Induction of Nitric Oxide Synthase is a Key Determinant of Progression to Pulmonary Injury in Experimental Pancreatitis

摘要

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-α; 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 pre-treatment (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.