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Ozone inhibition of Neuronal m2 receptor function

臭氧抑制神经元 m2 受体功能

基本信息

批准号：
7446628
负责人：
ALLISON Deborah FRYER
金额：
$ 32.85万
依托单位：
OREGON HEALTH & SCIENCE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
1996
资助国家：
美国
起止时间：
1996-05-01 至 2010-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7446628
关键词：
Acetylcholine Acute Address Adhesions Affect Animals Cell Adhesion Molecules Cell Culture Techniques Cells Chronic Dexamethasone Eosinophil Major Basic Protein Eotaxin Exposure to Fc Receptor Functional disorder Grant Human Integrin alpha4beta1 Intercellular adhesion molecule 1 Interleukin-1 LIF gene Lead Lung Measures Mediating Muscarinic M2 Receptor Muscarinics Nerve Nerve Growth Factors Neuroblastoma Neurons Neurotransmitters Ozone Production Proteins Role Signal Transduction Substance P TNF gene Testing Time Transcriptional Activation Up-Regulation Vagus nerve structure Vascular Cell Adhesion Molecule-1 afferent nerve airway hyperresponsiveness chemokine cytokine day eosinophil in vivo intercellular cell adhesion molecule leukemia inhibitory factor migration ozone exposure prevent receptor receptor function receptor upregulation research study response

项目摘要

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（申请人提供）：臭氧介导的高反应性是由迷走神经介导的。然而，臭氧诱导的高反应性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神经元M2受体功能丧失和随后乙酰胆碱释放增加。慢性高反应性由P物质介导，P物质也来自副交感神经。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，但现在通过与M2受体丧失不同的机制。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，一种通常局限于感觉神经的神经递质。嗜酸性粒细胞介导所有这些影响，因为嗜酸性粒细胞耗竭或阻断向肺部的迁移可防止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和气道神经之间的相互作用，从而导致副交感神经对乙酰胆碱、P物质及其受体的表达和释放发生急性和慢性变化。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（eotaxin， ICAM， VCAM）介导嗜酸性粒细胞向气道神经的募集，以及臭氧暴露增加的细胞因子TNF（和IL-1）如何影响嗜酸性粒细胞的募集。2)确定嗜酸性粒细胞如何诱导副交感神经P物质的表达。3)这些研究包括检查嗜酸性粒细胞粘附或释放细胞因子（如神经生长因子和LIF）诱导P物质表达所引发的信号传导机制。4)利用阻断抗体和受体拮抗剂确定臭氧在体内通过嗜酸性粒细胞诱导副交感神经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臭氧高反应性的多种机制有更深入的了解。