Abstract
BACKGROUND The airways of obese asthmatics have been shown to be NO deficient, and this contributes to airway dysfunction and reduced response to inhaled corticosteroids. In cultured airway epithelial cells, L-citrulline, a precursor of L-arginine recycling and NO formation, has been shown to prevent asymmetric dimethyl arginine–mediated (ADMA-mediated) NO synthase (NOS2) uncoupling, restoring NO and reducing oxidative stress.METHODS In a proof-of-concept, open-label pilot study in which participants were analyzed before and after treatment, we hypothesized that 15 g/d L-citrulline for 2 weeks would (a) increase the fractional excretion of NO (FeNO), (b) improve asthma control, and (c) improve lung function. To this end, we recruited obese (BMI >30) asthmatics on controller therapy, with a baseline FeNO of ≤30 ppb from the University of Colorado Medical Center and Duke University Health System.RESULTS A total of 41 subjects with an average FeNO of 17 ppb (95% CI, 15–19) and poorly controlled asthma (average asthma control questionnaire [ACQ] 1.5 [95% CI, 1.2–1.8]) completed the study. Compared with baseline, L-citrulline increased whereas ADMA and arginase concentration did not (values represent the mean Δ and 95% CI): plasma L-citrulline (190 μM, 84–297), plasma L-arginine (67 μM, 38–95), and plasma L-arginine/ADMA (ratio 117, 67–167). FeNO increased by 4.2 ppb (1.7–6.7 ppb); ACQ decreased by –0.46 (–0.67 to 0.27 points); the forced vital capacity and forced exhalation volume in 1 second, respectively, changed by 86 ml (10–161 ml) and 52 ml (–11 to 132 ml). In a secondary analysis, the greatest FEV1 increments occurred in those subjects with late-onset asthma (>12 years) (63 ml [95% CI, 1–137]), in females (80 ml [95% CI, 5–154]), with a greater change seen in late-onset females (100 ml, [95% CI, 2–177]). The changes in lung function or asthma control were not significantly associated with the changes before and after treatment in L-arginine/ADMA or FeNO.CONCLUSION Short-term L-citrulline treatment improved asthma control and FeNO levels in obese asthmatics with low or normal FeNO. Larger FEV1 increments were observed in those with late-onset asthma and in females.TRIAL REGISTRATION ClinicalTrials.gov NCT01715844.FUNDING NIH NHLBI R01 HL146542-01.
Authors
Fernando Holguin, Hartmut Grasemann, Sunita Sharma, Daniel Winnica, Karen Wasil, Vong Smith, Margaret H. Cruse, Nancy Perez, Erika Coleman, Timothy J. Scialla, Loretta G. Que
Figure 1
ADMA mediated NOS2 uncoupling in the airway epithelium.
