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Published ahead of print on April 20, 2006, doi:10.1164/rccm.200509-1439OC
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American Journal of Respiratory and Critical Care Medicine Vol 174. pp. 208-212, (2006)
© 2006 American Thoracic Society
doi: 10.1164/rccm.200509-1439OC

Original Article

Inhaled L-Arginine Improves Exhaled Nitric Oxide and Pulmonary Function in Patients with Cystic Fibrosis

Hartmut Grasemann, Fionn Kurtz and Felix Ratjen

Children's Hospital, University of Duisburg-Essen, Essen, Germany

Correspondence and requests for reprints should be addressed to Hartmut Grasemann, M.D., The Hospital for Sick Children, Division of Respiratory Medicine, 555 University Ave., Toronto, ON, M5G 1X8 Canada. E-mail: hartmut.grasemann{at}sickkids.ca


   ABSTRACT
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 ABSTRACT
METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Rationale: Nitric oxide formation is deficient in airways of patients with cystic fibrosis (CF). Since nitric oxide has bronchodilatory effects, nitric oxide deficiency may contribute to airway obstruction in CF.

Objectives: We reasoned that inhalation of L-arginine, the precursor of enzymatic nitric oxide formation, could improve airway nitric oxide formation and pulmonary function in patients with CF.

Measurements: Exhaled nitric oxide, pulmonary function, and peripheral oxygen saturation were measured before and after a single inhalation of nebulized L-arginine solution in patients with CF and in healthy subjects. A saline solution of similar osmolarity (1.7%) was used as control.

Results: Nebulized L-arginine not only significantly increased exhaled nitric oxide concentrations but also resulted in a sustained improvement of FEV1 in patients with CF. Oxygen saturation also increased significantly after the inhalation of L-arginine. Nebulized saline resulted in a small but significant increase in exhaled nitric oxide but a decrease in FEV1 in patients with CF. In control subjects inhalation of L-arginine increased exhaled nitric oxide concentrations, but FEV1 decreased. No effect of saline on exhaled nitric oxide, pulmonary function, or oxygen saturation was observed in healthy subjects.

Conclusions: These data suggest that a single inhalation of L-arginine acutely and transiently improves pulmonary function in CF through the formation of nitric oxide. Augmentation of airway nitric oxide formation by inhalation of L-arginine is a promising therapeutic approach in patients with CF.

Key Words: administration, inhalation • respiratory therapy • respiratory tract disease

Nitric oxide (NO) is a messenger molecule that is involved in a variety of biological and physiologic processes in the lung (1–6). Constitutive endogenous formation of NO in airways is thought to play a pivotal role in neurotransmission, smooth muscle relaxation, and bronchodilation (7). Airway NO formation by NO synthases (NOSs) can increase in response to inflammatory mediators, predominantly through induction of the calcium-independent isoform NOS2 (7). However, despite the inflammatory nature of lung disease in cystic fibrosis (CF), NO formation, as well as the expression of NOS2, has been found to be decreased in CF airways (8–10). This is reflected by reduced fractional exhaled NO (FeNO) and lower levels of the bioactive NO-metabolites S-nitrosothiols (SNOs) in airway fluids of patients with CF (8, 11, 12). While the reasons for impaired formation of airway NO remain incompletely understood, there is evidence that low NO formation contributes to lung pathophysiology in CF.

Animal experiments have shown that airway relaxation is significantly impaired in cftr–/– mice and that this relaxation defect in CF airways can be reversed by an improvement of enzymatic NO formation through the addition of the NOS substrate L-arginine (13). These data suggest that NO deficiency results in airway obstruction in patients with CF and may be improved by increasing L-arginine concentrations in the airways. Previous clinical studies in patients with CF had shown that FeNO could be increased by L-arginine given either orally or intravenously but had failed to demonstrate an effect on pulmonary function (14, 15). This lack of effect may be due to ineffective augmentation of L-arginine concentrations in CF airways. Since high doses of L-arginine can be delivered to the airways by inhalation, we here performed a pilot study to assess the effect of nebulized L-arginine solution on FENO and lung function in patients with CF. Some of the results of these studies have been previously reported in the form of abstracts (16, 17).


