A phospholipase A2 inhibitor decreases generation of thiobarbituric acid reactive substance during lung ischemia-reperfusion.
A novel active-site directed specific inhibitor of phospholipase A2 (PLA2), 1-hexadecyl-3-trifluoroethylglycero-sn-2-phosphomethanol (MJ33), administered endotracheally co-dispersed in liposomes, significantly reduced the formation of thiobarbituric acid reactive substances (TBARS) in isolated rat lungs subjected to ischemia-reperfusion. Elevated conjugated dienes were unaffected. This contrasts with the effects of the cyclo-/lipoxygenase inhibitor 5,8,11,14-eicosatetraynoic acid (ETYA), which decreased formation of both TBARS and conjugated dienes (CD). The effects of MJ33 plus ETYA were additive for TBARS but results for CD were similar to ETYA alone. A similar dissociation of inhibition of TBARS and CD formation by MJ33 was observed with t-butyl hydroperoxide induced lipid peroxidation of isolated lung microsomes. Assay of lung homogenate with phosphatidylcholine as substrate showed that MJ33 selectively inhibited the Ca(2+)-independent acidic PLA2. MJ33 had no effect on thromboxane B2 release by the isolated lung, indicating the effects of acidic PLA2 inhibition do not involve the arachidonate cascade. MJ33 also partially prevented lung edema and lactate dehydrogenase release associated with ischemia-reperfusion. The observations show that this PLA2 inhibitor can be delivered to oxidant-sensitive lung sites by its co-dispersal in liposomes, and that oxidant-induced lipid peroxidation in this model of lung injury occurs in a complex lipid prior to PLA2 activity.
al-Mehdi
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Institute for Environmental Medicine, University of Pennsylvania Medical Center, Philadelphia 19104-6068.
Dodia
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Jain
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Fisher
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D015117:5,8,11,14-Eicosatetraynoic Acid / Q000494:pharmacology; D000818:Animals; D005994:Glycerophosphates / Q000494:pharmacology*; D007511:Ischemia / Q000201:enzymology*; D015227:Lipid Peroxidation; D008168:Lung / Q000098:blood supply* / Q000201:enzymology; D008297:Male; D009929:Organ Size; D010477:Perfusion; D010741:Phospholipases A / Q000037:antagonists & inhibitors*; D054467:Phospholipases A2; D051381:Rats; D017207:Rats, Sprague-Dawley; D017392:Thiobarbituric Acid Reactive Substances / Q000032:analysis*
D005994:Glycerophosphates; D017392:Thiobarbituric Acid Reactive Substances; D015117:5,8,11,14-Eicosatetraynoic Acid; C078587:1-hexadecyl-3-trifluoroethylglycero-sn-2-phosphomethanol; D010741:Phospholipases A; D054467:Phospholipases A2