sphingosine-1-phosphate 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

Acute heart failure (AHF) is a burden disease, with high mortality and re-hospitalisations. Using an ex-vivo model of AHF, we have previously reported that sphingosine-1-phosphate (S1P) confers cardioprotection. However, the mechanisms remain to be elucidated. In the present study, we aimed to examine the role of the cardioprotective signal transducer and activator of transcription 3 (STAT3) in S1P mediated improved functional recovery in AHF.. Isolated hearts from male Long-Evans rats were subjected to hypotensive AHF for 35 min followed by a recovery phase of 30 min (n ≥ 4/group). S1P (10 nM) was given during either the hypotensive or the recovery phase with/without an inhibitor of STAT3, AG490. Functional parameters were recorded throughout the experiment.. Following an AHF insult, S1P, given during the recovery phase, improved the heart rate (HR) compared to the control (175.2 ± 30.7 vs. 71.6 ± 27.4 beats per minute (BPM); p < 0.05), with no changes in the left ventricular developed pressure. This effect was associated with an increase in phosphorylated STAT3 levels in the nucleus. Addition of AG490 with S1P abolished the cardioprotective effect of S1P (42.3 ± 17.1 vs. 148.8 ± 26.4 BPM for S1P; p < 0.05).. Our data suggest that S1P protects in an ex-vivo rat heart model of AHF by activation of STAT3 and provide further evidence for the usage of S1P as a potential therapy in patients suffering from AHF.

Topics: Acute Disease; Animals; Blood Pressure; Cardiotonic Agents; Heart Failure; Heart Rate; In Vitro Techniques; Lysophospholipids; Male; Phosphorylation; Rats; Rats, Long-Evans; Sphingosine; STAT3 Transcription Factor; Tyrphostins; Ventricular Dysfunction, Left

Acute pancreatitis (AP) is a prevalent gastrointestinal disorder associated with systemic inflammatory response syndrome and, in the case of severe AP, a mortality rate ranging from 36% to 50%. Standard clinical treatment of AP includes intensive hydration, analgesia, and management of complications. Unfortunately, the direct treatment of AP at the level of its molecular pathomechanism has not yet been established. Recent studies indicate that the sphingolipid signaling pathway may be one of the important factors contributing to the development of inflammation in pancreatic diseases. In the current study, we sought to investigate this promising route. We examined the plasma sphingolipid profile of 44 patients with acute pancreatitis, dividing them into three groups: mild, moderate and severe AP. Samples were collected from these groups at days 1, 3 and 7 following their hospital admission. We demonstrated significant changes in blood plasma sphingolipids in relation to the time course of AP. We also found an inhibition of de novo ceramide synthesis in mild and moderate AP. However, the most important and novel finding was a significant elevation in sphingosine-1-phosphate (S1P) (a downstream metabolite of ceramide) in mild AP, as well as a dramatic reduction in the lipid molecule content in the early stage (days 1 and 3) of severe AP. This strongly indicates that plasma S1P could serve as a prognostic marker of AP severity.

Topics: Acute Disease; Adult; Aged; Ceramides; Female; Humans; Lysophospholipids; Male; Middle Aged; Pancreatitis; Signal Transduction; Sphingolipids; Sphingosine; Young Adult

Vascular leak is the hallmark of severe dengue infections and leads to complications such as shock and multi-organ failure. Although many mediators have been implicated in the vascular leak in dengue, the role of sphingosine 1-phosphate (S1P) has not been investigated.. As S1P has been shown to be important in barrier integrity, we assessed the S1P levels in 28 patients with acute dengue and 12 healthy individuals. The S1P levels were significantly lower in patients with acute dengue (p = 0.002) and the levels in patients with grade IV dengue haemorrhagic fever (DHF) were significantly lower than those with dengue fever (p = 0.005). We then investigated the kinetics of S1P levels throughout the course of the illness in another 32 patients in serum samples obtained twice a day. We found that S1P levels were low throughout the course of illness and S1P levels were <0.5 µM in 12/23 patients with DHF when compared to 1/9 with DF.. As S1P has shown to be important in the endothelial barrier integrity and increases transendothelial resistance, low levels of S1P in acute dengue infection are likely to contribute to increased vascular permeability.

Topics: Acute Disease; Adult; Dengue; Enzyme-Linked Immunosorbent Assay; Humans; Kinetics; Lysophospholipids; Severe Dengue; Severity of Illness Index; Sphingosine

Sphingosine-1-phosphate (S1P) is a cardioprotective sphingolipid present at high concentration in plasma and blood cells. However, effect of the myocardial infarction on S1P metabolism in blood is poorly recognized. Therefore, we aimed to examine the dynamics of changes in concentration of sphingolipids in blood of patients with acute ST-segment elevation myocardial infarction (STEMI). The study was performed on two groups of subjects: healthy controls (n=32) and patients with STEMI (n=32). In the latter group blood was taken upon admission to intensive heart care unit, and then on the second, fifth and thirtieth day, and approximately two years after admission. STEMI patients showed decreased plasma S1P concentration and accumulation of free sphingoid bases and their 1-phosphates in erythrocytes. This effect was already present upon admission, and was maintained for at least thirty days after the infarction. Interestingly, two years post-infarction plasma S1P level recovered only partially, whereas the content of erythrocyte sphingolipids decreased to the values observed in the control subjects. The most likely reason for the observed reduction in plasma S1P level was its decreased release or increased degradation by vascular endothelial cells, as we did not find any evidence for downregulation of S1P synthesis or release by blood cells. We conclude that patients with STEMI are characterized by marked alterations in sphingolipid metabolism in blood which could be a consequence of the infarction itself, the antiplatelet treatment given or both. Our data suggest that cardioprotective action of S1P may be diminished in patients with acute myocardial infarction.

