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  - Becker, Katrin Anne
A1  - Riethmueller, Joachim
A1  - Seitz, Aaron P.
A1  - Gardner, Aaron
A1  - Boudreau, Ryan
A1  - Kamler, Markus
A1  - Kleuser, Burkhard
A1  - Schuchman, Edward
A1  - Caldwell, Charles C.
A1  - Edwards, Michael J.
A1  - Grassme, Heike
A1  - Brodlie, Malcolm
A1  - Gulbins, Erich
T1  - Sphingolipids as targets for inhalation treatment of cystic fibrosis
JF  - Advanced drug delivery reviews
N2  - Studies over the past several years have demonstrated the important role of sphingolipids in cystic fibrosis (CF), chronic obstructive pulmonary disease and acute lung injury. Ceramide is increased in airway epithelial cells and alveolar macrophages of CF mice and humans, while sphingosine is dramatically decreased. This increase in ceramide results in chronic inflammation, increased death of epithelial cells, release of DNA into the bronchial lumen and thereby an impairment of mucociliary clearance; while the lack of sphingosine in airway epithelial cells causes high infection susceptibility in CF mice and possibly patients. The increase in ceramide mediates an ectopic expression of beta 1-integrins in the luminal membrane of CF epithelial cells, which results, via an unknown mechanism, in a down-regulation of acid ceramidase. It is predominantly this down-regulation of acid ceramidase that results in the imbalance of ceramide and sphingosine in CF cells. Correction of ceramide and sphingosine levels can be achieved by inhalation of functional acid sphingomyelinase inhibitors, recombinant acid ceramidase or by normalization of beta 1-integrin expression and subsequent re-expression of endogenous acid ceramidase. These treatments correct pulmonary inflammation and prevent or treat, respectively, acute and chronic pulmonary infections in CF mice with Staphylococcus aureus and mucoid or non-mucoid Pseudomonas aeruginosa. Inhalation of sphingosine corrects sphingosine levels only and seems to mainly act against the infection. Many antidepressants are functional inhibitors of the acid sphingomyelinase and were designed for systemic treatment of major depression. These drugs could be repurposed to treat CF by inhalation.
KW  - Ceramide
KW  - Acid sphingomyelinase
KW  - Cystic fibrosis
KW  - COPD
KW  - Inhalation
Y1  - 2018
U6  - https://doi.org/10.1016/j.addr.2018.04.015
SN  - 0169-409X
SN  - 1872-8294
VL  - 133
SP  - 66
EP  - 75
PB  - Elsevier
CY  - Amsterdam
ER  - 
TY  - JOUR
A1  - Gulbins, Anne
A1  - Schumacher, Fabian
A1  - Becker, Katrin Anne
A1  - Wilker, Barbara
A1  - Soddemann, Matthias
A1  - Boldrin, Francesco
A1  - Müller, Christian P.
A1  - Edwards, Michael J.
A1  - Goodman, Michael
A1  - Caldwell, Charles C.
A1  - Kleuser, Burkhard
A1  - Kornhuber, Johannes
A1  - Szabo, Ildiko
A1  - Gulbins, Erich
T1  - Antidepressants act by inducing autophagy controlled by sphingomyelin-ceramide
JF  - Molecular psychiatry
N2  - Major depressive disorder (MDD) is a common and severe disease characterized by mood changes, somatic alterations, and often suicide. MDD is treated with antidepressants, but the molecular mechanism of their action is unknown. We found that widely used antidepressants such as amitriptyline and fluoxetine induce autophagy in hippocampal neurons via the slow accumulation of sphingomyelin in lysosomes and Golgi membranes and of ceramide in the endoplasmic reticulum (ER). ER ceramide stimulates phosphatase 2A and thereby the autophagy proteins Ulk, Beclin, Vps34/Phosphatidylinositol 3-kinase, p62, and Lc3B. Although treatment with amitriptyline or fluoxetine requires at least 12 days to achieve sphingomyelin accumulation and the subsequent biochemical and cellular changes, direct inhibition of sphingomyelin synthases with tricyclodecan-9-yl-xanthogenate (D609) results in rapid (within 3 days) accumulation of ceramide in the ER, activation of autophagy, and reversal of biochemical and behavioral signs of stress-induced MDD. Inhibition of Beclin blocks the antidepressive effects of amitriptyline and D609 and induces cellular and behavioral changes typical of MDD. These findings identify sphingolipid-controlled autophagy as an important target for antidepressive treatment methods and provide a rationale for the development of novel antidepressants that act within a few days.
