Abstract
Increased arginase activity contributes to airway nitric oxide (NO) deficiency in cystic fibrosis (CF). Whether down-stream products of arginase activity contribute to CF lung disease is currently unknown. The objective of this study was to test whether L-ornithine derived polyamines are present in CF airways and contribute to airway pathophysiology. Polyamine concentrations were measured in sputum of patients with CF and in healthy controls, using liquid chromatography-tandem mass spectrometry. The effect of spermine on airway smooth muscle mechanical properties was assessed in bronchial segments of murine airways, using a wire myograph. Sputum polyamine concentrations in stable CF patients were similar to healthy controls for putrescine and spermidine but significantly higher for spermine. Pulmonary exacerbations were associated with an increase in sputum and spermine levels. Treatment for pulmonary exacerbations resulted in decreases in arginase activity, L-ornithine and spermine concentrations in sputum. The changes in sputum spermine with treatment correlated significantly with changes in L-ornithine but not with sputum inflammatory markers. Incubation of mouse bronchi with spermine resulted in an increase in acetylcholine-induced force and significantly reduced nitric oxide-induced bronchial relaxation. The polyamine spermine is increased in CF airways. Spermine contributes to airways obstruction by reducing the NO-mediated smooth muscle relaxation.
Highlights
The amino acid L-arginine is substrate for enzymatic conversion by nitric oxide synthases (NOSs) and arginases
Intravenous antibiotic treatments for exacerbations were given for 14 days and were directed against bacterial pathogens detected in patients’ sputum culture which were Staphylococcus aureus in 12, Haemophilus influenzae in 3, and Pseudomonas aeruginosa in 5 patients
While previous studies looking at imbalances in the L-arginine metabolism in cystic fibrosis have focused on the role of changes in NO production on airway physiology [1,2,3,4], the effects of downstream products of increased arginase activity for airways function were largely unknown
Summary
The amino acid L-arginine is substrate for enzymatic conversion by nitric oxide synthases (NOSs) and arginases. Recent evidence suggests an imbalance of the L-arginine metabolism in cystic fibrosis (CF) airways towards arginase as the activity of arginase is upregulated and levels of the endogenous nitric oxide synthase (NOS) inhibitor asymmetric dimethylarginine (ADMA) are increased in CF sputum. This imbalance contributes to the known decrease in CF airway nitric oxide (NO) production and results in increased concentrations of L-ornithine, the product of arginase activity [1,2,3,4] (Figure 1). Putrescine is further metabolized to the higher-order polyamines, spermidine and spermine, by spermidine synthase and spermine synthase, respectively [7,8] (Figure 1)
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