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

Ronald M. Stewart, Timothy Fabian, Mary P. McGinty, Matthew Fabian, Kenneth G. Proctor

Research output: Contribution to journalArticle

7 Citations (Scopus)

Abstract

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.

Original languageEnglish (US)
Pages (from-to)307-314
Number of pages8
JournalShock
Volume3
Issue number4
DOIs
StatePublished - Jan 1 1995

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Alprostadil
Lipopolysaccharides
Wounds and Injuries
Phosphates
Liposomes
Hydrocortisone
In Vitro Techniques
Tumor Necrosis Factor-alpha
Immunosuppressive Agents
Prostaglandins E
Neutrophils
Anti-Inflammatory Agents
Inflammation
Soft Tissue Injuries

All Science Journal Classification (ASJC) codes

  • Emergency Medicine
  • Critical Care and Intensive Care Medicine

Cite this

Actions of prostaglandin E1 on lipopolysaccharide-evoked responses in vivo and in vitro following resuscitated trauma. / Stewart, Ronald M.; Fabian, Timothy; McGinty, Mary P.; Fabian, Matthew; Proctor, Kenneth G.

In: Shock, Vol. 3, No. 4, 01.01.1995, p. 307-314.

Research output: Contribution to journalArticle

Stewart, Ronald M. ; Fabian, Timothy ; McGinty, Mary P. ; Fabian, Matthew ; Proctor, Kenneth G. / Actions of prostaglandin E1 on lipopolysaccharide-evoked responses in vivo and in vitro following resuscitated trauma. In: Shock. 1995 ; Vol. 3, No. 4. pp. 307-314.
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T1 - Actions of prostaglandin E1 on lipopolysaccharide-evoked responses in vivo and in vitro following resuscitated trauma

AU - Stewart, Ronald M.

AU - Fabian, Timothy

AU - McGinty, Mary P.

AU - Fabian, Matthew

AU - Proctor, Kenneth G.

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N2 - 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.

AB - 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.

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