title: Mechanical ventilation causes pulmonary mitochondrial dysfunction and delayed alveolarization in neonatal mice.
abstract: Hyperoxia inhibits pulmonary bioenergetics, causing delayed alveolarization in mice. We hypothesized that mechanical ventilation (MV) also causes a failure of bioenergetics to support alveolarization. To test this hypothesis, neonatal mice were ventilated with room air for 8 hours (prolonged) or for 2 hours (brief) with 15 μl/g (aggressive) tidal volume (Tv), or for 8 hours with 8 μl/g (gentle) Tv. After 24 hours or 10 days of recovery, lung mitochondria were examined for adenosine diphosphate (ADP)-phosphorylating respiration, using complex I (C-I)-dependent, complex II (C-II)-dependent, or cytochrome C oxidase (C-IV)-dependent substrates, ATP production rate, and the activity of C-I and C-II. A separate cohort of mice was exposed to 2,4-dinitrophenol (DNP), a known uncoupler of oxidative phosphorylation. At 10 days of recovery, pulmonary alveolarization and the expression of vascular endothelial growth factor (VEGF) were assessed. Sham-operated littermates were used as control mice. At 24 hours after aggressive MV, mitochondrial ATP production rates and the activity of C-I and C-II were significantly decreased compared with control mice. However, at 10 days of recovery, only mice exposed to prolonged-aggressive MV continued to exhibit significantly depressed mitochondrial respiration. This was associated with significantly poorer alveolarization and VEGF expression. In contrast, mice exposed to brief-aggressive or prolonged-gentle MV exhibited restored mitochondrial ADP-phosphorylation, normal alveolarization and pulmonary VEGF content. Exposure to DNP fully replicated the phenotype consistent with alveolar developmental arrest. Our data suggest that the failure of bioenergetics to support normal lung development caused by aggressive and prolonged ventilation should be considered a fundamental mechanism for the development of bronchopulmonary dysplasia in premature neonates.
authors: 1 Department of Pediatrics, Columbia University College of Physicians and Surgeons, New York, New York.
authors: Veniamin
authors: V
authors: Ratner
authors: Sergey A
authors: SA
authors: Sosunov
authors: Zoya V
authors: ZV
authors: Niatsetskaya
authors: Irina V
authors: IV
authors: Utkina-Sosunova
authors: Vadim S
authors: VS
authors: Ten
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D000831:Animals, Newborn; D001997:Bronchopulmonary Dysplasia / Q000209:etiology / Q000378:metabolism / Q000473:pathology; D004195:Disease Models, Animal; D004734:Energy Metabolism; D006801:Humans; D018496:Hyperoxia / Q000150:complications / Q000378:metabolism / Q000473:pathology; D007231:Infant, Newborn; D007234:Infant, Premature; D008168:Lung / Q000254:growth & development / Q000378:metabolism*; D055370:Lung Injury / Q000209:etiology / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D008928:Mitochondria / Q000378:metabolism; D011650:Pulmonary Alveoli / Q000254:growth & development / Q000378:metabolism; D012121:Respiration, Artificial / Q000009:adverse effects*; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism
chemical_list: D042461:Vascular Endothelial Growth Factor A; C467480:vascular endothelial growth factor A, mouse; D000255:Adenosine Triphosphate
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