sphingosine-1-phosphate and Respiratory-Distress-Syndrome

Hypoxia, or lack of oxygen, can occur in both physiological (high altitude) and pathological conditions (respiratory diseases). In this narrative review, we introduce high altitude pulmonary edema (HAPE), acute respiratory distress syndrome (ARDS), Chronic Obstructive Pulmonary Disease (COPD), and Cystic Fibrosis (CF) as examples of maladaptation to hypoxia, and highlight some of the potential mechanisms influencing the prognosis of the affected patients. Among the specific pathways modulated in response to hypoxia, iron metabolism has been widely explored in recent years. Recent evidence emphasizes hepcidin as highly involved in the compensatory response to hypoxia in healthy subjects. A less investigated field in the adaptation to hypoxia is the sphingolipid (SPL) metabolism, especially through Ceramide and sphingosine 1 phosphate. Both individually and in concert, iron and SPL are active players of the (mal)adaptation to physiological hypoxia, which can result in the pathological HAPE. Our aim is to identify some pathways and/or markers involved in the physiological adaptation to low atmospheric pressures (high altitudes) that could be involved in pathological adaptation to hypoxia as it occurs in pulmonary inflammatory diseases. Hepcidin, Cer, S1P, and their interplay in hypoxia are raising growing interest both as prognostic factors and therapeutical targets.

Topics: Adaptation, Physiological; Altitude Sickness; Ceramides; Cystic Fibrosis; Hepcidins; Humans; Hypertension, Pulmonary; Hypoxia; Iron; Lysophospholipids; Pulmonary Disease, Chronic Obstructive; Respiratory Distress Syndrome; Sphingolipids; Sphingosine

Acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) represent a spectrum of diseases that are commonly encountered in the intensive care unit and are associated with high mortality. Although significant advances have been made with respect to the ventilatory management of patients with ALI/ARDS with proven beneficial effects on outcomes, pharmacologic therapies remain nonexistent. Because the cardinal feature of ALI/ARDS is an increase in lung vascular permeability, often precipitated by an exuberant inflammatory response with subsequent endothelial barrier disruption, strategies aimed at promoting endothelial barrier function could serve as novel therapies in this setting. We have identified several promising agonists in this regard including sphingosine 1-phosphate, activated protein C, and statins, a class of 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors. These agonists all have in common the ability to directly mediate endothelial cell signaling and induce characteristic actin cytoskeletal rearrangement leading to endothelial cell barrier protection. Our in vitro findings have been extended to animal models of ALI/ARDS and suggest that effective pharmacologic therapies for patients with ALI/ARDS may soon be available.

Topics: Acute Lung Injury; Animals; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Lysophospholipids; Pharmaceutical Preparations; Protein C; Respiratory Distress Syndrome; Signal Transduction; Sphingosine

Sphingosine 1-phosphate (S1P), a biologically active lipid growth factor, induces robust endothelial cell activation resulting in cellular locomotion, vascular maturation and angiogenesis. Recent work by our laboratory has demonstrated S1P to enhance the cellular barrier function of the vascular endothelium. S1P-induced modulation of vascular permeability is effected through profound cytoskeletal reorganization initiated by cell surface receptor-mediated G protein activation and downstream signaling via the Rho family of small GTPases. The details of the downstream signaling mechanism remain an active area of in vitro investigation. Translational investigation suggests a profound impact of S1P administration in the modulation of edema formation in disease state manifest as acute inflammatory lung injury in which increased vascular permeability is a hallmark feature. These data support an exciting potential therapeutic role for S1P in vascular barrier enhancement necessary for the treatment of critically ill patients.

