title: Abca3 haploinsufficiency is a risk factor for lung injury induced by hyperoxia or mechanical ventilation in a murine model.
abstract: BACKGROUND
  Heterozygous ATP-binding-cassette subfamily A member 3 (ABCA3) mutations are associated with neonatal respiratory complications. In an adult murine model, we investigated whether Abca3 haploinsufficiency is a predisposing factor for lung injury induced by hyperoxia or mechanical ventilation.
  
  
  METHODS
  Abca3 haploinsufficient (Abca3(+/-)) and wild-type (WT) mice were prospectively randomized to 25 min of ventilation or 72 h of hyperoxia or left unchallenged in air.
  
  
  RESULTS
  As compared with WT mice, unchallenged Abca3(+/-) mice had significantly decreased lung phosphatidylcholine (PC) and phosphatidylglycerol (PG) levels (P < 0.02) and decreased lung compliance (P < 0.05). When ventilated for 25 min, Abca3(+/-) mice demonstrated a significantly greater increase in bronchoalveolar lavage (BAL) interleukins (P ≤ 0.01) and lung wet to dry ratio (P < 0.005). Hyperoxia resulted in increased compliance (P < 0.05) and total lung capacity (TLC) (P = 0.01) only in the Abca3(+/-) mice, consistent with enlarged alveolar spaces. The ratio of PC to PG in BAL-relevant for surfactant dysfunction-was significantly elevated by oxygen exposure, with the greatest increase in Abca3(+/-) mice.
  
  
  CONCLUSIONS
  In a murine model, Abca3 haploinsufficiency results in an altered biochemical and lung mechanical phenotype, as well as a greater lung injury induced by hyperoxia or mechanical ventilation. The inability to maintain a normal PC/PG ratio appears to play a key role.
authors.affiliation: Department of Neonatology, University Children's Hospital, Perinatal Center, Ludwig-Maximilians-Universität Munich, Grosshadern, Munich, Germany.
authors.forename: Susanne
authors.initials: S
authors.lastname: Herber-Jonat
authors.forename: Rashmi
authors.initials: R
authors.lastname: Mittal
authors.forename: Marceline
authors.initials: M
authors.lastname: Huppmann
authors.forename: Markus
authors.initials: M
authors.lastname: Hammel
authors.forename: Gerhard
authors.initials: G
authors.lastname: Liebisch
authors.forename: Ali Önder
authors.initials: AÖ
authors.lastname: Yildirim
authors.forename: Oliver
authors.initials: O
authors.lastname: Eickelberg
authors.forename: Gerd
authors.initials: G
authors.lastname: Schmitz
authors.forename: Martin
authors.initials: M
authors.lastname: Hrabé de Angelis
authors.forename: Andreas W
authors.initials: AW
authors.lastname: Flemmer
authors.forename: Andreas
authors.initials: A
authors.lastname: Holzinger
mesh_terms: D018528:ATP-Binding Cassette Transporters / Q000235:genetics*; D000704:Analysis of Variance; D000818:Animals; D015153:Blotting, Western; D001992:Bronchoalveolar Lavage Fluid / Q000737:chemistry; D017931:DNA Primers / Q000235:genetics; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D057895:Haploinsufficiency / Q000235:genetics*; D006652:Histological Techniques; D018496:Hyperoxia / Q000150:complications*; D007378:Interleukins / Q000032:analysis; D008168:Lung / Q000378:metabolism / Q000473:pathology; D008170:Lung Compliance / Q000502:physiology; D051379:Mice; D010713:Phosphatidylcholines / Q000032:analysis; D010715:Phosphatidylglycerols / Q000032:analysis; D060888:Real-Time Polymerase Chain Reaction; D012121:Respiration, Artificial / Q000009:adverse effects*; D012128:Respiratory Distress Syndrome / Q000209:etiology* / Q000235:genetics
chemical_list: D018528:ATP-Binding Cassette Transporters; C512026:Abca3 protein, mouse; D017931:DNA Primers; D007378:Interleukins; D010713:Phosphatidylcholines; D010715:Phosphatidylglycerols