Introduction: We had reported that activated protein C (APC) administration had cytoprotective effects on hepatic ischemic reperfusion (IR) injury in rat and mice models. Recent studies reported that the cytoprotective effect of APC could be mediated through specific protease activated receptors and sphingosine-1-phosphate receptor 1 (S1PR1). S1PR1s located on various cells are associated with suppression of lymphocytes and stabilization of endothelial cells. In our preliminary studies, the expression of S1PR1 was up-regulated in the IR liver treated by APC administration compared to control liver. Therefore, it was considered that S1PR1 could be new therapeutic target for hepatic IRI. The aim of study was to investigate the cytoprotective effects of S1PR1 agonist (SEW2871) on hepatic IRI.

Methods & Results: Using 60-min partial ischemia model, C57/BL6 mice were treated with oral administration of SEW2871 or vehicle (control). Liver and blood samples were obtained at 4h and 24h after reperfusion. SEW2871 significantly attenuated liver damage, evidenced by AST: 1522±658 vs 2837±1176, ALT: 1092±479 vs 2999±897 IU/L, p<0.05, compared to controls. Additionally, SEW2871-treated liver showed significantly less sign of vascular congestion at 4h (Suzuki scores: 6.4±1.3 vs 3.9±1.7, p<0.05) and necrosis area at 24h. In the liver treated with SEW2871 at 24h, Ly-6G and MAC-1 positive cells infiltrations were significantly reduced (p<0.05). Expression of IFNγ, IL-6, TNF-α and VCAM-1 at 4h after reperfusion were significantly lower than in control liver. Particularly, the expressions of IFN-γ (6.5 ±4.9 vs 0.6 ±0.3 /β actin, p<0.01), which were cytokines mainly derived by lymphocyte, were remarkably reduced because the number of lymphocyte in blood was significantly decreased (2060±129 vs 710±194 /[mu]l, p<0.05) at 4h. Moreover, the expressions of endothelial nitric oxide synthase (e-NOS) on IR liver with SEW2871 were significantly higher than control.

Conclusion: S1PR1 agonist affects protectively on IR liver by reducing the number of lymphocytes in blood, inflammatory cell infiltrations and pro-inflammatory cytokines. It is also considered that S1PR1 agonist attenuates sinusoidal endothelial cell injury evidenced by overexpression of eNOS.

CITATION INFORMATION: Ito T, Kuriyama N, Matsuda A, Kato H, Iizawa Y, Murata Y, Tanemura A, Azumi Y, Kishiwada M, Mizuno S, Usui M, Sakurai H, Isaji S. Sphingosine-1 Phosphate Receptor 1 Agonist SEW2871 Ameliorates Hepatocellular Injury on Ischemic Reperfusion in Mice: A New Therapeutic Target. Am J Transplant. 2016;16 (suppl 3).

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