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Papers In Press, published online ahead of print March 16, 2005
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Institute for Environmental Medicine, University of Pennsylvania, Philadelphia, PA 19104
Corresponding Author: abf{at}mail.med.upenn.edu
ABSTRACT Lung surfactant phospholipids are endocytosed from the alveolar space and reprocessed by alveolar epithelial cells. Our previous studies showed that a lysosomal-type phospholipase A2 (aiPLA2) has an important role in degradation of internalized dipalmitoylphosphatidylcholine (DPPC) by rat lungs. This enzyme is identical to peroxiredoxin 6 (Prdx6), a bi-functional protein with both PLA2 and GSH peroxidase activities. A Prdx6 -/- mouse was developed by targeted deletion of exon 3. Lysosomal-type PLA2 activity (pH 4; zero Ca2+) was reduced by 97% in Prdx6 -/- lungs and 90% in alveolar macrophages. Content of total phospholipids (PL), phosphatidylcholine (PC) and disaturated PC (DSPC) in bronchoalveolar lavage fluid, lamellar bodies and lung homogenate was 25-77% greater in Prdx6 -/- compared to wild-type mice at 10 weeks of age and increased progressively with age. To study PL metabolism, unilamellar liposomes [3H-DPPC:PC: cholesterol:phosphatidyl glycerol, 10:5:3:2, mol fraction] were instilled into mouse lungs which were removed for isolated lung perfusion. Although, net uptake of liposomes by the lungs were similar, degradation of internalized 3H-DPPC in 2 h was significantly decreased in Prdx6 -/- mice (13.6±0.3 vs. 26.8±0.8% of recovered dpm), reflected by a decrease of dpm in the lysoPC and the unsaturated PC fractions. Incorporation of 14C-choline into lung disaturated PC at 24 h after intravenous injection was only slightly decreased in the Prdx6 -/- mice while incorporation of 3H-palmitate was decreased by 73% in lamellar bodies and 54% in alveolar lavage surfactant. The decrease of degradation and of 3H-palmitate incorporation in Prdx6 -/- lungs was of similar magnitude to that observed in wild-type lungs treated with MJ33, an inhibitor of aiPLA2 activity. These results confirm that Prdx6 expresses PLA2 activity that is physiologically relevant and that this enzyme has a major role in degradation of internalized lung DPPC and its re-synthesis by the reacylation pathway.
Revised on February 23, 2005
Accepted on March 4, 2005
Altered lung phospholipid metabolism in mice with targeted deletion of lysosomal-type phospholipase A2
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