Ketone body augmentation decreases methacholine hyperresponsiveness in mouse models of allergic asthma.

Autor:	Mank MM; Department of Medicine, Division of Pulmonary Disease and Critical Care, University of Vermont, and The Vermont Lung Center, Burlington., Reed LF; Department of Medicine, Division of Pulmonary Disease and Critical Care, University of Vermont, and The Vermont Lung Center, Burlington., Fastiggi VA; Department of Medicine, Division of Pulmonary Disease and Critical Care, University of Vermont, and The Vermont Lung Center, Burlington., Peña-García PE; Department of Medicine, Division of Pulmonary Disease and Critical Care, University of Vermont, and The Vermont Lung Center, Burlington., Hoyt LR; Department of Medicine, Division of Pulmonary Disease and Critical Care, University of Vermont, and The Vermont Lung Center, Burlington., Van Der Vliet KE; Department of Medicine, Division of Pulmonary Disease and Critical Care, University of Vermont, and The Vermont Lung Center, Burlington., Ather JL; Department of Medicine, Division of Pulmonary Disease and Critical Care, University of Vermont, and The Vermont Lung Center, Burlington., Poynter ME; Department of Medicine, Division of Pulmonary Disease and Critical Care, University of Vermont, and The Vermont Lung Center, Burlington.
Jazyk:	angličtina
Zdroj:	The journal of allergy and clinical immunology. Global [J Allergy Clin Immunol Glob] 2022 Nov; Vol. 1 (4), pp. 282-298. Date of Electronic Publication: 2022 Sep 07.
DOI:	10.1016/j.jacig.2022.08.001
Abstrakt:	Background: Individuals with allergic asthma exhibit lung inflammation and remodeling accompanied by methacholine hyperresponsiveness manifesting in proximal airway narrowing and distal lung tissue collapsibility, and they can present with a range of mild-to-severe disease amenable or resistant to therapeutic intervention, respectively. There remains a need for alternatives or complements to existing treatments that could control the physiologic manifestations of allergic asthma. Objectives: Our aim was to examine the hypothesis that because ketone bodies elicit anti-inflammatory activity and are effective in mitigating the methacholine hyperresponsiveness associated with obese asthma, increasing systemic concentrations of ketone bodies would diminish pathologic outcomes in asthma-relevant cell types and in mouse models of allergic asthma. Methods: We explored the effects of ketone bodies on allergic asthma-relevant cell types (macrophages, airway epithelial cells, CD4 T cells, and bronchial smooth muscle cells) in vitro as well as in vivo by using preclinical models representative of several endotypes of allergic asthma to determine whether promotion of ketosis through feeding a ketogenic diet or providing a ketone precursor or a ketone ester dietary supplement could affect immune and inflammatory parameters as well as methacholine hyperresponsiveness. Results: In a dose-dependent manner, the ketone bodies acetoacetate and β-hydroxybutyrate (BHB) decreased proinflammatory cytokine secretion from mouse macrophages and airway epithelial cells, decreased house dust mite (HDM) extract-induced IL-8 secretion from human airway epithelial cells, and decreased cytokine production from polyclonally and HDM-activated T cells. Feeding a ketogenic diet, providing a ketone body precursor, or supplementing the diet with a ketone ester increased serum BHB concentrations and decreased methacholine hyperresponsiveness in several acute HDM sensitization and challenge models of allergic asthma. A ketogenic diet or ketone ester supplementation decreased methacholine hyperresponsiveness in an HDM rechallenge model of chronic allergic asthma. Ketone ester supplementation synergized with corticosteroid treatment to decrease methacholine hyperresponsiveness in an HDM-driven model of mixed-granulocytic severe asthma. HDM-induced morphologic changes in bronchial smooth muscle cells were inhibited in a dose-dependent manner by BHB, as was HDM protease activity. Conclusions: Increasing systemic BHB concentrations through dietary interventions could provide symptom relief for several endotypes of allergic asthmatic individuals through effects on multiple asthma-relevant cells. Competing Interests: Disclosure of potential conflict of interest: The authors declare that they have no relevant conflicts of interest.
Databáze:	MEDLINE
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