Activated protein C prevents hepatic ischaemia-reperfusion injury in rats.
BACKGROUND
Hepatic ischaemia-reperfusion injury (IRI) is a serious complication of liver surgery, especially extended hepatectomy and liver transplantation. Activated protein C (APC), a potent anticoagulant serine protease, has been shown to have cell-protective properties by virtue of its anti-inflammatory and anti-apoptotic activities.


METHODS
The present study was designed to examine the cytoprotective effects of APC in a 60-min warm-IRI rat model.


RESULTS
Following a single intravenous injection of APC before reperfusion, APC exerted cytoprotective effects 4 h after reperfusion, as evidenced by: (i) decreased levels of transaminase and improved histological findings of IRI, (ii) reduced infiltration and activation of neutrophils, macrophages and T cells, (iii) reduced expression of tumour necrosis factor-alpha, (iv) reduced expression of P-selectin and intracellular adhesion molecule-1, (v) inhibited coagulation and attenuated sinusoidal endothelial cell injury, (vi) improved hepatic microcirculation and (vii) decreased transferase-mediated dUTP nick end-labelling-positive cells. These effects of APC were observed 4 h but not 24 h after reperfusion. However, multiple injections of APC after reperfusion significantly decreased the levels of transaminase and the activity of myeloperoxidase, and improved histological findings of IRI 24 h after reperfusion.


CONCLUSIONS
These results suggest that APC is a promising therapeutic option for hepatic warm-IRI; however, multiple injections of APC are necessary to maintain its cell-protective action over the long term.
Department of Hepatobiliary Pancreatic Surgery, Mie University Graduate School of Medicine, Mie, Japan. naokun@clin.medic.mie-u.ac.jp
Naohisa
N
Kuriyama
Shuji
S
Isaji
Takashi
T
Hamada
Masashi
M
Kishiwada
Ichiro
I
Ohsawa
Masanobu
M
Usui
Hiroyuki
H
Sakurai
Masami
M
Tabata
Koji
K
Suzuki
Shinji
S
Uemoto
D000818:Animals; D017209:Apoptosis; D053148:Caspase 3 / Q000378:metabolism; D007150:Immunohistochemistry; D020287:In Situ Nick-End Labeling; D007275:Injections, Intravenous; D008099:Liver / Q000098:blood supply*; D008297:Male; D019007:P-Selectin / Q000378:metabolism; D009195:Peroxidase / Q000378:metabolism; D011486:Protein C / Q000008:administration & dosage / Q000627:therapeutic use*; D051381:Rats; D017208:Rats, Wistar; D015427:Reperfusion Injury / Q000517:prevention & control*; D013997:Time Factors; D000637:Transaminases / Q000097:blood; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
D019007:P-Selectin; D011486:Protein C; D014409:Tumor Necrosis Factor-alpha; D009195:Peroxidase; D000637:Transaminases; D053148:Caspase 3