l-Arginine supplementation in severe asthma

BACKGROUND: Dysregulation of l-arginine metabolism has been proposed to occur in patients with severe asthma. The effects of l-arginine supplementation on l-arginine metabolite profiles in these patients are unknown. We hypothesized that individuals with severe asthma with low fractional exhaled nitric oxide (FeNO) would have fewer exacerbations with the addition of l-arginine to their standard asthma medications compared with placebo and would demonstrate the greatest changes in metabolite profiles. METHODS: Participants were enrolled in a single-center, crossover, double-blind l-arginine intervention trial at UCD. Subjects received placebo or l-arginine, dosed orally at 0.05 mg/kg (ideal body weight) twice daily. The primary end point was moderate asthma exacerbations. Longitudinal plasma metabolite levels were measured using mass spectrometry. A linear mixed-effect model with subject-specific intercepts was used for testing treatment effects. RESULTS: A cohort of 50 subjects was included in the final analysis. l-Arginine did not significantly decrease asthma exacerbations in the overall cohort. Higher citrulline levels and a lower arginine availability index (AAI) were associated with higher FeNO (P = 0.005 and P = 2.51 × 10(–9), respectively). Higher AAI was associated with lower exacerbation events. The eicosanoid prostaglandin H(2) (PGH(2)) and N(α)-acetyl-l-arginine were found to be good predictors for differentiating clinical responders and nonresponders. CONCLUSIONS: There was no statistically significant decrease in asthma exacerbations in the overall cohort with l-arginine intervention. PGH(2), N(α)-acetyl-l-arginine, and the AAI could serve as predictive biomarkers in future clinical trials that intervene in the arginine metabolome. TRIAL REGISTRATION: ClinicalTrials.gov NCT01841281. FUNDING: This study was supported by NIH grants R01HL105573, DK097154, UL1 TR001861, and K08HL114882. Metabolomics analysis was supported in part by a grant from the University of California Tobacco-Related Disease Research Program program (TRDRP).