Cytosolic phospholipase A2 inhibition attenuates ischemia-reperfusion injury in an isolated rat lung model.

Abstract

BACKGROUND:

Arachidonic acid metabolites and platelet-activating factor (PAF) are potentially involved in ischemia-reperfusion (IR) lung injury. A key enzyme regulating their metabolism is cytosolic phospholipase A2 (cPLA2). Arachidonyl trifluoromethyl ketone (AACOCF3) is reported to be a potent cPLA2 inhibitor. In the present study, we hypothesized that pharmacological inhibition of cPLA2 might ameliorate IR lung injury.

METHODS:

To test the hypothesis, we examined the effects of AACOCF3 in an isolated rat lung model. Three groups were defined (n=6, each): in the vehicle group, lungs were perfused for 2 hours without an ischemic period. In the ischemic groups, 20 mg/kg of AACOCF3 (AACOCF3 group) or saline (control group) was i.v. administered 15 min before lung harvest. Lungs were flushed with LPD solution, cold-stored 18 hours, and reperfused for 2 hours.

RESULTS:

IR increased cPLA2 activity mainly via alveolar macrophages, sPLA2 activity, thromboxane and leukotriene formation, and the expression of PAF receptor, whereas AACOCF3 treatment significantly reduced all of these. Compared to the vehicle group, the wet-to-dry ratio, proteins in BAL, and MPO activity increased significantly by twofold, fourfold, and threefold, respectively. Furthermore, the PO2 dropped from 615.7+/-31.2 to 452.1+/-30.9 mmHg at the end of reperfusion (P<0.001). AACOCF3 treatment maintained the PO2 at a level similar to the vehicle group throughout reperfusion and reduced significantly the alveolar-capillary leakage, edema formation, and neutrophil extravasation.

CONCLUSION:

Pharmacological inhibition of the cPLA2 cascade decreases bioactive lipid formation and attenuates IR-induced lung injury.

• Authors: Yury A Bellido-Reyes, Hideki Akamatsu, Katsuo Kojima, Hirokuni Arai, Hiroyuki Tanaka, Makoto Sunamori
• Journal: Transplantation (Transplantation) Vol. 81 Issue 12 Pg. 1700-7 (Jun 27 2006) ISSN: 0041-1337 [Print] United States
• PMID: 16794537 (Publication Type: Journal Article)

Chemical References

• Arachidonic Acids
• Eicosanoids
• Platelet Membrane Glycoproteins
• Receptors, G-Protein-Coupled
• platelet activating factor receptor
• arachidonyltrifluoromethane
• Phospholipases A
• Group IV Phospholipases A2
• Group VI Phospholipases A2
• Phospholipases A2
• Pla2g4a protein, rat

Topics

• Animals
• Arachidonic Acids (pharmacology)
• Disease Models, Animal
• Eicosanoids (biosynthesis)
• Group IV Phospholipases A2
• Group VI Phospholipases A2
• In Vitro Techniques
• Lung (blood supply, drug effects, enzymology)
• Lung Transplantation
• Male
• Neutrophils
• Phospholipases A (antagonists & inhibitors, metabolism)
• Phospholipases A2
• Phosphorylation
• Platelet Membrane Glycoproteins (metabolism)
• Rats
• Rats, Sprague-Dawley
• Receptors, G-Protein-Coupled (metabolism)
• Reperfusion Injury (drug therapy, prevention & control)