Topics: Acute Disease; Aged; Erythrocytes; Female; Humans; Lysophospholipids; Male; Middle Aged; Myocardial Infarction; Sphingosine

Lysophospholipids may play an important protective role during primary infection of Mycobacterium tuberculosis (MTB) by enhancing innate antimycobacterial immune response of both macrophages and alveolar epithelial cells. Here, we show that treatment with lysophosphatidic acid (LPA) of mice aerogenically infected with MTB immediately after infection results in a significant early reduction of pulmonary CFUs and of histopathological damage in comparison with control mice. In contrast, treatment of acute disease does not result in any improvement of both microbiological and histopathological parameters. Altogether, these results show that LPA treatment can exert protective effect if administrated during primary infection, only.

Topics: Acute Disease; Animals; Colony Count, Microbial; Female; Lung; Lysophospholipids; Mice; Mice, Inbred BALB C; Mycobacterium tuberculosis; Sphingosine; Time Factors; Treatment Outcome; Tuberculosis, Pulmonary

Although several cultured endothelial cell studies indicate that sphingosine-1-phosphate (S1P), via GTPase Rac1 activation, enhances endothelial barriers, very few in situ studies have been published. We aimed to further investigate the mechanisms whereby S1P modulates both baseline and increased permeability in intact microvessels.. We measured attenuation by S1P of platelet-activating factor (PAF)- or bradykinin (Bk)-induced hydraulic conductivity (L(p)) increase in mesenteric microvessels of anaesthetized rats. S1P alone (1-5 µM) attenuated by 70% the acute L(p) increase due to PAF or Bk. Immunofluorescence methods in the same vessels under identical experimental conditions showed that Bk or PAF stimulated the loss of peripheral endothelial cortactin and rearrangement of VE-cadherin and occludin. Our results are the first to show in intact vessels that S1P pre-treatment inhibited rearrangement of VE-cadherin and occludin induced by PAF or Bk and preserved peripheral cortactin. S1P (1-5 µM, 30 min) did not increase baseline L(p). However, 10 µM S1P (60 min) increased L(p) two-fold.. Our results conform to the hypothesis that S1P inhibits acute permeability increase in association with enhanced stabilization of peripheral endothelial adhesion proteins. These results support the idea that S1P can be useful to attenuate inflammation by enhancing endothelial adhesion through activation of Rac-dependent pathways.

Topics: Acute Disease; Animals; Antigens, CD; Bradykinin; Cadherins; Capillary Permeability; Cell Adhesion; Cells, Cultured; Cortactin; Endothelial Cells; Fluorescent Antibody Technique; Humans; Inflammation; Lysophospholipids; Male; Membrane Proteins; Mesentery; Microscopy, Confocal; Occludin; Platelet Activating Factor; rac GTP-Binding Proteins; Rats; Sphingosine; Time Factors; Venules

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

Excessive mechanical stress is a key component of ventilator-associated lung injury, resulting in profound vascular leak and an intense inflammatory response. To extend our in vitro observations concerning the barrier-protective effects of the lipid growth factor sphingosine 1-phosphate (Sph 1-P), we assessed the ability of Sph 1-P to prevent regional pulmonary edema accumulation in clinically relevant rodent and canine models of acute lung injury induced by combined intrabronchial endotoxin administration and high tidal volume mechanical ventilation. Intravenously delivered Sph 1-P significantly attenuated both alveolar and vascular barrier dysfunction while significantly reducing shunt formation associated with lung injury. Whole lung computed tomographic image analysis demonstrated the capability of Sph 1-P to abrogate significantly the accumulation of extravascular lung water evoked by 6-hour exposure to endotoxin. Axial density profiles and vertical density gradients localized the Sph 1-P response to transitional zones between aerated and consolidated lung regions. Together, these results indicate that Sph 1-P represents a novel therapeutic intervention for the prevention of pulmonary edema related to inflammatory injury and increased vascular permeability.

Topics: Acute Disease; Animals; Bronchoalveolar Lavage Fluid; Capillary Permeability; Disease Models, Animal; Dogs; Extravascular Lung Water; Female; Linear Models; Lung Injury; Lysophospholipids; Male; Mice; Mice, Inbred C57BL; Probability; Pulmonary Circulation; Pulmonary Edema; Respiration, Artificial; Respiratory Function Tests; Severity of Illness Index; Sphingosine; Tomography, X-Ray Computed