title: Inhaled NO restores lung structure in eNOS-deficient mice recovering from neonatal hypoxia.
abstract: We have previously shown that neonatal mice deficient in endothelial nitric oxide synthase (eNOS-/-) are more susceptible to hypoxic inhibition of alveolar and vascular growth. Although eNOS is downregulated, the role of nitric oxide (NO) during recovery after neonatal lung injury is poorly understood. We hypothesized that lung vascular and alveolar growth would remain impaired in eNOS-/- mice during recovery in room air and that NO therapy would augment compensatory lung growth in the eNOS-/- mice during recovery. Mice (1 day old) from heterozygous (eNOS+/-) parents were placed in hypobaric hypoxia (Fi(O2) = 0.16). After 10 days, pups were to recovered in room air (HR group) or inhaled NO (10 parts/million; HiNO group) until 3 wk of age, when lung tissue was collected. Morphometric analysis revealed that the eNOS-/- mice in the HR group had persistently abnormal lung structure compared with eNOS-sufficient (eNOS+/+) mice (increased mean linear intercept and reduced radial alveolar counts, nodal point density, and vessel density). Lung morphology of the eNOS+/- was not different from eNOS+/+. Inhaled NO after neonatal hypoxia stimulated compensatory lung growth in eNOS-/- mice that completely restored normal lung structure. eNOS+/- mice (HR group) had a 2.5-fold increase in lung vascular endothelial growth factor (VEGFR)-2 protein compared with eNOS+/+ (P < 0.05). eNOS-/- mice (HiNO group) had a 66% increase in lung VEGFR-2 protein compared with eNOS-/- (HR group; P < 0.01). We conclude that deficiency of eNOS leads to a persistent failure of lung growth during recovery from neonatal hypoxia and that, after hypoxia, inhaled NO stimulates alveolar and vascular growth in eNOS-/- mice.
authors.affiliation: Pediatric Heart Lung Center, Dept. of Pediatrics, UCHSC at Fitzsimmons, Pediatrics 8317, PO Box 6511, Aurora, CO 80045, USA. vivek.balasubramaniam@uchsc.edu
authors.forename: Vivek
authors.initials: V
authors.lastname: Balasubramaniam
authors.forename: Anne M
authors.initials: AM
authors.lastname: Maxey
authors.forename: Danielle B
authors.initials: DB
authors.lastname: Morgan
authors.forename: Neil E
authors.initials: NE
authors.lastname: Markham
authors.forename: Steven H
authors.initials: SH
authors.lastname: Abman
mesh_terms: D000280:Administration, Inhalation; D000388:Air; D000818:Animals; D000831:Animals, Newborn; D001835:Body Weight; D005260:Female; D000860:Hypoxia / Q000188:drug therapy* / Q000473:pathology* / Q000503:physiopathology; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D018919:Neovascularization, Physiologic / Q000187:drug effects; D009569:Nitric Oxide / Q000494:pharmacology*; D052247:Nitric Oxide Synthase Type II / Q000235:genetics*; D052250:Nitric Oxide Synthase Type III; D019408:Platelet Endothelial Cell Adhesion Molecule-1 / Q000378:metabolism; D011650:Pulmonary Alveoli / Q000098:blood supply / Q000473:pathology* / Q000503:physiopathology; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000378:metabolism
chemical_list: D019408:Platelet Endothelial Cell Adhesion Molecule-1; D042461:Vascular Endothelial Growth Factor A; C467480:vascular endothelial growth factor A, mouse; D009569:Nitric Oxide; D052247:Nitric Oxide Synthase Type II; D052250:Nitric Oxide Synthase Type III; C496315:Nos3 protein, mouse; D040301:Vascular Endothelial Growth Factor Receptor-2