title: Role of arginase in impairing relaxation of lung parenchyma of hyperoxia-exposed neonatal rats.
abstract: 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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Department of Pediatrics, Rainbow Babies and Children's Hospital, Case Western Reserve University, Cleveland, Ohio 44106-6009, USA.
authors.forename: Nuzhat K M
authors.initials: NK
authors.lastname: Ali
authors.forename: Anjum
authors.initials: A
authors.lastname: Jafri
authors.forename: Ramadan B
authors.initials: RB
authors.lastname: Sopi
authors.forename: Y S
authors.initials: YS
authors.lastname: Prakash
authors.forename: Richard J
authors.initials: RJ
authors.lastname: Martin
authors.forename: Syed I A
authors.initials: SI
authors.lastname: Zaidi
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D001119:Arginase / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000502:physiology*; D001120:Arginine / Q000031:analogs & derivatives / Q000494:pharmacology; D018723:Bethanechol / Q000494:pharmacology; D004558:Electric Stimulation; D018496:Hyperoxia / Q000378:metabolism / Q000503:physiopathology*; D008168:Lung / Q000166:cytology / Q000201:enzymology* / Q000502:physiology*; D009126:Muscle Relaxation / Q000502:physiology*; D009130:Muscle, Smooth / Q000187:drug effects / Q000503:physiopathology; D009569:Nitric Oxide / Q000096:biosynthesis; D010277:Parasympathomimetics / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction / Q000187:drug effects; D015854:Up-Regulation
chemical_list: D010277:Parasympathomimetics; D018723:Bethanechol; C021064:norarginine; D009569:Nitric Oxide; D001120:Arginine; C113162:Arg2 protein, rat; D001119:Arginase; C542908:arginase I, rat