sphingosine-kinase and Acute-Lung-Injury

Cellular level of sphingosine-1-phosphate (S1P), the simplest bioactive sphingolipid, is tightly regulated by its synthesis catalyzed by sphingosine kinases (SphKs) 1 & 2 and degradation mediated by S1P phosphatases, lipid phosphate phosphatases, and S1P lyase. The pleotropic actions of S1P are attributed to its unique inside-out (extracellular) signaling via G-protein-coupled S1P1-5 receptors, and intracellular receptor independent signaling. Additionally, S1P generated in the nucleus by nuclear SphK2 modulates HDAC1/2 activity, regulates histone acetylation, and transcription of pro-inflammatory genes. Here, we present data on the role of S1P lyase mediated S1P signaling in regulating LPS-induced inflammation in lung endothelium. Blocking S1P lyase expression or activity attenuated LPS-induced histone acetylation and secretion of pro-inflammatory cytokines. Degradation of S1P by S1P lyase generates Δ2-hexadecenal and ethanolamine phosphate and the long-chain fatty aldehyde produced in the cytoplasmic compartment of the endothelial cell seems to modulate histone acetylation pattern, which is different from the nuclear SphK2/S1P signaling and inhibition of HDAC1/2. These in vitro studies suggest that S1P derived long-chain fatty aldehyde may be an epigenetic regulator of pro-inflammatory genes in sepsis-induced lung inflammation. Trapping fatty aldehydes and other short chain aldehydes such as 4-hydroxynonenal derived from S1P degradation and lipid peroxidation, respectively by cell permeable agents such as phloretin or other aldehyde trapping agents may be useful in treating sepsis-induced lung inflammation via modulation of histone acetylation. .

Topics: Acetylation; Acute Lung Injury; Aldehyde-Lyases; Aldehydes; Animals; Cytokines; Epigenesis, Genetic; Histone Deacetylase 1; Histone Deacetylase 2; Histones; Humans; Lipopolysaccharides; Lysophospholipids; Membrane Proteins; Mice; Phosphoric Monoester Hydrolases; Phosphotransferases (Alcohol Group Acceptor); Receptors, Lysosphingolipid; Signal Transduction; Sphingosine

Acute lung injury (ALI) attributable to sepsis or mechanical ventilation and subacute lung injury because of ionizing radiation (RILI) share profound increases in vascular permeability as a key element and a common pathway driving increased morbidity and mortality. Unfortunately, despite advances in the understanding of lung pathophysiology, specific therapies do not yet exist for the treatment of ALI or RILI, or for the alleviation of unremitting pulmonary leakage, which serves as a defining feature of the illness. A critical need exists for new mechanistic insights that can lead to novel strategies, biomarkers, and therapies to reduce lung injury. Sphingosine 1-phosphate (S1P) is a naturally occurring bioactive sphingolipid that acts extracellularly via its G protein-coupled S1P1-5 as well as intracellularly on various targets. S1P-mediated cellular responses are regulated by the synthesis of S1P, catalyzed by sphingosine kinases 1 and 2, and by the degradation of S1P mediated by lipid phosphate phosphatases, S1P phosphatases, and S1P lyase. We and others have demonstrated that S1P is a potent angiogenic factor that enhances lung endothelial cell integrity and an inhibitor of vascular permeability and alveolar flooding in preclinical animal models of ALI. In addition to S1P, S1P analogues such as 2-amino-2-(2-[4-octylphenyl]ethyl)-1,3-propanediol (FTY720), FTY720 phosphate, and FTY720 phosphonates offer therapeutic potential in murine models of lung injury. This translational review summarizes the roles of S1P, S1P analogues, S1P-metabolizing enzymes, and S1P receptors in the pathophysiology of lung injury, with particular emphasis on the development of potential novel biomarkers and S1P-based therapies for ALI and RILI.

Topics: Acute Lung Injury; Animals; Anti-Inflammatory Agents; Biomarkers; Capillary Permeability; Fingolimod Hydrochloride; Humans; Lung; Lysophospholipids; Membrane Proteins; Nerve Tissue Proteins; Phosphotransferases (Alcohol Group Acceptor); Pneumonia; Propylene Glycols; Receptors, Lysosphingolipid; Sepsis; Sphingosine; Transferases (Other Substituted Phosphate Groups); Translational Research, Biomedical

