The tyrosine kinase inhibitor tyrphostin AG 126 reduces the multiple organ failure induced by zymosan in the rat.
OBJECTIVE
To investigate the effects of tyrphostin AG 126, a tyrosine kinase inhibitor, on the multiple organ failure (MOF) caused by zymosan in the rat.


METHODS
Zymosan (500 mg/kg, suspended in saline solution, i.p.) causes an enhanced formation of reactive oxygen species, which contribute to the pathophysiology of MOF. After zymosan or saline administration, animals were monitored for 12 days.


RESULTS
Treatment of rats with tyrphostin AG 126 (10 mg/kg, 3 mg/kg or 1 mg/kg intraperitoneally, 1 h and 6 h after zymosan) attenuated the peritoneal exudation and the migration of polymorphonuclear cells caused by zymosan in a dose-dependent fashion. Tyrphostin AG 126 also attenuated the lung, liver, and intestinal injury (histology) as well as the increase in the levels of myeloperoxidase and malondialdehyde caused by zymosan in the lung, liver, and intestine. Immunohistochemical analysis for nitrotyrosine, poly (ADP-ribose) polymerase (PAR), iNOS, and COX-2 revealed a positive staining in lung, liver and intestine from zymosan-treated rats. The degree of staining for nitrotyrosine, PAR, iNOS, and COX-2 were markedly reduced in tissue sections obtained from zymosan-treated rats which had received tyrphostin AG 126. Furthermore, treatment of rats with tyrphostin AG 126 significantly reduced the production of peroxynitrite and of pro-inflammatory cytokines TNF-alpha and IL-1beta.


CONCLUSIONS
This study provides the first evidence that the protein kinase inhibitor tyrphostin AG 126 attenuates the degree of MOF associated with zymosan-induced peritonitis in the rat.
Dugo
L
L
Department of Experimental Medicine and Pharmacology, School of Medicine, University of Messina, torre Biologica- Policlinico Universitario Via C. Valeria - Gazzi - 98100 Messina, Italy.
Chatterjee
P K
PK
Mazzon
E
E
McDonald
M C
MC
Paola
R Di
RD
Fulia
F
F
Caputi
A P
AP
Thiemermann
C
C
Cuzzocrea
S
S
D000818:Animals; D004791:Enzyme Inhibitors / Q000627:therapeutic use*; D008297:Male; D023421:Models, Animal; D009102:Multiple Organ Failure / Q000139:chemically induced / Q000473:pathology / Q000517:prevention & control*; D009569:Nitric Oxide / Q000097:blood; D010538:Peritonitis / Q000139:chemically induced; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors*; D051381:Rats; D017207:Rats, Sprague-Dawley; D020032:Tyrphostins / Q000627:therapeutic use*; D015054:Zymosan / Q000633:toxicity*
D004791:Enzyme Inhibitors; D020032:Tyrphostins; C069028:AG 127; D009569:Nitric Oxide; D015054:Zymosan; D011505:Protein-Tyrosine Kinases