Angiotensin II inhibitor DuP753 attenuates burn- and endotoxin-induced gut ischemia, lipid peroxidation, mucosal permeability, and bacterial translocation

Tamer Tadros, Daniel L. Traber, J. P. Heggers, David Herndon

Research output: Contribution to journalArticle

49 Citations (Scopus)

Abstract

Objective: To investigate the role of angiotensin II as a mediator of burn- and sepsis-induced gut ischemia and reperfusion injury and to determine whether treatment with the angiotensin II inhibitor DuP753 can attenuate mucosal injury and bacterial translocation in a burn/endotoxemia porcine model. Summary Background Data: Thermal injuries and endotoxemia have been shown to induce ischemia and reperfusion injury to the intestine, leading to increased mucosal permeability and bacterial translocation. Angiotensin II, the production of which has been reported to increase after burn, is thought to be one of the primary mediators of postburn mesenteric vasoconstriction. Methods: An ultrasonic flow probe was inserted into the superior mesenteric artery and a catheter into the superior mesenteric vein in 21 female pigs. After 5 days, all animals were anesthetized, and 14 received 40% total body surface area third-degree bum. DuP753 was administered intravenously at 1 μg/kg to seven pigs immediately after burn. Eighteen hours after bum, 100 μg/kg Escherichia coli lipopolysaccharide (LPS) was intravenously administered. Systemic and splanchnic hemodynamics were measured and blood samples were drawn for blood gas analysis. Plasma conjugated dienes (PCDs), an index of lipid peroxidation, were measured every 6 hours. Intestinal permeability was assessed every 6 hours by measuring the lactulose/mannitol excretion ratio. At the end of the study (42 hours), tissue samples were harvested for bacteriologic cultures. Results: Burn caused a significant decrease in mesenteric blood flow, to approximately 58% of baseline. Postburn endotoxemia significantly reduced the blood flow in the superior mesenteric artery to 53% of baseline. Treatment with DuP753 prevented postbum vasoconstriction and subsequently abrogated the impact of postbum endotoxemia on blood flow in the superior mesenteric artery. Mesenteric oxygen supply was significantly reduced after bum and endotoxin to 60% and 51% of baseline levels, respectively. DuP753 administration significantly improved mesenteric oxygen supply after both insults. Bum- and LPS-induced mesenteric hypoxia, as indicated by decreased mesenteric oxygen consumption, was also ameliorated by DuP753 treatment. PCD levels were significantly elevated 8 hours after bum. LPS caused a higher and prolonged increase in PCD levels. Treatment with DuP753 significantly reduced PCD levels after bum and after LPS. Intestinal permeability, as assessed by the lactulose/mannitol ratio, showed 6-fold and 12-fold increases after thermal injury and LPS, respectively. In contrast, the lactulose/mannitol ratio was only doubled in DuP753-treated animals. Bacterial translocation was significantly increased after burn and endotoxin. The incidence of bacterial translocation in the DuP753-treated animals was similar to that in the sham group. Conclusions: Angiotensin II appears to play a pivotal role in the bum- and endotoxin-induced intestinal ischemia and reperfusion injury, with subsequent increases in permeability and bacterial translocation. Postburn administration of the angiotensin II receptor antagonist DuP753 significantly reduces the extent of these events.

Original languageEnglish (US)
Pages (from-to)566-576
Number of pages11
JournalAnnals of Surgery
Volume231
Issue number4
DOIs
StatePublished - Apr 2000

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Bacterial Translocation
Burns
Endotoxins
Endotoxemia
Angiotensin II
Lipid Peroxidation
Lipopolysaccharides
Permeability
Lactulose
Ischemia
Superior Mesenteric Artery
Mannitol
Reperfusion Injury
Swine
Vasoconstriction
Wounds and Injuries
Hot Temperature
Oxygen
Mesenteric Veins
Blood Gas Analysis

ASJC Scopus subject areas

  • Surgery

Cite this

Angiotensin II inhibitor DuP753 attenuates burn- and endotoxin-induced gut ischemia, lipid peroxidation, mucosal permeability, and bacterial translocation. / Tadros, Tamer; Traber, Daniel L.; Heggers, J. P.; Herndon, David.

In: Annals of Surgery, Vol. 231, No. 4, 04.2000, p. 566-576.

