TY - JOUR A1 - Hoehn, Richard S. A1 - Jernigan, Peter L. A1 - Japtok, Lukasz A1 - Chang, Alex L. A1 - Midura, Emily F. A1 - Caldwell, Charles C. A1 - Kleuser, Burkhard A1 - Lentsch, Alex B. A1 - Edwards, Michael J. A1 - Gulbins, Erich A1 - Pritts, Timothy A. T1 - Acid sphingomyelinase inhibition in stored erythrocytes reduces transfusion-associated lung inflammation JF - Annals of surgery : a monthly review of surgical science and practice N2 - Objective: We aimed to identify the role of the enzyme acid sphingomyelinase in the aging of stored units of packed red blood cells (pRBCs) and subsequent lung inflammation after transfusion. Summary Background Data: Large volume pRBC transfusions are associated with multiple adverse clinical sequelae, including lung inflammation. Microparticles are formed in stored pRBCs over time and have been shown to contribute to lung inflammation after transfusion. Methods: Human and murine pRBCs were stored with or without amitriptyline, a functional inhibitor of acid sphingomyelinase, or obtained from acid sphingomyelinase-deficient mice, and lung inflammation was studied in mice receiving transfusions of pRBCs and microparticles isolated from these units. Results: Acid sphingomyelinase activity in pRBCs was associated with the formation of ceramide and the release of microparticles. Treatment of pRBCs with amitriptyline inhibited acid sphingomyelinase activity, ceramide accumulation, and microparticle production during pRBC storage. Transfusion of aged pRBCs or microparticles isolated from aged blood into mice caused lung inflammation. This was attenuated after transfusion of pRBCs treated with amitriptyline or from acid sphingomyelinase-deficient mice. Conclusions: Acid sphingomyelinase inhibition in stored pRBCs offers a novel mechanism for improving the quality of stored blood. KW - acid sphingomyelinase KW - blood banking KW - ceramide KW - lung inflammation KW - microparticle Y1 - 2017 U6 - https://doi.org/10.1097/SLA.0000000000001648 SN - 0003-4932 SN - 1528-1140 VL - 265 IS - 1 SP - 218 EP - 226 PB - Lippincott Williams & Wilkins CY - Philadelphia ER - TY - JOUR A1 - McVey, Mark J. A1 - Kim, Michael A1 - Tabuchi, Arata A1 - Srbely, Victoria A1 - Japtok, Lukasz A1 - Arenz, Christoph A1 - Rotstein, Ori A1 - Kleuser, Burkhard A1 - Semple, John W. A1 - Kuebler, Wolfgang M. T1 - Acid sphingomyelinase mediates murine acute lung injury following transfusion of aged platelets JF - American journal of physiology : Lung cellular and molecular physiology N2 - Pulmonary complications from stored blood products are the leading cause of mortality related to transfusion. Transfusion-related acute lung injury is mediated by antibodies or bioactive mediators, yet underlying mechanisms are incompletely understood. Sphingolipids such as ceramide regulate lung injury, and their composition changes as a function of time in stored blood. Here, we tested the hypothesis that aged platelets may induce lung injury via a sphingolipid-mediated mechanism. To assess this hypothesis, a two-hit mouse model was devised. Recipient mice were treated with 2 mg/kg intraperitoneal lipopolysaccharide (priming) 2 h before transfusion of 10 ml/kg stored (1-5 days) platelets treated with or without addition of acid sphingomyelinase inhibitor ARC39 or platelets from acid sphingomyelinase-deficient mice, which both reduce ceramide formation. Transfused mice were examined for signs of pulmonary neutrophil accumulation, endothelial barrier dysfunction, and histological evidence of lung injury. Sphingolipid profiles in stored platelets were analyzed by mass spectrophotometry. Transfusion of aged platelets into primed mice induced characteristic features of lung injury, which increased in severity as a function of storage time. Ceramide accumulated in platelets during storage, but this was attenuated by ARC39 or in acid sphingomyelinase-deficient platelets. Compared with wild-type platelets, transfusion of ARC39-treated or acid sphingomyelinase-deficient aged platelets alleviated lung injury. Aged platelets elicit lung injury in primed recipient mice, which can be alleviated by pharmacological inhibition or genetic deletion of acid sphingomyelinase. Interventions targeting sphingolipid