ACTIONS OF PROSTAGLANDIN E(1) ON LIPOPOLYSACCHARIDE-EVOKED RESPONSES IN-VIVO AND IN-VITRO FOLLOWING RESUSCITATED TRAUMA

Prostaglandins of the E series (PGE(1), PGE(2)) have well-described im munosuppressive (antiinflammatory) as well as vasodilator (pro-inflamm atory) actions. The net effect on an acute inflammatory response would depend on the dose, timing, and site of action. Egg phosphatidyl lipo somes are novel drug delivery vehicles that can alter the in vivo disp osition of PGE(1). The purpose of this study was to explore the therap eutic potential of PGE(1), with or without liposome encapsulation, on the systemic inflammatory response evoked by endotoxin following traum a. Anesthetized pigs received a soft tissue injury + hemorrhage, and f luid resuscitation after 1 h. In one series, whole blood was incubated with PGE(1) (0, 40, or 200 mu g/ml) and Escherichia coil endotoxin (L PS; 0, 1, 5, or 10 mu g/ml) in vitro and neutrophil CD18 adherence rec eptor density was measured with immunomonitoring. In another series, L PS (5 mu g/kg) was administered 3 days following trauma to animals pre treated with either phosphate-buffered saline (PBS) + PGE(1) (62 ng/kg /min x 40 min, 2.5 mu g/kg total, n = 8), PBS (n = 12), liposomes alon e (Lipo, n = 10) or liposome-encapsulated PGE(1) (Lipo + PGE, n = 7). This PGE(1) dose had minimal effects on blood pressure in baseline con ditions. Hemodynamics, cell differential counts, plasma cortisol, and plasma tumor necrosis factor (TNF) were measured for 3 h post-LPS. LPS in vitro caused a dose-related increase in neutrophil CD18 expression that was not altered by < 200 mu g/mL PGE(1) before or after trauma. LPS in vivo increased pulmonary vascular resistance and heart rate and both were blunted by PGE(1): .73 + .14 vs. .40 +/- .06 mmHg/mL/min/kg , PBS vs. PBS + PGE(1), p = .0167 and 128 +/- 7 vs. 93 + 9 beats/min, PBS vs. PBS+PGE(1), p = .0020, respectively. In addition, stroke index (and therefore cardiac efficiency) was improved with PGE(1) + PBS vs. PBS (p = .0024). These cardiovascular effects were eliminated when PG E, was liposome encapsulated. Plasma TNF was increased to 300-600 pg/m L following LPS and there was no effect of PGE(1) or liposomes, but th e LPS increased plasma cortisol to 7.8 +/- .8 vs. 4.0 +/- 1.0 mu g/100 mL for PBS vs. PBS + PGE(1) (p = .0732) and 8.5 + 2.1 vs. 2.9 + 1.1 m u g/100 mL for Lipo vs. Lipo + PGE(1) (p = .0131). Conclusions are as follows: 1) PGE(1) reduced the LPS-evoked cortisol increase and improv ed cardiac function, but had no detectable effect on the evoked TNF sp ike or neutropenia; 2) Liposome encapsulation eliminated the cardiac, but not the cortisol-lowering, effect; 3) the relative lack of PGE(1) on LPS-evoked acute inflammation could reflect a desensitization to it s immunosuppressive actions. Alternatively, the results are consistent with the interpretation that PGE(1) is not a primary regulator for ac ute inflammation, but is rather ne of a myriad of pro- and anti-inflam matory factors that balance the process.