Research output: Contribution to journalArticle

Tadros, Tamer ; Traber, Daniel L. ; Heggers, J. P. ; Herndon, David. / Angiotensin II inhibitor DuP753 attenuates burn- and endotoxin-induced gut ischemia, lipid peroxidation, mucosal permeability, and bacterial translocation. In: Annals of Surgery. 2000 ; Vol. 231, No. 4. pp. 566-576.
@article{8ff85672e77540b68a0bb2d619661f6e,
title = "Angiotensin II inhibitor DuP753 attenuates burn- and endotoxin-induced gut ischemia, lipid peroxidation, mucosal permeability, and bacterial translocation",
abstract = "Objective: To investigate the role of angiotensin II as a mediator of burn- and sepsis-induced gut ischemia and reperfusion injury and to determine whether treatment with the angiotensin II inhibitor DuP753 can attenuate mucosal injury and bacterial translocation in a burn/endotoxemia porcine model. Summary Background Data: Thermal injuries and endotoxemia have been shown to induce ischemia and reperfusion injury to the intestine, leading to increased mucosal permeability and bacterial translocation. Angiotensin II, the production of which has been reported to increase after burn, is thought to be one of the primary mediators of postburn mesenteric vasoconstriction. Methods: An ultrasonic flow probe was inserted into the superior mesenteric artery and a catheter into the superior mesenteric vein in 21 female pigs. After 5 days, all animals were anesthetized, and 14 received 40{\%} total body surface area third-degree bum. DuP753 was administered intravenously at 1 μg/kg to seven pigs immediately after burn. Eighteen hours after bum, 100 μg/kg Escherichia coli lipopolysaccharide (LPS) was intravenously administered. Systemic and splanchnic hemodynamics were measured and blood samples were drawn for blood gas analysis. Plasma conjugated dienes (PCDs), an index of lipid peroxidation, were measured every 6 hours. Intestinal permeability was assessed every 6 hours by measuring the lactulose/mannitol excretion ratio. At the end of the study (42 hours), tissue samples were harvested for bacteriologic cultures. Results: Burn caused a significant decrease in mesenteric blood flow, to approximately 58{\%} of baseline. Postburn endotoxemia significantly reduced the blood flow in the superior mesenteric artery to 53{\%} of baseline. Treatment with DuP753 prevented postbum vasoconstriction and subsequently abrogated the impact of postbum endotoxemia on blood flow in the superior mesenteric artery. Mesenteric oxygen supply was significantly reduced after bum and endotoxin to 60{\%} and 51{\%} of baseline levels, respectively. DuP753 administration significantly improved mesenteric oxygen supply after both insults. Bum- and LPS-induced mesenteric hypoxia, as indicated by decreased mesenteric oxygen consumption, was also ameliorated by DuP753 treatment. PCD levels were significantly elevated 8 hours after bum. LPS caused a higher and prolonged increase in PCD levels. Treatment with DuP753 significantly reduced PCD levels after bum and after LPS. Intestinal permeability, as assessed by the lactulose/mannitol ratio, showed 6-fold and 12-fold increases after thermal injury and LPS, respectively. In contrast, the lactulose/mannitol ratio was only doubled in DuP753-treated animals. Bacterial translocation was significantly increased after burn and endotoxin. The incidence of bacterial translocation in the DuP753-treated animals was similar to that in the sham group. Conclusions: Angiotensin II appears to play a pivotal role in the bum- and endotoxin-induced intestinal ischemia and reperfusion injury, with subsequent increases in permeability and bacterial translocation. Postburn administration of the angiotensin II receptor antagonist DuP753 significantly reduces the extent of these events.",
author = "Tamer Tadros and Traber, {Daniel L.} and Heggers, {J. P.} and David Herndon",
year = "2000",
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T1 - Angiotensin II inhibitor DuP753 attenuates burn- and endotoxin-induced gut ischemia, lipid peroxidation, mucosal permeability, and bacterial translocation

AU - Tadros, Tamer

AU - Traber, Daniel L.

AU - Heggers, J. P.