Y1  - 2018
U6  - https://doi.org/10.1038/s41380-018-0090-9
SN  - 1359-4184
SN  - 1476-5578
VL  - 23
IS  - 12
SP  - 2324
EP  - 2346
PB  - Nature Publ. Group
CY  - London
ER  - 
TY  - GEN
A1  - Beckmann, Nadine
A1  - Becker, Katrin Anne
A1  - Kadow, Stephanie
A1  - Schumacher, Fabian
A1  - Kramer, Melanie
A1  - Kühn, Claudine
A1  - Schulz-Schaeffer, Walter J.
A1  - Edwards, Michael J.
A1  - Kleuser, Burkhard
A1  - Gulbins, Erich
A1  - Carpinteiro, Alexander
T1  - Acid sphingomyelinase deficiency ameliorates Farber disease
T2  - Postprints der Universität Potsdam : Mathematisch-Naturwissenschaftliche Reihe
N2  - Farber disease is a rare lysosomal storage disorder resulting from acid ceramidase deficiency and subsequent ceramide accumulation. No treatments for Farber disease are clinically available, and affected patients have a severely shortened lifespan. We have recently reported a novel acid ceramidase deficiency model that mirrors the human disease closely. Acid sphingomyelinase is the enzyme that generates ceramide upstream of acid ceramidase in the lysosomes. Using our acid ceramidase deficiency model, we tested if acid sphingomyelinase could be a potential novel therapeutic target for the treatment of Farber disease. A number of functional acid sphingomyelinase inhibitors are clinically available and have been used for decades to treat major depression. Using these as a therapeutic for Farber disease, thus, has the potential to improve central nervous symptoms of the disease as well, something all other treatment options for Farber disease can’t achieve so far. As a proof-of-concept study, we first cross-bred acid ceramidase deficient mice with acid sphingomyelinase deficient mice in order to prevent ceramide accumulation. Double-deficient mice had reduced ceramide accumulation, fewer disease manifestations, and prolonged survival. We next targeted acid sphingomyelinase pharmacologically, to test if these findings would translate to a setting with clinical applicability. Surprisingly, the treatment of acid ceramidase deficient mice with the acid sphingomyelinase inhibitor amitriptyline was toxic to acid ceramidase deficient mice and killed them within a few days of treatment. In conclusion, our study provides the first proof-of-concept that acid sphingomyelinase could be a potential new therapeutic target for Farber disease to reduce disease manifestations and prolong survival. However, we also identified previously unknown toxicity of the functional acid sphingomyelinase inhibitor amitriptyline in the context of Farber disease, strongly cautioning against the use of this substance class for Farber disease patients
T3  - Zweitveröffentlichungen der Universität Potsdam : Mathematisch-Naturwissenschaftliche Reihe - 1087 
KW  - Farber disease
KW  - lysosomal storage disorders
KW  - acid ceramidase
KW  - acid sphingomyelinase
KW  - amitriptyline
Y1  - 2021
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:kobv:517-opus4-441282
SN  - 1866-8372
IS  - 1087
ER  - 
TY  - JOUR
A1  - Seitz, Aaron P.
A1  - Schumacher, Fabian
A1  - Baker, Jennifer
A1  - Soddemann, Matthias
A1  - Wilker, Barbara
A1  - Caldwell, Charles C.
A1  - Gobble, Ryan M.
A1  - Kamler, Markus
A1  - Becker, Katrin Anne
A1  - Beck, Sascha
A1  - Kleuser, Burkhard
A1  - Edwards, Michael J.
A1  - Gulbins, Erich
T1  - Sphingosine-coating of plastic surfaces prevents ventilator-associated pneumonia
JF  - Journal of molecular medicine
N2  - Ventilator-associated pneumonia (VAP) is a major cause of morbidity and mortality in critically ill patients. Here, we employed the broad antibacterial effects of sphingosine to prevent VAP by developing a novel method of coating surfaces of endotracheal tubes with sphingosine and sphingosine analogs. Sphingosine and phytosphingosine coatings of endotracheal tubes prevent adherence and mediate killing of Pseudomonas aeruginosa, Acinetobacter baumannii, and Staphylococcus aureus, even in biofilms. Most importantly, sphingosine-coating of endotracheal tubes also prevented P. aeruginosa and S. aureus pneumonia in vivo. Coating of the tubes with sphingosine was stable, without obvious side effects on tracheal epithelial cells and did not induce inflammation. In summary, we describe a novel method to coat plastic surfaces and provide evidence for the application of sphingosine and phytosphingosine as novel antimicrobial coatings to prevent bacterial adherence and induce killing of pathogens on the surface of endotracheal tubes with potential to prevent biofilm formation and VAP.Key messagesNovel dip-coating method to coat plastic surfaces with lipids.Sphingosine and phytosphingosine as novel antimicrobial coatings on plastic surface.Sphingosine coatings of endotracheal tubes prevent bacterial adherence and biofilms.Sphingosine coatings of endotracheal tubes induce killing of pathogens.Sphingosine coatings of endotracheal tubes ventilator-associated pneumonia.
