Attenuation of ischemia and reperfusion injury of canine livers by inhibition of type II phospholipase A2 with LY329722.
BACKGROUND
Membrane phospholipid breakdown, caused by ischemia and reperfusion (I/R) of the liver, releases free fatty acids including arachidonic acids and lysophospholipids, which serve as precursors of various inflammatory lipid derivatives. Phospholipase A2 (PLA2) is a key enzyme that initiates this reaction. In this study, we tested our hypothesis that a type II PLA2 inhibitor, LY329722, could attenuate hepatic I/R injury caused by a 2-hr total hepatic vascular exclusion (THVE) in dogs.


METHODS
Eighteen beagle dogs, subjected to a 2-hr THVE, were divided into three groups. Group 1 (n=6) was untreated and served as a control group. LY329722 was administered to animals in group 2 (n=6) intravenously (0.2 mg x kg(-1) x hr(-1)) for 60 min before ischemia, and to animals in group 3 (n=6) for 60 min starting 15 min before reperfusion (0.2 mg x kg(-1) x hr(-1)). Animal survival, systemic and splanchnic hemodynamics, hepatic tissue blood flow, liver functions, energy metabolism, hepatic venous thromboxane B2 and endothelin-1 levels, phospholipid levels and tumor necrosis factor-a mRNA expression in liver tissue, and histopathologic findings were evaluated.


RESULTS
Two-week animal survival was 33% (two of six) in group 1, and 100% (six of six) in groups 2 and 3. LY329722 improved systemic and splanchnic hemodynamics, hepatic tissue blood flow, and energy metabolism, reduced liver enzyme, thromboxane B2, and endothelin-1 release, prevented hepatic phospholipid degradation and tumor necrosis factor-alpha mRNA expression, and lessened histopathologic damage and the number of neutrophil infiltrating into the liver tissue.


CONCLUSIONS
The present study demonstrated that a type II PLA2 inhibitor, LY329722, attenuated hepatic I/R injury caused by a 2-hr THVE model in dogs.
Ogata
K
K
First Department of Surgery, Hokkaido University School of Medicine, Sapporo, Japan.
Jin
M B
MB
Taniguchi
M
M
Suzuki
T
T
Shimamura
T
T
Kitagawa
N
N
Magata
S
S
Fukai
M
M
Ishikawa
H
H
Ono
T
T
Furukawa
H
H
Fujita
M
M
Todo
S
S
D000085:Acetates / Q000494:pharmacology*; D000818:Animals; D015237:Dinoprost / Q000097:blood; D004285:Dogs; D019332:Endothelin-1 / Q000097:blood; D004734:Energy Metabolism; D004791:Enzyme Inhibitors / Q000493:pharmacokinetics / Q000494:pharmacology*; D005260:Female; D006439:Hemodynamics / Q000187:drug effects / Q000502:physiology*; D007211:Indoles / Q000494:pharmacology*; D007511:Ischemia / Q000503:physiopathology* / Q000517:prevention & control; D008099:Liver / Q000098:blood supply* / Q000502:physiology / Q000503:physiopathology; D008102:Liver Circulation / Q000187:drug effects / Q000502:physiology; D008111:Liver Function Tests; D010741:Phospholipases A / Q000037:antagonists & inhibitors*; D054467:Phospholipases A2; D012039:Regional Blood Flow; D015427:Reperfusion Injury / Q000517:prevention & control*; D013152:Splanchnic Circulation / Q000187:drug effects / Q000502:physiology; D013929:Thromboxane B2 / Q000097:blood; D013997:Time Factors; D014158:Transcription, Genetic / Q000235:genetics; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics
C078129:6-keto-prostaglandin F2alpha; D000085:Acetates; D019332:Endothelin-1; D004791:Enzyme Inhibitors; D007211:Indoles; C428265:LY 329722; D014409:Tumor Necrosis Factor-alpha; D013929:Thromboxane B2; D015237:Dinoprost; D010741:Phospholipases A; D054467:Phospholipases A2