sphingosine-kinase and Acute-Disease

Increasing evidence suggests that High-density lipoproteins (HDL) are a direct cardioprotective agent in the setting of acute myocardial ischemia/reperfusion injury, and that this cardioprotection occurs independently of their atheroprotective effect. Studies on the involved mechanisms have revealed that the biologically active HDL-compound sphingosine-1-phosphate (S1P) is responsible for the beneficial effect of HDL on the myocardium. There appears to be an intricate interplay between known preconditioning agents and components of the S1P synthesis machinery in the heart, which makes S1P signalling an attractive downstream convergence point of preconditioning and cardioprotection at the level of its G protein-coupled receptors. While local S1P production has been known to protect the heart against ischemia/reperfusion injury and to mediate preconditioning, systemic S1P supply via HDL adds a novel aspect to the regulation of cardioprotection. Thus the S1P-content of HDL may serve both as a potential cardiovascular risk marker and a novel therapeutic target. Strategies for short-term "acute" HDL elevation as well as S1P analogues may prove beneficial not only in the high-risk patient but also in any patient at risk of myocardial ischemia.

Topics: Acute Disease; Cardiovascular Diseases; Creatine Kinase; Humans; Ischemic Preconditioning, Myocardial; Lipoproteins, HDL; Lysophospholipids; Myocardial Ischemia; Myocardial Reperfusion; Myocardium; Phosphotransferases (Alcohol Group Acceptor); Risk Factors; Signal Transduction; Sphingosine

To investigate the role of sphingosine kinase 1 (SphK1)/sphingosine 1-phosphate (S1P) signaling in inflammatory response in severe acute pancreatitis (SAP).. SAP is an acute inflammatory process of the pancreas, which may lead to systemic inflammatory response syndrome and multiorgan dysfunction syndrome. SphK1 and its product S1P have been implicated in inflammatory response and various immune cell functions. However, the potential role for SphK1/S1P in inflammatory response in SAP is still unclear.. Twenty-two patients with SAP were enrolled in this study. SphK1 expression on peripheral neutrophils, monocytes, and lymphocytes was evaluated by flow cytometry. SphK enzymatic activity in neutrophils and lymphocytes was measured using a radiometric assay. The expression of S1P1 and S1P3 mRNA was determined by reverse transcriptase-polymerase chain reaction (RT-PCR). The serum levels of tumor necrosis factor-α (TNF-α), interleukin-1 (IL-1β), and IL-6 were measured by ELISA.. The expression of SphK1 and SphK activity were markedly increased in peripheral immune cells in the early stage of SAP and then reduced in the restoration stage in the patients. Moreover, we found that the level of S1P3 mRNA in peripheral neutrophils and lymphocytes of SAP patients was significantly elevated in the early stage as compared with the healthy volunteers, and it reduced in the restoration period. SphK1 expression on human peripheral neutrophils, monocytes, and CD4(+) T lymphocytes were positively correlated with the APACHE (Acute Physiological and Chronic Health Evaluation) II scores in patients with SAP. The levels of serum proinflammatory cytokines including TNF-α, IL-1β, and IL-6 showed similar shifts with intracellular SphK1 expression in SAP patients.. The authors identified a link between the SphK1 expression on peripheral immune cells and the severity of SAP. Observations showed a possible immunomodulating role for SphK1/S1P signaling in inflammatory response in SAP, suggesting that regulation of SphK1/S1P pathway may represent novel targets in the treatment of SAP.

