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Journal of Lipid Research, Vol. 46, 1248-1256, June 2005
Copyright © 2005 by American Society for Biochemistry and Molecular Biology

Altered lung phospholipid metabolism in mice with targeted deletion of lysosomal-type phospholipase A₂¹

Aron B. Fisher^2,*, Chandra Dodia^*, Sheldon I. Feinstein^* and Ye-Shih Ho

^* Institute for Environmental Medicine, University of Pennsylvania Medical Center, Philadelphia, PA
Institute of Environmental Health Sciences, Wayne State University, Detroit, MI

¹ These results were presented in preliminary form at the Experimental Biology meeting in Washington, DC, in April 2004, the FASEB Surfactant Conference in Saxtons River, VT, in July 2004, and the 2nd International Symposium on Phospholipases A₂ in Berlin, Germany, in October 2004.

Published, JLR Papers in Press, March 16, 2005. DOI 10.1194/jlr.M400499-JLR200

² To whom correspondence should be addressed. e-mail: abf{at}mail.med.upenn.edu

Lung surfactant dipalmitoylphosphatidylcholine (DPPC) is endocytosed by alveolar epithelial cells and degraded by lysosomal-type phospholipase A₂ (aiPLA₂). This enzyme is identical to peroxiredoxin 6 (Prdx6), a bifunctional protein with PLA₂ and GSH peroxidase activities. Lung phospholipid was studied in Prdx6 knockout (Prdx6^–/–) mice. The normalized content of total phospholipid, phosphatidylcholine (PC), and disaturated phosphatidylcholine (DSPC) in bronchoalveolar lavage fluid, lung lamellar bodies, and lung homogenate was unchanged with age in wild-type mice but increased progressively in Prdx6^–/– animals. Degradation of internalized [³H]DPPC in isolated mouse lungs after endotracheal instillation of unilamellar liposomes labeled with [³H]DPPC was significantly decreased at 2 h in Prdx6^–/– mice (13.6 ± 0.3% vs. 26.8 ± 0.8% in the wild type), reflected by decreased dpm in the lysophosphatidylcholine and the unsaturated PC fractions. Incorporation of [¹⁴C]palmitate into DSPC at 24 h after intravenous injection was decreased by 73% in lamellar bodies and by 54% in alveolar lavage surfactant in Prdx6^–/– mice, whereas incorporation of [³H]choline was decreased only slightly. Phospholipid metabolism in Prdx6^–/– lungs was similar to that in wild-type lungs treated with MJ33, an inhibitor of aiPLA₂ activity.

These results confirm an important role for Prdx6 in lung surfactant DPPC degradation and synthesis by the reacylation pathway.

Supplementary key words peroxiredoxin 6 • lung surfactant • dipalmitoylphosphatidylcholine • phospholipid remodeling • phospholipid synthesis

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