Dysregulated Arginine Metabolism in Young Patients with Chronic Persistent Asthma and in Human Bronchial Epithelial Cells

Abstract

Background: Recent metabolomics studies have found circulatory metabolism alterations in patients with asthma, indicating that altered metabolites played a significant role in asthma. However, the regulatory mechanisms in asthma, especially in young chronic persistent asthma remain underexplored. Methods: In this study, a prospective cohort of 162 patients diagnosed of asthma admitted to the First Affiliated Hospital of Xi’an Jiaotong University from January 2018 to December 2019 was used to perform a nested case-control study. Among them, we included 30 patients with chronic persistent asthma between 20 to 35 years old; 30 health control with evenly distributed age and sex were then recruited. Nontargeted metabolomics was applied to identify serum metabolic profiles and altered metabolic pathways. Results: In vitro, human bronchial epithelial cells (HBECs) line BEAS-2B with the addition of L-citrulline and/or asymmetric dimethylarginine (ADMA) model was utilized and the concentrations of nitric oxide (NO) metabolites were tested to evaluate the therapeutic potential of L-citrulline. The young patients with chronic persistent asthma displayed dysregulated serum metabolic profiles, especially enriched in arginine metabolism. The ratio of L-citrulline to ornithine is associated with blood eosinophil count. In vitro, adding L-citrulline could reverse ADMA-mediated reduction of NOx at lower L-arginine concentration (25 μM), but was ineffective in the higher L-arginine concentration (100 μM) media. Conclusions: The arginine metabolism balance is of vital importance during the pathogenesis and progression of chronic asthma. L-citrulline could be a powerful approach to restore airway NO production, potentially exhibiting therapeutic benefits among young patients with chronic asthma.

Phenotypic characteristics of asthma and morbidity are associated with distinct longitudinal changes in L-arginine metabolism

“…In animal models, airway hyperresponsiveness (AHR) is caused by reduced L-arginine availability, NO deficiency and increased arginase activity 2–4. In humans, L-arginine metabolism via arginase is associated with increased exacerbation rates, obesity and decreased markers of T2 inflammation 2 4–7. However, expression and activity of inducible NOS is associated with eosinophilic inflammation and asthma severity 2–4 8 9.…”

Proline is increased in allergic asthma and promotes airway remodeling

“…Several studies have mentioned that the plasma concentrations of lipids and amino acids, including sphingolipids, uric acid, tryptophan, and arginine or proline, correlate with the prevalence of asthma ( 41 , 42 ). Abdulnaby et al revealed higher uric acid in patients with asthma ( 43 ), while several documents reported alterations in metabolites of the arginine metabolism pathway in the asthma group ( 41 , 44 , 45 ). Moreover, Comhair et al reported elevated levels of taurine and bile acids in asthmatic plasma ( 46 ).…”

Genetic association and bidirectional Mendelian randomization for causality between gut microbiota and six lung diseases

“…For individuals with asthma, an increase in the abundance of these bacteria may heighten their susceptibility to allergic reactions and inflammation. Conversely, the family Acidaminococcaceae, known for its ability to ferment amino acids, has shown potential therapeutic values in asthma (34). The genera Allisonella and Phascolarctobacterium produce butyric acid and propionic acid, respectively, and an animal study demonstrated that the levels of both were significantly downregulated in asthmatic mice (35).…”