Attenuation of microcirculatory disturbance after liver ischemia by newly synthesized inflammatory cytokine suppressor, FR167653.
OBJECTIVE
Inflammatory cytokines, such as interleukin-1 beta and tumor necrosis factor-alpha, which activate neutrophils, contribute to hepatic warm ischemia-reperfusion injury. However, the role of the cytokines in hepatic microcirculation immediately after reperfusion is still unclear. This study was carried out to investigate whether FR167653, a dual inhibitor of interleukin-1 beta and tumor necrosis factor-alpha, attenuates hepatic microcirculatory disturbance at the initial phase of reperfusion following liver ischemia.


METHODS
Adult mongrel dogs were subjected to 90 minutes of liver ischemia by a Pringle's maneuver under portosystemic bypass. The animals were divided into two groups: a control group (n = 10), subjected to hepatic warm ischemia only, and a FR167653 administered group (n = 5), which received 1 mg/kg/h FR167653 for 4 hours since 30 minutes before the ischemia to 2 hours after the reperfusion continuously. Seven days animal survival, hepatic tissue blood flow, liver function test, hepatic venous blood concentration of endothelin-1 and plasminogen activator inhibitor-1, liver tissue biochemistry, and histopathology were analyzed.


RESULTS
The treatment with FR167653 attenuated microcirculatory disturbance, lessened liver injury, enhanced adenine nucleotides resynthesis, and improved animal survival after liver ischemia. In addition, FR167653 significantly inhibited release of both endothelin-1 and plasminogen activator inhibitor-1 from the liver cells.


CONCLUSIONS
These results suggest that the inflammatory cytokines induce microcirculatory disturbance in the initial phase of reperfusion following liver ischemia.
Takiguchi
Makoto
M
Second Department of Surgery, Hirosaki University School of Medicine, 5 Zaifu-cho, Hirosaki, Aomori, 036-8562 Japan.
Totsuka
Eishi
E
Umehara
Minoru
M
Ono
Hiroaki
H
Nara
Masaki
M
Nozaki
Tsuyoshi
T
Wajima
Naoki
N
Takahashi
Katsuro
K
Narumi
Shunji
S
Hakamada
Kenichi
K
Sugai
Michihiro
M
Sasaki
Mutsuo
M
D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology*; D004285:Dogs; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D007262:Infusions, Intravenous; D007375:Interleukin-1 / Q000037:antagonists & inhibitors*; D007511:Ischemia / Q000276:immunology* / Q000473:pathology; D008099:Liver / Q000098:blood supply* / Q000473:pathology; D008111:Liver Function Tests; D008833:Microcirculation / Q000187:drug effects / Q000276:immunology / Q000473:pathology; D011292:Premedication; D011720:Pyrazoles / Q000494:pharmacology*; D011725:Pyridines / Q000494:pharmacology*; D012039:Regional Blood Flow / Q000187:drug effects; D015427:Reperfusion Injury / Q000276:immunology; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors*
D000894:Anti-Inflammatory Agents, Non-Steroidal; C104334:FR 167653; D007166:Immunosuppressive Agents; D007375:Interleukin-1; D011720:Pyrazoles; D011725:Pyridines; D014409:Tumor Necrosis Factor-alpha