Impact of obesity on airway responses to air pollution

描述（由申请人提供）：肥胖是一个重要的公共卫生问题，是心血管疾病、II型糖尿病、某些形式的癌症和哮喘的风险因素。初步数据表明，肥胖者对空气污染的易感性也是“危险的”，空气污染是哮喘的诱因之一。本提案的目的是使用肥胖的动物模型来检查肥胖和哮喘之间关系的机制基础，使用肺对空气污染物臭氧（O3）的反应作为结果指标。初步数据表明，肥胖小鼠比瘦小鼠有更大的O3诱导的气道炎症和气道高反应性。我们的假设是，肥胖的全身炎症增加，特别是IL-6和TNF α的升高，引发肺细胞对吸入污染物的反应，具有更大的炎症反应和增强的肺功能变化。此外，我们假设这种全身性炎症是脂肪组织来源的。将采用两种类型的肥胖小鼠，均以C57 BL/6为背景：Cpefat小鼠和高脂肪饮食小鼠。将瘦小鼠和肥胖小鼠暴露于过滤空气或O3。暴露后，将评估肺力学和气道对乙酰甲胆碱的反应性，进行支气管肺泡灌洗（BAL），并测量损伤和炎症的BAL标志物。从肺和腹部脂肪制备RNA，并通过真实的时间PCR分析炎症基因mRNA表达。还将分析血清中肥胖全身性炎症的标志物。在目标1中，我们将确定肥胖相关的O3反应增加是否与肥胖发展过程中脂肪组织炎症基因，特别是IL-6和TNF α的表达在时间上相对应。在目标2中，我们将通过基因或抗体消除IL-6和TNF α，并通过实验增加全身IL-6和TNF α，以检查IL-6和TNF α在肥胖对肺对O3反应的影响中的作用。在目标3中，我们将检验这一假设，即浸润肥胖小鼠脂肪组织的巨噬细胞是增加肥胖小鼠气道对O3反应的炎症分子的来源。为了做到这一点，我们将对小鼠进行致命的照射，以消除造血干细胞，然后用基因改变小鼠的胎肝细胞重建它们。了解肺对空气污染的反应增强的机制基础，可能会导致治疗策略，减少对空气污染的反应，在这一风险人群。

DESCRIPTION (provided by applicant): Obesity is an important public health problem that is a risk factor for cardiovascular disease, type II diabetes, some forms of cancer, and for asthma. Preliminary data indicates that the obese are also "at risk" in terms of their susceptibility to air pollution, one of the triggers for asthma. The purpose of this proposal is to use animal models of obesity to examine the mechanistic basis for the relationship between obesity and asthma, using pulmonary responses to the air pollutant ozone (O3) as the outcome indicator. Preliminary data indicates obese mice have greater O3-induced airway inflammation and airway hyperresponsiveness than lean mice. Our hypothesis is that the increased systemic inflammation of obesity, particularly elevations in IL-6 and TNFa, prime lung cells to respond to inhaled pollutants with greater inflammatory responses and enhanced changes in lung function. Moreover, we hypothesize that this systemic inflammation is adipose tissue derived. Two types of obese mice will be employed, both on a C57BL/6 background: Cpefat mice and mice on high fat diets. Lean and obese mice will be exposed to filtered air or O3. After exposure, pulmonary mechanics and airway responsiveness to methacholine will be assessed, bronchoalveolar lavage (BAL) performed, and BAL markers of injury and inflammation measured. RNA will be prepared from the lungs and abdominal fat and analyzed for inflammatory gene mRNA expression by real time PCR. Serum will also be analyzed for markers of obese systemic inflammation. In aim 1, we will determine whether obesity-related increases in responses to O3 correspond temporally with the expression of adipose tissue inflammatory genes, particularly IL-6 and TNFa, during the development of obesity. In aim 2, we will ablate IL-6 and TNFa genetically or with antibodies, and increase systemic IL-6 and TNFa experimentally, to examine the role of IL-6 and TNFa in the effects of obesity on lung responses to O3. In aim 3, we will examine the hypothesis that macrophages that infiltrate adipose tissue of obese mice are the source of the inflammatory molecules that augment airway responses to O3 in obesity. To do so, we will lethally irradiate mice to eradicate hematopoietic stem cells and then reconstitute them with fetal liver cells from genetically altered mice. Understanding the mechanistic basis for the augmented pulmonary responses to air pollution may lead to therapeutic strategies for reductions in responses to air pollution in this at risk population.