PAF-ANTAGONIST ADMINISTRATION AFTER HEMORRHAGE-RESUSCITATION PREVENTSSPLENOCYTE IMMUNODEPRESSION

A number of studies have suggested that the inflammatory and chemotact ic autocoid platelet activating factor (PAF), together with various cy tokines, plays an important role in the pathophysiology of trauma, sep sis, and shock. However, little is known about PAF's contribution to t he immunosuppression associated with hemorrhage. The aim of our study was, therefore, to determine if the use of a PAF-antagonist following hemorrhage has any salutary effects on splenocyte lymphokine productio n. To study this, mice were bled to and maintained at a mean arterial pressure of 35 mm Hg for 60 min. The mice were then segregated into th ree groups and were resuscitated with shed blood plus lactated Ringer' s solution (2X the volume of shed blood), containing either a potent P AF-antagonist (Ro 24-4736, a thienodiazepine) in dimethyl sulfoxide (D MSO) or DMSO-vehicle. Sham-operated mice received either DMSO-vehicle in saline or saline alone. Twenty-four hours thereafter the animals we re sacrificed and splenocyte cultures established and stimulated for 4 8 hr with Con A (2.5 mu g/ml). Supernatant lymphokine levels were dete rmined by bioassay. The cellular release of interleukin-2 and -3 (IL-2 and IL-3) by splenocytes was significantly depressed in the nontreate d or vehicle-treated hemorrhaged animals compared to shams. Treatment with the PAF-antagonist Ro 24-4736 restored IL-2 and IL-3 release valu es to levels comparable to those of the sham-operated animals. Thus, ( 1) PAF appears to play a significant role in hemorrhage-induced immuno suppression and (2) the use of a PAF-antagonist to uncouple the PAF-ge nerated feedback loops prevents the depression in splenocyte function following hemorrhage. We propose that PAF-antagonists may be useful in the treatment of hemorrhage-induced immunodepression. (C) 1995 Academ ic Press, Inc.