Topics: Adherens Junctions; Angiogenesis Inducing Agents; Animals; Anti-Inflammatory Agents; Capillary Permeability; Cytoskeleton; Endothelium, Vascular; Extracellular Matrix; Focal Adhesions; Humans; Lysophospholipids; Models, Biological; rac GTP-Binding Proteins; Respiratory Distress Syndrome; Signal Transduction; Sphingosine

Sphingosine-1-phosphate (S1P) is a signaling phospholipid involved in pathophysiologic progression of acute respiratory distress syndrome (ARDS) through its roles in endothelial barrier function and immune modulation. We hypothesized that decreased serum S1P level is associated with the clinical outcomes of ARDS and polymorphisms in the S1P gene are associated with serum S1P levels.. This multicenter prospective study includes ARDS patients and healthy blood donors as controls. Serum S1P levels were quantified using enzyme-linked immunosorbent assays. Eight tag single nucleotide polymorphisms (SNPs) in the S1P gene were detected, and their associations with S1P levels were evaluated.. A total of 121 ARDS patients and 100 healthy individuals were enrolled. Serum S1P levels were lower in ARDS patients than in controls (P < 0.001). Decreased S1P levels correlated with more organ dysfunction and higher Acute Physiology and Chronic Health Evaluation II scores. Changes in S1P levels in ARDS patients were associated with the clinical outcomes. The recessive model for SNP rs3743631 suggests that GG homozygote is associate with a higher risk for ARDS. The dominant model for SNP rs907045 suggests that AA or TA genotype might increase the risk for ARDS. In ARDS patients, the rs3743631 GG genotype showed lower S1P levels than those harboring AG and AA genotypes. The serum S1P levels of rs907045 AA or TA genotype patients were lower than those of TT genotype.. Serum S1P levels are dramatically decreased in ARDS patients. Reduced S1P levels are associated with worse clinical outcomes. There is a significant association between S1P rs3743631, rs907045 polymorphisms and susceptibility of ARDS.

Topics: Humans; Lysophospholipids; Prospective Studies; Respiratory Distress Syndrome; Sphingosine

The genetic mechanisms underlying the susceptibility to acute respiratory distress syndrome (ARDS) are poorly understood. We previously demonstrated that sphingosine 1-phosphate (S1P) and the S1P receptor S1PR3 are intimately involved in lung inflammatory responses and vascular barrier regulation. Furthermore, plasma S1PR3 protein levels were shown to serve as a biomarker of severity in critically ill ARDS patients. This study explores the contribution of single nucleotide polymorphisms (SNPs) of the S1PR3 gene to sepsis-associated ARDS. S1PR3 SNPs were identified by sequencing the entire gene and tagging SNPs selected for case-control association analysis in African- and ED samples from Chicago, with independent replication in a European case-control study of Spanish individuals. Electrophoretic mobility shift assays, luciferase activity assays, and protein immunoassays were utilized to assess the functionality of associated SNPs. A total of 80 variants, including 29 novel SNPs, were identified. Because of limited sample size, conclusive findings could not be drawn in African-descent ARDS subjects; however, significant associations were found for two promoter SNPs (rs7022797 -1899T/G; rs11137480 -1785G/C), across two ED samples supporting the association of alleles -1899G and -1785C with decreased risk for sepsis-associated ARDS. In addition, these alleles significantly reduced transcription factor binding to the S1PR3 promoter; reduced S1PR3 promoter activity, a response particularly striking after TNF-α challenge; and were associated with lower plasma S1PR3 protein levels in ARDS patients. These highly functional studies support S1PR3 as a novel ARDS candidate gene and a potential target for individualized therapy.

Topics: Base Sequence; Biomarkers; Case-Control Studies; Electrophoretic Mobility Shift Assay; Female; Genetic Association Studies; Genetic Predisposition to Disease; Genotype; Humans; Lysophospholipids; Male; Middle Aged; Molecular Sequence Data; Polymorphism, Single Nucleotide; Promoter Regions, Genetic; Receptors, Lysosphingolipid; Respiratory Distress Syndrome; Sepsis; Sequence Analysis, DNA; Sphingosine; Sphingosine-1-Phosphate Receptors

Topics: Animals; Ceramides; Humans; Inflammation; Lung; Lysophospholipids; Mice; Platelet Activating Factor; Respiratory Distress Syndrome; Sphingomyelin Phosphodiesterase; Sphingosine; Tumor Necrosis Factor-alpha