KW  - Coating
KW  - Plastic surfaces
KW  - Sphingosine
KW  - Ventilation
KW  - Acinetobacter baumannii
KW  - Pseudomonas aeruginosa
KW  - Staphylococcus aureus
Y1  - 2019
U6  - https://doi.org/10.1007/s00109-019-01800-1
SN  - 0946-2716
SN  - 1432-1440
VL  - 97
IS  - 8
SP  - 1195
EP  - 1211
PB  - Springer
CY  - Heidelberg
ER  - 
TY  - JOUR
A1  - Beckmann, Nadine
A1  - Becker, Katrin Anne
A1  - Kadow, Stephanie
A1  - Schumacher, Fabian
A1  - Kramer, Melanie
A1  - Kuehn, Claudine
A1  - Schulz-Schaeffer, Walter J.
A1  - Edwards, Michael J.
A1  - Kleuser, Burkhard
A1  - Gulbins, Erich
A1  - Carpinteiro, Alexander
T1  - Acid Sphingomyelinase Deficiency Ameliorates Farber Disease
JF  - International journal of molecular sciences
N2  - Farber disease is a rare lysosomal storage disorder resulting from acid ceramidase deficiency and subsequent ceramide accumulation. No treatments for Farber disease are clinically available, and affected patients have a severely shortened lifespan. We have recently reported a novel acid ceramidase deficiency model that mirrors the human disease closely. Acid sphingomyelinase is the enzyme that generates ceramide upstream of acid ceramidase in the lysosomes. Using our acid ceramidase deficiency model, we tested if acid sphingomyelinase could be a potential novel therapeutic target for the treatment of Farber disease. A number of functional acid sphingomyelinase inhibitors are clinically available and have been used for decades to treat major depression. Using these as a therapeutic for Farber disease, thus, has the potential to improve central nervous symptoms of the disease as well, something all other treatment options for Farber disease can’t achieve so far. As a proof-of-concept study, we first cross-bred acid ceramidase deficient mice with acid sphingomyelinase deficient mice in order to prevent ceramide accumulation. Double-deficient mice had reduced ceramide accumulation, fewer disease manifestations, and prolonged survival. We next targeted acid sphingomyelinase pharmacologically, to test if these findings would translate to a setting with clinical applicability. Surprisingly, the treatment of acid ceramidase deficient mice with the acid sphingomyelinase inhibitor amitriptyline was toxic to acid ceramidase deficient mice and killed them within a few days of treatment. In conclusion, our study provides the first proof-of-concept that acid sphingomyelinase could be a potential new therapeutic target for Farber disease to reduce disease manifestations and prolong survival. However, we also identified previously unknown toxicity of the functional acid sphingomyelinase inhibitor amitriptyline in the context of Farber disease, strongly cautioning against the use of this substance class for Farber disease patients.
KW  - Farber disease
KW  - lysosomal storage disorders
KW  - acid ceramidase
KW  - acid sphingomyelinase
KW  - amitriptyline
Y1  - 2019
U6  - https://doi.org/10.3390/ijms20246253
SN  - 1422-0067
VL  - 20
IS  - 24
PB  - MDPI
CY  - Basel
ER  - 
TY  - JOUR
A1  - Nojima, Hiroyuki
A1  - Freeman, Christopher M.
A1  - Schuster, Rebecca M.
A1  - Japtok, Lukasz
A1  - Kleuser, Burkhard
A1  - Edwards, Michael J.
A1  - Gulbins, Erich
A1  - Lentsch, Alex B.
