Introduction: Hepatic ischemia-reperfusion injury (IRI) is a serious comlication during liver surgery. As for therapeutic strategies on hepatic IRI, we previously demonstrated that activated protein C (APC) exerted multiple protective effects on mice/rat hepatic IRI. However, APC is associated with a higher risk of bleeding, because of its anticoagulant activity, making it problematic for clinical use. As one of the cytoprotective mechanisms of APC, protease-activated receptor 1 (PAR1) and sphingosine 1 phosphate receptor 1 (S1PR1) on cellular membrane are activated as signling of APC. Therefore, we hypothesize that stimulation of PAR1 or S1PR1 may become a therapeutic target on hepatic IRI without anticoagulant effects. This study aimed to clarify the effects of PAR1 agonist/antagonist and S1PR1 agonist on mice hepatic IRI.

Methods: Using 60-min partial ischemia model, C57/BL6 mice were treated with TFLLR (PAR1 agonist), SCH79797 (PAR1 antagonist), SEW2871 (S1PR1 agonist), and vehicle. Liver and blood samples were obtained at 4h after reperfusion. Study 1: Mice were classified into the three groups: SCH7979, TFLLR and control groups and treated by intravenous administration of agents. Study 2: Mice were classified into the two groups: SEW2871 and control group and treated by oral administration of agents.

Results: Study 1: Administration of SCH79797 significantly exacerbated serum ALT levels and histological damage. On the other hand, TFLLR did not show any significant effect on liver damage. Study 2: SEW2871 administration significantly improved serum ALT levels and liver histological damage. Moreover, SEW2871 significantly suppressed infiltration of inflammatory cells and cytokines in the liver; and enhanced endothelial nitric oxide synthase and vascular endothelial cadherin in the liver.

Conclusion: It is considered that S1PR1 agonist is a therapeutic target on hepatic IRI through anti-inflammatory action and sinusoidal endothelial protection without anti-coagulant action. On the other hand, PAR1 agonist is considered insufficient as a therapeutic target on hepatic IRI, although its antagonist exacerbates liver damage. Further studies using several different agents are required to clarify effect of PAR1 agonism.

CITATION INFORMATION: Ito T, Kuriyama N, Kato H, Iizawa Y, Tanemura A, Murata Y, Azumi Y, Kishiwada M, Mizuno S, Usui M, Sakurai H, Isaji S. Role of Protease Activated Receptor 1 and Sphingosine-1-Phospate Receptor 1 in Mice Hepatic Ischemia-Reperfusion Injury for Targeting Cell Signal Pathways of Activated Protein C. Am J Transplant. 2017;17 (suppl 3).

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