Effects of Sizofiran on Endotoxin-Enhanced Cold Ischemia-Reperfusion Injury of the Rat Liver

M. KUKAN, Z. SZATMÁRY, M. LUTTEROVÁ, D. KUBA, K. VAJDOVÁ, J. HORECKÝ

Laboratory of Perfused Organs, SCOT, Institute of Preventive and Clinical Medicine, Bratislava, Slovak Republic

Received June 25, 2003
Accepted October 3, 2003



Summary
Kupffer cells (KC), resident macrophages of the liver, have been strongly implicated in lipopolysaccharide (LPS)-induced liver graft injury. However, our recent study showed that sizofiran (schizophyllan glucan) (SPG), which activates KC, did not influence cold ischemia-reperfusion liver injury of LPS-exposed rats. Here we investigated some mechanisms by which SPG does not aggravate LPS-enhanced cold ischemia-reperfusion rat liver injury. Control and SPG-treated rats were exposed to LPS for 2 h prior to hepatectomy. The livers were cold-preserved in University of Wisconsin solution followed by reperfusion with Krebs-Henseleit buffer. We found that SPG dramatically inhibited LPS-induced increases of tumor necrosis factor-α (TNF-α) in the plasma and bile in vivo. Moreover, LPS-induced TNF- release into the washout solution after cold ischemia was also abrogated by SPG pretreatment. However, SPG increased TNF-α release into the perfusate after reperfusion. On the other hand, SPG completely abolished expression of c-myc protooncogene, which is known to sensitize cells to TNF-α cytotoxicity. In conclusion, inhibition of both TNF-α release after LPS challenge and c-myc expression may explain why activation of KC with SPG does not aggravate endotoxin-enhanced cold ischemia-reperfusion liver injury.


Key words
Liver • Cold ischemia-reperfusion • Kupffer cells • Sizofiran (Schizophyllan glucan) • Tumor necrosis factor-α •
c-myc protooncogene