Impact of obesity on airway responses to air pollution

肥胖对空气污染气道反应的影响

• 批准号: 7433197
• 负责人: Stephanie A Shore
• 金额: $ 32.57万
• 依托单位: HARVARD SCHOOL OF PUBLIC HEALTH
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-07-01 至 2010-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7433197
• 关键词: Adipocytes; Adipose tissue; Adolescent; Air; Air Pollutants; Air Pollution; Animal Model; Antibodies; Asthma; Blood; Breathing; Bronchoalveolar Lavage; C57BL/6 Mouse; CCL2 gene; Cardiovascular Diseases; Cells; Child; Chronic; Condition; Cytokine Receptors; Data; Development; Diabetes Mellitus; Diet; Elevation; Epidemic; Exposure to; Fatty acid glycerol esters; Fetal Liver; Flow Cytometry; Gene Expression; Genes; Harvest; Hematopoietic stem cells; Hepatocyte; Implant; Inflammation; Inflammatory; Inflammatory Response; Injury; Insulin Resistance; Interleukin-6; Lead; Lung; Lung diseases; Malignant Neoplasms; Measurement; Measures; Mechanics; Modality; Modeling; Mus; Non-Insulin-Dependent Diabetes Mellitus; Obese Mice; Obesity; Outcome; Overweight; Ozone; Polymerase Chain Reaction; Populations at Risk; Predisposition; Proteins; Public Health; Pump; Purpose; RNA; Respiratory physiology; Risk; Risk Factors; Role; Serum; Source; Staining method; Stains; Stimulus; Syndrome; TNFRSF1A gene; TNFRSF1B gene; Techniques; Therapeutic; Time; Tumor Necrosis Factor Receptor; abdominal fat; air filter; airway hyperresponsiveness; airway inflammation; base; chemokine; cytokine; instrument; mRNA Expression; macrophage; methacholine; pollutant; pulmonary function; reconstitution; research study; response

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.

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危险因素。初步数据显示，就空气污染的易感性而言，肥胖者也有“风险”，空气污染是哮喘的诱因之一。这项建议的目的是使用肥胖的动物模型来研究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(臭氧)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臭氧诱导的呼吸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TNFa的升高，促使肺细胞对吸入污染物做出更大的炎症反应和肺功能的增强变化。此外，我们假设这种全身性炎症是脂肪组织来源的。将使用两种类型的肥胖小鼠，均以C57BL/6为背景：Cpe胖小鼠和高脂饮食小鼠。瘦小和肥胖的小鼠将暴露在过滤空气或臭氧中。暴露后，将评估肺力学和呼吸道对乙酰甲胆碱的反应性，进行支气管肺泡灌洗(BAL)，并测量BAL损伤和炎症标志物。将从肺和腹部脂肪中提取RNA，并用实时荧光定量聚合酶链式反应分析炎症基因的mRNA表达。还将分析血清中肥胖全身炎症的标志物。在目标1中，我们将确定肥胖相关的臭氧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TNFa的表达在时间上相对应。在目标2中，我们将从基因上或用抗体去除IL-6和TNFa，并在实验上增加全身IL-6和TNFa，以探讨IL-6和TNFa在肥胖对O_3肺反应中的作用。在目标3中，我们将检验这样一种假设，即渗透到肥胖小鼠脂肪组织的巨噬细胞是炎症分子的来源，这些炎症分子增强了肥胖小鼠对臭氧的呼吸道反应。要做到这一点，我们将对小鼠进行致命性照射，以根除造血干细胞，然后用转基因小鼠的胎肝细胞重建它们。了解肺部对空气污染反应增强的机制基础可能会导致在这一高危人群中减少对空气污染的反应的治疗策略。