   METHODS
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 ABSTRACT
 METHODS
RESULTS
 DISCUSSION
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Study Cohort
Thirteen patients with CF (7 females) aged 14 to 45 yr (mean ± SD; 20.1 ± 9.1 yr) were studied. Mean FVC at baseline was 66 ± 25% (range, 35–120%) and mean FEV1 was 47 ± 21% (range, 24–95%) of predicted values. The diagnosis of CF in participating patients had been confirmed by repeated sweat tests with chloride concentrations exceeding 60 mmol/L and by mutation analysis of the CFTR gene. All patients were chronically infected with Pseudomonas aeruginosa; five were co-colonized with Staphylococcus aureus. None of the patients received systemic or inhaled corticosteroids at the time of study. All patients were included in clinically stable condition. Exclusion criteria were allergic bronchopulmonary aspergillosis, Burkholdia cepacia infection, or an additional diagnosis of asthma. Patients were compared with nine (4 females) nonsmoking, healthy control subjects 22 to 28 yr (25.1 ± 1.3 yr) of age. The study was approved by the ethics committee of the University of Duisburg-Essen. Written informed consent was obtained by all patients and/or their parents as well as by all control subjects.

Study Protocol
The study medications consisted of 18 ml of a 7% L-arginine hydrochloride solution (600 mOsmol/kg, pH 5–6) containing 1.3 g of L-arginine or 18 ml of 1.7% saline (NaCl) with similar osmolarity and pH as a control. The L-arginine solution was prepared by diluting with sterile water a 21% (wt/vol) L-arginine hydrochloride solution that is licensed for intravenous use (Braun Melsungen AG, Melsungen, Germany). Osmolarity was measured by cryoscopy. The study medications were administered in the morning 15 min after pretreatment with two puffs albuterol. The solutions were nebulized via a customized PARI eFlow electronic nebulizer from pilot series 03 (PARI, Starnberg, Germany) on two separate days in random order with at least 72 h between the two inhalations. The study medication was blinded to the participants. No additional albuterol or other bronchodilatory drug was given within 6 h after the nebulized solutions, or 8 h before study end (24 h). Pulmonary function (bell-spirometer, Volugraph; Mijnhardt, Bunnik, The Netherlands), FENO, and peripheral oxygen saturation were recorded at baseline, immediately after inhalation, once every hour for 6 h, and after 24 h. Blood was collected in EDTA-containing 2.7-ml tubes by venipuncture at the same time points. Spontaneously expectorated sputum was collected at baseline, after 4 h, and after 24 h.

Measurements of FENO
Single-breath online measurements for the assessment of lower airway NO were performed at a constant expiratory flow of 50 ml x min–1 (FeNO50), in accordance with published ERS/ATS standards (18, 19). A chemiluminescence analyzer (NOA 280; Sievers, Boulder, CO), that was calibrated before each study with 0 and 185-ppb NO calibration gas (Linde AG, Unterschleissheim, Germany) was used to measure FeNO. The mean value of three end-expiratory NO concentrations within a variation of 15% was calculated for each subject.

Amino Acid Measurements
Plasma and sputum samples were deproteinized within 30 min after collection. Amino acids were determined by ion exchange chromatography (LC 3000; Eppendorf, Hamburg, Germany). Sputum samples were diluted with buffer 1:1 and vortexed for 2 min, followed by 10 min of centrifugation at 1,000 x g for 10 min. Clear supernatant was used for chromatography.

Statistics
Data are shown as means ± SEM. Comparisons of time courses of FeNO, pulmonary function, oxygen saturation, and amino acid concentrations within groups were done by repeated-measure one-way ANOVA.


