The cytoprotective effects of addition of activated protein C into preservation solution on small-for-size grafts in rats.
Small-for-size liver grafts are a serious obstacle for partial orthotopic liver transplantation. Activated protein C (APC), a potent anticoagulant serine protease, is known to have cell-protective properties due to its anti-inflammatory and antiapoptotic activities. This study was designed to examine the cytoprotective effects of a preservation solution containing APC on small-for-size liver grafts, with special attention paid to ischemia-reperfusion injury and shear stress in rats. APC exerted cytoprotective effects, as evidenced by (1) increased 7-day graft survival; (2) decreased initial portal pressure and improved hepatic microcirculation; (3) decreased levels of aminotransferase and improved histological features of hepatic ischemia-reperfusion injury; (4) suppressed infiltration of neutrophils and monocytes/macrophages; (5) reduced hepatic expression of tumor necrosis factor alpha and interleukin 6; (6) decreased serum levels of hyaluronic acid, which indicated attenuation of sinusoidal endothelial cell injury; (7) increased hepatic levels of nitric oxide via up-regulated hepatic endothelial nitric oxide synthesis expression together with down-regulated hepatic inducible nitric oxide synthase expression; (8) decreased hepatic levels of endothelin 1; and (9) reduced hepatocellular apoptosis by down-regulated caspase-8 and caspase-3 activities. These results suggest that a preservation solution containing APC is a potential novel and safe product for small-for-size liver transplantation, alleviating graft injury via anti-inflammatory and antiapoptotic effects and vasorelaxing conditions.
Kuriyama
Naohisa
N
Department of Hepatobiliary Pancreatic Surgery, Mie University Graduate School of Medicine, Mie, Japan. naokun@clin.medic.mie-u.ac.jp
Isaji
Shuji
S
Hamada
Takashi
T
Kishiwada
Masashi
M
Ohsawa
Ichiro
I
Usui
Masanobu
M
Sakurai
Hiroyuki
H
Tabata
Masami
M
Hayashi
Tatsuya
T
Suzuki
Koji
K
D000818:Animals; D000925:Anticoagulants / Q000494:pharmacology / Q000627:therapeutic use*; D017209:Apoptosis / Q000187:drug effects; D019332:Endothelin-1 / Q000378:metabolism; D006085:Graft Survival / Q000187:drug effects*; D006505:Hepatitis / Q000517:prevention & control; D015850:Interleukin-6 / Q000378:metabolism; D008099:Liver / Q000378:metabolism / Q000473:pathology; D008111:Liver Function Tests; D016031:Liver Transplantation; D008264:Macrophages / Q000187:drug effects; D008297:Male; D008833:Microcirculation / Q000187:drug effects; D020556:Neutrophil Infiltration / Q000187:drug effects; D009569:Nitric Oxide / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II / Q000378:metabolism; D052250:Nitric Oxide Synthase Type III / Q000378:metabolism; D019188:Organ Preservation Solutions / Q000627:therapeutic use*; D017082:Portal Pressure; D055031:Primary Graft Dysfunction / Q000517:prevention & control*; D011486:Protein C / Q000494:pharmacology / Q000627:therapeutic use*; D051381:Rats; D017208:Rats, Wistar; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
D000925:Anticoagulants; D019332:Endothelin-1; D015850:Interleukin-6; D019188:Organ Preservation Solutions; D011486:Protein C; D014409:Tumor Necrosis Factor-alpha; D009569:Nitric Oxide; D052247:Nitric Oxide Synthase Type II; D052250:Nitric Oxide Synthase Type III; C496318:Nos2 protein, rat; C496316:Nos3 protein, rat