Inhaled S-nitrosoglutathione in asthma: AirwayAKR1A1 expression and determinants of the human bronchodilator response.
Description
Asthma is characterized by airway inflammation and bronchoconstriction. Recent therapies have addressed inflammation, but few innovations have targeted bronchoconstriction. S-Nitrosoglutathione (GSNO), an endogenous bronchial smooth muscle relaxant, is deficient in asthmatic populations and impacts β2-adrenergic responsivity. However, inhaled GSNO (iGSNO) has not been studied in human asthma. Here we found that iGSNO increased forced expiratory volume at one second (FEV1) in asthmatic subjects and the magnitude of increase was linearly related, and additive, to inhaled β2-agonists. Spatial transcriptomic analysis of endobronchial biopsies revealed that AKR1A1, encoding a GSNO degrading enzyme, was upregulated in airway epithelium, and higher AKR1A1 expression was associated with reduced iGSNO bronchodilation. Conversely, sustained elevation in FeNO (fraction of exhaled NO) after iGSNO, indicative of reduced GSNO catabolism, served as a biomarker for iGSNO effectiveness. Thus, iGSNO could represent a novel, personalized asthma therapy, potentially combined with AKR1A1 inhibition.
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Institutions
- Indiana University School of Medicine