Obesity and Airway Responsiveness

描述(申请人提供)：肥胖是哮喘的一个重要危险因素。我们建议研究这种关系的机制基础。我们的数据表明，肥胖小鼠的呼吸道反应性增强，并且肥胖小鼠对常见哮喘诱因的反应增强。肥胖患者的血清脂联素水平降低，我们的数据表明，外源性脂联素可以减轻与卵蛋白致敏和气道攻击相关的气道炎症和高反应性。我们的数据还显示，卵清蛋白攻击降低了血清脂联素和肺脂联素受体的表达。此外，呼吸道平滑肌(ASM)细胞表达脂联素受体，并随着细胞功能的改变而对脂联素做出反应。根据这些数据，我们假设脂联素既有抗炎作用，也有对ASM的直接作用，从而减轻哮喘的素质，而且肥胖相关的血清脂联素的下降降低了这种激素的保护作用。为了解决这一假设，我们将测量暴露在臭氧或过敏原下的野生型小鼠、脂联素缺陷小鼠和T-钙粘蛋白缺陷小鼠的气道反应性、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。我们还将确定外源性脂联素是否可以逆转肥胖小鼠固有的呼吸道高反应性，以及对过敏原和臭氧的反应增加。由于ASM是哮喘的关键效应细胞，而且ASM细胞表达脂联素受体，我们还将检测脂联素对小鼠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机制和重塑。由于在其他类型的细胞中，脂联素的作用是通过AMP激酶(AMPK)的激活来介导的，所以我们将通过AMPK激活剂和AMPK的化学或分子抑制来研究AMPK在脂联素对ASM的影响中的作用。阐明脂联素在这些模型中的作用和作用机制可能会直接和迅速地影响肥胖相关哮喘的治疗。小结：肥胖是哮喘的一个重要危险因素。这项研究项目的目标是试图了解肥胖是如何导致或加重哮喘的。我们研究的重点是脂肪细胞产生的一种荷尔蒙。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。

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.