Attenuation of ischemia and reperfusion injury of canine livers by inhibition of type II phospholipase A2 with LY329722.

Abstract

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.

CONCLUSION:

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.

• Authors: K Ogata, M B Jin, M Taniguchi, T Suzuki, T Shimamura, N Kitagawa, S Magata, M Fukai, H Ishikawa, T Ono, H Furukawa, M Fujita, S Todo
• Journal: Transplantation (Transplantation) Vol. 71 Issue 8 Pg. 1040-6 (Apr 27 2001) ISSN: 0041-1337 [Print] United States
• PMID: 11374398 (Publication Type: Journal Article)

Chemical References

• 6-keto-prostaglandin F2alpha
• Acetates
• Endothelin-1
• Enzyme Inhibitors
• Indoles
• LY 329722
• Tumor Necrosis Factor-alpha
• Thromboxane B2
• Dinoprost
• Phospholipases A
• Phospholipases A2

Topics

• Acetates (pharmacology)
• Animals
• Dinoprost (blood)
• Dogs
• Endothelin-1 (blood)
• Energy Metabolism
• Enzyme Inhibitors (pharmacokinetics, pharmacology)
• Female
• Hemodynamics (drug effects, physiology)
• Indoles (pharmacology)
• Ischemia (physiopathology, prevention & control)
• Liver (blood supply, physiology, physiopathology)
• Liver Circulation (drug effects, physiology)
• Liver Function Tests
• Phospholipases A (antagonists & inhibitors)
• Phospholipases A2
• Regional Blood Flow
• Reperfusion Injury (prevention & control)
• Splanchnic Circulation (drug effects, physiology)
• Thromboxane B2 (blood)
• Time Factors
• Transcription, Genetic (genetics)
• Tumor Necrosis Factor-alpha (genetics)