Protective effect of a novel, potent inhibitor of poly(adenosine 5′-diphosphate-ribose) synthetase in a porcine model of severe bacterial sepsis

Roy D. Goldfarb, Anita Marton, Éva Szabó, László Virág, Andrew L. Salzman, Dana Glock, Imran Akhter, Robert McCarthy, Joseph E. Parrillo, Csaba Szabo

Research output: Contribution to journalArticle

82 Citations (Scopus)

Abstract

Objective: To determine whether activation of the nuclear enzyme poly(adenosine 5′-diphosphate [ADP]-ribose) synthetase (PARS) contributes to mortality rate, myocardial dysfunction, and cardiovascular collapse in a porcine model of sepsis induced by implantation of an infected clot. Design: Prospective, random animal study. Setting: Research laboratory at Rush Presbyterian St. Luke's Medical Center. Subjects: Twenty pigs were chronically instrumented with intracardiac transducers to measure left ventricular pressure, sonomicrometer crystals in the left ventricle to measure short axis diameter, an ultrasonic flow meter to measure cardiac output, and catheters in the pulmonary artery and aorta to measure blood pressures and collect samples. Interventions: By using a randomized study design, we administered either the novel potent PARS inhibitor PJ34 (10 mg/kg for 1 hr, 2 mg·kg-1·hr-1 for 96 hrs) or vehicle to pigs immediately before intraperitoneal implantation of Escherichia coil 0111.B4 (2.3 ± 0.1 × 1010 colony-forming units/kg)-laden fibrin clots to produce peritonitis and bacteremia. Measurements and Main Results: In vehicle-treated pigs, 12% survival was recorded at 24 hrs, whereas 83% and 66% survival was recorded in the PJ34-treated animals at 24 and 96 hrs, respectively (p < .05). PJ34 treatment attenuated bacteremia-induced increases in systemic and pulmonary vascular resistances. In controls, peritonitis induced rapid increase in plasma tumor necrosis factor-α. PJ34 treatment significantly attenuated this cytokine response. The formation of peroxynitrite and the activation of PARS were confirmed in hearts and lungs of the septic pigs by the immunohistochemical detection of nitrotyrosine and poly(ADP-ribose), respectively. Inhibition of PARS with PJ34 abolished poly(ADP-ribose) formation in septic animals. Conclusions: Treatment with a potent PARS inhibitor improved survival and cardiovascular status and attenuated an important mediator component of the inflammatory response in a lethal porcine model of sepsis.

Original languageEnglish (US)
Pages (from-to)974-980
Number of pages7
JournalCritical Care Medicine
Volume30
Issue number5
StatePublished - 2002
Externally publishedYes

Fingerprint

Poly Adenosine Diphosphate Ribose
Ligases
Sepsis
Swine
Bacteremia
Peritonitis
Vascular Resistance
Cardiac Catheters
Escherichia
Peroxynitrous Acid
Enzyme Activation
Ventricular Pressure
Fibrin
Transducers
Ultrasonics
Cardiac Output
Pulmonary Artery
Heart Ventricles
Aorta
Stem Cells

Keywords

  • Cardiac inotropy
  • Contractility
  • Inflammation
  • Nitric oxide
  • Peroxynitrite
  • Pig
  • Pulmonary vascular resistance
  • Sepsis
  • Shock
  • Superoxide
  • Systemic vascular resistance
  • Tumor necrosis factor

ASJC Scopus subject areas

  • Critical Care and Intensive Care Medicine

Cite this

Protective effect of a novel, potent inhibitor of poly(adenosine 5′-diphosphate-ribose) synthetase in a porcine model of severe bacterial sepsis. / Goldfarb, Roy D.; Marton, Anita; Szabó, Éva; Virág, László; Salzman, Andrew L.; Glock, Dana; Akhter, Imran; McCarthy, Robert; Parrillo, Joseph E.; Szabo, Csaba.

In: Critical Care Medicine, Vol. 30, No. 5, 2002, p. 974-980.