   RESULTS
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DISCUSSION
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Inhalation of L-arginine and saline was well tolerated by all patients and control subjects. In patients with CF L-arginine resulted in a significant increase of FENO after inhalation (p < 0.0001, ANOVA). FENO had returned to baseline values after 24 h (Figure 1A). Mean FEV1 increased significantly 4 h after L-arginine inhalation (p < 0.0005). Similarly, FEV1 in % of baseline increased significantly (p = 0.03) (Figure 2A). No significant changes in FVC were seen (data not shown). Inhalation of saline in patients with CF resulted in a smaller but statistically significant (p < 0.05) increase of FENO (Figure 1A). In contrast to L-arginine, a significant decrease in FEV1 (p = 0.004) was seen immediately after the inhalation of saline that returned to baseline thereafter (Figure 2A). No significant changes in FVC or oxygen saturation were observed after the inhalation of saline. Mean peripheral oxygen saturation improved by approximately 1% immediately after L-arginine inhalation in patients with CF (p = 0.001) (data not shown).


Figure 1
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  		Figure 1. Effects of inhalation of a 7% L-arginine hydrochloride solution or 1.7% saline on exhaled nitric oxide (NO) in parts per billion (ppb) in (A) 13 patients with CF and (B) 9 healthy subjects. In patients with CF, FENO increased after L-arginine (p < 0.0001, ANOVA) and saline (p < 0.05). In healthy subjects, FENO increased after L-arginine (p < 0.0001), but not after saline inhalation.

 

Figure 2
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  		Figure 2. Effects of inhalation of a 7% L-arginine hydrochloride solution or 1.7% saline on changes in FEV1 in % from baseline ({Delta}FEV1) in (A) 13 patients with CF and (B) in 9 healthy subjects. Inhalation of L-arginine resulted in a significant increase of {Delta}FEV1 in patients with CF (p < 0.05, ANOVA), but a decrease of {Delta}FEV1 in control subjects (p < 0.001).

 
In healthy subjects inhalation of L-arginine solution, but not saline, led to an increase in FENO (p < 0.0001, ANOVA) (Figure 1B). In contrast to CF, inhalation of L-arginine was followed by a small but statistically significant reduction in FEV1 (p < 0.001) (Figure 2B). No effect of saline inhalation on pulmonary function was observed in the control subjects. Neither L-arginine nor saline inhalation resulted in significant changes of oxygen saturations in control subjects (data not shown).

Sputum amino acid concentrations after the inhalation of nebulized L-arginine are shown in Figure 3. L-arginine concentrations increased significantly (p < 0.0001) after inhalation and had returned to baseline after 24 h. The increases in sputum L-citrulline and L-ornithine concentrations were not statistically significant (Figure 3).


Figure 3
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  		Figure 3. Concentrations of the amino acids L-arginine, L-citrulline, and L-ornithine in sputum of patients with CF before and after the inhalation of a 7% L-arginine hydrochloride solution. The increase in L-arginine in sputum was statistically significant (p < 0.0001, ANOVA).

 
Plasma amino acid concentrations after the inhalation of nebulized L-arginine are shown in Table 1. The concentrations of L-arginine and L-citrulline, the product of L-arginine conversion by NOSs, did not change significantly over time. However, the concentrations of L-ornithine, the product of L-arginine conversion by arginase, significantly increased (p < 0.001), but had returned to baseline after 24 h.


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  		TABLE 1. PLASMA AMINO ACID LEVELS BEFORE (PRE) AND AFTER THE INHALATION OF A 7% L-ARGININE HYDROCHLORIDE SOLUTION IN 12 PATIENTS WITH CYSTIC FIBROSIS

 

   DISCUSSION
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 ABSTRACT
 METHODS
 RESULTS
 DISCUSSION
REFERENCES
 
This is the first controlled study showing that L-arginine supplementation in patients with CF not only increases FENO but also improves pulmonary function. Our data confirm previous findings of reduced NO formation in CF and also provide evidence that improvement of NO deficiency has a positive effect on lung function in patients with CF.

