Background: Prolonged exposure of immature lungs to hyperoxia contributes to neonatal lung injury and airway hyperreactivity. We have previously demonstrated that neonatal exposure of rat pups to ≧95% O2 impairs airway relaxation due to disruption of nitric oxide (NO)-cyclic guanosine monophosphate (cGMP) signaling. Objective: We now hypothesize that these impaired relaxation responses are secondary to hyperoxia-induced upregulation of arginase, which competes with NO synthase for L-arginine. Methods: Rat pups were exposed to moderate neonatal hyperoxia (50% O2) or room air for 7 days from birth. In additional hyperoxic and room air groups, exogenous L-arginine (300 mg/kg/day i.p.) or arginase inhibitor (Nω-hydroxy-nor-arginine, 30 mg/kg/day i.p.) were administered daily. After 7 days, animals were anesthetized and sacrificed either for preparation of lung parenchymal strips or lung perfusion. Results: In response to electrical field stimulation (EFS), bethanechol-preconstricted lung parenchymal strips from hyperoxic pups exhibited significantly reduced relaxation compared to room air controls. Supplementation of L-arginine or arginase blockade restored hyperoxia-induced impairment of relaxation. Expression of arginase I in airway epithelium was increased in response to hyperoxia but reduced by arginase blockade. Arginase activity was also significantly increased in hyperoxic lungs as compared to room air controls and reduced following arginase blockade. EFS-induced production of NO was decreased in hyperoxia-exposed airway smooth muscle and restored by arginase blockade. Conclusion: These data suggest that NO-cGMP signaling is disrupted in neonatal rat pups exposed to even moderate hyperoxia due to increased arginase activity and consequent decreased bioavailability of the substrate L-arginine. We speculate that supplementation of arginine and/or inhibition of arginase may be a useful therapeutic tool to prevent or treat neonatal lung injury.
© 2011 S. Karger AG, Basel
- Nitric oxide production
- Lung strips
- Jobe AH, Bancalari E: Bronchopulmonary dysplasia. Am J Respir Crit Care Med 2001;163:1723–1729.
- Hack M, Taylor HG, Drotar D, Schluchter M, Cartar L, Andreias L, Wilson-Costello D, Klein N: Chronic conditions, functional limitations and special health care needs of school-aged children born with extremely low-birth-weight in the 1990s. JAMA 2005;294:318–325.
- Pelkonen AS, Hakulinen AL, Turpeinen M: Bronchial lability and responsiveness in school children born very preterm. Am J Respir Crit Care Med 1997;156:1178–1184.
- Belik J, Jankov RP, Pan J, Tanswell AK: Chronic O2 exposure enhances vascular and airway smooth muscle contraction in the newborn but not adult rat. J Appl Physiol 2003;94:2303–2312.
- Mhanna MJ, Haxhiu MA, Jaber MA, Walenga RW, Chang C-H, Liu S, Martin RJ: Hyperoxia impairs airway relaxation in immature rats via a cAMP-mediated mechanism. J Appl Physiol 2004;96:1854–1860.
- Potter CF, Kuo N-T, Farver CF, McMahon JT, Chang C-H, Agani FH, Haxhiu MA, Martin RJ: Effects of hyperoxia on nitric oxide synthase expression, nitric oxide activity, and lung injury in rat pups. Pediatr Res 1999;45:8–13.
- Warner BB, Stuart LA, Papes RA, Wispé JR: Functional and pathological effects of prolonged hyperoxia in neonatal mice. Am J Physiol 1998;275:L110–L117.
- Sopi RB, Haxhiu MA, Martin RJ, Dreshaj IA, Kamath S, Zaidi SI: Disruption of NO-cGMP signaling by neonatal hyperoxia impairs relaxation of lung parenchyma. Am J Physiol Lung Cell Mol Physiol 2007;293:L1029–L1036.
- Sopi RB, Martin RJ, Haxhiu MA, Dreshaj IA, Yao Q, Jafri A, Zaidi SI: Role of brain-derived neurotrophic factor in hyperoxia-induced enhancement of contractility and impairment of relaxation in lung parenchyma. Am J Physiol Lung Cell Mol Physiol 2008;295:L348–L355.
- Solway J, Hershenson MB: Structural and functional abnormalities of the airways of hyperoxia-exposed immature rats. Chest 1995;107(3 suppl):89S–93S.
- Belvisi MG, Stretton D, Barnes PJ: Nitric oxide as an endogenous modulator of cholinergic neurotransmission in guinea-pig airways. Eur J Pharmacol 1991;198:219–221.
- Lin YJ, Markham NE, Balasubramanium V, Tang JR, Maxey A, Kinsella JP, Abman SH: Inhaled nitric oxide enhances distal lung growth after exposure to hyperoxia in neonatal rats. Pediatr Res 2005;58:22–29.
- Murad F: Shattuck Lecture. Nitric oxide and cyclic GMP in cell signaling and drug development. N Engl J Med 2006;355:2003–2011.
