Attenuation of ischemia and reperfusion injury of canine livers by inhibition of type II phospholipase A(2) with LY329722

Background. Membrane phospholipid breakdown, caused by ischemia and reperfu sion (I/R) of the liver, releases free fatty acids including arachidonic ac ids and lysophospholipids, which serve as precursors of various inflammator y lipid derivatives. Phospholipase A(2) (PLA(2)) is a key enzyme that initi ates this reaction. In this study, we tested our hypothesis that a type II PLA(2) inhibitor, LY329722, could attenuate hepatic YR 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. LY 329722 was administered to animals in group 2 (n=6) intravenously (0.2 mg.k g(-1).hr(-1)) for 60 min before ischemia, and to animals in group 3 (n=6) f or 60 min starting 15 min before reperfusion (0.2 mg.kg(-1).hr(-1)). Animal survival, systemic and splanchnic hemodynamics, hepatic tissue blood flow, liver functions, energy metabolism, hepatic venous thromboxane B, and endo thelin-1 levels, phospholipid levels and tumor necrosis factor-alpha mRNA e xpression 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 liv er enzyme, thromboxane B-2, and endothelin-1 release, prevented hepatic pho spholipid degradation and tumor necrosis factor-alpha mRNA expression, and lessened histopathologic damage and the number of neutrophil infiltrating i nto the liver tissue. Conclusion. The present study demonstrated that a type II PLA, inhibitor, L Y329722, attenuated hepatic I/R injury caused by a 2-hr THVE model in dogs.