An increase in FENO after supplementation of L-arginine in patients with CF had been shown previously for single doses of L-arginine given intravenously (500 mg/kg body weight) or orally (200 mg/kg body weight). These regimens, however, had no effects on pulmonary function (16, 17). A 6-wk trial of oral L-arginine supplementation (200 mg/kg body weight three times daily) versus placebo also showed no effect on pulmonary function (17). Similar to results from the previous studies, FENO did not normalize after L-arginine supplementation; however, increases in FENO in the previous studies were less pronounced than after the inhalation of L-arginine. This can be explained by differences of L-arginine distribution in the compartments after different routes of L-arginine supplementation with higher L-arginine levels being achieved in the lungs after inhalation.

Improvements in FENO and oxygen saturation in patients with CF occurred early after the inhalation of L-arginine, while the most apparent increase in FEV1 was seen after 4 h. However, in contrast to saline, there was no initial decrease in FEV1 after the inhalation of L-arginine in patients with CF. This may reflect a protective effect of NO on airway constriction, as previously demonstrated for airway hyperresponsiveness in patients with asthma (20). In addition, these different time courses may also suggest that some effects of increased airway NO formation may not be mediated by NO itself but through formation of biologically active metabolites.

Studies in patients with asthma had shown that S-nitrosothiols (SNOs), which are formed by protein S-nitrosylation, act as natural bronchodilators, and that depletion of SNOs may aggravate airway obstruction (21–23). We have previously demonstrated that SNOs are decreased in CF airway fluids even in patients with mild lung disease in whom stable NO metabolites were within normal range (12). Inhalation of S-nitrosoglutathione (GSNO) improved oxygenation in patients with CF in a pilot study (24). Whether this effect could be directly attributed to SNOs or to restoration of depleted glutathione (GSH) stores in CF airways is unclear; however, glutathione inhalation alone, as well as the inhalation of NO containing gas in concentrations of 100 ppb to 40 ppm, had no immediate effect on lung function or oxygenation (25, 26). It is therefore possible that some of the effect of inhaled L-arginine on airway diameter and oxygen saturation observed was mediated through the formation of NO metabolites such as SNOs. In fact, recent data suggest that most actions of NOSs are not mediated by NO itself but by protein S-nitrosylation (27). Alternatively, positive effects of increased L-arginine levels in the airways on pulmonary function and oxygen saturation could also reflect mucolytic activities of the amino acid, as suggested by the authors of a preliminary study on inhaled L-arginine in patients with CF that was performed at a time before the role of arginine as substrate for the formation of NO was known (28). However, these initial studies have not been confirmed, and mucolytic activity of L-arginine was later found to be rather limited (29). The observation that FENO and FEV1 significantly outlasted the increase in L-arginine concentrations in sputum may be explained by either conversion of L-arginine to NO-storing metabolites that are both bioactive and capable of releasing NO over time, or a transport of the inhaled L-arginine from the airway surface to a different compartment, for instance to intracellular sources. Therefore, the level of L-arginine in cells or tissues responsible for NO formation and smooth muscle relaxation may not be adequately reflected in airway secretions.

There is increasing evidence for a functional relevance of low NO concentrations in CF. A positive correlation between FENO and pulmonary function has been observed repeatedly (8, 11, 30, 31). In addition, it was recently reported that neuronal NOS gene (NOS1) variants that are associated with low FENO predispose to a more rapid decline in pulmonary function in children with CF (32). Genetic variants in the NOS1 and NOS3 genes that lead to low FENO were also found to be associated with an increased rate of colonisation of CF airways with P. aeruginosa (33, 34). These studies support the concept that NO augmentation may have beneficial effects in patients with CF.