T1  - Hepatocyte exosomes mediate liver repair and regeneration via sphingosine-1-phosphate
JF  - Journal of hepatology
N2  - Background & Aims: Exosomes are small membrane vesicles involved in intercellular communication. Hepatocytes are known to release exosomes, but little is known about their biological function. We sought to determine if exosomes derived from hepatocytes contribute to liver repair and regeneration after injury. Methods: Exosomes derived from primary murine hepatocytes were isolated and characterized biochemically and biophysically. Using cultures of primary hepatocytes, we tested whether hepatocyte exosomes induced proliferation of hepatocytes in vitro. Using models of ischemia/reperfusion injury and partial hepatectomy, we evaluated whether hepatocyte exosomes promote hepatocyte proliferation and liver regeneration in vivo. Results: Hepatocyte exosomes, but not exosomes from other liver cell types, induce dose-dependent hepatocyte proliferation in vitro and in vivo. Mechanistically, hepatocyte exosomes directly fuse with target hepatocytes and transfer neutral ceramidase and sphingosine kinase 2 (SK2) causing increased synthesis of sphingosine-1-phosphate (S1P) within target hepatocytes. Ablation of exosomal SK prevents the proliferative effect of exosomes. After ischemia/reperfusion injury, the number of circulating exosomes with proliferative effects increases. Conclusions: Our data shows that hepatocyte-derived exosomes deliver the synthetic machinery to form S1P in target hepatocytes resulting in cell proliferation and liver regeneration after ischemia/reperfusion injury or partial hepatectomy. These findings represent a potentially novel new contributing mechanism of liver regeneration and have important implications for new therapeutic approaches to acute and chronic liver disease. (C) 2015 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.
KW  - Liver injury
KW  - Sphingolipids
KW  - Sphingosine kinase
KW  - Ischemia/reperfusion
KW  - Transplantation
Y1  - 2016
U6  - https://doi.org/10.1016/j.jhep.2015.07.030
SN  - 0168-8278
SN  - 1600-0641
VL  - 64
SP  - 60
EP  - 68
PB  - Elsevier
CY  - Amsterdam
ER  - 
TY  - JOUR
A1  - Nojima, Hiroyuki
A1  - Konishi, Takanori
A1  - Freeman, Christopher M.
A1  - Schuster, Rebecca M.
A1  - Japtok, Lukasz
A1  - Kleuser, Burkhard
A1  - Edwards, Michael J.
A1  - Gulbins, Erich
A1  - Lentsch, Alex B.
T1  - Chemokine Receptors, CXCR1 and CXCR2, Differentially Regulate Exosome Release in Hepatocytes
JF  - PLoS one
N2  - Exosomes are small membrane vesicles released by different cell types, including hepatocytes, that play important roles in intercellular communication. We have previously demonstrated that hepatocyte-derived exosomes contain the synthetic machinery to form sphingosine-1-phosphate (S1P) in target hepatocytes resulting in proliferation and liver regeneration after ischemia/reperfusion (I/R) injury. We also demonstrated that the chemokine receptors, CXCR1 and CXCR2, regulate liver recovery and regeneration after I/R injury. In the current study, we sought to determine if the regulatory effects of CXCR1 and CXCR2 on liver recovery and regeneration might occur via altered release of hepatocyte exosomes. We found that hepatocyte release of exosomes was dependent upon CXCR1 and CXCR2. CXCR1-deficient hepatocytes produced fewer exosomes, whereas CXCR2-deficient hepatocytes produced more exosomes compared to their wild-type controls. In CXCR2-deficient hepatocytes, there was increased activity of neutral sphingomyelinase (Nsm) and intracellular ceramide. CXCR1-deficient hepatocytes had no alterations in Nsm activity or ceramide production. Interestingly, exosomes from CXCR1-deficient hepatocytes had no effect on hepatocyte proliferation, due to a lack of neutral ceramidase and sphingosine kinase. The data demonstrate that CXCR1 and CXCR2 regulate hepatocyte exosome release. The mechanism utilized by CXCR1 remains elusive, but CXCR2 appears to modulate Nsm activity and resultant production of ceramide to control exosome release. CXCR1 is required for packaging of enzymes into exosomes that mediate their hepatocyte proliferative effect.
Y1  - 2016
U6  - https://doi.org/10.1371/journal.pone.0161443
SN  - 1932-6203
VL  - 11
SP  - 6900
EP  - +
PB  - PLoS
CY  - San Fransisco
ER  - 
TY  - GEN
A1  - Nojima, Hiroyuki
A1  - Konishi, Takanori
A1  - Japtok, Lukasz
A1  - Kleuser, Burkhard
A1  - Edwards, Michael J.
A1  - Gulbins, Erich
A1  - Lentsch, Alex B.
T1  - Chemokine receptors, CXCR1 and CXCR2, differentially regulate exosome release in hepatocytes
T2  - Hepatology : official journal of the American Association for the Study of Liver Diseases
Y1  - 2016
SN  - 0270-9139
SN  - 1527-3350
VL  - 64
SP  - 165A
EP  - 165A
PB  - Wiley-Blackwell
CY  - Hoboken
ER  - 
TY  - GEN
A1  - Nojima, Hiroyuki
A1  - Konishi, Takanori
A1  - Freeman, Christopher M.
