Obese Allergic Asthma and the Impact of Weight Loss on Airway Epithelial Function

摘要 在美国，大多数严重的哮喘患者都是肥胖的，而在肥胖的哮喘患者中， 变应性（EOA）疾病具有特别严重疾病。代谢，免疫， 和生理改变，以及它们如何受到体重减轻的影响，在EOA肥胖中仍然知之甚少。 哮喘尤其引人注目的是，人们对脂肪源性介质如何影响肺， 气道上皮线粒体功能的改变增加了基线和变应原诱导的细胞因子 产生导致肥胖过敏性哮喘特征的肺结构和生理改变。我们 早发性过敏性肥胖哮喘患者内脏脂肪循环因子研究 导致气道上皮细胞线粒体功能障碍，增加对过敏原触发物的敏感性， 可溶性因子的释放放大了肥胖症患者的EOA哮喘，这些事件可通过减肥逆转。我们 将通过使用从入组受试者中收集的材料进行的研究组合来解决这一假设 在对接受减肥手术的（EOA）哮喘患者的纵向研究中，以及通过使用新的小鼠 模型 在具体目标#1中，我们将确定体重减轻对体内过敏原激发反应的影响， 肥胖过敏性哮喘患者以及这与线粒体活性氧变化的关系， 钙处理影响气道上皮细胞对变应原的细胞因子应答。 在具体目标2中，我们将确定肥胖哮喘患者中哪些循环介质升高，以及 内脏脂肪组织产生的因子诱导气道上皮细胞分泌细胞因子。我们将 定量测定血浆和脂肪组织中的特异性蛋白，然后培养人细支气管 上皮（HBE）细胞和鼻上皮细胞与血浆或脂肪组织条件培养基， 和HDM提取物的存在以鉴定分泌的上皮来源的细胞因子。我们还将分析主要 正常体重和肥胖哮喘患者在减肥手术前后的鼻上皮细胞， 确定细胞因子表达和产生的差异。最后，我们要中和气道上皮细胞- 激活血浆中的介质以确定对上皮因子分泌的影响。 在具体目标#3中，我们将确定脂肪激活的气道上皮细胞对功能的影响。 使用饮食诱导的肥胖和手术或饮食减肥的新型小鼠模型，以及 体内中和脂肪和上皮源性因子，以检查对过敏性哮喘的影响 与肥胖有关。将评估气道上皮细胞线粒体代谢的改变， 评估介质抑制对肺结构和乙酰甲胆碱反应性的影响。 这些临床和临床前研究将提供一个更好的了解如何改变气道细胞功能 受肥胖的影响，并影响肥胖相关哮喘的发病机制， 这减肥elevening临床效益，并将测试潜在的生物疗法的疗效，在有价值的 临床前疾病模型。

ABSTRACT The majority of severe asthmatics in the U.S. are obese, and among obese asthmatics, those with early-onset allergic (EOA) disease suffer with particularly severe disease. Relationships between metabolic, immunologic, and physiologic alterations, and how they are affected by weight loss, remain poorly understood in EOA obese asthma. Especially striking is a gap in knowledge of how adipose-derived mediators affect the lung to cause alterations in airway epithelial mitochondrial function that augment baseline and allergen-induced cytokine production to cause the structural and physiologic lung alterations characteristic of obese allergic asthma. We hypothesize that circulating factors from visceral adipose tissue of early onset allergic (EOA) obese asthmatics cause mitochondrial dysfunction in airway epithelial cells that increases sensitivity to allergenic triggers, and the release of soluble factors that amplify EOA asthma in obesity, events that are reversed by weight loss. We will address this hypothesis through a combination of studies using materials collected from subjects enrolled in a longitudinal study of (EOA) asthmatics undergoing bariatric surgery, as well as by using novel mouse models. In Specific Aim #1, we will determine the effects of weight loss on the response to in vivo allergen challenge in obese allergic asthmatic patients and how this relates to changes in mitochondrial reactive oxygen species and calcium handling affecting cytokine response to allergen in airway epithelial cells. In Specific Aim #2, we will determine which circulating mediators elevated in obese asthmatics, as well as factors produced from visceral adipose tissue, induce cytokine secretion from airway epithelium. We will quantitate specific proteins in the plasma and made by adipose tissue, then culture human bronchiolar epithelial (HBE) cells and nasal epithelial cells with plasma or adipose tissue-conditioned media in the absence and presence of HDM extract to identify secreted epithelial-derived cytokines. We will also analyze primary nasal epithelial cells from normal weight and obese asthmatics prior to and following bariatric surgery to determine differences in cytokine expression and production. Finally, we will neutralize airway epithelial- activating mediators in the plasma to determine the impact on secretion of epithelial factors. In Specific Aim #3, we will determine the consequences of adipose-activated airway epithelial cells on features of asthma using novel mouse models of diet-induced obesity and surgical or dietary weight loss, as well as the in vivo neutralization of adipose- and epithelial-derived factors, to examine the impact on allergic asthma associated with obesity. Airway epithelial cells will be assessed for alterations in mitochondrial metabolism and the impact of mediator inhibition on lung structure and methacholine responsiveness will be assessed. These clinical and preclinical studies will provide a better understanding of how altered airway cellular function is affected by obesity and impacts upon the pathogenesis of obesity-associated asthma, the mechanisms by which weight loss elicits clinical benefit, and will test the efficacy of potential biological therapeutics in valuable preclinical disease models.