Pneumonia-induced sepsis and gut injury: effects of a poly-(ADP-ribose) polymerase inhibitor.
BACKGROUND
Pseudomonas aeruginosa is commonly associated with nosocomial pneumonia. Ileal mucosal injury may be induced by severe lung infection. During septic shock, peroxynitrite-mediated DNA strand-breaks activate the enzyme poly-(ADP)-ribose polymerase (PARP) resulting in cellular energetic suppression and cell dysfunction. The aim of this study was to determine whether gut injury could be demonstrated in sepsis induced by P. aeruginosa and the effects of a PARP inhibitor (PJ34) on the associated gut injury.


METHODS
After baseline measurements, 20 rabbits were randomized into three groups: Sham (n = 5): transtracheally inoculated (TI) with 2 ml of phosphate buffer solution (PBS); P. aeruginosa + saline (n = 8), TI with 4 x 10(12) CFU/ml of P. aeruginosa in 2 ml/kg of PBS + i.v. saline; and P. aeruginosa + PJ34 (n = 7), TI with 4 x 10(12) CFU/ml of P. aeruginosa and i.v. treatment with PJ34.


RESULTS
P. aeruginosa caused a hyperdynamic response with increased blood flow also in the superior mesenteric artery. No significant differences were found in luminal gut lactate concentrations or PCO(2)-gap between groups. Histological specimens showed moderate or diffuse alveolar infiltrate in the P. aeruginosa + saline group (6/8) and in the P. aeruginosa + PJ34 group (6/7). Gut wet-to-dry weight ratio was significantly higher in the P. aeruginosa + saline group than in Shams (7.5 +/- 0.8 versus 6.4 +/- 0.7, P < 0.05) and significantly lower in the P. aeruginosa + PJ34 group (6.1 + 0.5, P < 0.05 versus the other groups). Blood cultures were positive in 1/5 (Sham), 8/8 (P. aeruginosa + saline group) and 4/7 (P. aeruginosa + PJ34 group) (RR 0.57 CI 95% 0.30-1.08).


CONCLUSIONS
Pharmacological inhibition of PARP reduces gut inflammation and may limit bacterial translocation.
Lobo
Suzana M
SM
Intensive Care Unit, Hospital de Base, Faculdade de Medicina, Sao Jose do Rio Preto, Brazil.
Orrico
Susana R Perez
SR
Queiroz
Márcio M
MM
Cunrath
Geni S
GS
Chibeni
Gisela S A
GS
Contrin
Ligia M
LM
Cury
Patricia M
PM
Burdmann
Emanuel de Almeida
EA
de Oliveira Machado
Antonia M
AM
Togni
Paulo
P
De Backer
Daniel
D
Preiser
Jean-Charles
JC
Szabó
Czaba
C
Vincent
Jean-Louis
JL
D000818:Animals; D001011:Aorta; D001794:Blood Pressure; D004751:Enteritis / Q000188:drug therapy* / Q000382:microbiology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D007422:Intestines / Q000098:blood supply / Q000382:microbiology / Q000473:pathology; D017538:Mesenteric Artery, Superior; D010616:Phenanthrenes / Q000494:pharmacology*; D018410:Pneumonia, Bacterial / Q000150:complications / Q000188:drug therapy* / Q000382:microbiology; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D011552:Pseudomonas Infections / Q000188:drug therapy / Q000209:etiology; D011550:Pseudomonas aeruginosa / Q000302:isolation & purification; D011817:Rabbits; D012039:Regional Blood Flow; D018805:Sepsis / Q000188:drug therapy* / Q000382:microbiology; D013047:Specific Pathogen-Free Organisms; D014132:Trachea
D004791:Enzyme Inhibitors; C434926:N-(oxo-5,6-dihydrophenanthridin-2-yl)-N,N-dimethylacetamide hydrochloride; D010616:Phenanthrenes; D000067856:Poly(ADP-ribose) Polymerase Inhibitors