TRANSGENIC MODEL FOR THE DISCOVERY OF NOVEL HUMAN SECRETORY NONPANCREATIC PHOSPHOLIPASE A(2) INHIBITORS

Transgenic mice were created which overexpress human secretory non-pan creatic phospholipase A(2) (sPLA(2)) pansomatically as a potential dis ease and drug-testing model. The mice were produced using a DNA constr uct in which the inducible mouse metallothionein gene promoter drives expression of a human sPLA(2) minigene. High levels of sPLA(2) were de tected in several tissues by immunofluorescence localization. Expressi on in the testes caused hypospermia and male infertility. Circulating catalytically active sPLA(2) could be induced to levels observed in pa tients undergoing a systemic inflammatory response but had no detectab le effect on the mice. Therefore, these results suggest that sPLA(2) h yperphospholipasemia alone may have only limited pathophysiological co nsequences. We further show that [3-acetamide-1-benzyl-2-ethylindolyl- 5-oxy]propane phosphonic acid (LY311727), a potent new inhibitor of ph ospholipase Az catalysis developed by our group, dramatically suppress es the circulating enzyme activity in these animals whereas 3-acetamid e-1-benzyl-2-propylindolyl-5-oxy]propane phosphonic acid (LY314024), a substantially less potent LY311727 analog, is without effect. These l ater results thus motivate the further development of this compound as a potential new therapeutic agent and valuable research tool.