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）：虽然臭氧 (O3) 会诱发哮喘加重、乙酰甲胆碱气道高反应性 (AHR) 以及与 TNFα 和 IL-1β 水平增加相关的中性粒细胞气道炎症，但介导臭氧对哮喘和过敏原影响的机制是：诱发的 AHR 仍未知。初步数据显示，臭氧和过敏原联合使用可显着增加气道中性粒细胞、基线气道张力、AHR 和 KCl 诱导的气道平滑肌 (ASM) 力的产生，这在一定程度上表明对 ASM 兴奋-收缩耦合有直接影响。我们假设 O3 通过促进中性粒细胞介导的气道炎症和直接增加激动剂诱导的 ASM 力的产生来增强小鼠中过敏原诱导的 AHR。为了检验这些假设，在目标 1 中，将使用消耗或增加气道中性粒细胞和/或细胞因子的策略来确定中性粒细胞、TNFα 和 IL-1β 在介导臭氧增强的过敏性 AHR 和气道炎症中的作用。肺阻力和 Penh 将测量 AHR，并通过表征细胞特征以及细胞因子和趋化因子的水平，在支气管肺泡灌洗中评估气道炎症。在目标 2 中，将使用人类 ASM 细胞和来自经过敏原和臭氧处理的野生型和基因敲除小鼠的小鼠气管环，定义臭氧对关键 ASM 兴奋-收缩耦合途径的影响。这些重要途径包括臭氧对激动剂诱导的钙反应、磷酸肌醇代谢以及 RhoA/RhoA 激酶激活和肌球蛋白轻链磷酸酶抑制的钙敏化过程的影响。将确定每个激动剂诱导的信号事件在介导臭氧和过敏原对 ASM 细胞功能或气管环力产生的影响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，并深入了解新的治疗目标，以预防哮喘恶化并降低哮喘发病率和死亡率。