title: Neonatal hyperoxia causes pulmonary vascular disease and shortens life span in aging mice.
abstract: Bronchopulmonary dysplasia is a chronic lung disease observed in premature infants requiring oxygen supplementation and ventilation. Although the use of exogenous surfactant and protective ventilation strategies has improved survival, the long-term pulmonary consequences of neonatal hyperoxia are unknown. Here, we investigate whether neonatal hyperoxia alters pulmonary function in aging mice. By 67 weeks of age, mice exposed to 100% oxygen between postnatal days 1 to 4 showed significantly a shortened life span (56.6% survival, n = 53) compared to siblings exposed to room air as neonates (100% survival, n = 47). Survivors had increased lung compliance and decreased elastance. There was also right ventricular hypertrophy and pathological evidence for pulmonary hypertension, defined by reduction of the distal microvasculature and the presence of numerous dilated arterioles expressing von Willebrand factor and α-smooth muscle actin. Consistent with recent literature implicating bone morphogenetic protein (BMP) signaling in pulmonary vascular disease, BMP receptors and downstream phospho-Smad1/5/8 were reduced in lungs of aging mice exposed to neonatal oxygen. BMP signaling alterations were not observed in 8-week-old mice. These data suggest that loss of BMP signaling in aged mice exposed to neonatal oxygen is associated with a shortened life span, pulmonary vascular disease, and associated cardiac failure. People exposed to hyperoxia as neonates may be at increased risk for pulmonary hypertension.
authors.affiliation: Department of Pediatrics, School of Medicine and Dentistry, the University of Rochester, Rochester, New York, USA.
authors.forename: Min
authors.initials: M
authors.lastname: Yee
authors.forename: R James
authors.initials: RJ
authors.lastname: White
authors.forename: Hani A
authors.initials: HA
authors.lastname: Awad
authors.forename: Wendy A
authors.initials: WA
authors.lastname: Bates
authors.forename: Sharon A
authors.initials: SA
authors.lastname: McGrath-Morrow
authors.forename: Michael A
authors.initials: MA
authors.lastname: O'Reilly
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D015415:Biomarkers / Q000378:metabolism; D001835:Body Weight / Q000187:drug effects; D019485:Bone Morphogenetic Proteins / Q000378:metabolism; D018496:Hyperoxia / Q000150:complications* / Q000473:pathology / Q000503:physiopathology; D006976:Hypertension, Pulmonary / Q000473:pathology / Q000503:physiopathology; D008136:Longevity / Q000187:drug effects / Q000502:physiology*; D008168:Lung / Q000254:growth & development / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D008171:Lung Diseases / Q000150:complications* / Q000473:pathology / Q000503:physiopathology; D051379:Mice; D009929:Organ Size / Q000187:drug effects; D010100:Oxygen / Q000633:toxicity; D011650:Pulmonary Alveoli / Q000187:drug effects / Q000473:pathology / Q000503:physiopathology; D012129:Respiratory Function Tests; D015398:Signal Transduction / Q000187:drug effects; D014652:Vascular Diseases / Q000150:complications* / Q000503:physiopathology
chemical_list: D015415:Biomarkers; D019485:Bone Morphogenetic Proteins; D010100:Oxygen