L-Citrulline increases nitric oxide and improves control in obese asthmatics

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 FEV 1 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.

A network medicine approach to investigation and population-based validation of disease manifestations and drug repurposing for COVID-19

“…assembled asthma cohort [61]. By matching the enzymes of the differential metabolites and the proteins in the PPI network, we found 3 key metabolites: arachidonate, L-arginine, and Lcitrulline.…”

l-Arginine supplementation in severe asthma

“…A recent clinical trial of l-citrulline supplementation in individuals with asthma found that l-citrulline increased FeNO and modestly improved forced expiratory volume in 1 second (FEV 1 ), especially in females with late-onset asthma (17). We and others have found in murine models that manipulation of l-arginine content in the airway compartment via l-arginine treatment or inhibition of the arginase enzyme decreases airway inflammatory cell counts, lung lavage cytokine levels, airways hyperresponsiveness, and arginase activity (18)(19)(20).…”

A Network Medicine Approach to Investigation and Population-based Validation of Disease Manifestations and Drug Repurposing for COVID-19

“…L-arginine and L-citrulline were decreased in the sera of COVID-19 patients ( 50 ). A previous study showed that these metabolites were also decreased in asthma patients ( 49 ). Arachidonate, the precursor of a variety of products that regulate inflammatory pathways ( 51 ), was found to have an increased level in the inflamed airways of asthmatics ( 52 ).…”

“…The unique plasma metabolome of asthmatics versus healthy controls also suggests activated inflammatory and immune pathways ( 48 ). Therefore, in addition to PPIs, we also integrated metabolomics data generated in a previously assembled asthma cohort ( 49 ). By matching the enzymes of the differential metabolites and the proteins in the PPI network, we found three key metabolites, including arachidonate, L-arginine, and L-citrulline.…”

“…5B ). Second, decreased levels of L-arginine and L-citrulline were found in SARS-CoV-2 infected patients ( 50 ), while it has been shown that higher levels of these metabolites are protective against asthma ( 49 ). L-arginine can be converted to nitric oxide by the nitric oxide synthases, and it was shown that nitric oxide protects against viral infection through multiple potential mechanisms ( 78 ).…”