Modulating sphingosine 1-phosphate signaling with DOP or FTY720 alleviates vascular and immune defects in mouse sepsis.
Sepsis is a systemic inflammatory response to pathogens and a leading cause of hospital related mortality worldwide. Sphingosine 1-phosphate (S1P) regulates multiple cellular processes potentially involved in the pathogenesis of sepsis, including antigen presentation, lymphocyte egress, and maintenance of vascular integrity. We thus explored the impact of manipulating S1P signaling in experimental polymicrobial sepsis in mice. Administration of 4-deoxypyridoxine (DOP), an inhibitor of the S1P-degrading enzyme S1P-lyase, or of the sphingosine analog FTY720 that serves as an S1P receptor agonist after phosphorylation ameliorated morbidity, improved recovery from sepsis in surviving mice, and reduced sepsis-elicited hypothermia and body weight loss. Treated mice developed lymphopenia, leading to an accumulation of lymphocytes in peripheral lymph nodes, and reduced bacterial burden in liver, but not in blood. Sepsis-induced upregulation of mRNA expression of cytokines in spleen remained unchanged, but reduction of IL-6, TNF-α, MCP-1, and IL-10 in plasma was evident. DOP and FTY720 treatment significantly reduced levels of Evans blue leakage from blood into liver and lung, decreased hematocrit values, and lowered plasma levels of VEGF-A in septic mice. Collectively, our results indicate that modulation of S1P signaling showed a protective phenotype in experimental sepsis by modulating vascular and immune functions.
Department of Anesthesiology and Intensive Care Medicine, Center for Sepsis Control and Care (CSCC), and the Center for Molecular Biomedicine (CMB), University Hospital Jena, Jena, Germany.
Nasr Y A
NY
Hemdan
Department of Anesthesiology and Intensive Care Medicine, Center for Sepsis Control and Care (CSCC), and the Center for Molecular Biomedicine (CMB), University Hospital Jena, Jena, Germany.|Fritz Lipmann Institute, Leibniz Institute on Aging, Jena, Germany.
Cynthia
C
Weigel
Department of Anesthesiology and Intensive Care Medicine, Center for Sepsis Control and Care (CSCC), and the Center for Molecular Biomedicine (CMB), University Hospital Jena, Jena, Germany.
Christina-Maria
CM
Reimann
Department of Anesthesiology and Intensive Care Medicine, Center for Sepsis Control and Care (CSCC), and the Center for Molecular Biomedicine (CMB), University Hospital Jena, Jena, Germany.
Markus H
MH
Gräler
D000818:Animals; D002199:Capillary Permeability / Q000187:drug effects; D002478:Cells, Cultured; D016207:Cytokines / Q000378:metabolism; D000068876:Fingolimod Hydrochloride / Q000627:therapeutic use*; D056747:Immunomodulation; D008246:Lysophospholipids / Q000378:metabolism*; D008565:Membrane Proteins / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D010744:Phosphoric Monoester Hydrolases / Q000378:metabolism; D011736:Pyridoxine / Q000031:analogs & derivatives* / Q000627:therapeutic use; D049349:Receptors, Lysosphingolipid / Q000378:metabolism*; D018805:Sepsis / Q000188:drug therapy* / Q000276:immunology; D015398:Signal Transduction; D013110:Sphingosine / Q000031:analogs & derivatives* / Q000378:metabolism; D042461:Vascular Endothelial Growth Factor A / Q000097:blood
D016207:Cytokines; D008246:Lysophospholipids; D008565:Membrane Proteins; D049349:Receptors, Lysosphingolipid; D042461:Vascular Endothelial Growth Factor A; C060506:sphingosine 1-phosphate; C004675:4-deoxypyridoxine; C401298:sphingosine-1-phosphate phosphatase; D010744:Phosphoric Monoester Hydrolases; D000068876:Fingolimod Hydrochloride; D011736:Pyridoxine; D013110:Sphingosine
Cytokine; Endothelial barrier; Leukocytes; Lymphopenia; Peritoneal contamination and infection