title: Inhibition of sphingosine kinase-2 suppresses inflammation and attenuates graft injury after liver transplantation in rats.
abstract: Inflammation mediates/promotes graft injury after liver transplantation (LT). This study investigated the roles of sphingosine kinase-2 (SK2) in inflammation after LT. Liver grafts were stored in UW solution with and without ABC294640 (100 µM), a selective inhibitor of SK2, before implantation. Hepatic sphingosine-1-phosphate (S1P) levels increased ∼4-fold after LT, which was blunted by 40% by ABC294640. Hepatic toll-like receptor-4 (TLR4) expression and nuclear factor-κB (NF-κB) p65 subunit phosphorylation elevated substantially after transplantation. The pro-inflammatory cytokines/chemokines tumor necrosis factor-α, interleukin-1β and C-X-C motif chemokine 10 mRNAs increased 5.9-fold, 6.1-fold and 16-fold, respectively following transplantation, while intrahepatic adhesion molecule-1 increased 5.7-fold and monocytes/macrophage and neutrophil infiltration and expansion of residential macrophage population increased 7.8-13.4 fold, indicating enhanced inflammation. CD4+ T cell infiltration and interferon-γ production also increased. ABC294640 blunted TLR4 expression by 60%, NF-κB activation by 84%, proinflammatory cytokine/chemokine production by 45-72%, adhesion molecule expression by 54% and infiltration of monocytes/macrophages and neutrophils by 62-67%. ABC294640 also largely blocked CD4+ T cell infiltration and interferon-γ production. Focal necrosis and apoptosis occurred after transplantation with serum alanine aminotransferase (ALT) reaching ∼6000 U/L and serum total bilirubin elevating to ∼1.5 mg/dL. Inhibition of SK2 by ABC294640 blunted necrosis by 57%, apoptosis by 74%, ALT release by ∼68%, and hyperbilirubinemia by 74%. Most importantly, ABC294640 also increased survival from ∼25% to ∼85%. In conclusion, SK2 plays an important role in hepatic inflammation responses and graft injury after cold storage/transplantation and represents a new therapeutic target for liver graft failure.
authors: Department of Pharmaceutical & Biomedical Sciences, Medical University of South Carolina, Charleston, South Carolina, United States of America.
authors: Qinlong
authors: Q
authors: Liu
authors: Hasibur
authors: H
authors: Rehman
authors: Yanjun
authors: Y
authors: Shi
authors: Yasodha
authors: Y
authors: Krishnasamy
authors: John J
authors: JJ
authors: Lemasters
authors: Charles D
authors: CD
authors: Smith
authors: Zhi
authors: Z
authors: Zhong
mesh_terms: D000218:Adamantane / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D000818:Animals; D015815:Cell Adhesion Molecules / Q000378:metabolism; D018925:Chemokines / Q000235:genetics; D004791:Enzyme Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D007249:Inflammation / Q000188:drug therapy; D007962:Leukocytes / Q000187:drug effects / Q000276:immunology; D008099:Liver / Q000187:drug effects* / Q000293:injuries* / Q000378:metabolism / Q000503:physiopathology; D016031:Liver Transplantation / Q000009:adverse effects*; D008246:Lysophospholipids / Q000096:biosynthesis; D008297:Male; D016328:NF-kappa B / Q000378:metabolism; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000037:antagonists & inhibitors*; D011725:Pyridines / Q000494:pharmacology* / Q000627:therapeutic use; D051381:Rats; D011917:Rats, Inbred Lew; D017382:Reactive Oxygen Species / Q000378:metabolism; D015427:Reperfusion Injury / Q000188:drug therapy / Q000276:immunology / Q000378:metabolism / Q000503:physiopathology; D013110:Sphingosine / Q000031:analogs & derivatives / Q000096:biosynthesis; D051197:Toll-Like Receptor 4 / Q000378:metabolism; D015854:Up-Regulation / Q000187:drug effects; D000099157:Sphingosine Kinase
chemical_list: D000218:Adamantane; D015815:Cell Adhesion Molecules; D018925:Chemokines; D004791:Enzyme Inhibitors; D008246:Lysophospholipids; D016328:NF-kappa B; D017853:Phosphotransferases (Alcohol Group Acceptor); D011725:Pyridines; D017382:Reactive Oxygen Species; D013110:Sphingosine; D051197:Toll-Like Receptor 4; D000099157:Sphingosine Kinase; C060506:sphingosine 1-phosphate; C548780:3-(4-chlorophenyl)-adamantane-1-carboxylic acid (pyridin-4-ylmethyl)amide