Attenuation of graft injury in porcine liver transplantation from non-heart beating donor by FR167653.
OBJECTIVE
Orthotopic liver transplantation (OLTx) from non-heart beating donor (NHBD) often involves hepatic warm ischemia and reperfusion injury which is triggered by the inflammatory cytokines. This study was carried out to investigate whether a newly synthesized cytokine suppressive anti-inflammatory agent, FR167653, attenuates graft injury in OLTx from NHBD.


METHODS
Porcine OLTx from NHBD was performed. No-heart beating time was scheduled to be 60 minutes. Animals were divided into two groups: no treatment control (CT) group (n=5), and FR167653 treated (FR) group (n=5), in which FR167653 was administered intravenously before the aortic cross clamp in the donor, and before and after the hepatic allograft reperfusion in the recipient continuously.


RESULTS
Four out of five pigs died within 24 hours and one on postoperative day 1 from graft liver failure in the CT group, while two pigs died on day 3, and three survived more than 7 days in the FR group (p<0.05). Microcirculatory disturbance was attenuated, liver injury was lessened, and ATP resynthesis was enhanced in the FR group. Additionally, FR167653 inhibited neutrophils infiltration in the liver tissue, and suppressed release of inflammatory cytokines after OLTx from NHBD.


CONCLUSIONS
The treatments with FR167653 successfully prevented graft injury after OLTx from NHBD by means of improvement of liver microcirculation, and attenuation of neutrophils activation. The inhibitory effect of FR167653 on the release of inflammatory cytokines played an important role in the liver graft protection.
Ono
Hiroaki
H
Second Department of Surgery, Hirosaki University School of Medicine, Hirosaki Aomori, Japan. hirochan@cc.hirosaki-u.ac.jp
Totsuka
Eishi
E
Hakamada
Kenichi
K
Ishizawa
Yoshiya
Y
Nishimura
Akimasa
A
Umehara
Minoru
M
Nara
Masaki
M
Takiguchi
Makoto
M
Takahashi
Katsuro
K
Murata
Akihiko
A
Toyoki
Yoshikazu
Y
Narumi
Shunji
S
Sasaki
Mutsuo
M
D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology*; D016207:Cytokines / Q000097:blood*; D006085:Graft Survival / Q000187:drug effects; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D008099:Liver / Q000098:blood supply*; D008111:Liver Function Tests; D016031:Liver Transplantation; D008833:Microcirculation / Q000187:drug effects; D018375:Neutrophil Activation / Q000187:drug effects; D009926:Organ Preservation; D011292:Premedication; D011720:Pyrazoles / Q000494:pharmacology*; D011725:Pyridines / Q000494:pharmacology*; D015427:Reperfusion Injury / Q000503:physiopathology*; D013552:Swine
D000894:Anti-Inflammatory Agents, Non-Steroidal; D016207:Cytokines; C104334:FR 167653; D007166:Immunosuppressive Agents; D011720:Pyrazoles; D011725:Pyridines; D000255:Adenosine Triphosphate