title: A competitive inhibitor of phospholipase A2 decreases surfactant phosphatidylcholine degradation by the rat lung.
abstract: We have shown previously that radiolabelled phosphatidylcholine (PC) in liposomes or natural surfactant is removed from the alveolar space and metabolically recycled in a process that is stimulated by cyclic AMP (cAMP). In this study, we evaluated the effect of a transition-state phospholipid analogue (MJ33; 1-hexadecyl-3-trifluoroethylglycero-sn-2-phosphomethanol) that competitively inhibited acidic phospholipase A2 (PLA2) activity (pH 4.0) of lung homogenate by more than 97%, but had no effect on PLA2 activity at pH 8.5. MJ33 incorporated into unilamellar liposomes (dipalmitoyl PC/egg PC/cholesterol/phosphatidylglycerol, molar proportions 10:5:3:2) or co-sonicated with biosynthesized natural surfactant was instilled into the trachea of the anaesthetized rat; lungs were then removed for 2 h perfusion in the absence or presence of 0.1 mM-8-bromo cAMP. Total uptake for phospholipid was unchanged in the presence of the inhibitor MJ33. Degradation of labelled PC during 2 h perfusion in the absence of MJ33 was approx. 26% of that instilled for choline-labelled liposomal PC, 16% for liposomal PC labelled in the second fatty-acyl position, and 33% for choline-labelled natural surfactant. Degradation of PC was decreased by approx. 25-40% for each substrate in the presence of MJ33. Inhibition of lipid degradation depended on the mole fraction of MJ33 in the liposomes and was maximal at 1 mol%. These studies demonstrate a significant role for acidic Ca(2+)-independent PLA2 in the degradation of internalized alveolar PC, but further indicate that this enzyme accounts for a minor fraction of total lung PC metabolism.
authors.affiliation: Institute For Environmental Medicine, University of Pennsylvania School of Medicine, Philadelphia 19104-6068.
authors.forename: A B
authors.initials: AB
authors.lastname: Fisher
authors.forename: C
authors.initials: C
authors.lastname: Dodia
authors.forename: A
authors.initials: A
authors.lastname: Chander
authors.forename: M
authors.initials: M
authors.lastname: Jain
mesh_terms: D000818:Animals; D005994:Glycerophosphates; D008081:Liposomes / Q000737:chemistry; D008168:Lung / Q000378:metabolism*; D008297:Male; D010713:Phosphatidylcholines / Q000378:metabolism*; D010741:Phospholipases A / Q000037:antagonists & inhibitors* / Q000145:classification / Q000378:metabolism; D054467:Phospholipases A2; D010743:Phospholipids; D011663:Pulmonary Surfactants / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D005994:Glycerophosphates; D008081:Liposomes; D010713:Phosphatidylcholines; D010743:Phospholipids; D011663:Pulmonary Surfactants; C078587:1-hexadecyl-3-trifluoroethylglycero-sn-2-phosphomethanol; D010741:Phospholipases A; D054467:Phospholipases A2