Lung Defense Mechanisms from Environmental Ozone

环境臭氧的肺部防御机制

• 批准号: 6839481
• 负责人: EDWARD S SCHELEGLE
• 金额: $ 29.7万
• 依托单位: UNIVERSITY OF CALIFORNIA AT DAVIS
• 依托单位国家: 美国
• 财政年份: 1996
• 资助国家: 美国
• 起止时间: 1996-06-04 至 2006-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6839481
• 关键词: C fiber; action potentials; afferent nerve; environmental toxicology; immunocytochemistry; inflammation; laboratory rat; lung alveolus; lung injury; mucosal immunity; neuropeptides; neurophysiology; oxidative stress; ozone; pulmonary respiration; pulmonary stretch receptors; respiratory airflow measurement; respiratory epithelium; respiratory toxin; statistics /biometry; substance K; substance P; tachykinin; transmission electron microscopy

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===========================================

超出所提供的空间。过去 20 年来，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。流行病学和人类临床研究表明，吸入光化学空气污染物臭氧会加剧哮喘。这种恶化可以通过两种反应来表征。首先，哮喘患者在急性接触臭氧时，会出现更严重的肺功能下降、症状和气道炎症。其次，急性吸入臭氧已被证明可以增加特应性哮喘患者对吸入过敏原的反应。这些臭氧与哮喘相互作用的潜在机制仍不清楚。我们假设这些臭氧与哮喘的相互作用是由涉及中枢神经系统的反射反应或气道传入神经末梢释放的神经肽介导的。为了检验这一假设，我们设计了以下四个具体目标： 具体目标 1，在用卵清蛋白致敏和激发的 Brown-Norway 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 纤维阻滞与冷阻结合起来，确定哪组肺迷走神经传入神经（有髓神经传入神经与无髓神经传入神经）有助于与臭氧-哮喘相互作用相关的气道反应。 有髓迷走神经纤维。具体目标 2，使用单神经纤维记录技术，我们将检查棕色挪威大鼠急性吸入臭氧后迷走神经传入纤维的放电模式，这些大鼠已被卵清蛋白致敏和激发，并在随后的过敏原气溶胶激发过程中。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，我们将检查正常大鼠和卵清蛋白致敏和攻击大鼠急性吸入臭氧后 SP、CGRP 和血管活性肠肽 (VIP) 在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过敏原致敏动物急性暴露于臭氧期间肺感觉神经介导的臭氧哮喘机制，并可能提供对影响涉及气道上皮损伤的疾病的基本机制的见解。表演网站==========================================章节结束===============================================

项目成果

Breathing pattern response and epithelial labeling in ozone-induced airway injury in neutrophil-depleted rats.

中性粒细胞耗竭大鼠臭氧诱导气道损伤的呼吸模式反应和上皮标记。

• DOI: 10.1165/ajrcmb.20.4.3362
• 发表时间: 1999
• 期刊: American journal of respiratory cell and molecular biology.
• 作者: Vesely,KR;Schelegle,ES;Stovall,MY;Harkema,JR;Green,JF;Hyde,DM
• 通讯作者: Hyde,DM

Activation of neurokinin-1 receptors during ozone inhalation contributes to epithelial injury and repair.

• DOI: 10.1165/rcmb.2008-0009oc
• 发表时间: 2008-09
• 期刊: American journal of respiratory cell and molecular biology
• 影响因子: 6.4
• 作者: K. Oslund;D. Hyde;L. Putney;M. F. Alfaro;W. Walby;N. Tyler;E. Schelegle

Vagal afferents contribute to exacerbated airway responses following ozone and allergen challenge.

• DOI: 10.1016/j.resp.2012.04.003
• 发表时间: 2012-05-31
• 期刊: RESPIRATORY PHYSIOLOGY & NEUROBIOLOGY
• 影响因子: 2.3
• 作者: Schelegle, Edward S.;Walby, William F.
• 通讯作者: Walby, William F.

Effect of rapid shallow breathing on the distribution of 18O-labeled ozone reaction product in the respiratory tract of the rat.

快速浅呼吸对大鼠呼吸道内18O标记臭氧反应产物分布的影响。

• DOI: 10.1080/08958370490264852
• 发表时间: 2004
• 期刊: Inhalation toxicology
• 影响因子: 2.1
• 作者: Alfaro,MarioF;Putney,Lei;Tarkington,BrianK;Hatch,GaryE;Hyde,DallasM;Schelegle,EdwardS
• 通讯作者: Schelegle,EdwardS

Differential effects of airway anesthesia on ozone-induced pulmonary responses in human subjects.

气道麻醉对人类受试者臭氧引起的肺部反应的不同影响。

• DOI: 10.1164/ajrccm.163.5.2003103
• 发表时间: 2001
• 期刊: American journal of respiratory and critical care medicine.
• 作者: Schelegle,ES;Eldridge,MW;Cross,CE;Walby,WF;Adams,WC
• 通讯作者: Adams,WC