TY - JOUR
T1 - Mechanical ventilation causes pulmonary mitochondrial dysfunction and delayed alveolarization in neonatal mice
AU - Ratner, Veniamin
AU - Sosunov, Sergey A.
AU - Niatsetskaya, Zoya V.
AU - Utkina-Sosunova, Irina V.
AU - Ten, Vadim S.
PY - 2013/12
Y1 - 2013/12
N2 - 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.
AB - 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.
KW - Alveolarization
KW - Bioenergetics
KW - Mechanical ventilation
KW - Mitochondrial dysfunction
KW - Mouse model of BPD
UR - http://www.scopus.com/inward/record.url?scp=84890055445&partnerID=8YFLogxK
U2 - 10.1165/rcmb.2012-0172OC
DO - 10.1165/rcmb.2012-0172OC
M3 - Article
C2 - 23980609
AN - SCOPUS:84890055445
SN - 1044-1549
VL - 49
SP - 943
EP - 950
JO - American Journal of Respiratory Cell and Molecular Biology
JF - American Journal of Respiratory Cell and Molecular Biology
IS - 6
ER -