Date: Monday, June 13, 2016
Session Time: 6:00pm-7:00pm
Presentation Time: 6:00pm-7:00pm
Location: Halls C&D
Background: Liver endothelial cells (LEC) suffer from ROS-mediated stress in the pathogenesis of liver ischemia-reperfusion injury (IRI). We used a novel recombinant form of soluble PSGL-1, called Tandem P-Selectin Glycoprotein Ligand-Ig (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 hepatic cold preservation (4C UW for 20h) followed by syngeneic orthotopic liver transplantation (OLT). To block hepatic expression of P-selectin, TSGL-Ig was infused into the liver (0.1mg via portal vein; after harvest and prior to reperfusion). Unlike in control Ig-treated group, TSGL-Ig protected OLT against IR-stress at both 6h and 1d post-transplant, evidenced by sALT levels ([6h] 3,300±711 U/L vs. 16,694±3,670 U/L in controls; [1d] 1,041±328 U/L vs. 5,081±1,291 U/L in controls; p<0.001) and 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 MPO and pro-inflammatory cytokine/chemokine programs (TNF-α, IL-1β, IFN-β and CXCL-10) along with Ly-6G+ neutrophil/CD68+ macrophage sequestration, and LEC activation (P-Selectin/E-Selectin/VCAM-1/ICAM-1 expression) were depressed in TSGL-Ig treated OLT. 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/ALT levels and increased anti-oxidation HIF-1α expression. Furthermore, we found TSGL-Ig induced translocation of anti-oxidant Nrf2 from cytoplasm to nucleus in LEC, and increased downstream Trx-1, GCLC, and NQO1 expression. Conclusion: Harnessing LEC cytoprotective mechanisms by TSGL-Ig: 1/ mitigated IRI and promoted OLT survival; 3/ depressed innate immune activation; 3/ preserved LEC viability via anti-oxidant Nrf2 signaling. Hence, negative regulation by TSGL-Ig provides the basis for novel therapeutic strategies against IRI in liver transplant recipients.
CITATION INFORMATION: Zhang C, Ji H, Liu Y, Zhang Y, Shen X.-D, Gao F, Busuttil R, Shaw G, Kupiec-Weglinski J. Recombinant TSGL-Ig Protects Liver Endothelial Cells Against Prolonged Cold Preservation Injury in Mouse Liver Transplantation. Am J Transplant. 2016;16 (suppl 3).
To cite this abstract in AMA style:Zhang C, Ji H, Liu Y, Zhang Y, Shen X-D, Gao F, Busuttil R, Shaw G, Kupiec-Weglinski J. Recombinant TSGL-Ig Protects Liver Endothelial Cells Against Prolonged Cold Preservation Injury in Mouse Liver Transplantation. [abstract]. Am J Transplant. 2016; 16 (suppl 3). https://atcmeetingabstracts.com/abstract/recombinant-tsgl-ig-protects-liver-endothelial-cells-against-prolonged-cold-preservation-injury-in-mouse-liver-transplantation/. Accessed April 2, 2020.
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