Etanercept attenuates the development of cerulein-induced acute pancreatitis in mice: a comparison with TNF-alpha genetic deletion.
TNF-alpha plays a pivotal role in the pathogenesis of acute pancreatitis. Recent studies have shown that TNF-alpha inhibition significantly ameliorates the course of experimental acute pancreatitis, but in this context, the effects of Etanercept, a novel anti-TNF-alpha agent, have not been investigated so far. The aims of the present study are (i) to assess the effects of pharmacological inhibition of TNF-alpha by means of Etanercept on the inflammatory response and apoptosis in a murine model of necrotizing acute pancreatitis and (ii) to compare the results to those observed in TNF-alpha receptor 1 knockout (TNFR1-KO) mice. Necrotizing acute pancreatitis was induced in TNF-alpha wild type for TNFR1 (WT) and TNFR1-KO mice by intraperitoneal injection of cerulein (hourly x5, 50 microg/kg). In another group of WT mice, Etanercept was administered (5 or 10 mg/kg, s.c.) at 1 h after first cerulein injection. Control groups received saline treatment. After 24 h, biochemical, histological, and immunohistochemical evidences of acute pancreatitis developed in all cerulein-treated mice; apoptosis was also present in the pancreas. Contrarily, pancreatitis histological features, amylase and lipase levels, pancreas water content, and myeloperoxidase activity were reduced in a similar degree in Etanercept-treated and TNFR1-KO mice. Likewise, in these two groups, immunohistochemical stainings and terminal deoxynucleotidyltransferase-mediated UTP nick-end labeling assay were found negative. TNF-alpha receptor 1 gene deletion and Etanercept administration ameliorate the course of experimental acute pancreatitis in a similar degree. Future studies on clinical applications of Etanercept in pancreatitis seem promising.
Malleo
Giuseppe
G
Department of Clinical, Experimental Medicine and Pharmacology, School of Medicine, University of Messina, Messina, Italy.
Mazzon
Emanuela
E
Genovese
Tiziana
T
Di Paola
Rosanna
R
Muià
Carmelo
C
Centorrino
Tommaso
T
Siriwardena
Ajith K
AK
Cuzzocrea
Salvatore
S
D000208:Acute Disease; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology / Q000627:therapeutic use; D017209:Apoptosis / Q000187:drug effects; D002108:Ceruletide / Q000633:toxicity; D004797:Enzyme-Linked Immunosorbent Assay; D000068800:Etanercept; D053222:Fas Ligand Protein / Q000032:analysis; D017353:Gene Deletion; D007074:Immunoglobulin G / Q000494:pharmacology / Q000627:therapeutic use*; D007150:Immunohistochemistry; D007249:Inflammation / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control; D018799:Intercellular Adhesion Molecule-1 / Q000032:analysis; D008233:Lymphotoxin-alpha / Q000032:analysis; D051379:Mice; D018345:Mice, Knockout; D019007:P-Selectin / Q000032:analysis; D010195:Pancreatitis / Q000139:chemically induced / Q000473:pathology / Q000517:prevention & control*; D009195:Peroxidase / Q000032:analysis; D018124:Receptors, Tumor Necrosis Factor / Q000627:therapeutic use*; D047888:Receptors, Tumor Necrosis Factor, Type I / Q000235:genetics*; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000378:metabolism*; D042461:Vascular Endothelial Growth Factor A / Q000032:analysis; D051028:bcl-2-Associated X Protein / Q000032:analysis; D051025:bcl-Associated Death Protein / Q000032:analysis
D000894:Anti-Inflammatory Agents, Non-Steroidal; D053222:Fas Ligand Protein; D007074:Immunoglobulin G; D008233:Lymphotoxin-alpha; D019007:P-Selectin; D018124:Receptors, Tumor Necrosis Factor; D047888:Receptors, Tumor Necrosis Factor, Type I; D014409:Tumor Necrosis Factor-alpha; D042461:Vascular Endothelial Growth Factor A; D051028:bcl-2-Associated X Protein; D051025:bcl-Associated Death Protein; D018799:Intercellular Adhesion Molecule-1; D002108:Ceruletide; D009195:Peroxidase; D000068800:Etanercept