L-Ornithine Derived Polyamines in Cystic Fibrosis Airways

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.

Metabolomic biomarkers predictive of early structural lung disease in cystic fibrosis

“…Increased concentrations of ornithine imply greater arginase activity in inflamed airways and are consistent with previously reported increases in CF sputum polyamines [19]. Since urea is another product of arginase activity, this relationship could impact the utility of urea as an airway dilution marker.…”

“…Arginine, citrulline, and fumarate are involved in generating the signaling molecule nitric oxide [18], and all of these metabolites were elevated in bronchitic samples. Arginine can also be metabolized to ornithine, the initial substrate in synthesis of polyamines [19]. Both ornithine and the polyamine putrescine were elevated in bronchitis, as was free adenine generated primarily within the polyamine synthesis pathway [20].…”

Evolutionary genomics of epidemic and nonepidemic strains of Pseudomonas aeruginosa

“…Third, the synthesis of the polyamine putrescine from arginine precursors produces agmatine as an intermediate, which inhibits NO synthases of macrophages (37) and diminishes the macrophage-derived oxidative burst. An imbalance of arginine and polyamine metabolism in the CF lung has been implicated in the pathophysiology of CF lung disease (38). The many LESAdivergent genes with roles in utilization and transport of arginine, ornithine, agmatine, and putrescine (SI Appendix, Tables S6 and S7) suggest LESA may be particularly well adapted to this aspect of the CF lung environment.…”

Putrescine Reduces Antibiotic-Induced Oxidative Stress as a Mechanism of Modulation of Antibiotic Resistance in Burkholderia cenocepacia

“…For example, the putrescine concentration was reported to be 3 mM in urine (11), whereas it was shown to be up to 0.2 mM in sputum samples from CF patients (39,40). However, it is difficult to predict the local concentration of putrescine and other polyamines in the lung of CF patients, as infection alters the rheology of the mucus and the lung environment (41).…”

“…However, it is difficult to predict the local concentration of putrescine and other polyamines in the lung of CF patients, as infection alters the rheology of the mucus and the lung environment (41). Moreover, putrescine levels increase dramatically (by 10-fold or more) during exacerbations of bacterial infections in CF patients (39,40). Hence, the concentrations used in this study could potentially resemble the physiological situation in certain body compartments.…”