Transgenic model for the discovery of novel human secretory non-pancreatic phospholipase A(2) inhibitors

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 immunofluorescence 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 Az 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.