title: Induction of nitric oxide synthase is a key determinant of progression to pulmonary injury in experimental pancreatitis.
abstract: 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.
authors.affiliation: Department of Surgery, Mater Misericordiae Hospital, and University College, Dublin, Ireland. conor@narrowpoint.com
authors.forename: Conor J
authors.initials: CJ
authors.lastname: Shields
authors.forename: Conor P
authors.initials: CP
authors.lastname: Delaney
authors.forename: Desmond C
authors.initials: DC
authors.lastname: Winter
authors.forename: Leonie
authors.initials: L
authors.lastname: Young
authors.forename: Thomas F
authors.initials: TF
authors.lastname: Gorey
authors.forename: John M
authors.initials: JM
authors.lastname: Fitzpatrick
mesh_terms: 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
chemical_list: D009569:Nitric Oxide; D019001:Nitric Oxide Synthase