Activated protein C prevents hepatic ischaemia–reperfusion injury in rats

Authors


Correspondence
Naohisa Kuriyama, Department of Hepatobiliary Pancreatic Surgery, Mie University Graduate School of Medicine, 2-174 Edobashi, Tsu City, Mie 514-8507, Japan
Tel: +81 59 232 1111
Fax: +81 59 232 8095
e-mail: naokun@clin.medic.mie-u.ac.jp

Abstract

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-α, (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.

Conclusion: 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.

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