Topics: Acute Disease; Adult; Aged; Female; Flow Cytometry; HLA-DR Antigens; Humans; Interleukin-1beta; Interleukin-6; Lymphocyte Subsets; Male; Middle Aged; Pancreatitis; Phosphotransferases (Alcohol Group Acceptor); Reverse Transcriptase Polymerase Chain Reaction; Tumor Necrosis Factor-alpha; Up-Regulation; Young Adult

Immunologic processes might contribute to the pathogenesis of pulmonary arterial hypertension (PAH), a fatal condition characterized by progressive pulmonary arterial remodeling, increased pulmonary vascular resistance, and right ventricular failure. Experimental allergen-driven lung inflammation evoked morphologic and functional vascular changes that resembled those observed in patients with PAH. Sphingosine kinase 1 (SphK1) is the main pulmonary contributor to sphingosine-1-phosphate (S1P) synthesis, a modulator of immune and vascular functions.. We sought to investigate the role of SphK1 in allergen-induced lung inflammation.. SphK1-deficient mice and C57Bl/6 littermates (wild-type [WT] animals) were subjected to acute or chronic allergen exposure.. After 4 weeks of systemic ovalbumin sensitization and local airway challenge, airway responsiveness increased less in SphK1(-/-) compared with WT mice, whereas pulmonary vascular responsiveness was greatly increased and did not differ between strains. Acute lung inflammation led to an increase in eosinophils and mRNA expression for S1P phosphatase 2 and S1P lyase in lungs of WT but not SphK1(-/-) mice. After repetitive allergen exposure for 8 weeks, airway responsiveness was not augmented in SphK1(-/-) or WT mice, but pulmonary vascular responsiveness was increased in both strains, with significantly higher vascular responsiveness in SphK1(-/-) mice compared with that seen in WT mice. Increased vascular responsiveness was accompanied by remodeling of the small and intra-acinar arteries.. : The data support a role for SphK1 and S1P in allergen-induced airway inflammation. However, SphK1 deficiency increased pulmonary vascular hyperresponsiveness, which is a component of PAH pathobiology. Moreover, we show for the first time the dissociation between inflammation-induced remodeling of the airways and pulmonary vasculature.

Topics: Acute Disease; Allergens; Animals; Bronchial Hyperreactivity; Chronic Disease; Cytokines; Hypertension, Pulmonary; Lung; Lysophospholipids; Mice; Mice, Inbred C57BL; Mice, Knockout; Ovalbumin; Phosphotransferases (Alcohol Group Acceptor); Pulmonary Artery; RNA, Messenger; Sphingosine

Sphingosine 1-phosphate (S1P) is a bioactive sphingolipid produced by sphingosine kinase (SphK1 and 2). We previously showed that S1P receptors (S1P1, S1P2, and S1P3) are expressed in hepatic myofibroblasts (hMF), a population of cells that triggers matrix remodeling during liver injury. Here we investigated the function of these receptors in the wound healing response to acute liver injury elicited by carbon tetrachloride, a process that associates hepatocyte proliferation and matrix remodeling. Acute liver injury was associated with the induction of S1P2, S1P3, SphK1, and SphK2 mRNAs and increased SphK activity, with no change in S1P1 expression. Necrosis, inflammation, and hepatocyte regeneration were similar in S1P2-/- and wild-type (WT) mice. However, compared with WT mice, S1P2-/- mice displayed reduced accumulation of hMF, as shown by lower induction of smooth muscle alpha-actin mRNA and lower induction of TIMP-1, TGF-beta1, and PDGF-BB mRNAs, overall reflecting reduced activation of remodeling in response to liver injury. The wound healing response was similar in S1P3-/- and WT mice. In vitro, S1P enhanced proliferation of cultured WT hMF, and PDGF-BB further enhanced the mitogenic effect of S1P. In keeping with these findings, PDGF-BB up-regulated S1P2 and SphK1 mRNAs, increased SphK activity, and S1P2 induced PDGF-BB mRNA. These effects were blunted in S1P2-/- cells, and S1P2-/- hMF exhibited reduced mitogenic and comitogenic responses to S1P. These results unravel a novel major role of S1P2 in the wound healing response to acute liver injury by a mechanism involving enhanced proliferation of hMF.

