UNEXPECTED ACTION OF PLATELET-ACTIVATING-FACTOR ANTAGONISM AFTER FLUID RESUSCITATION FROM TRAUMATIC SHOCK

Background. We have shown that therapy directed at polymorphonuclear n eutrophil (PMN) CD18 receptors attenuates sequelae associated with a p ost-trauma endotoxin (lipopolysaccharide [LPS]) challenge. Platelet ac tivating factor (PAF) stimulates PMN's by CD18-independent pathways, a nd WEB-2086, a PAF receptor antagonist, blunts septic symptoms in many experimental models. This study tested the hypothesis that the blocka de of non-CD18 dependent PMN adherence attenuates trauma- and LPS-evok ed pulmonary dysfunction. Methods. We Performed three experiments. Fir st, anesthetized swine were subjected to hind-limb trauma and 30% hemo rrhage. After 1 hour animals were resuscitated with shed blood lactate d Ringer's solution (LRS), and WEB-2086 (10 mg/kg/hr) or vehicle. Afte r a 72-hour recovery period LPS was administered. LPS was then adminis tered without an earlier episode of traumatic shack to animals treated with WEB-2086 or vehicle. Finally, PAF was infused before and after t rauma and a dose response curve was obtained. Results. Surprisingly, P AF blockade increased mortality after trauma (5 of 11 WEB-2086 animals versus 1 of 9 vehicle animals; p = 0.15) and depressed cardiac index and O-2 delivery at 72 hours ip < 0.05). After LPS administration WEB- 2086 treated Pigs were unable to manifest the hydrodynamic circulatory compensation seen in the vehicle pigs. In the absence of traumatic sh ock, WEB-2086 was associated with reduced mortality (four of five WEB- 2086 treated pigs versus two of five vehicle pigs survived 5 hours; p = 0.07) and improved arterial PO2 (p = 0.05) and base excess (p = 0.04 ) 60 minutes after LPS administration The dose response curve for PAF infusion on the cardiac index was altered after trauma compared with t he nontraumatized state. Conclusions. Because WEB-2086 had unexpected and fundamentally opposite properties before and after trauma, PAF may have a previously undescribed homeostatic role in the compensatory re sponse to injury. These results also suggest that blockade of endogeno us inflammatory mediators can have a positive or negative action, depe nding on the tinting of administration and the preexisting condition.