AU - Herndon, David

PY - 2000/4

Y1 - 2000/4

N2 - Objective: To investigate the role of angiotensin II as a mediator of burn- and sepsis-induced gut ischemia and reperfusion injury and to determine whether treatment with the angiotensin II inhibitor DuP753 can attenuate mucosal injury and bacterial translocation in a burn/endotoxemia porcine model. Summary Background Data: Thermal injuries and endotoxemia have been shown to induce ischemia and reperfusion injury to the intestine, leading to increased mucosal permeability and bacterial translocation. Angiotensin II, the production of which has been reported to increase after burn, is thought to be one of the primary mediators of postburn mesenteric vasoconstriction. Methods: An ultrasonic flow probe was inserted into the superior mesenteric artery and a catheter into the superior mesenteric vein in 21 female pigs. After 5 days, all animals were anesthetized, and 14 received 40% total body surface area third-degree bum. DuP753 was administered intravenously at 1 μg/kg to seven pigs immediately after burn. Eighteen hours after bum, 100 μg/kg Escherichia coli lipopolysaccharide (LPS) was intravenously administered. Systemic and splanchnic hemodynamics were measured and blood samples were drawn for blood gas analysis. Plasma conjugated dienes (PCDs), an index of lipid peroxidation, were measured every 6 hours. Intestinal permeability was assessed every 6 hours by measuring the lactulose/mannitol excretion ratio. At the end of the study (42 hours), tissue samples were harvested for bacteriologic cultures. Results: Burn caused a significant decrease in mesenteric blood flow, to approximately 58% of baseline. Postburn endotoxemia significantly reduced the blood flow in the superior mesenteric artery to 53% of baseline. Treatment with DuP753 prevented postbum vasoconstriction and subsequently abrogated the impact of postbum endotoxemia on blood flow in the superior mesenteric artery. Mesenteric oxygen supply was significantly reduced after bum and endotoxin to 60% and 51% of baseline levels, respectively. DuP753 administration significantly improved mesenteric oxygen supply after both insults. Bum- and LPS-induced mesenteric hypoxia, as indicated by decreased mesenteric oxygen consumption, was also ameliorated by DuP753 treatment. PCD levels were significantly elevated 8 hours after bum. LPS caused a higher and prolonged increase in PCD levels. Treatment with DuP753 significantly reduced PCD levels after bum and after LPS. Intestinal permeability, as assessed by the lactulose/mannitol ratio, showed 6-fold and 12-fold increases after thermal injury and LPS, respectively. In contrast, the lactulose/mannitol ratio was only doubled in DuP753-treated animals. Bacterial translocation was significantly increased after burn and endotoxin. The incidence of bacterial translocation in the DuP753-treated animals was similar to that in the sham group. Conclusions: Angiotensin II appears to play a pivotal role in the bum- and endotoxin-induced intestinal ischemia and reperfusion injury, with subsequent increases in permeability and bacterial translocation. Postburn administration of the angiotensin II receptor antagonist DuP753 significantly reduces the extent of these events.

AB - Objective: To investigate the role of angiotensin II as a mediator of burn- and sepsis-induced gut ischemia and reperfusion injury and to determine whether treatment with the angiotensin II inhibitor DuP753 can attenuate mucosal injury and bacterial translocation in a burn/endotoxemia porcine model. Summary Background Data: Thermal injuries and endotoxemia have been shown to induce ischemia and reperfusion injury to the intestine, leading to increased mucosal permeability and bacterial translocation. Angiotensin II, the production of which has been reported to increase after burn, is thought to be one of the primary mediators of postburn mesenteric vasoconstriction. Methods: An ultrasonic flow probe was inserted into the superior mesenteric artery and a catheter into the superior mesenteric vein in 21 female pigs. After 5 days, all animals were anesthetized, and 14 received 40% total body surface area third-degree bum. DuP753 was administered intravenously at 1 μg/kg to seven pigs immediately after burn. Eighteen hours after bum, 100 μg/kg Escherichia coli lipopolysaccharide (LPS) was intravenously administered. Systemic and splanchnic hemodynamics were measured and blood samples were drawn for blood gas analysis. Plasma conjugated dienes (PCDs), an index of lipid peroxidation, were measured every 6 hours. Intestinal permeability was assessed every 6 hours by measuring the lactulose/mannitol excretion ratio. At the end of the study (42 hours), tissue samples were harvested for bacteriologic cultures. Results: Burn caused a significant decrease in mesenteric blood flow, to approximately 58% of baseline. Postburn endotoxemia significantly reduced the blood flow in the superior mesenteric artery to 53% of baseline. Treatment with DuP753 prevented postbum vasoconstriction and subsequently abrogated the impact of postbum endotoxemia on blood flow in the superior mesenteric artery. Mesenteric oxygen supply was significantly reduced after bum and endotoxin to 60% and 51% of baseline levels, respectively. DuP753 administration significantly improved mesenteric oxygen supply after both insults. Bum- and LPS-induced mesenteric hypoxia, as indicated by decreased mesenteric oxygen consumption, was also ameliorated by DuP753 treatment. PCD levels were significantly elevated 8 hours after bum. LPS caused a higher and prolonged increase in PCD levels. Treatment with DuP753 significantly reduced PCD levels after bum and after LPS. Intestinal permeability, as assessed by the lactulose/mannitol ratio, showed 6-fold and 12-fold increases after thermal injury and LPS, respectively. In contrast, the lactulose/mannitol ratio was only doubled in DuP753-treated animals. Bacterial translocation was significantly increased after burn and endotoxin. The incidence of bacterial translocation in the DuP753-treated animals was similar to that in the sham group. Conclusions: Angiotensin II appears to play a pivotal role in the bum- and endotoxin-induced intestinal ischemia and reperfusion injury, with subsequent increases in permeability and bacterial translocation. Postburn administration of the angiotensin II receptor antagonist DuP753 significantly reduces the extent of these events.

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