Obesity and Airway Responsiveness

肥胖和气道反应性

• 批准号: 7435373
• 负责人: Stephanie A Shore
• 金额: $ 40.58万
• 依托单位: HARVARD SCHOOL OF PUBLIC HEALTH
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-07-01 至 2012-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7435373
• 关键词: Address; Adipocytes; Adipose tissue; Allergens; Anti-Asthmatic Agents; Anti-Inflammatory Agents; Anti-inflammatory; Asthma; Atherosclerosis; Attenuated; Binding; Binding Proteins; Biological Assay; Cell Proliferation; Cell physiology; Cells; Chemicals; Condition; Data; Disease susceptibility; Dose; Effector Cell; Event; Exposure to; Fatty acid glycerol esters; Freezing; Gene Expression; Goals; H-Cadherin; Hormones; In Vitro; Inflammation; Inflammatory; Irrigation; Knockout Mice; Lead; Lung; Lung Inflammation; Measures; Mechanics; Mediating; Mediator of activation protein; Messenger RNA; Modeling; Molecular; Molecular Weight; Mus; Nature; Obese Mice; Obesity; Obesity associated disease; Outcome; Ovalbumin; Overweight; Ozone; Patients; Phenotype; Polymerase Chain Reaction; Preparation; Property; Protein Isoforms; Protein Overexpression; Public Health; Purpose; RNA analysis; Research; Research Project Grants; Risk Factors; Role; Serum; Smooth Muscle; Smooth Muscle Myocytes; Syndrome; Techniques; Time; Vascular Smooth Muscle; Vasodilation; Visceral; Wild Type Mouse; adenylate kinase; adiponectin; airway hyperresponsiveness; airway inflammation; base; cell type; improved; mRNA Expression; methacholine; mimetics; mouse model; obesity treatment; protective effect; receptor; receptor expression; research study; respiratory smooth muscle; response; sensor

DESCRIPTION (provided by applicant): Obesity is an important risk factor for asthma. We propose to investigate the mechanistic basis for this relationship. Our data indicate that airway responsiveness is increased in obese mice and that obese mice have increased responses to common asthma triggers. Serum levels of adiponectin are reduced in obesity, and our data indicate that exogenous adiponectin attenuates the airway inflammation and hyperresponsiveness associated with ovalbumin sensitization and airway challenge in mice. Our data also show that ovalbumin challenge reduces serum adiponectin and lung adiponectin receptor expression. Moreover, airway smooth muscle (ASM) cells express adiponectin receptors and respond to adiponectin with changes in cell function. Based on these data we hypothesize that adiponectin has both anti-inflammatory effects and direct effects on ASM, which act to attenuate the asthmatic diathesis and that obesity-related decreases in serum adiponectin reduce the protective effects of this hormone. To address this hypothesis, we will measure airway responsiveness, airway inflammation, serum adiponectin, adipose tissue adiponectin mRNA expression, and lung adiponectin receptor expression in wild type mice, mice deficient in adiponectin, and mice deficient in T-cadherin, the receptor for the high molecular weight form of adiponectin, following exposure to ozone or allergen. We will also determine whether exogenous adiponectin can reverse the innate airway hyperresponsiveness and the increased responses to allergen and ozone observed in obese mice. Since ASM is a key effector cell in asthma, and since ASM cells express adiponectin receptors, we will also examine the dose related effects of adiponectin on murine ASM cells. Outcomes will include: 1) cell proliferation; 2) inflammatory gene expression; and 3) ASM mechanics and remodeling. Since in other cell types, the effects of adiponectin are mediated via AMP kinase (AMPK) activation, we will examine the role of AMPK in the effects of adiponectin on ASM using AMPK activators and chemical or molecular inhibition of AMPK. Demonstrating the role and mechanism of action of adiponectin in these models could directly and quickly impact the treatment of obesity-related asthma. Lay Summary: Obesity is an important risk factor for asthma. The goal of this research project is to try and understand how obesity causes or worsens asthma. The focus of our research is a hormone produced by fat cells. Understanding the relationship between obesity and asthma could lead to new strategies for treating asthma, particularly in patients who are overweight or obese.

描述（由申请人提供）：肥胖是哮喘的重要危险因素。我们建议调查这种关系的机制基础。我们的数据表明，肥胖小鼠的气道反应性增加，肥胖小鼠对常见哮喘触发因素的反应增加。肥胖者血清脂联素水平降低，我们的数据表明，外源性脂联素减弱与卵清蛋白致敏和小鼠气道激发相关的气道炎症和高反应性。我们的数据还表明，卵清蛋白攻击降低血清脂联素和肺脂联素受体的表达。此外，气道平滑肌（ASM）细胞表达脂联素受体，并对脂联素产生细胞功能变化的反应。基于这些数据，我们假设脂联素既有抗炎作用，又对ASM有直接作用，从而减轻哮喘素质，而肥胖相关的血清脂联素降低则降低了这种激素的保护作用。为了解决这一假设，我们将测量气道反应性，气道炎症，血清脂联素，脂肪组织脂联素mRNA表达，和肺脂联素受体表达在野生型小鼠，小鼠缺乏脂联素，和小鼠缺乏T-钙粘蛋白，脂联素的高分子量形式的受体，暴露于臭氧或过敏原。我们还将确定外源性脂联素是否可以逆转先天性气道高反应性和肥胖小鼠对过敏原和臭氧的反应增加。由于ASM是哮喘中的关键效应细胞，并且由于ASM细胞表达脂联素受体，因此我们还将研究脂联素对小鼠ASM细胞的剂量相关效应。结果将包括：1）细胞增殖; 2）炎症基因表达; 3）ASM力学和重塑。由于在其他细胞类型中，脂联素的作用是通过AMP激酶（AMPK）激活介导的，因此我们将使用AMPK激活剂和AMPK的化学或分子抑制来研究AMPK在脂联素对ASM的作用中的作用。证实脂联素在这些模型中的作用和作用机制可能会直接和快速地影响肥胖相关哮喘的治疗。摘要：肥胖是哮喘的一个重要危险因素。这个研究项目的目标是试图了解肥胖是如何导致哮喘的。我们研究的重点是脂肪细胞产生的一种激素。了解肥胖和哮喘之间的关系可能会导致治疗哮喘的新策略，特别是在超重或肥胖的患者中。