title: Weight Loss Decreases Inherent and Allergic Methacholine Hyperresponsiveness in Mouse Models of Diet-Induced Obese Asthma.
abstract: 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.
authors.affiliation: 1 Vermont Lung Center, Division of Pulmonary Disease and Critical Care, Department of Medicine, and.
authors.forename: Jennifer L
authors.initials: JL
authors.lastname: Ather
authors.affiliation: 1 Vermont Lung Center, Division of Pulmonary Disease and Critical Care, Department of Medicine, and.
authors.forename: Michael
authors.initials: M
authors.lastname: Chung
authors.affiliation: 1 Vermont Lung Center, Division of Pulmonary Disease and Critical Care, Department of Medicine, and.
authors.forename: Laura R
authors.initials: LR
authors.lastname: Hoyt
authors.affiliation: 1 Vermont Lung Center, Division of Pulmonary Disease and Critical Care, Department of Medicine, and.
authors.forename: Matthew J
authors.initials: MJ
authors.lastname: Randall
authors.affiliation: 1 Vermont Lung Center, Division of Pulmonary Disease and Critical Care, Department of Medicine, and.
authors.forename: Anna
authors.initials: A
authors.lastname: Georgsdottir
authors.affiliation: 1 Vermont Lung Center, Division of Pulmonary Disease and Critical Care, Department of Medicine, and.
authors.forename: Nirav A
authors.initials: NA
authors.lastname: Daphtary
authors.affiliation: 1 Vermont Lung Center, Division of Pulmonary Disease and Critical Care, Department of Medicine, and.
authors.forename: Minara I
authors.initials: MI
authors.lastname: Aliyeva
authors.affiliation: 1 Vermont Lung Center, Division of Pulmonary Disease and Critical Care, Department of Medicine, and.
authors.forename: Benjamin T
authors.initials: BT
authors.lastname: Suratt
authors.affiliation: 1 Vermont Lung Center, Division of Pulmonary Disease and Critical Care, Department of Medicine, and.
authors.forename: Jason H T
authors.initials: JH
authors.lastname: Bates
authors.affiliation: 1 Vermont Lung Center, Division of Pulmonary Disease and Critical Care, Department of Medicine, and.
authors.forename: Charles G
authors.initials: CG
authors.lastname: Irvin
authors.affiliation: 2 Department of Surgery, University of Vermont, Burlington, Vermont.
authors.forename: Sheila R
authors.initials: SR
authors.lastname: Russell
authors.affiliation: 2 Department of Surgery, University of Vermont, Burlington, Vermont.
authors.forename: Patrick M
authors.initials: PM
authors.lastname: Forgione
authors.affiliation: 1 Vermont Lung Center, Division of Pulmonary Disease and Critical Care, Department of Medicine, and.
authors.forename: Anne E
authors.initials: AE
authors.lastname: Dixon
authors.affiliation: 1 Vermont Lung Center, Division of Pulmonary Disease and Critical Care, Department of Medicine, and.
authors.forename: Matthew E
authors.initials: ME
authors.lastname: Poynter
mesh_terms: D000818:Animals; D001249:Asthma / Q000150:complications* / Q000473:pathology; D001419:Bacteria / Q000378:metabolism; D050110:Bariatric Surgery; D016535:Bronchial Hyperreactivity / Q000150:complications* / Q000473:pathology; D016207:Cytokines / Q000378:metabolism; D004032:Diet; D004195:Disease Models, Animal; D006967:Hypersensitivity / Q000150:complications* / Q000473:pathology; D018836:Inflammation Mediators / Q000378:metabolism; D007422:Intestines / Q000382:microbiology / Q000473:pathology; D008297:Male; D016210:Methacholine Chloride; D008810:Mice, Inbred C57BL; D008820:Mice, Obese; D009765:Obesity / Q000139:chemically induced* / Q000150:complications*; D015431:Weight Loss
chemical_list: D016207:Cytokines; D018836:Inflammation Mediators; D016210:Methacholine Chloride
keywords: airway hyperresponsiveness; asthma; bariatric surgery; obesity; weight loss