Induction of nitric oxide synthase is a key determinant of progression to pulmonary injury in experimental pancreatitis.
BACKGROUND
The immunomodulatory potential of nitric oxide provides prospective strategies to attenuate inappropriate inflammatory reactions. This study tested the hypothesis that inhibition of nitric oxide synthase (NOS) reduces end-organ injury in pancreatitis.


METHODS
Pancreatitis was induced in male Sprague-Dawley rats by intraperitoneal (i.p.) injection of 20% L-arginine (500 mg/100 g of body weight). Animals were randomized into four groups of 45: Pancreatitis without intervention; pre-treatment with i.p. aminoguanidine (AMG) (50 mg/kg), an isoform-specific inhibitor of inducible NOS; post-treatment with AMG (50 mg/kg); and controls. Pancreatic and pulmonary pathology, neutrophil infiltration (myeloperoxidase activity), endothelial permeability (bronchoalveolar lavage, wet:dry weight ratio), NOS expression, and concentrations of pro-inflammatory cytokines (tumor necrosis factor-alpha; interleukin-6) were assessed.


RESULTS
Inhibition of iNOS significantly reduced end-organ injury. Pancreatic and pulmonary injury scores were markedly attenuated in the AMG treatment groups compared with no intervention (p < 0.05). Increased endothelial permeability (2,411.1 +/- 47.9) and neutrophil sequestration (1.99 +/- 0.01) were manifest in the untreated animals compared with AMG pretreatment (1,286.8 +/- 35.1 and 1,548.0 +/- 0.1; p < 0.05). In addition, a significant reduction in inflammatory cytokine concentrations was observed (p < 0.05).


CONCLUSIONS
Inhibition of inducible NOS encourages a more benign immunologic profile, minimizing the deleterious effects of unrestrained neutrophil sequestration subsequent to pancreatitis.
Shields
Conor J
CJ
Department of Surgery, Mater Misericordiae Hospital, and University College, Dublin, Ireland. conor@narrowpoint.com
Delaney
Conor P
CP
Winter
Desmond C
DC
Young
Leonie
L
Gorey
Thomas F
TF
Fitzpatrick
John M
JM
D000818:Animals; D004790:Enzyme Induction; D008168:Lung / Q000276:immunology / Q000473:pathology*; D008297:Male; D009569:Nitric Oxide / Q000378:metabolism; D019001:Nitric Oxide Synthase / Q000096:biosynthesis*; D010179:Pancreas / Q000276:immunology / Q000473:pathology; D010195:Pancreatitis / Q000139:chemically induced / Q000188:drug therapy / Q000401:mortality / Q000473:pathology*; D051381:Rats; D017207:Rats, Sprague-Dawley
D009569:Nitric Oxide; D019001:Nitric Oxide Synthase