Actions of prostaglandin E₁ on lipopolysaccharide-evoked responses in vivo and in vitro following resuscitated trauma

Prostaglandins of the E series (PGE₁, PGE₂) have well-described immunosuppressive (antiinflammatory) as well as vasodilator (pro-inflammatory) actions. The net effect on an acute inflammatory response would depend on the dose, timing, and site of action. Egg phosphatidyl liposomes are novel drug delivery vehicles that can alter the in vivo disposition of PGE₁. The purpose of this study was to explore the therapeutic potential of PGE₁, with or without liposome encapsulation, on the systemic inflammatory response evoked by endotoxin following trauma. Anesthetized pigs received a soft tissue injury + hemorrhage, and fluid resuscitation after 1 h. In one series, whole blood was incubated with PGE₁ (0, 40, or 200 μg/mL) and Escherichia coli endotoxin (LPS; 0, 1, 5, or 10 μg/mL) in vitro and neutrophil CD18 adherence receptor density was measured with immunomonitoring. In another series, LPS (5 μg/kg) was administered 3 days following trauma to animals pretreated with either phosphate-buffered saline (PBS) + PGE₁ (62 ng/kg/min × 40 min, 2.5 μg/kg total, n = 8), PBS (n = 12), liposomes alone (Lipo, n = 10) or liposome-encapsulated PGE₁ (Lipo + PGE, n = 7). This PGE₁ dose had minimal effects on blood pressure in baseline conditions. 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 μg/mL PGE₁ before or after trauma. LPS in vivo increased pulmonary vascular resistance and heart rate and both were blunted by PGE₁: .73 ± .14 vs. .40 ± .06 mmHg/mL/min/kg, PBS vs. PBS + PGE₁, p = .0167 and 128 ± 7 vs. 93 ± 9 beats/min, PBS vs. PBS+PGE₁, p = .0020, respectively. In addition, stroke index (and therefore cardiac efficiency) was improved with PGE₁ + PBS vs. PBS (p = .0024). These cardiovascular effects were eliminated when PGE₁, was liposome encapsulated. Plasma TNF was increased to 300-600 pg/mL following LPS and there was no effect of PGE₁ or liposomes, but the LPS increased plasma cortisol to 7.8 ± .8 vs. 4.0 ± 1.0 μg/100 mL for PBS vs. PBS + PGE₁ (p = .0732) and 8.5 ± 2.1 vs. 2.9 ± 1.1 μg/100 mL for Lipo vs. Lipo + PGE₁ (p = .0131). Conclusions are as follows: 1) PGE₁ reduced the LPS-evoked cortisol increase and improved cardiac function, but had no detectable effect on the evoked TNF spike or neutropenia; 2) Liposome encapsulation eliminated the cardiac, but not the cortisol-lowering, effect; 3) the relative lack of PGE₁ on LPS-evoked acute inflammation could reflect a desensitization to its immunosuppressive actions. Alternatively, the results are consistent with the interpretation that PGE₁ is not a primary regulator for acute inflammation, but is rather one of a myriad of pro- and anti-inflammatory factors that balance the process.