Ozone inhibition of Neuronal m2 receptor function

臭氧抑制神经元 m2 受体功能

• 批准号: 6988166
• 负责人: ALLISON Deborah FRYER
• 金额: $ 34.31万
• 依托单位: OREGON HEALTH & SCIENCE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1996
• 资助国家: 美国
• 起止时间: 1996-05-01 至 2009-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6988166
• 关键词: bronchomotion; cell adhesion molecules; cell migration; eosinophil; guinea pigs; immunocytochemistry; muscarinic receptor; ozone; parasympathetic nervous system; pollution related respiratory disorder; receptor expression; receptor sensitivity; respiratory hypersensitivity; substance P; tissue /cell culture; vascular cell adhesion molecule; vascular smooth muscle nervous control; vasomotion

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.

描述（由申请人提供）：臭氧介导的高反应性由迷走神经介导。 然而，臭氧引起的过度反应的机制在单次暴露于臭氧后3天内发生变化。急性高反应性是由于抑制性神经元M2受体功能的丧失和随后增加的乙酰胆碱释放。慢性高反应性由P物质介导，也来自副交感神经。嗜酸性粒细胞介导的神经元M2功能障碍后立即臭氧，2天后仍然介导增加乙酰胆碱释放，但现在的机制独立于M2受体的损失。单次臭氧暴露后3天，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。嗜酸性粒细胞介导所有这些作用，因为嗜酸性粒细胞耗竭或阻断向肺中的迁移可防止臭氧诱导的神经功能变化。这是我们的假设，臭氧引起的高反应性需要嗜酸性粒细胞和气道神经之间的相互作用，导致急性和慢性的变化，表达和释放乙酰胆碱，P物质及其受体的副交感神经。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（嗜酸细胞活化趋化因子、ICAM、VCAM）介导嗜酸性粒细胞募集到气道神经，以及TNF α和IL-1 β（臭氧暴露增加的细胞因子）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)这些研究包括检查由嗜酸性粒细胞粘附或从嗜酸性粒细胞释放诱导P物质表达的细胞因子如神经生长因子和LIF引发的信号传导机制。4)使用阻断抗体和受体拮抗剂，以确定机制，臭氧，通过嗜酸性粒细胞，诱导P物质在体内副交感神经。预计这些研究将导致更好地了解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。