Ather Jennifer L, Chung Michael, Hoyt Laura R, Randall Matthew J, Georgsdottir Anna, Daphtary Nirav A, Aliyeva Minara I, Suratt Benjamin T, Bates Jason H T, Irvin Charles G, Russell Sheila R, Forgione Patrick M, Dixon Anne E, Poynter Matthew E
1 Vermont Lung Center, Division of Pulmonary Disease and Critical Care, Department of Medicine, and.
2 Department of Surgery, University of Vermont, Burlington, Vermont.
Am J Respir Cell Mol Biol. 2016 Aug;55(2):176-87. doi: 10.1165/rcmb.2016-0070OC.
Obese asthma presents with inherent hyperresponsiveness to methacholine or augmented allergen-driven allergic asthma, with an even greater magnitude of methacholine hyperresponsiveness. These physiologic parameters and accompanying obese asthma symptoms can be reduced by successful weight loss, yet the underlying mechanisms remain incompletely understood. We implemented mouse models of diet-induced obesity, dietary and surgical weight loss, and environmental allergen exposure to examine the mechanisms and mediators of inherent and allergic obese asthma. We report that the methacholine hyperresponsiveness in these models of inherent obese asthma and obese allergic asthma manifests in distinct anatomical compartments but that both are amenable to interventions that induce substantial weight loss. The inherent obese asthma phenotype, with characteristic increases in distal airspace tissue resistance and tissue elastance, is associated with elevated proinflammatory cytokines that are reduced with dietary weight loss. Surprisingly, bariatric surgery-induced weight loss further elevates these cytokines while reducing methacholine responsiveness to levels similar to those in lean mice or in formerly obese mice rendered lean through dietary intervention. In contrast, the obese allergic asthma phenotype, with characteristic increases in central airway resistance, is not associated with increased adaptive immune responses, yet diet-induced weight loss reduces methacholine hyperresponsiveness without altering immunological variables. Diet-induced weight loss is effective in models of both inherent and allergic obese asthma, and our examination of the fecal microbiome revealed that the obesogenic Firmicutes/Bacteroidetes ratio was normalized after diet-induced weight loss. Our results suggest that structural, immunological, and microbiological factors contribute to the manifold presentations of obese asthma.
肥胖型哮喘表现为对乙酰甲胆碱具有内在高反应性或过敏原驱动的过敏性哮喘加剧，且对乙酰甲胆碱的高反应性更强。通过成功减重可降低这些生理参数及伴随的肥胖型哮喘症状，但其潜在机制仍未完全明确。我们构建了饮食诱导肥胖、饮食及手术减重以及环境过敏原暴露的小鼠模型，以研究内在性和过敏性肥胖型哮喘的机制及介质。我们报告称，在这些内在性肥胖型哮喘和肥胖型过敏性哮喘模型中，乙酰甲胆碱高反应性在不同解剖区域表现不同，但二者均对能导致显著体重减轻的干预措施有反应。内在性肥胖型哮喘表型具有远端气腔组织阻力和组织弹性增加的特征，与促炎细胞因子升高有关，饮食减重可使其降低。令人惊讶的是，减肥手术导致的体重减轻会进一步升高这些细胞因子，同时将乙酰甲胆碱反应性降低至与瘦小鼠或通过饮食干预变瘦的既往肥胖小鼠相似的水平。相比之下,肥胖型过敏性哮喘表型具有中央气道阻力增加的特征，与适应性免疫反应增加无关，但饮食诱导的体重减轻可降低乙酰甲胆碱高反应性，而不改变免疫变量。饮食诱导的体重减轻在内在性和过敏性肥胖型哮喘模型中均有效，我们对粪便微生物群的研究表明，饮食诱导体重减轻后，致肥胖的厚壁菌门/拟杆菌门比例恢复正常。我们的结果表明，结构、免疫和微生物因素导致了肥胖型哮喘的多种表现形式。
