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 H2 O2 -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 H2 O2 -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: C Zhang, Y Zhang, Y Liu, Y Liu, S Kageyama, X-D Shen, F Gao, S Zheng, R W Busuttil, G D Shaw, H Ji, J W Kupiec-Weglinski
• Journal: American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons (Am J Transplant) Vol. 17 Issue 6 Pg. 1462-1475 (Jun 2017) ISSN: 1600-6143 [Electronic] United States
• PMID: 27977895 (Publication Type: Journal Article)
• Copyright: © 2016 The American Society of Transplantation and the American Society of Transplant Surgeons.

Chemical References

• Membrane Glycoproteins
• NF-E2-Related Factor 2
• Nfe2l2 protein, mouse
• P-selectin ligand protein

Topics

• Animals
• Cells, Cultured
• Endothelium, Vascular (metabolism, pathology)
• Liver Diseases (surgery)
• Liver Transplantation
• Macrophages (metabolism, pathology)
• Male
• Membrane Glycoproteins (metabolism)
• Mice
• Mice, Inbred C57BL
• NF-E2-Related Factor 2 (metabolism)
• Neutrophils (metabolism, pathology)
• Reperfusion Injury (metabolism, pathology, prevention & control)
• Signal Transduction