Background:Heterozygous ABCA3 (ATP-binding-cassette sub-family A member3) mutations are associated with neonatal respiratory complications. We investigated in an adult murine model 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 hours of hyperoxia or left unchallenged in air.Results:As compared to WT, 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.