formation represent a promising strategy to increase the safety and longevity of stored blood products. KW - transfusion-related acute lung injury KW - ceramide KW - acid sphingomyelinase KW - platelets KW - storage Y1 - 2017 U6 - https://doi.org/10.1152/ajplung.00317.2016 SN - 1040-0605 SN - 1522-1504 VL - 312 IS - 5 SP - 625 EP - 637 PB - American Physiological Society CY - Bethesda ER - TY - JOUR A1 - Folkesson, Maggie A1 - Vorkapic, Emina A1 - Gulbins, Erich A1 - Japtok, Lukasz A1 - Kleuser, Burkhard A1 - Welander, Martin A1 - Länne, Toste A1 - Wågsäter, Dick T1 - Inflammatory cells, ceramides, and expression of proteases in perivascular adipose tissue adjacent to human abdominal aortic aneurysms JF - Journal of vascular surgery N2 - Background: Abdominal aortic aneurysm (AAA) is a deadly irreversible weakening and distension of the abdominal aortic wall. The pathogenesis of AAA remains poorly understood. Investigation into the physical and molecular characteristics of perivascular adipose tissue (PVAT) adjacent to AAA has not been done before and is the purpose of this study. Methods and Results: Human aortae, periaortic PVAT, and fat surrounding peripheral arteries were collected from patients undergoing elective surgical repair of AAA. Control aortas were obtained from recently deceased healthy organ donors with no known arterial disease. Aorta and PVAT was found in AAA to larger extent compared with control aortas. Immunohistochemistry revealed neutrophils, macrophages, mast cells, and T-cells surrounding necrotic adipocytes. Gene expression analysis showed that neutrophils, mast cells, and T-cells were found to be increased in PVAT compared with AAA as well as cathepsin K and S. The concentration of ceramides in PVAT was determined using mass spectrometry and correlated with content of T-cells in the PVAT. Conclusions: Our results suggest a role for abnormal necrotic, inflamed, proteolytic adipose tissue to the adjacent aneurysmal aortic wall in ongoing vascular damage. Y1 - 2016 U6 - https://doi.org/10.1016/j.jvs.2015.12.056 SN - 0741-5214 VL - 65 IS - 4 SP - 1171 EP - 1179 PB - Elsevier CY - New York ER - TY - JOUR A1 - Fayyaz, Susann A1 - Japtok, Lukasz A1 - Schumacher, Fabian A1 - Wigger, Dominik A1 - Schulz, Tim Julius A1 - Haubold, Kathrin A1 - Gulbins, Erich A1 - Völler, Heinz A1 - Kleuser, Burkhard T1 - Lysophosphatidic acid inhibits insulin signaling in primary rat hepatocytes via the LPA(3) receptor subtype and is increased in obesity JF - Cellular physiology and biochemistry : international journal of experimental cellular physiology, biochemistry and pharmacology N2 - Background/Aims: Obesity is a main risk factor for the development of hepatic insulin resistance and it is accompanied by adipocyte hypertrophy and an elevated expression of different adipokines such as autotaxin (ATX). ATX converts lysophosphatidylcholine to lysophosphatidic acid (LPA) and acts as the main producer of extracellular LPA. This bioactive lipid regulates a broad range of physiological and pathological responses by activation of LPA receptors (LPA1-6). Methods: The activation of phosphatidylinositide 3-kinases (PI3K) signaling (Akt and GSK-3ß) was analyzed via western blotting in primary rat hepatocytes. Incorporation of glucose into glycogen was measured by using radio labeled glucose. Real-time PCR analysis and pharmacological modulation of LPA receptors were performed. Human plasma LPA levels of obese (BMI > 30, n = 18) and normal weight individuals (BMI 18.5-25, n = 14) were analyzed by liquid chromatography tandem-mass spectrometry (LC-MS/MS). Results: Pretreatment of primary hepatocytes with LPA resulted in an inhibition of insulin-mediated Gck expression, PI3K activation and glycogen synthesis. Pharmacological approaches revealed that the LPA3-receptor subtype is responsible for the inhibitory effect of LPA on insulin signaling. Moreover, human plasma LPA concentrations (16: 0 LPA) of obese participants (BMI > 30) are significantly elevated in comparison to normal weight individuals (BMI 18.5-25). Conclusion: LPA is able to interrupt insulin signaling in primary rat hepatocytes via the LPA3 receptor subtype. Moreover, the bioactive lipid LPA (16: 0) is increased in