Date: Monday, May 4, 2015
Session Time: 2:15pm-3:45pm
Presentation Time: 2:39pm-2:51pm
Location: Room 119-A
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).
To cite this abstract in AMA style:Zhang C, Ji H, Liu Y, Shen X, Gao F, Busuttil R, Shaw G, Kupiec-Weglinski J. Tandem P-Selectin Glycoprotein Ligand-Immunoglobulin (TSGL-Ig) Protects Liver Endothelial Cells Against Prolonged Cold Preservation Injury in Mouse Liver Transplantation [abstract]. Am J Transplant. 2015; 15 (suppl 3). https://atcmeetingabstracts.com/abstract/tandem-p-selectin-glycoprotein-ligand-immunoglobulin-tsgl-ig-protects-liver-endothelial-cells-against-prolonged-cold-preservation-injury-in-mouse-liver-transplantation/. Accessed June 15, 2021.
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