• Susanne Herber-Jonat, Rashmi Mittal, Marceline Huppmann, Markus Hammel, Gerhard Liebisch, Ali Önder Yildirim, Oliver Eickelberg, Gerd Schmitz, Martin Hrabé de Angelis, Andreas W Flemmer, and Andreas Holzinger.
• Department of Neonatology, University Children's Hospital, Perinatal Center, Ludwig-Maximilians-Universität Munich, Grosshadern, Munich, Germany.
• Pediatr. Res. 2013 Oct 1; 74 (4): 384-92.

BackgroundHeterozygous 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.MethodsAbca3 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.ResultsAs 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.ConclusionIn 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.

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