Unexpected action of platelet activating factor antagonism after fluid resuscitation from traumatic shock.
BACKGROUND
We have shown that therapy directed at polymorphonuclear neutrophil (PMN) CD18 receptors attenuates sequelae associated with a post-trauma endotoxin (lipopolysaccharide [LPS]) challenge. Platelet activating factor (PAF) stimulates PMNs by CD18-independent pathways, and WEB-2086, a PAF receptor antagonist, blunts septic symptoms in many experimental models. This study tested the hypothesis that the blockade of non-CD18 dependent PMN adherence attenuates trauma- and LPS-evoked pulmonary dysfunction.


METHODS
We performed three experiments. First, anesthetized swine were subjected to hind-limb trauma and 30% hemorrhage. After 1 hour animals were resuscitated with shed blood, lactated Ringer's solution (LRS), and WEB-2086 (10 mg/kg/hr) or vehicle. After a 72-hour recovery period, LPS was administered. LPS was then administered without an earlier episode of traumatic shock to animals treated with WEB-2086 or vehicle. Finally, PAF was infused before and after trauma and a dose response curve was obtained.


RESULTS
Surprisingly, PAF 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 O2 delivery at 72 hours (p < 0.05). After LPS administration WEB-2086 treated pigs were unable to manifest the hyperdynamic circulatory compensation seen in the vehicle pigs. In the absence of traumatic shock, 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 the 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 response to injury. These results also suggest that blockade of endogenous inflammatory mediators can have a positive or negative action, depending on the timing of administration and the preexisting condition.
Schurr
M J
MJ
Department of Surgery (Trauma Division), University of Tennessee Health Science Center, Memphis, USA.
Fabian
T C
TC
Croce
M A
MA
Geraci
S A
SA
Proctor
K G
KG
D000818:Animals; D001381:Azepines / Q000494:pharmacology*; D001784:Blood Gas Analysis; D005440:Fluid Therapy; D006439:Hemodynamics / Q000187:drug effects; D008070:Lipopolysaccharides / Q000494:pharmacology; D010972:Platelet Activating Factor / Q000037:antagonists & inhibitors* / Q000494:pharmacology; D010975:Platelet Aggregation Inhibitors / Q000494:pharmacology*; D012151:Resuscitation; D012774:Shock, Traumatic / Q000097:blood / Q000276:immunology* / Q000503:physiopathology / Q000628:therapy; D013552:Swine; D014230:Triazoles / Q000494:pharmacology*
D001381:Azepines; D008070:Lipopolysaccharides; D010972:Platelet Activating Factor; D010975:Platelet Aggregation Inhibitors; D014230:Triazoles; C052518:WEB 2086