TY - JOUR
T1 - 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
AU - Zhang, C.
AU - Zhang, Y.
AU - Liu, Y.
AU - Liu, Y.
AU - Kageyama, S.
AU - Shen, X.
AU - Gao, F.
AU - Zheng, S.
AU - Busuttil, R. W.
AU - Shaw, G. D.
AU - Ji, H.
AU - Kupiec-Weglinski, J. W.
N1 - Publisher Copyright:
© 2016 The American Society of Transplantation and the American Society of Transplant Surgeons
PY - 2017/6
Y1 - 2017/6
N2 - 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.
AB - 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.
KW - adhesion molecules/integrins
KW - basic (laboratory) research/science
KW - ischemia reperfusion injury (IRI)
KW - liver disease: immune/inflammatory
KW - liver transplantation/hepatology
KW - molecular biology
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UR - http://www.scopus.com/inward/citedby.url?scp=85011999532&partnerID=8YFLogxK
U2 - 10.1111/ajt.14159
DO - 10.1111/ajt.14159
M3 - Article
C2 - 27977895
AN - SCOPUS:85011999532
SN - 1600-6135
VL - 17
SP - 1462
EP - 1475
JO - American Journal of Transplantation
JF - American Journal of Transplantation
IS - 6
ER -