Research output: Contribution to journalArticle

Goldfarb, RD, Marton, A, Szabó, É, Virág, L, Salzman, AL, Glock, D, Akhter, I, McCarthy, R, Parrillo, JE & Szabo, C 2002, 'Protective effect of a novel, potent inhibitor of poly(adenosine 5′-diphosphate-ribose) synthetase in a porcine model of severe bacterial sepsis', Critical Care Medicine, vol. 30, no. 5, pp. 974-980.
Goldfarb, Roy D. ; Marton, Anita ; Szabó, Éva ; Virág, László ; Salzman, Andrew L. ; Glock, Dana ; Akhter, Imran ; McCarthy, Robert ; Parrillo, Joseph E. ; Szabo, Csaba. / Protective effect of a novel, potent inhibitor of poly(adenosine 5′-diphosphate-ribose) synthetase in a porcine model of severe bacterial sepsis. In: Critical Care Medicine. 2002 ; Vol. 30, No. 5. pp. 974-980.
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abstract = "Objective: To determine whether activation of the nuclear enzyme poly(adenosine 5′-diphosphate [ADP]-ribose) synthetase (PARS) contributes to mortality rate, myocardial dysfunction, and cardiovascular collapse in a porcine model of sepsis induced by implantation of an infected clot. Design: Prospective, random animal study. Setting: Research laboratory at Rush Presbyterian St. Luke's Medical Center. Subjects: Twenty pigs were chronically instrumented with intracardiac transducers to measure left ventricular pressure, sonomicrometer crystals in the left ventricle to measure short axis diameter, an ultrasonic flow meter to measure cardiac output, and catheters in the pulmonary artery and aorta to measure blood pressures and collect samples. Interventions: By using a randomized study design, we administered either the novel potent PARS inhibitor PJ34 (10 mg/kg for 1 hr, 2 mg·kg-1·hr-1 for 96 hrs) or vehicle to pigs immediately before intraperitoneal implantation of Escherichia coil 0111.B4 (2.3 ± 0.1 × 1010 colony-forming units/kg)-laden fibrin clots to produce peritonitis and bacteremia. Measurements and Main Results: In vehicle-treated pigs, 12{\%} survival was recorded at 24 hrs, whereas 83{\%} and 66{\%} survival was recorded in the PJ34-treated animals at 24 and 96 hrs, respectively (p < .05). PJ34 treatment attenuated bacteremia-induced increases in systemic and pulmonary vascular resistances. In controls, peritonitis induced rapid increase in plasma tumor necrosis factor-α. PJ34 treatment significantly attenuated this cytokine response. The formation of peroxynitrite and the activation of PARS were confirmed in hearts and lungs of the septic pigs by the immunohistochemical detection of nitrotyrosine and poly(ADP-ribose), respectively. Inhibition of PARS with PJ34 abolished poly(ADP-ribose) formation in septic animals. Conclusions: Treatment with a potent PARS inhibitor improved survival and cardiovascular status and attenuated an important mediator component of the inflammatory response in a lethal porcine model of sepsis.",
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T1 - Protective effect of a novel, potent inhibitor of poly(adenosine 5′-diphosphate-ribose) synthetase in a porcine model of severe bacterial sepsis

AU - Goldfarb, Roy D.

AU - Marton, Anita

AU - Szabó, Éva

AU - Virág, László

AU - Salzman, Andrew L.

AU - Glock, Dana

AU - Akhter, Imran

AU - McCarthy, Robert

AU - Parrillo, Joseph E.

