Abstract 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 delivered iGSNO to 10 healthy control subjects and 19 subjects with asthma. We found that iGSNO increased forced expiratory volume at one second (FEV1) in asthmatic subjects, and the magnitude of increase was linearly related (R2 = 0.653, p 0.001), and additive, to inhaled β2-agonists (p 0.001). Spatial transcriptomic analysis of endobronchial biopsies revealed that AKR1A1, encoding a GSNO degrading enzyme, was upregulated in airway epithelium (Figure), and higher AKR1A1 expression was associated with reduced iGSNO bronchodilation (p 0.001). Conversely, sustained elevation in FeNO (fraction of exhaled NO) after iGSNO, indicative of decreased GSNO catabolism, served as a biomarker for iGSNO effectiveness. Thus, iGSNO could represent a novel, personalized asthma therapy, potentially combined with AKR1A1 inhibition. This abstract is funded by: NHLBI Program Project Grant
Gaston et al. (Fri,) studied this question.