Acute lung injury (ALI) is a life-threatening clinical problem with high mortality rate and limited treatments or preventive options that represents a major challenge for clinicians. Diacerein (DIA) is a multi-target anthraquinone derivative with potent anti-inflammatory action. The aim of this study is to assess the protective effect of DIA and its potential molecular targets against lipopolysaccharide (LPS)-induced ALI in rats.. Adult male Sprague-Dawley rats were orally administrated DIA (50 mg/kg) for 5 consecutive days followed by a single intraperitoneal injection of LPS (5mg/kg).. DIA mitigated oxidative lung injury in LPS-challenged rats via significantly decreasing lung wet/dry (W/D) ratio, inflammatory cells infiltration, and lipid peroxidation, with concomitant elevation in enzymatic and non-enzymatic antioxidant levels in lung tissue. Likewise, DIA alleviated endoplasmic reticulum stress and markedly halted inflammation triggered by LPS challenge in pulmonary tissue by suppressing NLRP3/IL-1β and TLR4/NF-κB signaling with parallel decrease in proinflammatory cytokine levels. Interestingly, DIA down regulated Sphk1/S1P axis, reduced GSK-3β and STAT3 proteins expression, and markedly decreased caspase-3 besides increasing Bcl-2 levels in lung tissue of LPS-challenged animals. These biochemical findings was simultaneously associated with marked improvement in histological alterations of lung tissue.. These findings verify the protective effect of DIA against LPS-induced ALI through targeting oxidative stress, endoplasmic reticulum stress, and apoptosis. Importantly, DIA halted the hyperinflammatory state triggered by LPS via multi-faceted inhibitory effect on different signaling pathways, hence DIA could potentially reduce mortality in patients with ALI.

Topics: Acute Lung Injury; Animals; Anthraquinones; Anti-Inflammatory Agents; Antioxidants; Apoptosis; Caspase 3; Cytokines; Endoplasmic Reticulum Stress; Glycogen Synthase Kinase 3 beta; Lipopolysaccharides; Male; NF-kappa B; NLR Family, Pyrin Domain-Containing 3 Protein; Phosphotransferases (Alcohol Group Acceptor); Proprotein Convertases; Proto-Oncogene Proteins c-bcl-2; Rats; Rats, Sprague-Dawley; Serine Endopeptidases; Signal Transduction; Toll-Like Receptor 4

This study aimed to investigate the expression of sphingosine kinase 1 (SphK-1) and sphingosine 1-phosphate receptor 3 (S1PR-3) in a mouse model of malaria-associated acute lung injury/acute respiratory distress syndrome (ALI/ARDS). DBA/2 mice were infected with Plasmodium berghei ANKA to generate an experimental model of malaria-associated ALI/ARDS. The infected mice were divided into 2 groups based on the histopathological study of lung tissues: those with and those without ALI/ARDS. The expression of the SphK-1 and S1PR-3 proteins in the lung tissues was investigated using immunohistochemical staining and Western blot analysis. In addition, the S1P level was quantified in plasma and lung tissues using an enzyme-linked immunosorbent assay (ELISA). The results demonstrated that the cellular expression of the SphK-1 and S1PR-3 proteins was significantly upregulated in endothelial cells, alveolar epithelial cells and alveolar macrophages in the lung tissues of malaria-infected mice with ALI/ARDS compared with those in the control groups. The increased expression of the SphK-1 and S1PR-3 proteins was confirmed using Western blot analysis. The concentration of S1P in plasma and lung tissues was significantly decreased in malaria-infected mice with ALI/ARDS compared with non-ALI/ARDS and control mice. Furthermore, increased expression of the SphK-1 and S1PR-3 proteins significantly correlated with lung injury scores and S1P concentrations in malaria-infected mice with ALI/ARDS. These findings highlight increased expression of SphK-1 and S1PR-3 in the lung tissues of malaria-infected mice with ALI/ARDS.

Topics: Acute Lung Injury; Animals; Disease Models, Animal; Gene Expression Regulation, Enzymologic; Lung; Malaria; Male; Mice; Phosphotransferases (Alcohol Group Acceptor); Respiratory Distress Syndrome; Sphingosine-1-Phosphate Receptors

