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doi: 10.1371/journal.pone.0046618. Epub 2012 Oct 5.

L-ornithine derived polyamines in cystic fibrosis airways

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L-ornithine derived polyamines in cystic fibrosis airways

Hartmut Grasemann et al. PLoS One. 2012.

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.

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Conflict of interest statement

Competing Interests: The authors have declared that no competing interests exist.

Figures

Figure 1
Figure 1. L-Arginine metabolism in cystic fibrosis sputum.
ADMA: asymmetric dimethylarginine, ARG: arginase, CAT: cationic amino acid transporter, NO: nitric oxide, NOS: nitric oxide synthase, OAT: ornithine aminotransferase, ODC: L-ornithine decarboxylase, SAM: S-adenosylmethionine, SpS: spermine synthase, SpdS: spermidine synthase.
Figure 2
Figure 2. Sputum concentrations of putrescine, spermidine and spermine in healthy controls (HC), stable cystic fibrosis (CF), and CF patients with a pulmonary exacerbation before (pre) and after (post) treatment with intravenous antibiotics (ABx).
Each dot represents an individual patient. Numbers indicate p-values for respective group comparison. * = p<0.0001 comparing pre vs. post treatment samples (paired t-test).
Figure 3
Figure 3. The ratio of spermidine/spermine in sputum of healthy controls (HC), stable cystic fibrosis (CF), and CF patients with a pulmonary exacerbation before (pre) and after (post) treatment with intravenous antibiotics (ABx).
Results are expressed as means ± SEM. Numbers indicate p-values for respective group comparison. * = p<0.001 comparing pre vs. post treatment samples (paired t-test).
Figure 4
Figure 4. Correlation of changes (Δ) in sputum L-ornithine and spermine concentrations in cystic fibrosis patients treated for a pulmonary exacerbation
. Each symbol represents one individual.
Figure 5
Figure 5. Spermine effect on mice bronchial smooth muscle contractile properties.
A) Bronchial rings stimulated with acethylcholine (10−5 M) in the absence (Control; N = 6 rings) and presence (N = 10 rings) of spermine (10−4 M) or KCl (128 mM). B) Sodium nitroprusside (SNP) dose-response relaxation curves of acetylcholine pre-contracted (E75 = 10−5 M) bronchial smooth muscle in the absence (Control; N = 6 rings) and presence (N = 10 rings) of spermine (10−4 M). A typical SNP-induced relaxation tracing in the absence (left panel) and presence (right panel) of spermine is shown. Following ACH Stimulation (open triangle) the sustained bronchial muscle force in the presence of spermine is greater than in controls. * P<0.01 versus control by unpaired Student t-test (A) or two-way ANOVA with Tukey-Kramer multiple comparison testing (B).

References

    1. Grasemann H, Schwiertz R, Matthiesen S, Racke K, Ratjen F (2005) Increased arginase activity in cystic fibrosis airways. Am J Respir Crit Care Med 172: 1523–1528. - PubMed
    1. Grasemann H, Schwiertz R, Grasemann C, Vester U, Racke K, et al. (2006) Decreased systemic bioavailability of L-arginine in patients with cystic fibrosis. Respir Res 7: 87. - PMC - PubMed
    1. Grasemann H, Al-Saleh S, Scott JA, Shehnaz D, Mehl A, et al. (2011) Asymmetric dimethylarginine contributes to airway nitric oxide deficiency in patients with cystic fibrosis. Am J Respir Crit Care Med 183: 1363–1368. - PubMed
    1. Grasemann H, Ratjen F (2012) Nitric oxide and L-arginine deficiency in cystic fibrosis. Curr Pharm Des 18: 726–736. - PubMed
    1. Grasemann H, Kurtz F, Ratjen F (2006) Inhaled L-arginine improves exhaled nitric oxide and pulmonary function in patients with cystic fibrosis. Am J Respir Crit Care Med 174: 208–212. - PubMed

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