TUMOR-NECROSIS-FACTOR AND ENDOTOXIN SYNERGISTICALLY ACTIVATE INTESTINAL PHOSPHOLIPASE A(2) IN MICE - ROLE OF ENDOGENOUS PLATELET-ACTIVATING-FACTOR AND EFFECT OF EXOGENOUS PLATELET-ACTIVATING-FACTOR

Previous studies have shown that: (a) platelet activating factor induces shock and intestinal injury, (b) exogenous platelet activating factor stimulates synthesis of endogenous platelet activating factor, and (c) tumour necrosis factor alpha and endotoxin synergise to induce shock and bowel injury in animals. These last two effects are largely mediated by platelet activating factor forming phospholipase A(2) A(2), a key enzyme for platelet activating factor synthesis, was examined in mouse intestine. It was found that tumour necrosis factor alpha and endotoxin synergise to stimulate platelet activating factor forming phospholipase A(2) activity in the intestine, as well as platelet activating factor production, and these effects were blocked by pretreatment with platelet activating factor antagonists, SRI-63-441 and WEB 2086. In addition, exogenous platelet activating factor stimulates intestinal phospholipase A(2) activity. These results show that tumour necrosis factor alpha and lipopolysaccharide synergistically activate the phospholipase A(2) that participates in platelet activating factor formation, and this activation is largely mediated by endogenous platelet activating factor. Furthermore, platelet activating factor itself increases phospholipase A(2) activity, suggesting that platelet activating factor induces its own synthesis, probably by phospholipase A(2) activation.