Our prior in vitro studies indicate that sphingosine 1-phosphate (S1P), a phospholipid angiogenic factor, produces endothelial cell barrier enhancement through ligation of endothelial differentiation gene family receptors. We hypothesized that S1P may reduce the vascular leak associated with acute lung injury and found that S1P infusion produced a rapid and significant reduction in lung weight gain (more than 50%) in the isolated perfused murine lung. The effect of S1P was next assessed in a murine model of LPS-mediated microvascular permeability and inflammation with marked increases in parameters of lung injury at both 6 and 24 hours after intratracheal LPS. Each parameter assessed was significantly reduced by intravenous S1P (1 microM final) and in selected experiments by the S1P analogue FTY720 (0.1 mg/kg, intraperitoneally) delivered 1 hour after LPS. S1P produced an approximately 40-50% reduction in LPS-mediated extravasation of Evans blue dye albumin, bronchoalveolar lavage protein content, and lung tissue myeloperoxidase activity (reflecting phagocyte infiltration). Consistent with systemic barrier enhancement, S1P significantly decreased Evans blue dye albumin extravasation and myeloperoxidase content in renal tissues of LPS-treated mice. These studies indicate that S1P significantly decreases pulmonary/renal vascular leakage and inflammation in a murine model of LPS-mediated acute lung injury and may represent a novel therapeutic strategy for vascular barrier dysfunction.

Topics: Animals; Bronchoalveolar Lavage Fluid; Capillary Permeability; Disease Models, Animal; Endothelial Cells; Endotoxins; Fingolimod Hydrochloride; Immunosuppressive Agents; Kidney; Kidney Diseases; Lipopolysaccharides; Lung; Lysophospholipids; Male; Mice; Mice, Inbred C57BL; Neutrophils; Organ Size; Perfusion; Peroxidase; Pneumonia; Propylene Glycols; Respiratory Distress Syndrome; Sphingosine; Time Factors

Prolonged elevations of cytosolic calcium concentrations ([Ca2+]i) are required for optimal neutrophil (PMN) activation responses to G-Protein coupled chemoattractants. We recently showed that the coupling of endosomal Ca2+ store depletion to more prolonged entry of external Ca2+ depends on cellular conversion of sphingosine to sphingosine 1-phosphate (S1P) by sphingosine kinase (SK). We therefore hypothesized that inhibition of SK might inhibit PMN activation and thus ameliorate lung injury after trauma and hemorrhagic shock (T/HS).. Chemotaxis (CTX) of human PMN was studied using modified Boyden chambers in the presence or absence of the selective SK inhibitor, SKI-2. After determining the concentration of SKI-2 that inhibited human PMN CTX by 50% (IC50) we subjected rats to T/HS (laparotomy, hemorrhage to 30-40 mm Hg x 90 minutes, 3 hours resuscitation). We then studied rat PMN CD11b expression using flow cytometry and lung injury using the Evans Blue dye technique in the presence of IC50 doses of SKI-2 or vehicle given in pretreatment at laparotomy.. Human PMN CTX was suppressed slightly more than 50% by 40 micromol/L SKI-2 (233 +/- 20 vs 103 +/- 12 x 10(3) cells/well, p < 0.001). Rat PMN expression of CD11b after T/HS was decreased from 352 +/- 30 to 232 +/- 7 MFU (p < 0.001) in the presence 30 micromol/L SKI-2. Lung permeability to Evans Blue was decreased from 9.5 +/- 2 to 4.1 +/- 0.7% (p = 0.036.). SKI-2 did not cause hemodynamic instability or alter resuscitation requirements.. Modulation of PMN Ca entry via SK inhibition inhibits PMN CTX in vitro, and inhibits CD11b expression in vivo without major effects on hemodynamics. These cellular changes were associated with amelioration of lung injury in vivo in a rat model of T/HS. These findings suggest that SK inhibition allows modulation of inflammation via control of [Ca2+]i without the cardiovascular compromise expected with Ca2+ channel blockade. SK inhibition therefore appears to be an important novel candidate therapy for inflammatory organ injury after shock.

Topics: Animals; Calcium; Chemotaxis, Leukocyte; Disease Models, Animal; Humans; Inflammation; Lysophospholipids; Neutrophils; Phosphotransferases (Alcohol Group Acceptor); Rats; Rats, Sprague-Dawley; Receptors, G-Protein-Coupled; Respiratory Distress Syndrome; Shock, Hemorrhagic; Shock, Traumatic; Sphingosine