Ketone Body Supplementation in Obese Asthma

摘要 与肥胖相关的哮喘日益流行，表现为严重的疾病，很难 请客。肥胖哮喘以被称为“先天”(体重的结果)和“过敏”(制造)的表型存在 肥胖更严重)，这两种情况都可以在小鼠身上有效地建模。肥胖患者的氧化应激增加 哮喘患者，并可能成为治疗干预的目标。而减肥和与之相关的动员 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 可取性和高昂的成本限制了它们作为肥胖性哮喘治疗的成功。在减肥期间，胖子 脂肪组织中的酸随后在肝脏中分解为酮体。 乙酰乙酸酯(AcAc)和β-羟基丁酸酯(BHb)。酮体起抗氧化剂的作用，提供能量 使细胞减少对糖酵解的依赖，并发挥抗炎作用的来源。基于我们发布的 和初步数据，我们假设治疗性增加体内的酮体浓度。 循环将通过减少细胞氧化还原来改善肥胖先天和过敏性哮喘 应激和抑制促炎细胞因子的产生。在SA1中，确定是否以及哪种酮 身体对肥胖先天哮喘的主要方面提供保护，我们将使用小鼠模型 饮食诱导肥胖与饮食或药物相关肥胖的两种遗传模式 通过喂食低脂肪饮食或生酮饮食来增加循环酮体，或 酮体(BHB和AAC)的给药，一种促进酮体形成的试剂(1，3- 丁二醇)，或酮酯。测量结果包括乙酰甲胆碱反应性、呼吸道炎症、 肺组织学、血清细胞因子和免疫表型。在SA2中，评估酮在体内的影响 身体调节对肥胖过敏性哮喘的病理生理表现，我们会揭露饮食--或 慢性吸入性粉尘变应原暴露致小鼠肥胖模型的建立 伴随着哮喘期间饮食或药物上的循环酮小体的增加 加重期。要测量的结果包括乙酰甲胆碱反应性、呼吸道炎症、 免疫表型和肺重塑。在SA3中，为了研究酮的身体作用机制，我们 将刺激来自瘦和肥胖、非过敏和HDM的原代呼吸道上皮细胞和白细胞培养- 过敏小鼠，在体外没有和存在酮体的情况下，以及检查来自 用SA1和SA2处理的小鼠。我们将评估细胞因子分泌、糖酵解、 瘦小鼠和肥胖小鼠细胞之间的线粒体氧化应激和内质网应激 被酮小体调节，并检查这些效应的候选受体。

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.