Background: Liver endothelial cell (LEC) damage is central in the pathogenesis of hepatic ischemia-reperfusion injury (IRI). LEC detachment/progressed denudation are typical during cold storage and warm reperfusion during liver transplantation. We used a novel recombinant form of soluble PSGL-1, called Tandem P-Selectin Glycoprotein Ligand-Immunoglobulin (TSGL-Ig), to test a hypothesis that preservation of LEC integrity is essential to promote liver graft survival. Methods&Results: We employed a mouse (C57/BL6) model of liver cold preservation (4C UW for 20h) and syngeneic orthotopic liver transplantation (OLT). To block hepatic P-selectin, TSGL-Ig was given into the liver (0.1mg via portal vein; after harvest and prior reperfusion). Unlike in untreated controls, TSGL-Ig protected OLT against IR-stress at 6h and 1d post-transplant, evidenced by sALT levels ([6h] 3300±711 U/L vs. 16694±3670 U/L in controls; [1d] 1041±328 U/L vs. 5081±1291 U/L in controls; p<0.001) and well-preserved hepatic architecture (no edema, vacuolization or necrosis) (n=6/gr). Strikingly, TSGL-Ig conditioning improved OLT survival at 14 days (92% vs. 42% in controls; n=12/gr). Hepatic myeloperoxidase (MPO) activity and proinflammatory cytokine/chemokine programs (TNF-α, IL-1b, IFN-b and CXCL-10) were depressed in TSGL-Ig treated OLT. In parallel, P-selectin blockade markedly decreased hepatic Ly-6G+ neutrophil and CD68+ macrophage sequestration, and abolished LEC activation, as shown by reduced VCAM-1/ICAM-1 expression. Next, we analyzed the function of TSGL-Ig in primary mouse LEC cultures. Indeed, addition of TSGL-Ig diminished H₂O₂-stressed LEC injury, evidenced by decreased LDH levels. Conclusion: Our novel findings provide evidence that harnessing LEC cytoprotective mechanism by targeting P-selectin with TSGL-Ig: 1) mitigated IR-hepatocellular damage and promoted OLT survival; 2) diminished local neutrophil infiltration and MPO activity; 3) abolished macrophage trafficking and innate immune activation; 4) preserved LEC viability and integrity. Hence, negative regulation by targeting endothelial P-selectin with TSGL-Ig provides the basis for novel therapeutic strategies against IRI in liver transplant recipients and may also suggest its use for treating sinusoidal obstruction syndrome (SOS).

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