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 4h 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 4h but not 24h 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 24h 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.