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 Szabó

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    82 Scopus citations

    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
    DOIs
    StatePublished - Jan 1 2002

    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

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    Goldfarb, R. D., Marton, A., Szabó, É., Virág, L., Salzman, A. L., Glock, D., Akhter, I., McCarthy, R., Parrillo, J. E., & Szabó, 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, 30(5), 974-980. https://doi.org/10.1097/00003246-200205000-00004