Abstract

Background: We recently reported that human protein C inhibitor (PCI), a major inhibitor of activated protein C (APC), inhibits hepatocyte growth factor activator (HGFA) by forming HGFA–PCI complexes in vitro. In this study, we evaluated whether PCI regulates HGFA-mediated liver regeneration in a human PCI gene transgenic (hPCI-Tg) mouse model.

Methods and results: After partial hepatectomy in hPCI-Tg and wild-type (WT) mice, the degree of liver regeneration, protein and mRNA expression of HGFA, proHGF activation, plasma levels of PCI and HGFA–PCI complex, and other markers were evaluated in the remnant liver. We also evaluated the effect of anti-human PCI antibody on liver regeneration, which significantly decreased in hPCI-Tg mice compared to WT mice. HGFA mRNA levels in naive and remnant livers after hepatectomy were the same in both WT and hPCI-Tg mice; however, plasma HGFA levels and HGF activation in the liver were lower in hPCI-Tg than in WT mice. There was no difference in plasma levels of transaminases and inflammatory cytokines. However, sinusoidal congestion and bleeding were detected and the serum hyaluronic acid level was elevated in hPCI-Tg mice, indicating that human PCI aggravates sinusoidal injury by inhibiting the cytoprotective effect of APC. APC decreased thrombin-induced IL-6 production in isolated hepatic nonparenchymal cells (NPCs) in vitro. This impaired liver regeneration was reversed by anti-human PCI antibody treatment in vivo.

Conclusion: PCI regulates liver regeneration after hepatectomy by forming an HGFA–PCI complex and aggravates hepatic NPC injury by inhibiting the cytoprotective effect of APC. Anti-PCI antibody treatment may be a novel therapy for improving liver regeneration.