Inhibition of tyrosine-kinase-mediated cellular signaling by tyrphostins AG 126 and AG556 modulates murine experimental acute pancreatitis.
BACKGROUND
The effects of the tyrosine kinase inhibitors, tyrphostin AG126 and AG556 in a murine model of acute pancreatitis are investigated.


METHODS
Intraperitoneal injection of cerulein in mice resulted in a severe, acute pancreatitis, which was characterized by edema, neutrophil infiltration, tissue hemorrhage, and cell necrosis as well as elevation in the serum activities of amylase or lipase.


RESULTS
Infiltration of the pancreatic tissue of these animals with neutrophils (measured as increase in myeloperoxidase activity) was associated with signs of enhanced lipid peroxidation (increased tissue levels of malondialdehyde). Immunohistochemical examination showed a marked increase in immunoreactivity for nitrotyrosine and poly (ADP-ribose) polymerase (PARP) in the pancreas of cerulein-treated mice. Pretreatment or posttreatment with tyrphostin AG126 and AG556, 2 different tyrosine kinase inhibitors, significantly reduced the degree of pancreatic inflammation and tissue injury (histologic score). In particular, the treatment with the 2 tyrosine kinase inhibitors reduced the cerulein-induced nitrotyrosine formation and PARP activation in the pancreas as well as the systemic release of tumor necrosis factor alpha.


CONCLUSIONS
This study provides the first evidence that (1) prevention of the activation of protein tyrosine kinases reduces the development of acute pancreatitis, and (2) inhibition of the activity of certain tyrosine kinases may represent a novel approach for the therapy of acute pancreatitis.
Balachandra
Srinivasan
S
Hepatobiliary Unit, Department of Surgery, Manchester Royal Infirmary, England.
Genovese
Tiziana
T
Mazzon
Emanuela
E
Di Paola
Rosanna
R
Thiemerman
Christoph
C
Siriwardena
Ajith K
AK
Cuzzocrea
Salvatore
S
D000208:Acute Disease; D000681:Amylases / Q000097:blood; D000818:Animals; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D008049:Lipase / Q000097:blood; D015227:Lipid Peroxidation / Q000187:drug effects; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D009504:Neutrophils / Q000473:pathology; D009569:Nitric Oxide / Q000378:metabolism; D010179:Pancreas / Q000201:enzymology / Q000276:immunology / Q000473:pathology; D010195:Pancreatitis / Q000188:drug therapy* / Q000276:immunology / Q000378:metabolism; D030421:Peroxynitrous Acid / Q000378:metabolism; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects*; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D014443:Tyrosine / Q000031:analogs & derivatives / Q000378:metabolism; D020032:Tyrphostins / Q000494:pharmacology*
D004791:Enzyme Inhibitors; D014409:Tumor Necrosis Factor-alpha; D020032:Tyrphostins; C069028:AG 127; D030421:Peroxynitrous Acid; C098981:AG 556; D009569:Nitric Oxide; C002744:3-nitrotyrosine; D014443:Tyrosine; D011065:Poly(ADP-ribose) Polymerases; D011505:Protein-Tyrosine Kinases; D008049:Lipase; D000681:Amylases