Beneficial effect of FR167653 on cold ischemia/reperfusion injury in rat liver transplantation.
BACKGROUND
Proinflammatory cytokines such as interleukin 1-beta (IL-1beta) and tumor necrosis factor-a (TNF-alpha) play an important role in the development of hepatic ischemia/reperfusion injury. FR167653 has been characterized as a potent suppressant of IL-1beta and TNF-alpha production. The aim of this study was to evaluate the effect of FR167653 on cold ischemia/ reperfusion injury in rat liver transplantation.


METHODS
Donor livers were preserved with cold University of Wisconsin solution for 48 hr and transplanted orthotopically. Immediately after reperfusion, FR167653 (1 mg/kg, FR-treated group) or normal saline solution (control group) was administered i.v.. The severity of liver injury was determined by hepatic enzyme levels as well as by histological findings. The accumulation of IL-1beta and TNF-alpha mRNA in the liver was analyzed by semi-quantitative reverse transcription-polymerase chain reaction. Tissue factor expression was subjected to immunohistochemical analysis.


RESULTS
In the FR-treated group, release of aspartate aminotransferase and alanine aminotransferase after reperfusion was significantly lower (P<0.05 and P<0.02, respectively), and histological liver injury was less prominent, than in the control group. Accumulation of IL-1beta and TNF-alpha mRNA was suppressed in the FR-treated liver. Tissue factor expression on Kupffer cells and sinusoidal endothelial cells, marked in the control group, was almost absent in the FR-treated group. Seven-day survival in the FR-treated group (75%) was significantly better than that in the control group (12.5%) (P<0.01).


CONCLUSIONS
These results indicate that treatment with FR167653 ameliorates cold ischemia/reperfusion injury in liver transplantation.
Hashimoto
K
K
Department of Surgery II, Faculty of Medicine, Kyushu University, Fukuoka, Japan. hsmtkoji@surg2.med.kyushu-u.ac.jp
Nishizaki
T
T
Yoshizumi
T
T
Uchiyama
H
H
Okano
S
S
Ikegami
T
T
Yanaga
K
K
Sugimachi
K
K
D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology; D001706:Biopsy; D003080:Cold Temperature; D007150:Immunohistochemistry; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D007375:Interleukin-1 / Q000032:analysis; D008099:Liver / Q000201:enzymology / Q000473:pathology; D016031:Liver Transplantation / Q000276:immunology* / Q000401:mortality; D008297:Male; D011720:Pyrazoles / Q000494:pharmacology*; D011725:Pyridines / Q000494:pharmacology*; D051381:Rats; D011914:Rats, Inbred BN; D015427:Reperfusion Injury / Q000276:immunology*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015996:Survival Rate; D013925:Thromboplastin / Q000737:chemistry; D014409:Tumor Necrosis Factor-alpha / Q000032:analysis
D000894:Anti-Inflammatory Agents, Non-Steroidal; C104334:FR 167653; D007166:Immunosuppressive Agents; D007375:Interleukin-1; D011720:Pyrazoles; D011725:Pyridines; D014409:Tumor Necrosis Factor-alpha; D013925:Thromboplastin