Pulmonary abnormalities due to ABCA1 deficiency in mice

1 Institute for Environmental Medicine, 2 Department of Physiology, University of Pennsylvania, 3 Children's Hospital of Philadelphia, Philadelphia, Pennsylvania; and 4 Pfizer, Groton, Connecticut Submitted 31 May 2005 ; accepted in final form 17 July 2005 Mice gene targeted for ATP-binding cassette transporter A1 (ABCA1; Abca1 –/– ) have been shown to have low-serum high-density lipoprotein 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 (47). Lipid analysis of the lung tissue of –/– mice showed a 1.2- 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 compared with 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 with 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) compared with WT macrophages. More PL mass was cleared from the alveolar space of –/– mice lungs, measured using intratracheal installation of 3 H-PL liposomes. Compared with 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. lung; surfactant; type II cells; alveolar macrophages; cholesterol Address for reprint requests and other correspondence: S. R. Bates, 1 John Morgan Bldg., Institute for Environmental Medicine, 3620 Hamilton Walk, Univ. of Pennsylvania, Philadelphia, PA 19104 (e-mail: batekenn{at}mail.med.upenn.edu )