Tyrphostin AG-490 inhibited the acute phase of zymosan-induced inflammation.
Tyrphostins, derivatives of benzylidene malononitrile are recognized as tyrosine kinase inhibitors that have been applied in some models of acute inflammatory conditions, like LPS and zymosan-induced shock. In the present study, we have investigated the effects of tyrphostin AG-490, on the development of multiple organ failure induced by i.p. injection of zymosan (1 mg/g body weight) in mice. Organ dysfunction and systemic inflammation was estimated 24 h after zymosan administration. Treatment of mice with AG-490 (dose, 5 mg/kg i.p. simultaneously with zymosan) decreased the number of cells and the level of NO in the peritoneal lavage. The substance attenuated the elevation of creatinine (indicator of renal failure), alanine aminotransferase (ALT), aspartate aminotransferase (AST) and bilirubin (indicators for liver dysfunction) and prevented the accelerated coagulation time. The injection of zymosan resulted in a substantial increase in the serum level of TNF-alpha and IL-6, which was strongly inhibited by AG-490. Tyrphostin abolished the expression of iNOS and TNF-alphaR in the liver. Moreover, immunohistochemistry of liver showed decreased phosphorylation of Stat1 and Stat3. In conclusion, the administration of tyrphostin AG-490 in zymosan-induced nonseptic shock significantly improved the rate of survival and lead to less exerted signs of multiple organ failure.
Dimitrova
Petya
P
Department of Immunology, Institute of Microbiology, 1113 Sofia, Bulgaria.
Ivanovska
Nina
N
D000410:Alanine Transaminase / Q000032:analysis; D000818:Animals; D001219:Aspartate Aminotransferases / Q000032:analysis; D001663:Bilirubin / Q000032:analysis; D003404:Creatinine / Q000032:analysis; D007249:Inflammation / Q000139:chemically induced / Q000188:drug therapy* / Q000473:pathology; D015850:Interleukin-6 / Q000032:analysis; D008264:Macrophages / Q000276:immunology* / Q000378:metabolism; D008297:Male; D051379:Mice; D009102:Multiple Organ Failure / Q000139:chemically induced / Q000188:drug therapy* / Q000473:pathology; D009569:Nitric Oxide / Q000032:analysis; D052247:Nitric Oxide Synthase Type II / Q000032:analysis; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage / Q000627:therapeutic use*; D050791:STAT Transcription Factors / Q000032:analysis; D014409:Tumor Necrosis Factor-alpha / Q000032:analysis; D020032:Tyrphostins / Q000008:administration & dosage / Q000627:therapeutic use*; D014914:Whole Blood Coagulation Time; D015054:Zymosan / Q000494:pharmacology
D015850:Interleukin-6; D047428:Protein Kinase Inhibitors; D050791:STAT Transcription Factors; D014409:Tumor Necrosis Factor-alpha; D020032:Tyrphostins; C095512:alpha-cyano-(3,4-dihydroxy)-N-benzylcinnamide; D009569:Nitric Oxide; D015054:Zymosan; D003404:Creatinine; D052247:Nitric Oxide Synthase Type II; C496317:Nos2 protein, mouse; D001219:Aspartate Aminotransferases; D000410:Alanine Transaminase; D001663:Bilirubin