AU - Szabo, Csaba

PY - 2002

Y1 - 2002

N2 - Objective: To determine whether activation of the nuclear enzyme poly(adenosine 5′-diphosphate [ADP]-ribose) synthetase (PARS) contributes to mortality rate, myocardial dysfunction, and cardiovascular collapse in a porcine model of sepsis induced by implantation of an infected clot. Design: Prospective, random animal study. Setting: Research laboratory at Rush Presbyterian St. Luke's Medical Center. Subjects: Twenty pigs were chronically instrumented with intracardiac transducers to measure left ventricular pressure, sonomicrometer crystals in the left ventricle to measure short axis diameter, an ultrasonic flow meter to measure cardiac output, and catheters in the pulmonary artery and aorta to measure blood pressures and collect samples. Interventions: By using a randomized study design, we administered either the novel potent PARS inhibitor PJ34 (10 mg/kg for 1 hr, 2 mg·kg-1·hr-1 for 96 hrs) or vehicle to pigs immediately before intraperitoneal implantation of Escherichia coil 0111.B4 (2.3 ± 0.1 × 1010 colony-forming units/kg)-laden fibrin clots to produce peritonitis and bacteremia. Measurements and Main Results: In vehicle-treated pigs, 12% survival was recorded at 24 hrs, whereas 83% and 66% survival was recorded in the PJ34-treated animals at 24 and 96 hrs, respectively (p < .05). PJ34 treatment attenuated bacteremia-induced increases in systemic and pulmonary vascular resistances. In controls, peritonitis induced rapid increase in plasma tumor necrosis factor-α. PJ34 treatment significantly attenuated this cytokine response. The formation of peroxynitrite and the activation of PARS were confirmed in hearts and lungs of the septic pigs by the immunohistochemical detection of nitrotyrosine and poly(ADP-ribose), respectively. Inhibition of PARS with PJ34 abolished poly(ADP-ribose) formation in septic animals. Conclusions: Treatment with a potent PARS inhibitor improved survival and cardiovascular status and attenuated an important mediator component of the inflammatory response in a lethal porcine model of sepsis.

AB - Objective: To determine whether activation of the nuclear enzyme poly(adenosine 5′-diphosphate [ADP]-ribose) synthetase (PARS) contributes to mortality rate, myocardial dysfunction, and cardiovascular collapse in a porcine model of sepsis induced by implantation of an infected clot. Design: Prospective, random animal study. Setting: Research laboratory at Rush Presbyterian St. Luke's Medical Center. Subjects: Twenty pigs were chronically instrumented with intracardiac transducers to measure left ventricular pressure, sonomicrometer crystals in the left ventricle to measure short axis diameter, an ultrasonic flow meter to measure cardiac output, and catheters in the pulmonary artery and aorta to measure blood pressures and collect samples. Interventions: By using a randomized study design, we administered either the novel potent PARS inhibitor PJ34 (10 mg/kg for 1 hr, 2 mg·kg-1·hr-1 for 96 hrs) or vehicle to pigs immediately before intraperitoneal implantation of Escherichia coil 0111.B4 (2.3 ± 0.1 × 1010 colony-forming units/kg)-laden fibrin clots to produce peritonitis and bacteremia. Measurements and Main Results: In vehicle-treated pigs, 12% survival was recorded at 24 hrs, whereas 83% and 66% survival was recorded in the PJ34-treated animals at 24 and 96 hrs, respectively (p < .05). PJ34 treatment attenuated bacteremia-induced increases in systemic and pulmonary vascular resistances. In controls, peritonitis induced rapid increase in plasma tumor necrosis factor-α. PJ34 treatment significantly attenuated this cytokine response. The formation of peroxynitrite and the activation of PARS were confirmed in hearts and lungs of the septic pigs by the immunohistochemical detection of nitrotyrosine and poly(ADP-ribose), respectively. Inhibition of PARS with PJ34 abolished poly(ADP-ribose) formation in septic animals. Conclusions: Treatment with a potent PARS inhibitor improved survival and cardiovascular status and attenuated an important mediator component of the inflammatory response in a lethal porcine model of sepsis.

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KW - Peroxynitrite

KW - Pig

KW - Pulmonary vascular resistance

KW - Sepsis

KW - Shock

KW - Superoxide

KW - Systemic vascular resistance

KW - Tumor necrosis factor

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