Topics: Acute Disease; Animals; Becaplermin; Carbon Tetrachloride Poisoning; Cell Division; Cells, Cultured; Chemical and Drug Induced Liver Injury; DNA Replication; Enzyme Induction; Extracellular Matrix; Fibroblasts; Gene Expression Regulation; Liver Regeneration; Lysophospholipids; Mice; Mice, Inbred C57BL; Mice, Knockout; Myoblasts, Smooth Muscle; Necrosis; Phosphotransferases (Alcohol Group Acceptor); Platelet-Derived Growth Factor; Proliferating Cell Nuclear Antigen; Proto-Oncogene Proteins c-sis; Receptors, Lysosphingolipid; Sphingosine; Sphingosine-1-Phosphate Receptors; Tissue Inhibitor of Metalloproteinase-1; Transforming Growth Factor beta1

We examined the involvement of sphingosine kinase-1, a critical regulator of the sphingolipid balance, in susceptibility to antineoplastic agents of either sensitive or multidrug-resistant acute myeloid leukemia cells. Contrary to parental HL-60 cells, doxorubicin and etoposide failed to trigger apoptosis in chemoresistant HL-60/Doxo and HL-60NP16 cells overexpressing MRP1 and MDR1, respectively. Chemosensitive HL-60 cells displayed sphingosine kinase-1 inhibition coupled with ceramide generation. In contrast, chemoresistant HL-60/ Doxo and HL-60/VP16 had sustained sphingosine kinase-1 activity and did not produce ceramide during treatment. Enforced expression of sphingosine kinase-1 in chemosensitive HL-60 cells resulted in marked inhibition of apoptosis that was mediated by blockade of mitochondrial cytochrome c efflux hence suggesting a control of apoptosis at the pre-mitochondrial level. Incubation with cell-permeable ceramide of chemoresistant cells led to a sphingosine kinase-1 inhibition and apoptosis both prevented by sphingosine kinase-1 over-expression. Furthermore, F-12509a, a new sphingosine kinase inhibitor, led to ceramide accumulation, decrease in sphingosine 1-phosphate content and caused apoptosis equally in chemosensitive and chemoresistant cell lines that is inhibited by adding sphingosine 1-phosphate or overexpressing sphingosine kinase-1. F-12509a induced classical apoptosis hallmarks namely nuclear fragmentation, caspase-3 cleavage as well as downregulation of antiapoptotic XIAP, and release of cytochrome c and SMAC/Diablo.

Topics: Acute Disease; Apoptosis; Benzoquinones; Cell Line, Tumor; Cell Survival; Ceramides; Doxorubicin; Drug Resistance, Multiple; Drug Resistance, Neoplasm; Etoposide; HL-60 Cells; Humans; Leukemia, Myeloid; Mitochondria; Phosphotransferases (Alcohol Group Acceptor); Receptors, Lysosphingolipid; RNA Interference

Sphingosine-1-phosophate, generated from the phosphorylation of sphingosine by sphingosine kinase enzymes, is suggested to function as an intracellular second messenger for inflammatory mediators, including formyl peptide, C5a, and Fc. More recently, a role for sphingosine kinases during inflammation has also been proposed. Here we show that sphingosine kinase 1 knockout mice exhibit normal inflammatory cell recruitment during thioglycollate-induced peritonitis and that sphingosine kinase 1-null neutrophils respond normally to formyl peptide. In the collagen-induced arthritis model of rheumatoid arthritis, sphingosine kinase 1 knockout mice developed arthritis with normal incidence and severity. Our findings show that sphingosine kinase 1 is dispensable for inflammatory responses and support the need for more extensive studies of sphingosine kinases in inflammation.

Topics: Acute Disease; Animals; Base Sequence; Chronic Disease; DNA Primers; Inflammation; Male; Mice; Mice, Knockout; N-Formylmethionine Leucyl-Phenylalanine; NADPH Oxidases; Neutrophils; Phosphotransferases (Alcohol Group Acceptor); Signal Transduction