Altered lung phospholipid metabolism in mice with targeted deletion of lysosomal-type phospholipase A2.
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.
Fisher
Aron B
AB
Institute for Environmental Medicine, University of Pennsylvania Medical Center, Philadelphia, PA, USA. abf@mail.med.upenn.edu
Dodia
Chandra
C
Feinstein
Sheldon I
SI
Ho
Ye-Shih
YS
D015060:1,2-Dipalmitoylphosphatidylcholine / Q000737:chemistry; D000818:Animals; D001992:Bronchoalveolar Lavage Fluid; D002118:Calcium / Q000378:metabolism; D004847:Epithelial Cells / Q000166:cytology; D017353:Gene Deletion; D005979:Glutathione Peroxidase / Q000378:metabolism; D006863:Hydrogen-Ion Concentration; D008081:Liposomes / Q000378:metabolism; D008168:Lung / Q000378:metabolism* / Q000473:pathology; D008244:Lysophosphatidylcholines / Q000378:metabolism; D008247:Lysosomes / Q000201:enzymology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D010477:Perfusion; D010544:Peroxidases / Q000235:genetics* / Q000378:metabolism / Q000502:physiology*; D054465:Peroxiredoxin VI; D054464:Peroxiredoxins; D010641:Phenotype; D010713:Phosphatidylcholines / Q000378:metabolism; D010741:Phospholipases A / Q000235:genetics* / Q000502:physiology*; D054467:Phospholipases A2; D010743:Phospholipids / Q000378:metabolism; D011650:Pulmonary Alveoli / Q000378:metabolism; D013501:Surface-Active Agents / Q000378:metabolism; D013997:Time Factors
D008081:Liposomes; D008244:Lysophosphatidylcholines; D010713:Phosphatidylcholines; D010743:Phospholipids; D013501:Surface-Active Agents; D015060:1,2-Dipalmitoylphosphatidylcholine; D010544:Peroxidases; D054465:Peroxiredoxin VI; D054464:Peroxiredoxins; C515983:Prdx6 protein, mouse; D005979:Glutathione Peroxidase; D010741:Phospholipases A; D054467:Phospholipases A2; D002118:Calcium