Abstract |
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.
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Authors | Petya Dimitrova, Nina Ivanovska |
Journal | International immunopharmacology
(Int Immunopharmacol)
Vol. 8
Issue 11
Pg. 1567-77
(Nov 2008)
ISSN: 1567-5769 [Print] Netherlands |
PMID | 18656556
(Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
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Chemical References |
- Interleukin-6
- Protein Kinase Inhibitors
- STAT Transcription Factors
- Tumor Necrosis Factor-alpha
- Tyrphostins
- alpha-cyano-(3,4-dihydroxy)-N-benzylcinnamide
- Nitric Oxide
- Zymosan
- Creatinine
- Nitric Oxide Synthase Type II
- Nos2 protein, mouse
- Aspartate Aminotransferases
- Alanine Transaminase
- Bilirubin
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Topics |
- Alanine Transaminase
(analysis)
- Animals
- Aspartate Aminotransferases
(analysis)
- Bilirubin
(analysis)
- Creatinine
(analysis)
- Inflammation
(chemically induced, drug therapy, pathology)
- Interleukin-6
(analysis)
- Macrophages
(immunology, metabolism)
- Male
- Mice
- Multiple Organ Failure
(chemically induced, drug therapy, pathology)
- Nitric Oxide
(analysis)
- Nitric Oxide Synthase Type II
(analysis)
- Protein Kinase Inhibitors
(administration & dosage, therapeutic use)
- STAT Transcription Factors
(analysis)
- Tumor Necrosis Factor-alpha
(analysis)
- Tyrphostins
(administration & dosage, therapeutic use)
- Whole Blood Coagulation Time
- Zymosan
(pharmacology)
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