title: A Soluble Form of P Selectin Glycoprotein Ligand 1 Requires Signaling by Nuclear Factor Erythroid 2-Related Factor 2 to Protect Liver Transplant Endothelial Cells Against Ischemia-Reperfusion Injury.
abstract: Liver endothelial cell (LEC) damage is essential in the pathogenesis of ischemia-reperfusion injury (IRI) in transplant recipients. We analyzed the mechanism of LEC resistance against IRI by using a novel recombinant soluble form of P selectin glycoprotein ligand 1, tandem P selectin glycoprotein ligand immunoglobulin (TSGL-Ig), in a mouse model of hepatic cold preservation (4°C in University of Wisconsin solution for 20 h) and syngeneic orthotopic liver transplantation (OLT). Unlike controls, TSGL-Ig protected orthotopic liver transplants against ischemia-reperfusion (IR) stress, shown by depressed serum alanine aminotransferase levels, well-preserved hepatic architecture, and improved survival (42% vs. 92%). TSGL-Ig suppressed neutrophil/macrophage sequestration and proinflammatory cytokine/chemokine programs in OLT. Treatment with TSGL-Ig mitigated LEC activation (P and E selectin, VCAM-1 and intercellular adhesion molecule 1 expression). In parallel in vitro studies, TSGL-Ig diminished cellular damage in H2O2-stressed LEC cultures (lactic acid dehydrogenase and alanine aminotransferase levels). Increased thioredoxin, glutamate-cysteine ligase, NAD(P)H quinone dehydrogenase 1, and hypoxia-inducible factor 1α expression, along with transcription factor nuclear factor erythroid 2-related factor 2 (Nrf2), implied that TSGL-Ig exerts antioxidant functions in IR-stressed OLT and H2O2-stressed LECs. Indeed, Nrf2-deficient livers suffered fulminant IRI compared with WT despite concomitant TSGL-Ig therapy. Thus, TSGL-Ig is not only acting as a competitive antagonist blocking leukocyte migration into IR-stressed liver, but it may also act directly as an agonist stimulating Nrf2-mediated cytoprotection in LECs. This study supports the role of P selectin signaling in hepatic homeostasis in OLT, with broad implications for tissue damage conditions.
authors.affiliation: Dumont-UCLA Transplant Center, Division of Liver and Pancreas Transplantation, Department of Surgery, David Geffen School of Medicine at University of California-Los Angeles, Los Angeles, CA.|Department of Surgery, Division of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, China.
authors.forename: C
authors.initials: C
authors.lastname: Zhang
authors.affiliation: Dumont-UCLA Transplant Center, Division of Liver and Pancreas Transplantation, Department of Surgery, David Geffen School of Medicine at University of California-Los Angeles, Los Angeles, CA.|Department of Surgery, Division of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, China.
authors.forename: Y
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Dumont-UCLA Transplant Center, Division of Liver and Pancreas Transplantation, Department of Surgery, David Geffen School of Medicine at University of California-Los Angeles, Los Angeles, CA.|Department of Surgery, Division of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, China.
authors.forename: Y
authors.initials: Y
authors.lastname: Liu
authors.affiliation: Dumont-UCLA Transplant Center, Division of Liver and Pancreas Transplantation, Department of Surgery, David Geffen School of Medicine at University of California-Los Angeles, Los Angeles, CA.|Department of Liver Surgery, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China.
authors.forename: Y
authors.initials: Y
authors.lastname: Liu
authors.affiliation: Dumont-UCLA Transplant Center, Division of Liver and Pancreas Transplantation, Department of Surgery, David Geffen School of Medicine at University of California-Los Angeles, Los Angeles, CA.
authors.forename: S
authors.identifier: http://orcid.org/0000-0002-2398-2428
authors.initials: S
authors.lastname: Kageyama
authors.affiliation: Dumont-UCLA Transplant Center, Division of Liver and Pancreas Transplantation, Department of Surgery, David Geffen School of Medicine at University of California-Los Angeles, Los Angeles, CA.
authors.forename: X-D
authors.initials: XD
authors.lastname: Shen
authors.affiliation: Dumont-UCLA Transplant Center, Division of Liver and Pancreas Transplantation, Department of Surgery, David Geffen School of Medicine at University of California-Los Angeles, Los Angeles, CA.
authors.forename: F
authors.initials: F
authors.lastname: Gao
authors.affiliation: Department of Surgery, Division of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, China.
authors.forename: S
authors.initials: S
authors.lastname: Zheng
authors.affiliation: Dumont-UCLA Transplant Center, Division of Liver and Pancreas Transplantation, Department of Surgery, David Geffen School of Medicine at University of California-Los Angeles, Los Angeles, CA.
authors.forename: R W
authors.initials: RW
authors.lastname: Busuttil
authors.affiliation: Quell Pharma Inc., Half Moon Bay, CA.
authors.forename: G D
authors.initials: GD
authors.lastname: Shaw
authors.affiliation: Dumont-UCLA Transplant Center, Division of Liver and Pancreas Transplantation, Department of Surgery, David Geffen School of Medicine at University of California-Los Angeles, Los Angeles, CA.
authors.forename: H
authors.initials: H
authors.lastname: Ji
authors.affiliation: Dumont-UCLA Transplant Center, Division of Liver and Pancreas Transplantation, Department of Surgery, David Geffen School of Medicine at University of California-Los Angeles, Los Angeles, CA.
authors.forename: J W
authors.initials: JW
authors.lastname: Kupiec-Weglinski
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D004730:Endothelium, Vascular / Q000378:metabolism* / Q000473:pathology; D008107:Liver Diseases / Q000601:surgery; D016031:Liver Transplantation; D008264:Macrophages / Q000378:metabolism / Q000473:pathology; D008297:Male; D008562:Membrane Glycoproteins / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D051267:NF-E2-Related Factor 2 / Q000378:metabolism*; D009504:Neutrophils / Q000378:metabolism / Q000473:pathology; D015427:Reperfusion Injury / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D015398:Signal Transduction
chemical_list: D008562:Membrane Glycoproteins; D051267:NF-E2-Related Factor 2; C495636:Nfe2l2 protein, mouse; C084882:P-selectin ligand protein
keywords: adhesion molecules/integrins; basic (laboratory) research/science; ischemia reperfusion injury (IRI); liver disease: immune/inflammatory; liver transplantation/hepatology; molecular biology