However, NO augmentation may also have detrimental effects in CF: Excessive NO formation from upregulated NOS2 in asthma is believed to aggravate airway inflammation (7, 35). Decreased expression of NOS2 and subsequently reduced airway NO formation in CF may thus protect the CF airways from NO-mediated damage, a mechanism that could be counteracted by increasing the substrate for NO formation. In addition, high amino acid concentrations in airways may promote growth of auxotrophic P. aeruginosa in CF (36, 37), and, since Pseudomonas can use arginine as substrate, delivery of L-arginine into CF airways may have a positive effect on Pseudomonas growth. However, there is also evidence that augmentation of airway NO formation has an inhibitory effect on bacterial growth. This is supported by the observation that the NO donor sodium nitroprusside induced a dose-dependent killing of P. aeruginosa in vitro in high concentrations (9). So far, there is insufficient in vivo evidence that NO concentrations adequate to promote bacterial killing can be achieved with NO augmentation therapy, but this will need to be studied in subsequent trials of L-arginine inhalation in CF. Based on the observation that L-arginine in sputum had returned to baseline values 24 h after the inhalation, it appears that the amino acid does not accumulate in the airways. Further trials are needed to study dose response and kinetics of arginine metabolism in CF airways after repeated inhalations.

The mechanisms resulting in reduced expression of NOS2 in CF airways are currently unknown, but seem to be related to inflammation (38) and may involve altered transforming growth factor (TGF)-beta1 signaling (39). Of interest, the expression of NOS2 is also inhibited in conditions with reduced arginine availability (40–43), and there may be multiple mechanisms by which L-arginine affects NOS2 expression, such as control of NOS protein stability or induction of NOS2 mRNA, as recently reviewed (44). One factor that may reduce the availability of L-arginine for NO synthesis in CF is the expression of arginase, an enzyme that competes with NOSs for the common substrate L-arginine (45). Arginase activity was recently found to be increased in CF sputum (46). The increase in L-ornithine plasma levels after L-arginine inhalation most likely reflects arginase activity, since L-ornithine is the product of L-arginine conversion by arginase. As specific arginase inhibitors become available, they could potentially be useful to enhance the effect of L-arginine supplementation therapy in patients with CF.

In conclusion, our preliminary observations suggest that a single inhalation of L-arginine results in an acute and transient improvement of pulmonary function and oxygenation in patients with CF. These promising data will stimulate larger trials assessing the efficacy of increased L-arginine availability in airways on nitric oxide formation, lung function, P. aeruginosa growth, and inflammation in patients with CF.


   FOOTNOTES
 
Originally Published in Press as DOI: 10.1164/rccm.200509-1439OC on April 20, 2006

Conflict of Interest Statement: H.G. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript. F.K. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript. F.R. received royalties in 2004 and 2005 for speaking at conferences and lecturing at CF centers sponsored by Chiron and Roche. He also received a grant for a study sponsored by Chiron in 2003–2004 that compared two different doses of inhaled tobramycim.

Received in original form September 14, 2005; accepted in final form April 19, 2006


   REFERENCES
TOP
 ABSTRACT
 METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 

