A competitive inhibitor of phospholipase A2 decreases surfactant phosphatidylcholine degradation by the rat lung.
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.
Fisher
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Institute For Environmental Medicine, University of Pennsylvania School of Medicine, Philadelphia 19104-6068.
Dodia
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C
Chander
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A
Jain
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M
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
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