- Que LG, Kantrow SP, Jenkinson CP, Piatadosi CA, Huang Y-C: Induction of arginase isoforms in the lung during hyperoxia. Am J Physiol 1998;275:L96–L102.
- Iben SC, Dreshaj IA, Farver CF, Haxhiu MA, Martin RJ: Role of endogenous nitric oxide in hyperoxia induced airway hyperreactivity in maturing rats. J Appl Physiol 2000;89:1205–1212.
- Meurs H, McKay S, Maarsingh H, Hamer MA, Macic L, Molendijk N, Zaagsma J: Increased arginase activity underlies allergen-induced deficiency of cNOS-derived nitric oxide and airway hyperresponsiveness. Br J Pharmacol 2002;136:391–398.
- Morris SM Jr: Recent advances in arginine metabolism: roles and regulation of the arginases. Br J Pharmacol 2009;157:922–930.
- 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.
- Maarsingh H, Zuidhof AB, Bos IS, van Duin M, Boucher JL, Zaagsma J, Meurs H: Arginase inhibition protects against allergen-induced airway obstruction, hyperresponsiveness, and inflammation. Am J Respir Crit Care Med 2008;178:565–573.
- North ML, Khanna N, Marsden PA, Grasemann H, Scott JA: Functionally important role for arginase I in airway hyperresponsiveness of asthma. Am J Physiol Lung Cell Mol Physiol 2009;296:L911–L920.
- Takahashi N, Ogino K, Takemoto K, Hamanishi S, Wang D, Takigawa T, Shibamori M, Ishiyama H, Fujikura Y: Direct inhibition of arginase attenuated airway allergic reactions and inflammation in a Dermatophagoides farinae-induced NC/Nga mouse model. Am J Physiol Lung Cell Mol Physiol 2010;299:L17–L24.
- Sheridan BC, McIntyrre RC, Meldrum DR, Fullerton DA: L-Arginine prevents lung neutrophil accumulation and preserves pulmonary endothelial function after endotoxin. Am J Physiol 1998;274:L337–L342.
- Strapkova A, Antosova M, Nosalova G: Relation of L-arginine to airway hyperreactivity. Gen Physiol Biophys 2008;27:85–91.
- Bratt JM, Franzi LM, Linderholm AL, O’Roark EM, Kenyon NJ, Last JA: Arginase inhibition in airways from normal and nitric oxide synthase 2-knockout mice exposed to ovalbumin. Toxicol Appl Pharmacol 2010;242:1–8.
- Bagnost T, Berthelot A, Bouhaddi M, Laurant P, Andre C, Guillaume Y, Demougeot C: Treatment with arginase inhibitor N[omega]-hydroxy-nor-L-arginine improves vascular function and lowers blood pressure in adult spontaneously hypertensive rat. J Hypertens 2008;26:1110–1118.
- Jenkinson CP, Grigor MR: Rat mammary arginase isolation and characterization. Biochem Med Metab Biol 1994,51:156–165.
- Meuchel LW, Thompson MA, Pabelick CM, Prakash YS: Neurotrophins induce nitric oxide in pulmonary endothelial cells. Cardiovasc Res, in press.
- Denis D, Fayon MJ, Berger P, Molimard M, DeLara MT, Roux E, Marthan R: Prolonged moderate hyperoxia induces hyperresponsiveness and airway inflammation in newborn rats. Pediatr Res 2001;50:515–519.
- Moali C, Boucher JL, Sari MA, Stuehr DJ, Mansuy D: Substrate specificity of NO synthases: detailed comparison of L-arginine, homo-L-arginine, their N omega-hydroxy derivatives, and N omega-hydroxynor-L-arginine. Biochemistry 1998;37:10453–10460.
- Bevers LM, Braam B, Post JA, vanZonneveld AJ, Rabelink TJ, Koomans HA, Verhaar MC, Joles JA: Tetrahydrobiopterin, but not L-arginine, decreases NO synthase uncoupling in cells expressing high levels of endothelial NO synthase. Hypertension 2006;47:87–94.
- Hibbs AM, Walsh MC, Martin RJ, Truog WE, Lorch SA, Alessandrini E, Cnaan A, Palermo L, Wadlinger SR, Coburn CE, Ballard PL, Ballard RA: One-year respiratory outcomes of preterm infants enrolled in the Nitric Oxide (to prevent) Chronic Lung Disease trial. J Pediatr 2008;153:525–529.
Syed I.A. Zaidi, PhD
Department of Pediatrics, Rainbow Babies and Children’s Hospital
Case Western Reserve University, 11100 Euclid Avenue
Cleveland, OH 44106-6009 (USA)
Tel. +1 216 844 7359, E-Mail email@example.com
N.K.M.A., A.J. and R.B.S. contributed equally to this paper, and their names are presented in alphabetical order.
Received: December 22, 2010
Accepted after revision: April 18, 2011
Published online: September 23, 2011
Number of Print Pages : 10
Number of Figures : 7, Number of Tables : 0, Number of References : 31
Neonatology (Fetal and Neonatal Research)
Vol. 101, No. 2, Year 2012 (Cover Date: February 2012)
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