Inducible nitric oxide synthase-deficient mice exhibit resistance to the acute pancreatitis induced by cerulein.
Oxidative stress plays an important role in the early stage of acute pancreatitis as well as the associated multiple organ injury. Here we compare the degree of pancreatitis caused by cerulein in mice lacking the inducible (or type 2) nitric oxide synthase (iNOS) and in the corresponding wild-type mice. Intraperitoneal injection of cerulein resulted in wild-type mice in a severe, acute pancreatitis, which was characterized by edema, neutrophil infiltration, tissue hemorrhage and cell necrosis as well as increases in the serum levels of amylase and/or lipase. The infiltration of the pancreatic tissue of these animals with neutrophils (measured as increase in myeloperoxidase activity) was associated with up-regulation/expression of the adhesion molecules ICAM-1 and P-selectin as well as signs of enhanced lipid peroxidation (e.g., increased tissue levels of malondialdehyde). Immunohistochemical examination demonstrated a marked increase in the staining (immunoreactivity) for nitrotyrosine and poly (ADP-ribose) synthetase (PARS) in the pancreas of cerulein-treated iNOS wild-type mice. In contrast, the degree of pancreatic inflammation and tissue injury (histological score), upregulation/expression of P-selectin and ICAM-1, the staining for nitrotyrosine and PARS, and lipid peroxidation was markedly reduced in pancreatic tissue sections obtained from cerulein-treated iNOS-deficient mice. These findings support the view that iNOS plays an important, pro-inflammatory role in the acute pancreatitis caused by cerulein in mice.
Cuzzocrea
Salvatore
S
Institute of Pharmacology, School of Medicine, University of Messina, Torre Biologica, Gazzi, Italy.
Mazzon
Emanuela
E
Dugo
Laura
L
Serraino
Ivana
I
Centorrino
Tommaso
T
Ciccolo
Antonio
A
Van de Loo
Fons A J
FA
Britti
Domenico
D
Caputi
Achille P
AP
Thiemermann
Christoph
C
D000681:Amylases / Q000097:blood; D000818:Animals; D002108:Ceruletide / Q000633:toxicity; D004268:DNA-Binding Proteins / Q000378:metabolism; D020672:I-kappa B Proteins; D018799:Intercellular Adhesion Molecule-1 / Q000378:metabolism; D008049:Lipase / Q000097:blood; D015227:Lipid Peroxidation; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D008817:Mice, Mutant Strains; D009026:Mortality; D000072000:NF-KappaB Inhibitor alpha; D020556:Neutrophil Infiltration; D019001:Nitric Oxide Synthase / Q000172:deficiency* / Q000235:genetics; D052247:Nitric Oxide Synthase Type II; D019007:P-Selectin / Q000378:metabolism; D010195:Pancreatitis / Q000139:chemically induced / Q000235:genetics / Q000503:physiopathology*; D030421:Peroxynitrous Acid / Q000378:metabolism; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism; D014443:Tyrosine / Q000031:analogs & derivatives* / Q000378:metabolism
D004268:DNA-Binding Proteins; D020672:I-kappa B Proteins; C000606205:Nfkbia protein, mouse; D019007:P-Selectin; D018799:Intercellular Adhesion Molecule-1; D000072000:NF-KappaB Inhibitor alpha; D030421:Peroxynitrous Acid; C002744:3-nitrotyrosine; D014443:Tyrosine; D002108:Ceruletide; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; C496317:Nos2 protein, mouse; D011065:Poly(ADP-ribose) Polymerases; D008049:Lipase; D000681:Amylases