Transgenic model for the discovery of novel human secretory non-pancreatic phospholipase A2 inhibitors

Abstract Transgenic mice were created which overexpress human secretory non-pancreatic phospholipase A 2 (sPLA 2 ) pansomatically as a potential disease and drug-testing model. The mice were produced using a DNA construct in which the inducible mouse metallothionein gene promoter drives expression of a human sPLA 2 minigene. High levels of sPLA 2 were detected in several tissues by immunofluo-rescence localization. Expression in the testes caused hypospermia and male infertility. Circulating catalytically active sPLA 2 could be induced to levels observed in patients undergoing a systemic inflammatory response but had no detectable effect on the mice. Therefore, these results suggest that sPLA 2 hyperphospholipasemia alone may have only limited pathophysiological consequences. We further show that 3-[3-acetamide-1-benzyl-2-ethylindolyl-5-oxy]propane phosphonic acid (LY311727), a potent new inhibitor of phospholipase A 2 catalysis developed by our group, dramatically suppresses the circulating enzyme activity in these animals whereas 3-[3-acetamide-1-benzyl-2-propylindolyl-5-oxy]propane phosphonic acid (LY314024), a substantially less potent LY311727 analog, is without effect. These later results thus motivate the further development of this compound as a potential new therapeutic agent and valuable research tool.