Apelin attenuates hyperoxic lung and heart injury in neonatal rats.
BACKGROUND
Apelin, a potent vasodilator and angiogenic factor, may be a novel therapeutic agent in neonatal chronic lung disease, including bronchopulmonary dysplasia.


OBJECTIVE
To determine the beneficial effect of apelin in neonatal rats with hyperoxia-induced lung injury, a model for premature infants with bronchopulmonary dysplasia.


METHODS
The cardiopulmonary effects of apelin treatment (62 μg/kg/d) were studied in neonatal rats by exposure to 100% oxygen, using two treatment strategies: early concurrent treatment during continuous exposure to hyperoxia for 10 days and late treatment and recovery in which treatment was started on Day 6 after hyperoxic injury for 9 days and continued during the 9-day recovery period. We investigated in both models the role of the nitric oxide-cyclic guanosine monophosphate (cGMP) pathway in apelin treatment by specific inhibition of the nitric oxide synthase activity with N(ω)-nitro-L-arginine methyl ester (L-NAME, 25 mg/kg/d).


RESULTS
Parameters investigated include survival, lung and heart histopathology, pulmonary fibrin deposition and inflammation, alveolar vascular leakage, lung cGMP levels, right ventricular hypertrophy, and differential mRNA expression in lung and heart tissue. Prophylactic treatment with apelin improved alveolarization and angiogenesis, increased lung cGMP levels, and reduced pulmonary fibrin deposition, inflammation, septum thickness, arteriolar wall thickness, and right ventricular hypertrophy. These beneficial effects were completely absent in the presence of L-NAME. In the injury-recovery model apelin also improved alveolarization and angiogenesis, reduced arteriolar wall thickness, and attenuated right ventricular hypertrophy.


CONCLUSIONS
Apelin reduces pulmonary inflammation, fibrin deposition, and right ventricular hypertrophy, and partially restores alveolarization in rat pups with neonatal hyperoxic lung injury via a nitric oxide synthase-dependent mechanism.
Visser
Yvonne P de
YP
Department of Pediatrics, Leiden University Medical Center, The Netherlands.
Walther
Frans J
FJ
Laghmani
El Houari
el H
Laarse
Arnoud van der
Av
Wagenaar
Gerry T M
GT
D000818:Animals; D000831:Animals, Newborn; D000073861:Apelin; D000075244:Apelin Receptors; D002352:Carrier Proteins / Q000096:biosynthesis / Q000502:physiology / Q000627:therapeutic use*; D006152:Cyclic GMP / Q000032:analysis; D006335:Heart Injuries / Q000188:drug therapy* / Q000503:physiopathology; D018496:Hyperoxia / Q000188:drug therapy* / Q000503:physiopathology; D017403:In Situ Hybridization; D007249:Inflammation / Q000188:drug therapy / Q000473:pathology / Q000503:physiopathology; D036341:Intercellular Signaling Peptides and Proteins; D008168:Lung / Q000737:chemistry / Q000254:growth & development / Q000473:pathology / Q000503:physiopathology; D055370:Lung Injury / Q000188:drug therapy*; D009206:Myocardium / Q000378:metabolism / Q000473:pathology; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D043562:Receptors, G-Protein-Coupled / Q000096:biosynthesis / Q000502:physiology; D020133:Reverse Transcriptase Polymerase Chain Reaction
D000073861:Apelin; D000075244:Apelin Receptors; C498579:Apln protein, rat; C491284:Aplnr protein, rat; D002352:Carrier Proteins; D036341:Intercellular Signaling Peptides and Proteins; D043562:Receptors, G-Protein-Coupled; D006152:Cyclic GMP; D019331:NG-Nitroarginine Methyl Ester