  1. Rimeika D, Nyren S, Wiklund NP, Koskela LR, Torring A, Gustafsson LE, Larsson SA, Jacobsson H, Lindahl SG, Wiklund CU. Regulation of regional lung perfusion by nitric oxide. Am J Respir Crit Care Med 2004;170:450–455.[Abstract/Free Full Text]
  2. Morris CR, Poljakovic M, Lavrisha L, Machado L, Kuypers FA, Morris SM Jr. Decreased arginine bioavailability and increased serum arginase activity in asthma. Am J Respir Crit Care Med 2004;170:148–153.[Abstract/Free Full Text]
  3. Ladha F, Bonnet S, Eaton F, Hashimoto K, Korbutt G, Thebaud B. Sildenafil improves alveolar growth and pulmonary hypertension in hyperoxia-induced lung injury. Am J Respir Crit Care Med 2005;172:750–756.[Abstract/Free Full Text]
  4. Berger MM, Hesse C, Dehnert C, Siedler H, Kleinbongard P, Bardenheuer HJ, Kelm M, Bartsch P, Haefeli WE. Hypoxia impairs systemic endothelial function in individuals prone to high-altitude pulmonary edema. Am J Respir Crit Care Med 2005;172:763–767.[Abstract/Free Full Text]
  5. Peng X, Abdulnour RE, Sammani S, Ma SF, Han EJ, Hasan EJ, Tuder R, Garcia JG, Hassoun PM. Inducible nitric oxide synthase contributes to ventilator-induced lung injury. Am J Respir Crit Care Med 2005;172:470–479.[Abstract/Free Full Text]
  6. Razavi HM, Wang le F, Weicker S, Rohan M, Law C, McCormack DG, Mehta S. Pulmonary neutrophil infiltration in murine sepsis: role of inducible nitric oxide synthase. Am J Respir Crit Care Med 2004;170:227–233.[Abstract/Free Full Text]
  7. Ricciardolo FL, Sterk PJ, Gaston B, Folkerts G. Nitric oxide in health and disease of the respiratory system. Physiol Rev 2004;84:731–765.[Abstract/Free Full Text]
  8. Grasemann H, Ratjen F. Cystic fibrosis lung disease: the role of nitric oxide. Pediatr Pulmonol 1999;28:442–448.[CrossRef][Medline]
  9. Kelly TJ, Drumm ML. Inducible nitric oxide synthase expression is reduced in cystic fibrosis murine and human airway epithelial cells. J Clin Invest 1998;102:1200–1207.[Medline]
  10. Meng QH, Springall DR, Bishop AE, Morgan K, Evans TJ, Habib S, Gruenert DC, Gyi KM, Hodson ME, Yacoub MH, et al. Lack of inducible nitric oxide synthase in bronchial epithelium: a possible mechanism of susceptibility to infection in cystic fibrosis. J Pathol 1998;184:323–331.[CrossRef][Medline]
  11. Grasemann H, Michler E, Wallot M, Ratjen F. Decreased concentration of exhaled nitric oxide (NO) in patients with cystic fibrosis. Pediatr Pulmonol 1997;24:173–177.[CrossRef][Medline]
  12. Grasemann H, Gaston B, Fang K, Paul K, Ratjen F. Decreased levels of nitrosothiols in the lower airways of patients with cystic fibrosis and normal pulmonary function. J Pediatr 1999;135:770–772.[CrossRef][Medline]
  13. Mhanna MJ, Ferkol T, Martin RJ, Dreshaj IA, van Heeckeren AM, Kelley TJ, Haxhiu MA. Nitric oxide deficiency contributes to impairment of airway relaxation in cystic fibrosis mice. Am J Respir Cell Mol Biol 2001;24:621–626.[Abstract/Free Full Text]
  14. Grasemann H, Kurtz F, Ratjen F. Effect of inhaled L-arginine on airway nitric oxide in cystic fibrosis patients. Eur Respir J 2005;26:240s.
  15. Grasemann H, Kurtz F, Ratjen F. Inhalation of nebulized L-arginine increases exhaled nitric oxide and improves pulmonary function in patients with cystic fibrosis. Pediatr Pulmonol 2005;339.
  16. Grasemann H, Gärtig SS, Wiesemann HG, Teschler H, Konietzko N, Ratjen F. Effect of L-arginine infusion on airway NO in cystic fibrosis and primary ciliary dyskinesia syndrome. Eur Respir J 1999;13:114–118.[Abstract]
