Activated L-Arginine/Nitric Oxide Pathway in Pediatric Cystic Fibrosis and Its Association with Pancreatic Insufficiency, Liver Involvement and Nourishment: An Overview and New Results

Abstract

Cystic fibrosis (CF; OMIM 219700) is a rare genetic disorder caused by a chloride channel defect, resulting in lung disease, pancreas insufficiency and liver impairment. Altered L-arginine (Arg)/nitric oxide (NO) metabolism has been observed in CF patients’ lungs and in connection with malnutrition. The aim of the present study was to investigate markers of the Arg/NO pathway in the plasma and urine of CF patients and to identify possible risk factors, especially associated with malnutrition. We measured the major NO metabolites nitrite and nitrate, Arg, a semi-essential amino acid and NO precursor, the NO synthesis inhibitor asymmetric dimethylarginine (ADMA) and its major urinary metabolite dimethylamine (DMA) in plasma and urine samples of 70 pediatric CF patients and 78 age-matched healthy controls. Biomarkers were determined by gas chromatography–mass spectrometry and high-performance liquid chromatography. We observed higher plasma Arg (90.3 vs. 75.6 µM, p < 0.0001), ADMA (0.62 vs. 0.57 µM, p = 0.03), Arg/ADMA ratio (148 vs. 135, p = 0.01), nitrite (2.07 vs. 1.95 µM, p = 0.03) and nitrate (43.3 vs. 33.1 µM, p < 0.001) concentrations, as well as higher urinary DMA (57.9 vs. 40.7 µM/mM creatinine, p < 0.001) and nitrate (159 vs. 115 µM/mM creatinine, p = 0.001) excretion rates in the CF patients compared to healthy controls. CF patients with pancreatic sufficiency showed plasma concentrations of the biomarkers comparable to those of healthy controls. Malnourished CF patients had lower Arg/ADMA ratios (p = 0.02), indicating a higher NO synthesis capacity in sufficiently nourished CF patients. We conclude that NO production, protein-arginine dimethylation, and ADMA metabolism is increased in pediatric CF patients. Pancreas and liver function influence Arg/NO metabolism. Good nutritional status is associated with higher NO synthesis capacity and lower protein-arginine dimethylation.

Local and Systemic Alterations of the L-Arginine/Nitric Oxide Pathway in Sputum, Blood, and Urine of Pediatric Cystic Fibrosis Patients and Effects of Antibiotic Treatment

“…Recently, we reported that the Arg/NO pathway is activated in pediatric CF. We found higher nitrate, nitrite, Arg, and ADMA concentrations in the plasma of pediatric CF patients compared to healthy controls as well as higher urine nitrate and DMA concentrations [24]. Changes in the Arg/NO metabolism resulting in reduced NO levels have been reported in CF patients by others as well [25][26][27][28].…”

“…All CF patients (n = 70) and healthy controls (n = 78) were recruited as previously reported [24], with an additional subset of each five controls and CF patients who exclusively gave sputum. The diagnosis of CF was either verified with repeated pathological sweat-tests and/or genetic analysis.…”

“…Exacerbation was defined as loss of lung function and/or increased sputum production that required antibiotic treatment [31]. Pediatric otherwise healthy controls who underwent elective control gastroscopies of asymptomatic patients at the University Children's Hospital in Bochum or small elective surgery (e.g., circumcision or inguinal hernia surgery) at the Hannover Medical School were included into the study [24]. Written informed consent was given by parents or legal guardians.…”

“…Age-corrected FENO was further classified as low, normal, or high using reference FENO data [32]. Low FENO is defined as < 3rd percentile, high FENO is defined as > 95th as described before [24].…”

“…All biochemical parameters were analyzed as described elsewhere [24] by using previously reported validated methods and by considering analyte-specific features including blood and urine collection, centrifugation, sample storage, and sample work-up. Study samples were analyzed alongside quality control (QC) samples as described elsewhere for the individual analytes [33][34][35][36][37][38][39][40][41][42][43][44][45][46].…”