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


METHODS
Prospective, random animal study.


METHODS
Research laboratory at Rush Presbyterian St. Luke's Medical Center.


METHODS
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.


METHODS
By using a randomized study design, we administered either the novel potent PARS inhibitor PJ34 (10 mg/kg for 1 hr, 2 mg x kg(-1) x hr(-1) for 96 hrs) or vehicle to pigs immediately before intraperitoneal implantation of Escherichia coli 0111.B4 (2.3 +/- 0.1 x 10(10) colony-forming units/kg)-laden fibrin clots to produce peritonitis and bacteremia.


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-alpha. 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.
Goldfarb
Roy D
RD
Inotek Corporation, Beverly, MA 01915, USA.
Marton
Anita
A
Szabó
Eva
E
Virág
László
L
Salzman
Andrew L
AL
Glock
Dana
D
Akhter
Imran
I
McCarthy
Robert
R
Parrillo
Joseph E
JE
Szabó
Csaba
C
D000818:Animals; D001424:Bacterial Infections / Q000188:drug therapy*; D004195:Disease Models, Animal; D004791:Enzyme Inhibitors / Q000627:therapeutic use*; D004927:Escherichia coli Infections / Q000188:drug therapy; D006439:Hemodynamics / Q000187:drug effects; D010538:Peritonitis / Q000188:drug therapy; D010616:Phenanthrenes / Q000627:therapeutic use*; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D011446:Prospective Studies; D011897:Random Allocation; D013552:Swine; D014409:Tumor Necrosis Factor-alpha / Q000032:analysis
D004791:Enzyme Inhibitors; C434926:N-(oxo-5,6-dihydrophenanthridin-2-yl)-N,N-dimethylacetamide hydrochloride; D010616:Phenanthrenes; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D014409:Tumor Necrosis Factor-alpha