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1 Institute for Environmental Medicine, University of Pennsylvania School of Medicine, Philadelphia, PA, USA; Department of Physiology, University of Pennsylvania School of Medicine, Philadelphia, PA, USA
2 Institute for Environmental Medicine, University of Pennsylvania School of Medicine, Philadelphia, PA, USA
3 Children's Hospital of Philadelphia, Philadelphia, PA, USA
4 Pfizer, Groton, CT, USA
* To whom correspondence should be addressed. E-mail: batekenn{at}mail.med.upenn.edu.
Mice gene-targeted for ABCA1 (Abca1-/-) have been shown to have low serum HDL and abnormal lung morphology. We examined alterations in the structure and function of lungs from -/- mice (DBA1/J). Electron microscopy of the diseased mouse lung revealed areas of focal disease confirming previous results (49). Lipid analysis of the lung tissue of -/- mice showed a 1.2-fold and 1.4-fold elevation in total phospholipid (PL) and saturated phosphatidylcholine, respectively, and a marked 50% enrichment in total cholesterol content predominately due to a 17.5-fold increase in cholesteryl ester in comparison to wild type (WT). Lung surfactant in the -/- mice was characterized by alveolar proteinosis (161%), a slight increase in total PL (124%) and a marked increase in free cholesterol (155%) compared to WT. Alveolar macrophages were enriched in cholesterol (4.8-fold) due to elevations in free cholesterol (2.4-fold) and in cholesteryl ester (14.8-fold) as compared to WT macrophages. More PL mass was cleared from the alveolar space of -/- mice lungs, measured using intratracheal installation of 3H-PL liposomes. As compared to WT mice, the Abca1-/- mice demonstrated respiratory distress with rapid, shallow breathing. Thus, the lungs of mice lacking ABCA1 protein demonstrated abnormal morphology and physiology, with alveolar proteinosis and cholesterol-enrichment of tissue, surfactant and macrophages. The results indicate that the activity of ABCA1 is important for the maintenance of normal lung lipid composition, structure and function.
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