Pyrrolidine dithiocarbamate reduces the severity of cerulein-induced murine acute pancreatitis.
The nuclear factor-kappaB (NF-kappaB) is a transcription factor that plays a pivotal role in the induction of genes involved in the response to injury and inflammation. Dithiocarbamates are antioxidants that are potent inhibitors of NF-kappaB. This study tested the hypothesis that pyrrolidine dithiocarbamate (PDTC) attenuates experimental acute pancreatitis. Intraperitoneal injection of cerulein in mice resulted in severe, acute pancreatitis characterized by edema, neutrophil infiltration, tissue hemorrhage and necrosis, and elevated serum levels of amylase and lipase. Infiltration of pancreatic and lung tissue with neutrophils (measured as increase in myeloperoxidase activity) was associated with enhanced lipid peroxidation (increased tissue levels of malondialdehyde). Immunohistochemical examination demonstrated a marked increase in immunoreactivity for nitrotyrosine and intracellular adhesion molecule-1 in the pancreas and lung of cerulein-treated mice. In contrast, the degree of 1) pancreas and lung injury, 2) upregulation/expression of intracellular adhesion molecule-1, 3) staining for nitrotyrosine, and 4) lipid peroxidation was markedly reduced by pretreatment with PDTC. This study demonstrates that prevention of the activation of NF-kappaB by PDTC ameliorates the tissue injury associated with experimental murine acute pancreatitis and provides an important insight into the molecular biology of acute pancreatitis.
Virlos
Ioannis
I
Hepatobiliary Unit, Department of Surgery, Manchester Royal infirmary, Manchester, United Kingdom.
Mazzon
Emanuela
E
Serraino
Ivana
I
Di Paola
Rosanna
R
Genovese
Tiziana
T
Britti
Domenico
D
Thiemerman
Christoph
C
Siriwardena
Ajith
A
Cuzzocrea
Salvatore
S
D000681:Amylases / Q000097:blood; D000818:Animals; D000975:Antioxidants / Q000494:pharmacology / Q000627:therapeutic use*; D015153:Blotting, Western; D002108:Ceruletide / Q000378:metabolism; D004487:Edema; D020672:I-kappa B Proteins / Q000378:metabolism; D007150:Immunohistochemistry; D007249:Inflammation; D018799:Intercellular Adhesion Molecule-1 / Q000378:metabolism; D008049:Lipase / Q000097:blood; D015227:Lipid Peroxidation; D008297:Male; D051379:Mice; D000072000:NF-KappaB Inhibitor alpha; D016328:NF-kappa B / Q000378:metabolism; D009336:Necrosis; D009504:Neutrophils / Q000378:metabolism; D010195:Pancreatitis / Q000139:chemically induced* / Q000188:drug therapy*; D009195:Peroxidase / Q000378:metabolism; D011759:Pyrrolidines / Q000627:therapeutic use*; D051381:Rats; D013859:Thiocarbamates / Q000627:therapeutic use*; D014443:Tyrosine / Q000031:analogs & derivatives* / Q000378:metabolism; D015854:Up-Regulation
D000975:Antioxidants; D020672:I-kappa B Proteins; D016328:NF-kappa B; C000606205:Nfkbia protein, mouse; C000606206:Nfkbia protein, rat; D011759:Pyrrolidines; D013859:Thiocarbamates; D018799:Intercellular Adhesion Molecule-1; D000072000:NF-KappaB Inhibitor alpha; C020972:pyrrolidine dithiocarbamic acid; C002744:3-nitrotyrosine; D014443:Tyrosine; D002108:Ceruletide; D009195:Peroxidase; D008049:Lipase; D000681:Amylases