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.

CONCLUSION:

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: 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, Andreas Holzinger
• Journal: Pediatric research (Pediatr Res) Vol. 74 Issue 4 Pg. 384-92 (Oct 2013) ISSN: 1530-0447 [Electronic] United States
• PMID: 23881110 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• ATP-Binding Cassette Transporters
• Abca3 protein, mouse
• DNA Primers
• Interleukins
• Phosphatidylcholines
• Phosphatidylglycerols

Topics

• ATP-Binding Cassette Transporters (genetics)
• Analysis of Variance
• Animals
• Blotting, Western
• Bronchoalveolar Lavage Fluid (chemistry)
• DNA Primers (genetics)
• Genetic Predisposition to Disease (genetics)
• Haploinsufficiency (genetics)
• Histological Techniques
• Hyperoxia (complications)
• Interleukins (analysis)
• Lung (metabolism, pathology)
• Lung Compliance (physiology)
• Mice
• Phosphatidylcholines (analysis)
• Phosphatidylglycerols (analysis)
• Real-Time Polymerase Chain Reaction
• Respiration, Artificial (adverse effects)
• Respiratory Distress Syndrome (etiology, genetics)