  17. Grasemann H, Grasemann C, Kurtz F, Tietze-Schillings G, Vester U, Ratjen F. Oral L-arginine supplementation in cystic fibrosis patients: a placebo-controlled study. Eur Respir J 2005;25:62–68.[Abstract/Free Full Text]
  18. Baraldi E, de Jongste JC; European Respiratory Society. American Thoracic Society. Measurement of exhaled nitric oxide in children, 2001. Eur Respir J 2002;20:223–237.[Abstract/Free Full Text]
  19. American Thoracic Society/European Respiratory Society. ATS/ERS Recommendations for standardized procedures for the online and offline measurement of exhaled lower respiratory nitric oxide and nasal nitric oxide, 2005. Am J Respir Crit Care Med 2005;171:912–930.[Free Full Text]
  20. Taylor DA, McGrath JL, Orr LM, Barnes PJ, O'Connor BJ. Effect of endogenous nitric oxide inhibition on airway responsiveness to histamine and adenosine-5'-monophosphate in asthma. Thorax 1998;53:483–489.[Abstract/Free Full Text]
  21. Gaston B, Sears S, Woods J, Hunt J, Ponaman M, McMahon T, Stamler JS. Bronchodilator S-nitrosothiol deficiency in asthmatic respiratory failure. Lancet 1998;351:1317–1319.[CrossRef][Medline]
  22. Que LG, Liu L, Yan Y, Whitehead GS, Gavett SH, Schwartz DA, Stamler JS. Protection from experimental asthma by an endogenous bronchodilator. Science 2005;308:1618–1621.[Abstract/Free Full Text]
  23. Fang K, Johns R, Macdonald T, Kinter M, Gaston B. S-nitrosoglutathione breakdown prevents airway smooth muscle relaxation in the guinea pig. Am J Physiol Lung Cell Mol Physiol 2000;279:L716–L721.[Abstract/Free Full Text]
  24. Snyder AH, McPherson ME, Hunt JF, Johnson M, Stamler JS, Gaston B. Acute effects of aerosolized S-nitrosoglutathione in cystic fibrosis. Am J Respir Crit Care Med 2002;165:922–926.[Abstract/Free Full Text]
  25. Griese M, Ramakers J, Krasselt A, Starosta V, Van Koningsbruggen S, Fischer R, Ratjen F, Mullinger B, Huber RM, Maier K, et al. Improvement of alveolar glutathione and lung function but not oxidative state in cystic fibrosis. Am J Respir Crit Care Med 2004;169:822–828.[Abstract/Free Full Text]
  26. Ratjen F, Gartig S, Wiesemann HG, Grasemann H. Effect of inhaled nitric oxide on pulmonary function in cystic fibrosis. Respir Med 1999;93:579–583.[CrossRef][Medline]
  27. Gaston B, Singel D, Doctor A, Stamler JS. S-nitrosothiol signaling in respiratory biology. Am J Respir Crit Care Med 2006;173:1186–1193.[Abstract/Free Full Text]
  28. Solomons CC, Cotton EK, Dubois R. The use of buffered L-arginine in the treatment of cystic fibrosis. Pediatrics 1971;47:384–390.[Abstract/Free Full Text]
  29. Dietzsch HJ, Gottschalk B, Heyne K, Leupoid W, Wunderlich P. Cystic fibrosis: comparison of two mucolytic drugs for inhalation treatment (acetylcysteine and arginine hydrochloride). Pediatrics 1975;55:96–100.[Abstract/Free Full Text]
  30. Ho LP, Innes JA, Greening AP. Exhaled nitric oxide is not elevated in the inflammatory airways diseases of cystic fibrosis and bronchiectasis. Eur Respir J 1998;12:1290–1294.[Abstract]
  31. Grasemann H, Lax H, Treseler JW, Colin AA. Dornase alpha and exhaled NO in cystic fibrosis. Pediatr Pulmonol 2004;38:379–385.[CrossRef][Medline]
  32. Texereau J, Marullo S, Hubert D, Coste J, Dusser DJ, Dall'Ava-Santucci J, Dinh-Xuan AT. Nitric oxide synthase 1 as a potential modifier gene of decline in lung function in patients with cystic fibrosis. Thorax 2004;59:156–158.[Abstract/Free Full Text]
  33. Grasemann H, Knauer N, Büscher R, Hübner K, Drazen JM, Ratjen F. Airway nitric oxide levels in cystic fibrosis patients are related to a polymorphism in the neuronal nitric oxide synthase gene. Am J Respir Crit Care Med 2000;162:2172–2176.[Abstract/Free Full Text]
