Effects of sizofiran on endotoxin-enhanced cold ischemia-reperfusion injury of the rat liver.
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-alpha (TNF-alpha) 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- 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-alpha cytotoxicity. In conclusion, inhibition of both TNF- 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.
Kukan
M
M
Laboratory of Perfused Organs, SCOT, Institute of Preventive and Clinical Medicine, Limbová 14, 83301 Bratislava, Slovak Republic. kukan@upkm.sk
Szatmáry
Z
Z
Lutterová
M
M
Kuba
D
D
Vajdová
K
K
Horecký
J
J
D000818:Animals; D003080:Cold Temperature / Q000009:adverse effects*; D004731:Endotoxins / Q000633:toxicity*; D008099:Liver / Q000098:blood supply* / Q000187:drug effects / Q000378:metabolism*; D008297:Male; D051381:Rats; D017208:Rats, Wistar; D015427:Reperfusion Injury / Q000139:chemically induced / Q000188:drug therapy / Q000378:metabolism*; D012566:Sizofiran / Q000494:pharmacology* / Q000627:therapeutic use
D004731:Endotoxins; D012566:Sizofiran