obesity. KW - Lysophosphatidic acid KW - Insulin signaling KW - Adipose tissue KW - Autotaxin KW - Hepatic insulin resistance KW - LPA(3) receptor subtype Y1 - 2017 U6 - https://doi.org/10.1159/000480470 SN - 1015-8987 SN - 1421-9778 VL - 43 SP - 445 EP - 456 PB - Karger CY - Basel ER - TY - JOUR A1 - Schwiebs, Anja A1 - Thomas, Dominique Jeanette A1 - Kleuser, Burkhard A1 - Pfeilschifter, Josef A1 - Radeke, Heinfried H. T1 - Nuclear translocation of SGPP-1 and decrease of SGPL-1 activity contribute to sphingolipid rheostat regulation of inflammatory dendritic cells JF - Mediators of inflammation N2 - A balanced sphingolipid rheostat is indispensable for dendritic cell function and survival and thus initiation of an immune response. Sphingolipid levels are dynamically maintained by the action of sphingolipid enzymes of which sphingosine kinases, S1P phosphatases (SGPP-1/2) and S1P lyase (SGPL-1), are pivotal in the balance of S1P and sphingosine levels. In this study, we present that SGPP-1 and SGPL-1 are regulated in inflammatory dendritic cells and contribute to S1P fate. TLR-dependent activation caused SGPL-1 protein downregulation with subsequent decrease of enzymatic activity by two-thirds. In parallel, confocal fluorescence microscopy revealed that endogenous SGPP-1 was expressed in nuclei of naive dendritic cells and was translocated into the cytoplasmatic compartment upon inflammatory stimulation resulting in dephosphorylation of S1P. Mass spectrometric determination showed that a part of the resulting sphingosine was released from the cell, increasing extracellular levels. Another route of diminishing intracellular S1P was possibly taken by its export via ATP-binding cassette transporter C1 which was upregulated in array analysis, while the S1P transporter, spinster homolog 2, was not relevant in dendritic cells. These investigations newly describe the sequential expression and localization of the endogenous S1P regulators SGPP-1 and SGPL-1 and highlight their contribution to the sphingolipid rheostat in inflammation. Y1 - 2017 U6 - https://doi.org/10.1155/2017/5187368 SN - 0962-9351 SN - 1466-1861 PB - Hindawi Publishing Corp. CY - London ER - TY - GEN A1 - Prüfer, Nicole A1 - Kleuser, Burkhard A1 - van der Giet, Markus T1 - The role of serum amyloid A and sphingosine-1-phosphate on high-density lipoprotein functionality N2 - The high-density lipoprotein (HDL) is one of the most important endogenous cardiovascular protective markers. HDL is an attractive target in the search for new pharmaceutical therapies and in the prevention of cardiovascular events. Some of HDL’s anti-atherogenic properties are related to the signaling molecule sphingosine-1-phosphate (S1P), which plays an important role in vascular homeostasis. However, for different patient populations it seems more complicated. Significant changes in HDL’s protective potency are reduced under pathologic conditions and HDL might even serve as a proatherogenic particle. Under uremic conditions especially there is a change in the compounds associated with HDL. S1P is reduced and acute phase proteins such as serum amyloid A (SAA) are found to be elevated in HDL. The conversion of HDL in inflammation changes the functional properties of HDL. High amounts of SAA are associated with the occurrence of cardiovascular diseases such as atherosclerosis. SAA has potent pro-atherogenic properties, which may have impact on HDL’s biological functions, including cholesterol efflux capacity, antioxidative and anti-inflammatory activities. This review focuses on two molecules that affect the functionality of HDL. The balance between functional and dysfunctional HDL is disturbed after the loss of the protective sphingolipid molecule S1P and the accumulation of the acute-phase protein SAA. This review also summarizes the biological activities of lipid-free and lipid-bound SAA and its impact on HDL function. T3 - Zweitveröffentlichungen der Universität Potsdam : Mathematisch-Naturwissenschaftliche Reihe - 340 KW - atherosclerosis KW - high-density lipoprotein (HDL) KW - inflammation KW - serum amyloid A (SAA) KW - sphingosine-1-phosphate (S1P) Y1 - 2017 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:kobv:517-opus4-398648 ER -