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.

Beatrice Hanusch,Dimitrios Tsikas,Anna Wiemers,Nico Derichs,Manfred Ballmann,Anjona Schmidt-Choudhury,Kathrin Jansen,Folke Brinkmann,Alexander Bollenbach,Kristine Chobanyan-Jürgens,Thomas Lücke,Sebene Mayorandan

doi:10.3390/jcm9123802

Abstract

Alterations in the L-arginine (Arg)/nitric oxide (NO) pathway have been reported in cystic fibrosis (CF; OMIM 219700) as the result of various factors including systemic and local inflammatory activity in the airways. The aim of the present study was to evaluate the Arg/NO metabolism in pediatric CF patients with special emphasis on lung impairment and antibiotic treatment. Seventy CF patients and 78 healthy controls were included in the study. CF patients (43% male, median age 11.8 years) showed moderately impaired lung functions (FEV1 90.5 ± 19.1% (mean ± SD); 21 (30%) had a chronic Pseudomonas aeruginosa (PSA) infection, and 24 (33%) had an acute exacerbation). Plasma, urinary, and sputum concentrations of the main Arg/NO metabolites, nitrate, nitrite, Arg, homoarginine (hArg), and asymmetric dimethylarginine (ADMA) were determined in pediatric CF patients and in healthy age-matched controls. Clinical parameters in CF patients included lung function and infection with PSA. Additionally, the Arg/NO pathway in sputum samples of five CF patients was analyzed before and after routine antibiotic therapy. CF patients with low fractionally exhaled NO (FENO) showed lower plasma Arg and nitrate concentrations. During acute exacerbation, sputum Arg and hArg levels were high and dropped after antibiotic treatment: Arg: pre-antibiotics: 4.14 nmol/25 mg sputum vs. post-antibiotics: 2.33 nmol/25 mg sputum, p = 0.008; hArg: pre-antibiotics: 0.042 nmol/25 mg sputum vs. post-antibiotics: 0.029 nmol/25 mg sputum, p = 0.035. The activated Arg/NO metabolism in stable CF patients may be a result of chronic inflammation. PSA infection did not play a major role regarding these differences. Exacerbation increased and antibiotic therapy decreased sputum Arg concentrations.

Highlights

About 1:3300 to 1:4800 newborns in Germany are affected by cystic fibrosis (CF; OMIM 219700), which is an autosomal recessively inherited disease [1]
As we found no differences of asymmetric dimethylarginine (ADMA) in CF patients with acute infection, ADMA clearance might not be impaired in these patients
In our stable pediatric CF patients, the Arg/nitric oxide (NO) pathway is upregulated independent of Pseudomonas aeruginosa (PSA) infection

Summary

Introduction

About 1:3300 to 1:4800 newborns in Germany are affected by cystic fibrosis (CF; OMIM 219700), which is an autosomal recessively inherited disease [1]. L-Arginine (Arg) is a semi-essential amino acid that can be synthesized via the urea cycle [10] It can be utilized as a substrate by nitric oxide (NO) synthase (NOS) to produce NO and L-citrulline [11,12]. The sum of urinary ADMA and DMA (i.e., ADMA + DMA) represents the whole-body asymmetric dimethylation of Arg residues in proteins. The sum of urinary ADMA, DMA, and SDMA (i.e., ADMA + DMA + SDMA) reflects the whole-body asymmetric and symmetric dimethylation of Arg residues in proteins [21]. In this context, the molar ratio of (ADMA + DMA)/SDMA in the urine is a measure of the ratio of asymmetric to symmetric dimethylation of proteinic Arg [21]. NO is involved in innate immune response, neurotransmission, protein function regulation, and acts as a platelet aggregation inhibitor [11,12,23]

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