title: L-citrulline prevents alveolar and vascular derangement in a rat model of moderate hyperoxia-induced lung injury.
abstract: BACKGROUND
  Moderate normobaric hyperoxia causes alveolar and vascular lung derangement in the newborn rat. Endogenous nitric oxide (NO), which promotes lung growth, is produced from the metabolism of L-arginine to L-citrulline in endothelial cells. We investigated whether administering L-citrulline by raising the serum levels of L-arginine and enhancing NO endogenous synthesis attenuates moderate hyperoxia-induced lung injury.
  
  
  METHODS
  Newborn rats were exposed to FiO(2) = 0.6 or room air for 14 days to induce lung derangement and then were administered L-citrulline or a vehicle (sham). Lung histopathology was studied with morphometric features. Lung tissues and bronchoalveolar lavage fluid (BALF) were collected for analysis. Lung vascular endothelial growth factor (VEGF), nitric oxide synthase (eNOS), and matrix metalloproteinase 2 (MMP2) gene and protein expressions were assessed.
  
  
  RESULTS
  Serum L-arginine rose in the L-citr + hyperoxia group (p = 0.05), as well as the Von Willebrand factor stained vessels count (p = 0.0008). Lung VEGF immune staining, localized on endothelial cells, was weaker in the sections under hyperoxia than the L-citr + hyperoxia and room air groups. This pattern was comparable with the VEGF gene and protein expression profiles. Mean alveolar size increased in the untreated hyperoxia and sham-treated groups compared with the groups reared in room air or treated with L-citrulline under exposure to hyperoxia (p = 0.0001). Lung VEGF and eNOS increased in the L-citrulline-treated rats, though this treatment did not change MMP2 gene expression but regulated the MMP2 active protein, which rose in BALF (p = 0.003).
  
  
  CONCLUSIONS
  We conclude that administering L: -citrulline proved effective in improving alveolar and vascular growth in a model of oxygen-induced pulmonary damage, suggesting better lung growth and matrix regulation than in untreated groups.
authors.affiliation: Neonatal Intensive Care Unit, Department of Pediatrics, University of Padova, Padova, Italy.
authors.forename: Davide
authors.initials: D
authors.lastname: Grisafi
authors.forename: Evelyne
authors.initials: E
authors.lastname: Tassone
authors.forename: Arben
authors.initials: A
authors.lastname: Dedja
authors.forename: Barbara
authors.initials: B
authors.lastname: Oselladore
authors.forename: Valentina
authors.initials: V
authors.lastname: Masola
authors.forename: Vincenza
authors.initials: V
authors.lastname: Guzzardo
authors.forename: Andrea
authors.initials: A
authors.lastname: Porzionato
authors.forename: Roberto
authors.initials: R
authors.lastname: Salmaso
authors.forename: Giovanna
authors.initials: G
authors.lastname: Albertin
authors.forename: Carlo
authors.initials: C
authors.lastname: Artusi
authors.forename: Martina
authors.initials: M
authors.lastname: Zaninotto
authors.forename: Maurizio
authors.initials: M
authors.lastname: Onisto
authors.forename: Anna
authors.initials: A
authors.lastname: Milan
authors.forename: Veronica
authors.initials: V
authors.lastname: Macchi
authors.forename: Raffaele
authors.initials: R
authors.lastname: De Caro
authors.forename: Ambrogio
authors.initials: A
authors.lastname: Fassina
authors.forename: Michela Alfiero
authors.initials: MA
authors.lastname: Bordigato
authors.forename: Lino
authors.initials: L
authors.lastname: Chiandetti
authors.forename: Marco
authors.initials: M
authors.lastname: Filippone
authors.forename: Patrizia
authors.initials: P
authors.lastname: Zaramella
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D001120:Arginine / Q000378:metabolism; D002956:Citrulline / Q000494:pharmacology / Q000627:therapeutic use*; D004195:Disease Models, Animal; D004730:Endothelium, Vascular / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*; D005260:Female; D018496:Hyperoxia / Q000150:complications*; D008168:Lung / Q000098:blood supply* / Q000378:metabolism / Q000473:pathology; D055370:Lung Injury / Q000209:etiology* / Q000473:pathology / Q000517:prevention & control*; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism; D009569:Nitric Oxide / Q000378:metabolism; D011650:Pulmonary Alveoli / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012720:Severity of Illness Index; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism
chemical_list: D042461:Vascular Endothelial Growth Factor A; D002956:Citrulline; D009569:Nitric Oxide; D001120:Arginine; D020778:Matrix Metalloproteinase 2