Ozone ALTERS Airway Smooth Muscle FUNCTION IN ASTHMA

臭氧改变哮喘患者的气道平滑肌功能

基本信息

批准号：
7058744
负责人：
Reynold Alexander Panettieri
金额：
$ 46.43万
依托单位：
UNIVERSITY OF PENNSYLVANIA
依托单位国家：
美国
项目类别：
财政年份：
2005
资助国家：
美国
起止时间：
2005-05-01 至 2009-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7058744
关键词：
allergens asthma bronchomotion calcium flux human tissue inflammation interleukin 1 laboratory mouse muscle function muscle strength neutrophil ozone phosphatidylinositols phosphoprotein phosphatase respiratory hypersensitivity serine threonine protein kinase tissue /cell culture tumor necrosis factor alpha

项目摘要

DESCRIPTION (provided by applicant): Although ozone (O3) induces asthma exacerbations, methacholine airway hyperresponsiveness (AHR) and neutrophilic airway inflammation associated with increases in levels of TNFalpha and IL-1beta, the mechanisms that mediate ozone effects in asthma and in allergen-induced AHR remain unknown. Preliminary data shows that ozone and allergen in combination markedly increased airway neutrophils, baseline airway tone, AHR and KCl-induced airway smooth muscle (ASM) force generation, suggesting in part a direct effect on ASM excitation-contraction coupling. We postulate that O3 enhances allergen-induced AHR in mice by promoting neutrophil-mediated airway inflammation and by directly increasing agonist-induced ASM force generation. To test these hypotheses, in Aim 1, the role of neutrophils, TNFalpha and IL-1beta in mediating ozone-enhanced allergic AHR and airway inflammation will be determined using strategies to deplete or augment airway neutrophils and/or cytokines. Lung resistance and Penh will measure AHR and airway inflammation will be assessed in bronchoalveolar lavage by characterizing cell profiles and levels of cytokines and chemokines. In Aim 2, using human ASM cells and murine tracheal rings from allergen-and ozone-treated wild type and knockout mice, the effects of ozone on critical ASM excitation-contraction coupling pathways will be defined. These essential pathways include ozone effects on agonist-induced: calcium responses, phosphoinositide metabolism and calcium sensitization processes of RhoA/RhoA kinase activation and of myosin light chain phosphatase inhibition. The sufficiency and necessity of each agonist-induced signaling event in mediating ozone and allergen effects on ASM cell function or on tracheal ring force generation will be determined. These studies will identify the mechanisms by which ozone enhances allergen-induced AHR and provide insight into new therapeutic targets to prevent asthma exacerbations and decrease asthma morbidity and mortality.

描述（由申请人提供）：尽管臭氧（O3）会引起哮喘恶化，甲基苯胺气道高反应性（AHR）以及中性粒细胞性气道炎症与TNFALPHA和IL-1BETA水平的升高相关，而介导臭氧在AsthMA和Asthma中介导臭氧的机制以及在异性ant虫中介导的臭氧介导的机制仍然不知所措，并且不知名。初步数据表明，组合中的臭氧和过敏原显着增加了气道中性粒细胞，基线气道音调，AHR和KCL诱导的气道平滑肌（ASM）力的产生，这部分暗示了ASM激发诱导耦合的直接影响。我们假设O3通过促进中性粒细胞介导的气道炎症并直接增加激动剂诱导的ASM力产生，从而增强了过敏原诱导的小鼠AHR。为了检验这些假设，在AIM 1中，中性粒细胞，TNFALPHA和IL-1BETA在介导臭氧增强的过敏AHR和气道炎症中的作用将使用耗尽或增强气道中性粒细胞和/或细胞因子的策略来确定。肺阻力和PENH将通过表征细胞谱以及细胞因子和趋化因子的水平来评估支气管肺泡灌洗中的AHR，气道炎症将进行评估。在AIM 2中，使用过敏原和臭氧处理的野生型和基因敲除小鼠的人类ASM细胞和鼠气管环，将定义臭氧对关键ASM激发诱导偶联途径的影响。这些基本途径包括对激动剂诱导的臭氧作用：钙反应，磷酸肌醇代谢和RhoA/RhoA激酶激活和肌球蛋白轻链磷酸酶抑制的钙敏化过程。将确定每个激动剂诱导的信号事件的充分性和必要性在介导臭氧和过敏原对ASM细胞功能或气管环力产生的效果中的充分性和必要性。这些研究将确定臭氧增强过敏原诱导的AHR的机制，并洞悉新的治疗靶标，以防止哮喘加重并降低哮喘的发病率和死亡率。