Obesity, Metabolic Syndrome and Asthma

过敏性哮喘是一种影响全球超过3亿人的疾病，通常由Th2主导的疾病驱动 对环境抗原的免疫反应。肥胖，一种困扰着全球5亿人的疾病， 与慢性炎症、促炎细胞因子产生增加和代谢功能障碍相关 导致糖尿病、心血管疾病、非酒精性脂肪性肝病和各种 癌症。最近的证据表明，存在几种哮喘“内型”--疾病亚型由 独特的潜在致病机制。“肥胖哮喘”的内型与：(1)转移 从以Th2为主的炎症向更倾向于炎症的表型转变；(2)治疗的减少 类固醇的疗效；以及(3)在患病率上明显的女性偏见。虽然临床上对这些问题达成了共识 参数，“肥胖性哮喘”潜在机制的确定因缺乏 雌性小鼠严重肥胖和哮喘的联合模型。尽管哮喘的可重复性模型是 在雄性和雌性小鼠中都实现了肥胖和代谢功能障碍的建模，很大程度上限于 雄鼠。这在很大程度上是由于雌性小鼠肥胖和代谢功能障碍的可控性差。 我们的新数据表明，将雌性小鼠安置在接近它们的温度中温带( 它们处于代谢动态平衡的温度-30-33°C)，同时补充HFD促进 严重肥胖症、肥胖症和代谢功能障碍的发展与雄性小鼠相似。 因此，我们现在能够同时评估肥胖、肥胖症、代谢功能障碍和 性对哮喘发病机制的影响。在本应用程序中，我们的两个独立但相关的特定目标寻求 验证我们的新模型概括肥胖哮喘患者的三个常见观察的能力：(1) 转向促炎状态；(2)类固醇疗效降低；(3)女性占优势。 具体目标1：确定患有代谢障碍的严重肥胖雌性小鼠是否会患上哮喘 类似于肥胖女性所描述的“肥胖哮喘”内型。使用HFD-或对照食物 饮食喂养的雄性和雌性小鼠，饲养在标准(22°C)或中温(30-33°C)条件下，我们将 在肥胖和代谢紊乱的模型上诱发实验性哮喘。实验课的特点 哮喘将与体重增加、肥胖、代谢功能障碍参数相关，在性别依赖的 举止。具体目标2：确定肥胖和代谢功能障碍是否与 雌性小鼠激素难治性哮喘。吸入性和全身性类固醇抑制实验性脑损伤的能力 哮喘和代谢功能障碍将在HDM挑战、HFD或对照饮食喂养、TS和TN中进行评估。 饲养雄性和雌性小鼠。更好地理解“肥胖哮喘”内型的发病机制 使肥胖哮喘患者的护理发生革命性变化，并允许发现新的治疗方法 有很大比例的人没有得到目前的治疗方式的服务。

Allergic asthma, a disease that affects over 300 million people worldwide, is typically driven by Th2-dominated immune responses to environmental antigens. Obesity, a disorder afflicting 500 million people worldwide, is associated with chronic inflammation, elevated proinflammatory cytokine production, and metabolic dysfunction leading to the development of diabetes, cardiovascular disease, non-alcoholic fatty liver disease and various cancers. Recent evidence suggests the existence of several asthma “endotypes”– disease subtypes driven by unique underlying pathogenic mechanisms. The “obese asthma” endotype is associated with: (1) a shift away from Th2-dominated inflammation towards a more proinflammatory phenotype; (2) a reduction in therapeutic efficacy of steroids; and (3) a clear female bias in prevalence. While there is consensus regarding these clinical parameters, identification of underlying mechanisms of “obese asthma” has been hampered by the absence of a combined model of severe obesity and asthma in female mice. Although reproducible modeling of asthma is achieved in both male and female mice, modeling of obesity and metabolic dysfunction is largely limited to male mice. This is largely in part due to poor tractability of obesity and metabolic dysfunction in female mice. Our novel data demonstrate that housing female mice in temperatures close to their thermoneutral zone (the temperature at which they are in metabolic homeostasis – 30-33°C) with concomitant HFD feeding promotes development of severe obesity, adiposity and metabolic dysfunction comparable to that observed in male mice. Thus, we are now able to simultaneously assess the influence of obesity, adiposity, metabolic dysfunction, and sex on asthma pathogenesis. In this application, our two independent, yet related, Specific Aims seek to validate the ability of our novel model to recapitulate three frequent observations in obese asthmatics: (1) the shift towards a proinflammatory profile; (2) reduced efficacy of steroids; and (3) female preponderance. Specific Aim 1: Determine if severely obese female mice with metabolic dysfunction develop asthma comparable to the “obese asthma” endotype described in obese women. Using HFD- or control chow diet-fed male and female mice, housed at either standard (22°C) or thermoneutral (30-33°C) conditions, we will induce experimental asthma in a model of robust obesity and metabolic dysfunction. Features of experimental asthma will be correlated with weight gain, adiposity, parameters of metabolic dysfunction, in a sex-dependent manner. Specific Aim 2: Determine if obesity and metabolic dysfunction associate with development of steroid refractory asthma in female mice. The ability of inhaled and systemic steroids to inhibit experimental asthma and metabolic dysfunction will be assessed in HDM-challenged, HFD- or control diet-fed, TS- and TN- housed male and female mice. A better understanding of the pathogenesis of the “obese asthma” endotype will revolutionize care of obese asthmatics and allow for discovery of novel therapeutic approaches benefiting a large proportion of those underserved by current therapeutic modalities.