Effects of Obesity on Airway Caliber and Airway Smooth Muscle Function

描述（由申请人提供）：在过去的二十年中，肥胖和哮喘的患病率显著增加。流行病学研究表明肥胖与气道高反应性（AHR）呈正相关，AHR是哮喘病理生理学的定义特征之一。尽管肥胖对气道的炎症和机械作用都被认为是可能的机制，但迄今为止，大多数研究都集中在肥胖的炎症介导作用上。然而，鉴于肥胖与已知与哮喘相关的炎症标志物之间缺乏关联，必须考虑其他机制，包括肥胖对AHR的机械作用。因此，我们的总体目标是确定肥胖对气道口径、气道平滑肌（ASM）张力和深吸气（DI）反应的机械影响，这些特征先前被证明与AHR有关。我们假设肥胖引起AHR的机械效应是通过降低气道上的力导致气道狭窄、ASM张力增加和DI反应受损。我们建议使用高分辨率CT研究年龄、性别、种族和身高密切匹配的四组（15例肥胖哮喘患者、15例非肥胖哮喘患者、15例肥胖非哮喘患者和15例对照）。此外，我们将使用改良的甲胆碱刺激来评估ASM对DI的反应，以研究肥胖对支气管保护和支气管收缩在肥胖控制哮喘状态中的作用。获得这个为期3年的奖项将促进我作为临床研究者的职业发展：1)为我提供支持时间来进行与本提案相关的教学培训；2)通过实施拟议的研究计划和与参与者直接实践经验来扩展我的技术技能；3)为我提供过渡到独立研究者所需的时间和支持。相关性（见说明）：拟议的项目将1)解决我们在肥胖的机械效应导致AHR的机制方面的重要知识空白；2)为这一高危人群的哮喘管理确定新的潜在的非药物靶点；3)作为一个平台来获得必要的经验和技能，以实现我成为一名独立的肺生理学临床研究者的最终目标。（摘要结束）

DESCRIPTION (provided by applicant): The prevalence of obesity and asthma has significantly increased over the past two decades. Epidemiologic studies show a positive association between obesity and ainway hyperresponsiveness (AHR), one of the defining features of asthma pathophysiology. Although both the inflammatory and mechanical effects of obesity on the airways have been implicated as possible mechanisms, the majority of studies to date have focused on the inflammatory-mediated effects of obesity. However, given the observed lack of association between obesity and inflammatory markers known to be associated with asthma, other mechanisms must be considered, including the mechanical effects of obesity on AHR. Thus our overall aim is to determine the mechanical effects of obesity on ainway caliber, ainway smooth muscle (ASM) tone and deep inspiration (DI) response, features previously shown to be involved in AHR. We hypothesize that the mechanical effects of obesity cause AHR by decreasing forces on the airways leading to airway narrowing and increased ASM tone and impairment in DI response. We propose to study four groups (15 obese asthmatics, 15 non-obese asthmatics, 15 obese non-asthmatics, and 15 controls) closely matched by age, sex, race and height using high resolution CT. In addition, we will assess ASM response to DI using a modified methacholine challenge to study the effects of obesity on bronchoprotection and bronchoconstriction in obesity controlling for asthma status. Receipt of this 3-year award will enhance my career development as a clinical investigator by 1) providing me with supported time to pursue didactic training relevant to this proposal, 2) expanding my technical skills through implementation of the proposed research plan and by having direct hands-on experience with participants, 3) providing me the time and support necessary to transition into an independent investigator. RELEVANCE (See instructions): The proposed project will 1) address important gaps in our knowledge regarding the mechanisms by which the mechanical effects of obesity contribute to AHR; 2) identify new potential non-pharmaceutical target(s) for the management of asthma in this high risk population; 3) serve as a platform to gain the experience and skills necessary to achieve my ultimate goal of becoming an independent clinical investigator in pulmonary physiology. (End of Abstract)