Lung Defense Mechanisms from Environmental Ozone

超出所提供的空间。在过去的20年里，工业化国家的哮喘发病率急剧上升。目前，美国约有1700万人被诊断患有哮喘，流行病学和人体临床研究表明，吸入光化学空气污染物臭氧会加剧哮喘。这种恶化可表现为两种反应。首先，哮喘患者在急性暴露于臭氧时，有更大的肺功能减退、症状和气道炎症。其次，急性吸入臭氧已被证明会增加特应性哮喘患者对吸入过敏原的反应性。臭氧-哮喘相互作用的潜在机制尚不清楚。我们假设这些臭氧-哮喘相互作用是由中枢神经系统的反射反应或来自气道传入神经末梢的神经肽释放介导的。为了验证这一假设，我们设计了以下四个具体目标：1、在卵清蛋白致敏和刺激的褐-挪威大鼠中，我们将通过神经周围辣椒素治疗阻断迷走神经c纤维传导，然后将c纤维阻滞与迷走神经mylenated纤维冷阻滞相结合，确定哪组肺迷走神经传入（myleated vs. nonmyleated）有助于与臭氧-哮喘相互作用相关的气道反应。具体目标2，使用单神经纤维记录技术，我们将检查布朗-挪威大鼠急性吸入臭氧后迷走神经传入纤维的放电模式，这些大鼠已致敏并受到卵清蛋白的刺激，并在随后的过敏原气溶胶刺激期间。具体目标3，我们将研究神经肽、P物质（SP）和降钙素基因相关肽（CGRP）对炎症/免疫细胞和上皮细胞的迁移和细胞因子产生的影响。具体目标4，我们将研究SP、CGRP和血管活性肠肽（VIP）在正常大鼠和卵清蛋白致敏大鼠急性吸入臭氧后气道上皮和淋巴结增殖反应中的作用。从这些研究中获得的信息将有助于确定在过敏原致敏动物急性暴露于臭氧时肺感觉神经介导的臭氧-哮喘机制，并可能为影响涉及气道上皮损伤的疾病的基本机制提供见解。网站性能 ======================================== 节结束 ===========================================

EXCEED THE SPACE PROVIDED. The incidence of asthma has increased dramatically in industrialized countries over the last 20 years. Currently approximately 17 million people have been diagnosed with asthma in the U.S. Epidemiological and human clinical studies have shown that inhalation of the photochemical air pollutant ozone exacerbates asthma. This exacerbation can be characterized by two responses. First, asthmatics have been shown to have greater pulmonary function decrements, symptoms and airway inflammation when acutely exposed to ozone. Second, the acute inhalation of ozone has been shown to increase the responsiveness to an inhaled allergen in patients with atopic asthma. The underlying mechanisms involved in these ozone-asthma interactions remain undefined. We hypothesize that these ozone-asthma interactions are mediated by either reflex responses involving the central nervous system or the release of neuropeptides from afferent nerve endings located in the airway. To test this hypothesis we have devised the following four specific aims: Specific Aim 1,In Brown-Norway rats sensitized and challenged with ovalbumin, we will determine which group of lung vagal afferents (myleinated vs. nonmyleinated) contribute to the airway responses associated with ozone-asthma interactions by blocking vagal C-fiber conduction with perineural capsaicln treatment and then combining the C-fiber block with cold block of mylenated vagal fibers. Specific Aim 2, using single nerve fiber recording techniques we will examine the discharge pattern of vagal afferent fibers following an acute inhalation of ozone in Brown-Norway rats that have been sensitized and challenged with ovalbumin and during a subsequent allergen aerosol challenge. Specific Aim 3, we will examine the influence that the neuropeptides, substance P (SP) and calcitonin gene related peptide (CGRP) have on the migration of and cytokine production from inflammatory/immunecells and epithelial cells. Specific Aim 4, we will examine the role of SP, CGRP and vasoactive intestinal peptide (VIP) in airway epithelial and lymph node proliferative responses following an acute inhalation of ozone in normal and ovalbumin sensitized and challenged rats. The information obtained from these studies will help define the ozone-asthma mechanisms that lung sensory nerves mediate during acute exposure to ozone in allergen sensitized animals and may provide insight into basic mechanisms that influence diseases that involve airway epithelial injury. PERFORMANCE SITE ========================================Section End===========================================