Mechanical ventilation causes pulmonary mitochondrial dysfunction and delayed alveolarization in neonatal mice

Veniamin Ratner, Sergey A. Sosunov, Zoya V. Niatsetskaya, Irina V. Utkina-Sosunova, Vadim S. Ten

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32 Scopus citations


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 ofoxidative phosphorylation.At 10 daysof 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.ExposuretoDNPfullyreplicatedthephenotypeconsistentwith 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 broncho pulmonary dysplasia in premature neonates.

Original languageEnglish
Pages (from-to)943-950
Number of pages8
JournalAmerican Journal of Respiratory Cell and Molecular Biology
Issue number6
StatePublished - Dec 2013
Externally publishedYes


  • Alveolarization
  • Bioenergetics
  • Mechanical ventilation
  • Mitochondrial dysfunction
  • Mouse model of BPD


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