Tumor necrosis factor-a antisense transfer remarkably improves hepatic graft viability.
BACKGROUND
Cold ischemia/reperfusion injury of the hepatic graft, an unsolved problem in liver transplantations, is attributed to the release of inflammatory cytokines, especially the tumor necrosis factor- (TNF) alpha, from activated Kupffer cells (KC). Therefore, the specific inhibition of TNF-alpha could improve the viability of the hepatic graft upon reperfusion.


METHODS
We assessed the efficacy of TNF-alpha antisense (TNF-AS) oligodeoxynucleotides (ODNs) delivery to KC in a rodent liver transplantation model.


RESULTS
Seventy-one percent of the animals that received 6 hours preserved grafts in baths of lactated Ringer's solution (4 degrees C) and were treated with TNF-AS survived for over 14 days. Eighty percent of the animals treated with vehicle, sense ODNs, or balanced salt saline (BSS) died. Four hours after reperfusion of the liver, a significant reduction was noted in livers treated with TNF-AS in the release of cytosolic enzymes from the hepatocytes and the serum TNF-alpha (P<0.05). The expressions of TNF-alpha on KC and of intercellular adhesion molecule-1 on sinusoidal endothelial cells were completely suppressed in TNF-AS-treated livers.


CONCLUSIONS
TNF-AS delivery improves the viability of the hepatic graft, and this technique may solve hepatic graft nonfunction in a clinical setting.
Yoshizumi
Tomoharu
T
Division of Pathophysiological and Experimental Pathology, Department of Pathology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan. yosizumi@surg2.med.kyushu-u.ac.jp
Yonemitsu
Yoshikazu
Y
Ikeda
Yasuhiro
Y
Kaneda
Yasufumi
Y
Yanaga
Katsuhiko
K
Sugimachi
Keizo
K
Sueishi
Katsuo
K
D000818:Animals; D018014:Gene Transfer Techniques; D018799:Intercellular Adhesion Molecule-1 / Q000235:genetics / Q000378:metabolism; D007728:Kupffer Cells / Q000378:metabolism / Q000473:pathology; D016031:Liver Transplantation / Q000401:mortality / Q000473:pathology / Q000502:physiology*; D008297:Male; D020319:Oligodeoxyribonucleotides, Antisense / Q000235:genetics*; D051381:Rats; D011914:Rats, Inbred BN; D015427:Reperfusion Injury / Q000378:metabolism / Q000517:prevention & control*; D029082:Sendai virus / Q000235:genetics; D015996:Survival Rate; D014022:Tissue Survival / Q000235:genetics / Q000502:physiology; D014162:Transfection / Q000379:methods; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000378:metabolism*
D020319:Oligodeoxyribonucleotides, Antisense; D014409:Tumor Necrosis Factor-alpha; D018799:Intercellular Adhesion Molecule-1