Unexpected action of platelet activating factor antagonism after fluid resuscitation from traumatic shock

Michael J. Schurr, Timothy C. Fabian, Martin A. Croce, Stephen A. Geraci, Kenneth G Proctor

Research output: Contribution to journalArticle

4 Citations (Scopus)

Abstract

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 I 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.

Original languageEnglish
Pages (from-to)493-500
Number of pages8
JournalSurgery
Volume121
Issue number5
StatePublished - May 1 1997
Externally publishedYes

Fingerprint

WEB 2086
Traumatic Shock
Platelet Activating Factor
Resuscitation
Lipopolysaccharides
Wounds and Injuries
Swine
Neutrophils
Preexisting Condition Coverage
Mortality
Endotoxins

ASJC Scopus subject areas

  • Surgery

Cite this

Schurr, M. J., Fabian, T. C., Croce, M. A., Geraci, S. A., & Proctor, K. G. (1997). Unexpected action of platelet activating factor antagonism after fluid resuscitation from traumatic shock. Surgery, 121(5), 493-500.

Unexpected action of platelet activating factor antagonism after fluid resuscitation from traumatic shock. / Schurr, Michael J.; Fabian, Timothy C.; Croce, Martin A.; Geraci, Stephen A.; Proctor, Kenneth G.

In: Surgery, Vol. 121, No. 5, 01.05.1997, p. 493-500.

Research output: Contribution to journalArticle

Schurr, MJ, Fabian, TC, Croce, MA, Geraci, SA & Proctor, KG 1997, 'Unexpected action of platelet activating factor antagonism after fluid resuscitation from traumatic shock', Surgery, vol. 121, no. 5, pp. 493-500.
Schurr, Michael J. ; Fabian, Timothy C. ; Croce, Martin A. ; Geraci, Stephen A. ; Proctor, Kenneth G. / Unexpected action of platelet activating factor antagonism after fluid resuscitation from traumatic shock. In: Surgery. 1997 ; Vol. 121, No. 5. pp. 493-500.
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abstract = "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 I 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.",
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