title: Intermittent hypoxia during recovery from neonatal hyperoxic lung injury causes long-term impairment of alveolar development: A new rat model of BPD.
abstract: Bronchopulmonary dysplasia (BPD) is a chronic lung injury characterized by impaired alveologenesis that may persist into adulthood. Rat models of BPD using varying degrees of hyperoxia to produce injury either cause early mortality or spontaneously recover following removal of the inciting stimulus, thus limiting clinical relevance. We sought to refine an established rat model induced by exposure to 60% O2from birth by following hyperoxia with intermittent hypoxia (IH). Rats exposed from birth to air or 60% O2until day 14 were recovered in air with or without IH (FIO2= 0.10 for 10 min every 6 h) until day 28 Animals exposed to 60% O2and recovered in air had no evidence of abnormal lung morphology on day 28 or at 10-12 wk. In contrast, 60% O2-exposed animals recovered in IH had persistently increased mean chord length, more dysmorphic septal crests, and fewer peripheral arteries. Recovery in IH also increased pulmonary vascular resistance, Fulton index, and arterial wall thickness. IH-mediated abnormalities in lung structure (but not pulmonary hypertension) persisted when reexamined at 10-12 wk, accompanied by increased pulmonary vascular reactivity and decreased exercise tolerance. Increased mean chord length secondary to IH was prevented by treatment with a peroxynitrite decomposition catalyst [5,10,15,20-Tetrakis(4-sulfonatophenyl)-21H,23H-porphyrin iron (III) chloride, 30 mg/kg/day, days 14-28], an effect accompanied by fewer inflammatory cells. We conclude that IH during recovery from hyperoxia-induced injury prevents recovery of alveologenesis and leads to changes in lung and pulmonary vascular function lasting into adulthood, thus more closely mimicking contemporary BPD.
authors.affiliation: Division of Neonatology, Department of Pediatrics, Neonatal-Perinatal Research Institute, Duke University Medical Center, Durham, North Carolina.|Physiology & Experimental Medicine Program, Hospital for Sick Children Research Institute, Toronto, Ontario, Canada.
authors.forename: Anastasiya
authors.initials: A
authors.lastname: Mankouski
authors.affiliation: Physiology & Experimental Medicine Program, Hospital for Sick Children Research Institute, Toronto, Ontario, Canada.
authors.forename: Crystal
authors.initials: C
authors.lastname: Kantores
authors.affiliation: Physiology & Experimental Medicine Program, Hospital for Sick Children Research Institute, Toronto, Ontario, Canada.|Faculty of Medicine, Department of Physiology, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Mathew J
authors.initials: MJ
authors.lastname: Wong
authors.affiliation: Physiology & Experimental Medicine Program, Hospital for Sick Children Research Institute, Toronto, Ontario, Canada.
authors.forename: Julijana
authors.initials: J
authors.lastname: Ivanovska
authors.affiliation: Faculty of Medicine, Department of Pediatrics, University of Toronto, Toronto, Ontario, Canada; and.|Faculty of Medicine, Department of Physiology, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Amish
authors.initials: A
authors.lastname: Jain
authors.affiliation: Division of Neonatology, Department of Pediatrics, Neonatal-Perinatal Research Institute, Duke University Medical Center, Durham, North Carolina.
authors.forename: Eric J
authors.initials: EJ
authors.lastname: Benner
authors.affiliation: Division of Neonatology, Department of Pediatrics, Neonatal-Perinatal Research Institute, Duke University Medical Center, Durham, North Carolina.
authors.forename: Stanley N
authors.initials: SN
authors.lastname: Mason
authors.affiliation: Physiology & Experimental Medicine Program, Hospital for Sick Children Research Institute, Toronto, Ontario, Canada.|Faculty of Medicine, Department of Pediatrics, University of Toronto, Toronto, Ontario, Canada; and.|Faculty of Medicine, Department of Physiology, University of Toronto, Toronto, Ontario, Canada.
authors.forename: A Keith
authors.initials: AK
authors.lastname: Tanswell
authors.affiliation: Division of Neonatology, Department of Pediatrics, Neonatal-Perinatal Research Institute, Duke University Medical Center, Durham, North Carolina.
authors.forename: Richard L
authors.initials: RL
authors.lastname: Auten
authors.affiliation: Physiology & Experimental Medicine Program, Hospital for Sick Children Research Institute, Toronto, Ontario, Canada; robert.jankov@sickkids.ca.|Faculty of Medicine, Department of Pediatrics, University of Toronto, Toronto, Ontario, Canada; and.|Faculty of Medicine, Department of Physiology, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Robert P
authors.initials: RP
authors.lastname: Jankov
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D015415:Biomarkers / Q000378:metabolism; D001997:Bronchopulmonary Dysplasia / Q000150:complications* / Q000473:pathology*; D002384:Catalysis; D004195:Disease Models, Animal; D005260:Female; D018496:Hyperoxia / Q000150:complications* / Q000473:pathology; D006976:Hypertension, Pulmonary / Q000150:complications; D000860:Hypoxia / Q000150:complications* / Q000473:pathology; D055370:Lung Injury / Q000150:complications* / Q000473:pathology; D008297:Male; D008665:Metalloporphyrins / Q000494:pharmacology; D030421:Peroxynitrous Acid / Q000378:metabolism; D010805:Physical Conditioning, Animal; D011014:Pneumonia / Q000150:complications; D011650:Pulmonary Alveoli / Q000254:growth & development* / Q000473:pathology*; D017207:Rats, Sprague-Dawley
chemical_list: C466420:5,10,15,20-tetrakis(4-sulfonatophenyl)porphyrinato iron(III) chloride; D015415:Biomarkers; D008665:Metalloporphyrins; D030421:Peroxynitrous Acid
keywords: bronchopulmonary dysplasia; chronic neonatal lung injury; oxygen toxicity, pulmonary hypertension