l-Arginine supplementation in severe asthma

Abstract

BACKGROUNDDysregulation 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.METHODSParticipants 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.RESULTSA 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 H2 (PGH2) and Nα-acetyl-l-arginine were found to be good predictors for differentiating clinical responders and nonresponders.CONCLUSIONSThere was no statistically significant decrease in asthma exacerbations in the overall cohort with l-arginine intervention. PGH2, Nα-acetyl-l-arginine, and the AAI could serve as predictive biomarkers in future clinical trials that intervene in the arginine metabolome.TRIAL REGISTRATIONClinicalTrials.gov NCT01841281.FUNDINGThis 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).

Keywords: Asthma; Pulmonology.

Conflict of interest statement

Conflict of interest: The authors have declared that no conflict of interest exists.

Figures

Figure 1. Consort diagram of l-arginine study.

The diagram depicts patient flow through clinical trial and metabolomics study.

Figure 2. Plasma metabolites by FeNO group and by l-arginine treatment status.

(A) Top metabolites (baseline metabolites) that differentiate high-FeNO (n = 21) (1) versus low FeNO (n = 22) (0) subjects using PLS-DA. (B) Top metabolites (metabolites at visit 3) that differentiate FeNO/treatment status using PLS-DA. Numbers in the left panel are participant identifiers.

Figure 3. Metabolites predicting response to l-arginine.

(A) Score plot; top metabolites that predicted treatment response using PLS-DA (n = 28 total); and PGH2/Nα-acetyl-l-arginine levels in the treatment response (green, 1) versus nonresponse group (red, 0). (B) Top metabolites that predict treatment response using hierarchical cluster analysis. For the metabolite intensity, red indicates higher intensity, while blue indicates lower intensity. For example, participants in the treatment response group (green, 1) have a higher prostaglandin level (mostly red).

Figure 4. Plasma dipeptide metabolites among study groups.

(A) Dipeptide- and arginine-related metabolites that differentiate FeNO/treatment status (n = 43) using hierarchical cluster analysis. For metabolite intensity, red indicates higher intensity, while blue indicates lower intensity. (B) Dipeptide- and arginine-related metabolites that predict treatment response (green, 1) versus nonresponse group (red, 0) using hierarchical cluster analysis (n = 28). For the metabolite intensity, red indicates higher intensity, while blue indicates lower intensity.

Figure 5. Plasma arginine pathway metabolites during treatment.

Change in pattern of arginine-related pathway metabolites in the treatment versus placebo phase. n = 46.