Severe pneumonia may evoke acute lung injury, and sphingosine-1-phosphate is involved in the regulation of vascular permeability and immune responses. However, the role of sphingosine-1-phosphate and the sphingosine-1-phosphate producing sphingosine kinase 1 in pneumonia remains elusive. We examined the role of the sphingosine-1-phosphate system in regulating pulmonary vascular barrier function in bacterial pneumonia.. Controlled, in vitro, ex vivo, and in vivo laboratory study.. Female wild-type and SphK1-deficient mice, 8-10 weeks old. Human postmortem lung tissue, human blood-derived macrophages, and pulmonary microvascular endothelial cells.. Wild-type and SphK1-deficient mice were infected with Streptococcus pneumoniae. Pulmonary sphingosine-1-phosphate levels, messenger RNA expression, and permeability as well as lung morphology were analyzed. Human blood-derived macrophages and human pulmonary microvascular endothelial cells were infected with S. pneumoniae. Transcellular electrical resistance of human pulmonary microvascular endothelial cell monolayers was examined. Further, permeability of murine isolated perfused lungs was determined following exposition to sphingosine-1-phosphate and pneumolysin.. Following S. pneumoniae infection, murine pulmonary sphingosine-1-phosphate levels and sphingosine kinase 1 and sphingosine-1-phosphate receptor 2 expression were increased. Pneumonia-induced lung hyperpermeability was reduced in SphK1 mice compared with wild-type mice. Expression of sphingosine kinase 1 in macrophages recruited to inflamed lung areas in pneumonia was observed in murine and human lungs. S. pneumoniae induced the sphingosine kinase 1/sphingosine-1-phosphate system in blood-derived macrophages and enhanced sphingosine-1-phosphate receptor 2 expression in human pulmonary microvascular endothelial cell in vitro. In isolated mouse lungs, pneumolysin-induced hyperpermeability was dose dependently and synergistically increased by sphingosine-1-phosphate. This sphingosine-1-phosphate-induced increase was reduced by inhibition of sphingosine-1-phosphate receptor 2 or its downstream effector Rho-kinase.. Our data suggest that targeting the sphingosine kinase 1-/sphingosine-1-phosphate-/sphingosine-1-phosphate receptor 2-signaling pathway in the lung may provide a novel therapeutic perspective in pneumococcal pneumonia for prevention of acute lung injury.

Topics: Acute Lung Injury; Animals; Female; Humans; Inflammation; Mice; Mice, Inbred C57BL; Phosphotransferases (Alcohol Group Acceptor); Pneumonia, Pneumococcal; Receptors, Lysosphingolipid; Sphingosine-1-Phosphate Receptors; Streptococcus pneumoniae

Sphingolipids, first described in the brain in 1884, are important structural components of biological membranes of all eukaryotic cells. In recent years, several lines of evidence support the critical role of sphingolipids such as sphingosine, sphingosine-1-phosphate (S1P), and ceramide as anti- or pro-inflammatory bioactive lipid mediators in a variety of human pathologies including pulmonary and vascular disorders. Among the sphingolipids, S1P is a naturally occurring agonist that exhibits potent barrier enhancing property in the endothelium by signaling via G protein-coupled S1P1 receptor. S1P, S1P analogs, and other barrier enhancing agents such as HGF, oxidized phospholipids, and statins also utilize the S1P/S1P1 signaling pathway to generate membrane protrusions or lamellipodia, which have been implicated in resealing of endothelial gaps and maintenance of barrier integrity. A better understanding of sphingolipids mediated regulation of lamellipodia formation and barrier enhancement of the endothelium will be critical for the development of sphingolipid-based therapies to alleviate pulmonary disorders such as sepsis-, radiation-, and mechanical ventilation-induced acute lung injury.

Topics: Acute Lung Injury; Endothelium, Vascular; Humans; Lysophospholipids; Phosphotransferases (Alcohol Group Acceptor); Pseudopodia; Reactive Oxygen Species; Signal Transduction; Simvastatin; Sphingolipids; Sphingosine

Acute lung injury (ALI) is a severe inflammatory disease for which no specific treatment exists. As glucocorticoids have potent immunosuppressive effects, their application in ALI is currently being tested in clinical trials. However, the benefits of this type of regimen remain unclear. Here we identify a mechanism of glucocorticoid action that challenges the long-standing dogma of cytokine repression by the glucocorticoid receptor. Contrarily, synergistic gene induction of sphingosine kinase 1 (SphK1) by glucocorticoids and pro-inflammatory stimuli via the glucocorticoid receptor in macrophages increases circulating sphingosine 1-phosphate levels, which proves essential for the inhibition of inflammation. Chemical or genetic inhibition of SphK1 abrogates the therapeutic effects of glucocorticoids. Inflammatory p38 MAPK- and mitogen- and stress-activated protein kinase 1 (MSK1)-dependent pathways cooperate with glucocorticoids to upregulate SphK1 expression. Our findings support a critical role for SphK1 induction in the suppression of lung inflammation by glucocorticoids, and therefore provide rationales for effective anti-inflammatory therapies.

Topics: Acute Lung Injury; Animals; Chromatin Immunoprecipitation; Cytokines; Flow Cytometry; Gene Expression Regulation; Glucocorticoids; Inflammation; Lysophospholipids; Macrophages; Mice; p38 Mitogen-Activated Protein Kinases; Phosphotransferases (Alcohol Group Acceptor); Real-Time Polymerase Chain Reaction; Receptors, Glucocorticoid; Ribosomal Protein S6 Kinases, 90-kDa; Sphingosine; Transcriptional Activation; Up-Regulation