的机制，取决于宿主是否特应性。我们推测，在一种特应性动物模型中(通过腹腔注射致敏卵清蛋白而不进行吸入性刺激)，随后的臭氧暴露将导致嗜酸性粒细胞的涌入。这将伴随着M2受体功能障碍和持续至少3天的高反应性，其特征更类似于抗原攻击后出现的特征(即，将被嗜酸性粒细胞耗尽所阻断，并将被肝素逆转)。在这项资助中，我们还将研究人类对臭氧的高反应性是否取决于特应性状态。这些数据将确定人类对臭氧和可能的其他空气污染物做出不同反应背后的机制，从而能够更好地预测哪些人处于危险之中，并制定干预措施。

Under normal circumstances, the release of acetylcholine from airway parasympathetic nerves is limited by inhibitory M2 muscarinic receptors. The negative feedback normally provided by these receptors is decreased or lost in some humans with asthma and in animal models of asthma, leading to hyper-responsiveness. In antigen challenged guinea pigs, we have demonstrated that eosinophils causes M2 receptor dysfunction by releasing major basic protein, which is an allosteric antagonist at the M2 receptor. Hyper-responsiveness can be blocked by an antibody to major basic protein, and can be acutely characterized by airway eosinophilia. Hyper-responsiveness 2 and 3 days after ozone exposure is not blocked by eosinophil depletion, or reversed by heparin, unless the animals are previously sensitized to an antigen. It has recently been demonstrated that the inflammatory response of the lungs may vary depending on the atopic status of the host. It is our hypothesis that the inflammatory response of the lungs to injury, and the mechanisms by which the inflammation causes airway hyper-responsiveness and dysfunction of inhibitory M2 muscarinic receptors, depends upon whether the host is atopic. We postulate that in an animal model of atopy (sensitization to ovalbumin by intraperitoneal injection without inhalational challenge), subsequent ozone exposure will cause an influx of eosinophils. This will be accompanied by M2 receptor dysfunction and by hyper- responsiveness lasting a minimum of 3 days with characteristics more similar to those seen after antigen challenge (i.e., will be blocked by depletion of eosinophils, and will be reversed by heparin). In this grant we will also examine whether development of hyperresponsiveness to ozone in humans is dependent upon atopic status. These data will identify the mechanism behind the different responses of humans to ozone and possibly other air pollutants, thus allowing for better prediction of which individuals are at risk and the development of interventions.