Tyrosine kinase inhibitor tyrphostin AG490 reduces liver injury in LPS-induced shock

Abstract

Sepsis remains a serious clinical problem despite continuous efforts to increase survival. Experimental animal models of sepsis are pointed to a great extent on blocking the activity of cytokines. A number of signal-transducing molecules are associated with the occurrence of excessive tissue inflammation. Through inhibition of tyrosine phosphorilation and thereby changing cell signaling, tyrosine kinase inhibitors can influence multiple inflammatory pathways. The purpose of the present investigation was to evaluate the effect of tyrosine kinase inhibitor tyrphostin AG490 in a mouse LPS-induced shock. Cytokine and chemokine blood levels were determined by ELISA assays. CD11b+ Ly6C+, CD3+CD69+ and C5aR positive cell populations in the peritoneal exudate were detected by flow cytometry. The expression of iNOS and Signal Transducer and Activator of Transcription (STAT) in the liver were observed by immunohistochemistry. We found that tyrphostin AG490 inhibited Regulated upon activation normal T cell expressed and secreted (RANTES), IL-6 and IL-12 serum levels, decreased the number of CD11b+Ly6C+ and CD3+CD69+ subpopulations in the peritoneal exudate and prevented the decrease of cells expressing C5a receptor and TNF-alpha receptor. Tyrphostin ameliorated liver injury associated with suppressed iNOS, STAT3 and pSTAT3 expression. Our data suggest that tyrphostin AG490 diminished the degree of inflammation starting in peritoneal cavity and minimized liver dysfunction thus representing one approach for better outcome of sepsis conditions.