Ketone Body Supplementation in Obese Asthma

摘要 肥胖相关性哮喘越来越普遍，并且表现为非常难以治疗的严重疾病。 请客肥胖性哮喘以称为“固有的”（体重的结果）和“过敏性”（ 更糟糕的是肥胖），这两种情况都可以在小鼠中有效地建模。肥胖者氧化应激增加 可能是治疗干预的目标。体重减轻及其相关的活动 脂肪组织中的脂肪酸对症状和客观疾病，生活方式的改变， 减肥手术和生物疗法存在的问题包括长期依从性差，缺乏 理想性和高成本限制了它们作为肥胖性哮喘治疗的成功。减肥期间，脂肪 从脂肪组织动员的酸随后在肝脏中分解代谢为酮体 乙酰乙酸（AcAc）和β-羟基丁酸（BHB）。酮体作为抗氧化剂，提供能量 这使得细胞对糖酵解的依赖性降低，并发挥抗炎作用。根据我们公布的 和初步数据，我们假设，治疗增加酮体浓度， 通过减少细胞氧化还原， 应激和抑制促炎细胞因子产生。在SA 1中，为了确定是否和哪种酮 身体提供对肥胖固有哮喘的主要方面的保护，我们将采用小鼠模型， 饮食诱导的肥胖症和两种肥胖症的遗传模型伴随饮食或药物 通过喂食低脂饮食或生酮饮食实现循环酮体增加，或 给予酮体（BHB和AcAc），一种促进酮体形成的药物（1，3- 丁二醇）或酮酯。测量的结果包括乙酰甲胆碱反应性，气道炎症， 肺组织学、血清细胞因子和免疫表型。在SA 2中，评价体内酮的影响 身体调制的病理生理表现的肥胖过敏性哮喘，我们将暴露的饮食-或 慢性吸入性屋尘螨变应原暴露的遗传诱导的小鼠肥胖模型 伴有哮喘期间饮食或药物增加循环酮体 加重期。待测量的结果包括乙酰甲胆碱反应性、气道炎症， 免疫表型和肺重塑。在SA 3中，为了研究酮体作用的机制，我们 将刺激来自瘦型和肥胖型、非过敏性和HDM的原代气道上皮细胞和白细胞培养物， 在体外不存在和存在酮体的情况下，以及检查来自 用SA 1和SA 2处理的小鼠。我们将评估细胞因子分泌，糖酵解， 线粒体氧化应激和内质网应激之间的细胞从瘦和肥胖小鼠， 调节酮体和检查候选受体的这些影响。

ABSTRACT Obesity-associated asthma is increasingly prevalent and presents as severe disease that is very difficult to treat. Obese asthma exists as phenotypes termed “inherent” (a consequence of weight) and “allergic” (made worse by obesity), both of which can be effectively modeled in mice. Oxidative stress is increased in obese asthmatics and may be a target for therapeutic intervention. While weight loss and its associated mobilization of fatty acids from adipose tissue has salutary effects on symptoms and objective disease, lifestyle alterations, bariatric surgery, and biological therapeutics have issues including poor long-term compliance, a lack of desirability, and high cost that limit their success as treatments for obese asthma. During weight loss, fatty acids mobilized from adipose tissue are subsequently catabolized in the liver to the ketone bodies acetoacetate (AcAc) and β-hydroxybutyrate (BHB). Ketone bodies function as antioxidants, provide an energy source that makes cells less reliant on glycolysis, and exert anti-inflammatory effects. Based on our published and preliminary data, we hypothesize that therapeutic augmentation of ketone body concentrations in the circulation will elicit improvements in obese inherent and allergic asthma through decreasing cellular redox stress and inhibiting pro-inflammatory cytokine production. In SA1, to ascertain whether and which ketone bodies afford protection against the major aspects of obese inherent asthma, we will employ mouse models of diet-induced obesity and two genetic models of obesity accompanied by dietary or pharmacological augmentation of circulating ketone bodies accomplished by feeding a low-fat diet or a ketogenic diet, or administration of ketone bodies (BHB and AcAc), an agent that promotes ketone body formation (1,3- butanediol), or ketone ester. Measured outcomes include methacholine responsiveness, airway inflammation, lung histology, serum cytokines, and immunophenotyping. In SA2, to evaluate the impact of in vivo ketone body modulation on the pathophysiological manifestations of obese allergic asthma, we will expose the diet- or genetically-induced mouse obesity models to chronic inhalational house dust mite allergen exposure accompanied by dietary or pharmacological augmentation of circulating ketone bodies during the asthma exacerbation phase. Outcomes to be measured include methacholine responsiveness, airway inflammation, immunophenotyping, and lung remodeling. In SA3, to investigate the mechanisms of ketone body actions, we will stimulate primary airway epithelial cell and leukocyte cultures from lean and obese, non-allergic and HDM- allergic mice, in the absence and presence of ketone bodies in vitro, as well as examine tissues and cells from mice treated in SA1 and SA2. We will assess whether the intrinsic differences in cytokine secretion, glycolysis, mitochondrial oxidative stress, and endoplasmic reticulum stress between cells from lean and obese mice are modulated by ketone bodies and examine candidate receptors for these effects.