Beta-Hydroxybutyrate Inhibits Bronchial Smooth Muscle Contraction

Asthma is a chronic respiratory condition characterized by airway inflammation, remodeling, and hyperresponsiveness to triggers causing airway constriction. Bronchial smooth muscle plays a critical role by narrowing airways, leading to obstruction and breathing difficulties, often exacerbated by mast cell infiltration and histamine release. Whereas current treatments, including bronchodilators, corticosteroids, and biologics provide effective management for most patients, alternative therapies are needed for difficult-to-treat asthma. Recent research highlights the potential of therapeutic ketosis, achieved through dietary interventions or supplementation with exogenous ketones, to reduce airway hyperresponsiveness and inflammation. Ketone bodies, known for providing energy during carbohydrate scarcity, also influence asthma by activating cell-surface receptors and transporters. In vivo, interventions like weight loss and caloric restriction increase ketone body levels, correlating with improved asthma symptoms, reduced oxidative stress, and inflammation. These effects suggest ketone bodies, particularly {beta}-hydroxybutyrate, may play a therapeutic role in mitigating bronchoconstriction and smooth muscle contraction in asthma. We utilize human bronchial smooth muscle cells (in vitro) and mouse precision-cut lung slices (PCLS) (ex vivo) to assess the effects of BHB on histamine-induced bronchoconstriction. Brightfield microscopy showed that BHB reduces contraction in human bronchial smooth muscle cells, an effect involving free fatty acid receptor 3 (FFAR3) activation. Light microscopy of PCLS revealed that BHB inhibits airway narrowing and cellular extrusion, demonstrating its ability to mitigate bronchoconstriction by suppressing smooth muscle contraction. These results implicate bronchial smooth muscle as a cellular target of therapeutic ketosis, an important contributor to the beneficial effects of BHB in preclinical models of asthma. Graphical AbstractIn accordance with journal requirements, a graphical abstract will be submitted if we are invited to revise this manuscript.