Ozone inhibition of Neuronal m2 receptor function

描述(申请人提供)：臭氧介导的高反应性是由迷走神经调节的。然而，臭氧诱导高反应性的机制在单次接触臭氧后3天内发生了变化。急性高反应性是由于神经元M2受体抑制功能的丧失和随后乙酰胆碱释放的增加。长期以来，高反应性是由P物质介导的，也来自副交感神经。嗜酸性粒细胞在臭氧后立即介导神经元M2功能障碍，2天后仍然介导乙酰胆碱释放增加，但现在是通过一种独立于M2受体丢失的机制。在一次臭氧暴露3天后，嗜酸性粒细胞刺激副交感神经表达和释放P物质，这是一种通常仅限于感觉神经的神经递质。嗜酸性粒细胞介导了所有这些效应，因为嗜酸性粒细胞耗尽或阻止迁移到肺部阻止了臭氧引起的神经功能变化。我们的假设是，臭氧诱导的高反应性需要嗜酸性粒细胞与呼吸道神经之间的相互作用，从而导致副交感神经对ACh、P物质及其受体的表达和释放的急性和慢性变化。为了解决这一假设，我们将1)确定在分离的副交感神经中，什么机制(嗜酸性粒细胞趋化因子、细胞间黏附分子、血管细胞黏附分子)介导嗜酸性粒细胞向呼吸道神经的募集，以及细胞因子肿瘤坏死因子和白介素1如何影响嗜酸性粒细胞募集。2)确定嗜酸性粒细胞如何诱导副交感神经中P物质的表达。3)这些研究包括检测嗜酸性粒细胞黏附或释放细胞因子如神经生长因子和LIF所启动的信号机制，以诱导P物质的表达。4)使用阻断抗体和受体拮抗剂来确定臭氧通过嗜酸性粒细胞在体内诱导副交感神经中P物质的机制。预计这些研究将导致对嗜酸性粒细胞与神经的相互作用以及对臭氧高反应性的多种机制有更深入的了解。

DESCRIPTION (provided by applicant): Ozone mediated hyperresponsiveness is mediated by the vagus nerves. However, the mechanisms of ozone induced hyperreaactivity change over 3 days after a single exposure to ozone. Acutely, hyperreactivity is due to loss of inhibitory neuronal M2 receptor function and subsequent increased acetylcholine release. Chronically, hyperreactivity is mediated by substance P, also from parasympathetic nerves. Eosinophils mediate neuronal M2 dysfunction immediately after ozone, and 2 days later still mediate increased acetylcholine release but now by a mechanism separate from M2 receptor loss. 3 days after a single ozone exposure, eosinophils stimulate parasympathetic nerves to express and release substance P, a neurotransmitter normally limited to sensory nerves. Eosinophils mediate all of these effects, as eosinophil depletion or blockade of migration into the lungs prevents ozone induced changes in nerve function. It is our hypothesis that ozone induced hyperreactivity requires an interaction between eosinophils and airway nerves that leads to acute and chronic changes in expression and release of ACh, substance P and their receptors by the parasympathetic nerves. To address this hypothesis we will 1) determine in isolated parasympathetic nerves what mechanisms (eotaxin, ICAM , VCAM) mediate eosinophil recruitment to airway-nerves and how TNF( and IL-1(, cytokines increased by ozone exposure, affect eosinopihl recruitment. 2) Determine how eosinophils induce expression of substance P in parasympathetic nerves. 3) These studies include examining signalling mechanisms initiated by eosinophils adhesion or release of cytokines such as nerve growth factor and LIF from eosinophils that induce substance P expression. 4) Using blocking antibodies and receptor antagonists to determine mechanisms by which ozone, via eosinophiils, induces substance P in parasympathetic nerves in vivo. It is anticipated that these studies will lead to a greater understanding of the interaction of eosinophils with nerves and the multiple mechanisms underlying hyperreactivity to ozone.