  34. Grasemann H, Storm van's Gravesande K, Büscher R, Knauer N, Silverman ES, Palmer LJ, Drazen JM, Ratjen F. Endothelial nitric oxide synthase variants in cystic fibrosis lung disease. Am J Respir Crit Care Med 2003;167:390–394.[Abstract/Free Full Text]
  35. King NE, Rothenberg ME, Zimmermann N. Arginine in asthma and lung inflammation. J Nutr 2004;134:2830S–2836S.[Abstract/Free Full Text]
  36. Barth AL, Pitt TL. The high amino-acid content of sputum from cystic fibrosis patients promotes growth of auxotrophic Pseudomonas aeruginosa. J Med Microbiol 1996;45:110–119.[Abstract]
  37. Thomas SR, Ray A, Hodson ME, Pitt TL. Increased sputum amino acid concentrations and auxotrophy of Pseudomonas aeruginosa in severe cystic fibrosis lung disease. Thorax 2000;55:795–797.[Abstract/Free Full Text]
  38. Wooldridge JL, Deutsch GH, Sontag MK, Osberg I, Chase DR, Silkoff PE, Wagener JS, Abman SH, Accurso FJ. NO pathway in CF and non-CF children. Pediatr Pulmonol 2004;37:338–350.[CrossRef][Medline]
  39. Kelley TJ, Elmer HL, Corey DA. Reduced Smad3 protein expression and altered transforming growth factor-beta1-mediated signaling in cystic fibrosis epithelial cells. Am J Respir Cell Mol Biol 2001;25:732–738.[Abstract/Free Full Text]
  40. Lee J, Ryu H, Ferrante RJ, Morris SM, Ratan RR. Translational control of inducible nitric oxide synthase expression by arginine can explain the arginine paradox. Proc Natl Acad Sci USA 2003;100:4843–4848.[Abstract/Free Full Text]
  41. El-Gayar S, Thuring-Nahler H, Pfeilschifter J, Rollinghoff M, Bogdan C. Translational control of inducible nitric oxide synthase by IL-13 and arginine availability in inflammatory macrophages. J Immunol 2003;171:4561–4568.[Abstract/Free Full Text]
  42. Manner CK, Nicholson B, MacLeod CL. CAT2 arginine transporter deficiency significantly reduces iNOS-mediated NO production in astrocytes. J Neurochem 2003;85:476–482.[CrossRef][Medline]
  43. Lange PS, Langley B, Lu P, Ratan RR. Novel roles for arginase in cell survival, regeneration and translation in the central nervous system. J Nutr 2004;134:2812S–2817S.[Abstract/Free Full Text]
  44. Morris SM. Enzymes of arginine metabolism. J Nutr 2004;134:2743S–2747S.[Abstract/Free Full Text]
  45. Grasemann H, Schwiertz R, Grasemann C, Vester U, Racke K, Ratjen F. Decreased systemic bioavailability of L-arginine in patients with cystic fibrosis. Respir Res 2006;7:87.[CrossRef][Medline]
  46. Grasemann H, Schwiertz R, Matthiesen S, Racké K, Ratjen F. Increased arginase activity in cystic fibrosis airways. Am J Respir Crit Care Med 2005;172:1523–1528.[Abstract/Free Full Text]



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J.-M. Tadie, P. Henno, I. Leroy, C. Danel, E. Naline, C. Faisy, M. Riquet, M. Levy, D. Israel-Biet, and C. Delclaux
Role of nitric oxide synthase/arginase balance in bronchial reactivity in patients with chronic obstructive pulmonary disease
Am J Physiol Lung Cell Mol Physiol, March 1, 2008; 294(3): L489 - L497.
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 Am. J. Physiol. Lung Cell. Mol. Physiol.Home page
J. Belik, D. Shehnaz, J. Pan, and H. Grasemann
Developmental changes in arginase expression and activity in the lung
Am J Physiol Lung Cell Mol Physiol, March 1, 2008; 294(3): L498 - L504.
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 Am. J. Respir. Crit. Care Med.Home page
F. J. Accurso
Update in Cystic Fibrosis 2006
Am. J. Respir. Crit. Care Med., April 15, 2007; 175(8): 754 - 757.
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