A1  - Schuster, Rebecca M.
A1  - Japtok, Lukasz
A1  - Kleuser, Burkhard
A1  - Edwards, Michael J.
A1  - Gulbins, Erich
A1  - Lentsch, Alex B.
T1  - Chemokine receptors, CXCR1 and CXCR2, differentially regulate exosome release in hepatocytes
T2  - Postprints der Universität Potsdam : Mathematisch-Naturwissenschaftliche Reihe
N2  - Exosomes are small membrane vesicles released by different cell types, including hepatocytes, that play important roles in intercellular communication. We have previously demonstrated that hepatocyte-derived exosomes contain the synthetic machinery to form sphingosine-1-phosphate (S1P) in target hepatocytes resulting in proliferation and liver regeneration after ischemia/reperfusion (I/R) injury. We also demonstrated that the chemokine receptors, CXCR1 and CXCR2, regulate liver recovery and regeneration after I/R injury. In the current study, we sought to determine if the regulatory effects of CXCR1 and CXCR2 on liver recovery and regeneration might occur via altered release of hepatocyte exosomes. We found that hepatocyte release of exosomes was dependent upon CXCR1 and CXCR2. CXCR1-deficient hepatocytes produced fewer exosomes, whereas CXCR2-deficient hepatocytes produced more exosomes compared to their wild-type controls. In CXCR2-deficient hepatocytes, there was increased activity of neutral sphingomyelinase (Nsm) and intracellular ceramide. CXCR1-deficient hepatocytes had no alterations in Nsm activity or ceramide production. Interestingly, exosomes from CXCR1-deficient hepatocytes had no effect on hepatocyte proliferation, due to a lack of neutral ceramidase and sphingosine kinase. The data demonstrate that CXCR1 and CXCR2 regulate hepatocyte exosome release. The mechanism utilized by CXCR1 remains elusive, but CXCR2 appears to modulate Nsm activity and resultant production of ceramide to control exosome release. CXCR1 is required for packaging of enzymes into exosomes that mediate their hepatocyte proliferative effect.
T3  - Zweitveröffentlichungen der Universität Potsdam : Mathematisch-Naturwissenschaftliche Reihe - 538 
KW  - hepatic ischemia-reperfusion
KW  - liver-regeneration
KW  - injury
KW  - ischemia/reperfusion
KW  - neutrophil
KW  - ceramide
KW  - homolog
KW  - mice
KW  - mechanisms
KW  - recovery
Y1  - 2019
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:kobv:517-opus4-410885
SN  - 1866-8372
IS  - 538
ER  - 
TY  - JOUR
A1  - Henry, Brian D.
A1  - Neill, Daniel R.
A1  - Becker, Katrin Anne
A1  - Gore, Suzanna
A1  - Bricio-Moreno, Laura
A1  - Ziobro, Regan
A1  - Edwards, Michael J.
A1  - Muehlemann, Kathrin
A1  - Steinmann, Joerg
A1  - Kleuser, Burkhard
A1  - Japtok, Lukasz
A1  - Luginbuehl, Miriam
A1  - Wolfmeier, Heidi
A1  - Scherag, Andre
A1  - Gulbins, Erich
A1  - Kadioglu, Aras
A1  - Draeger, Annette
A1  - Babiychuk, Eduard B.
T1  - Engineered liposomes sequester bacterial exotoxins and protect from severe invasive infections in mice
JF  - Nature biotechnology : the science and business of biotechnology
N2  - Gram-positive bacterial pathogens that secrete cytotoxic pore-forming toxins, such as Staphylococcus aureus and Streptococcus pneumoniae, cause a substantial burden of disease. Inspired by the principles that govern natural toxin-host interactions, we have engineered artificial liposomes that are tailored to effectively compete with host cells for toxin binding. Liposome-bound toxins are unable to lyse mammalian cells in vitro. We use these artificial liposomes as decoy targets to sequester bacterial toxins that are produced during active infection in vivo. Administration of artificial liposomes within 10 h after infection rescues mice from septicemia caused by S. aureus and S. pneumoniae, whereas untreated mice die within 24-33 h. Furthermore, liposomes protect mice against invasive pneumococcal pneumonia. Composed exclusively of naturally occurring lipids, tailored liposomes are not bactericidal and could be used therapeutically either alone or in conjunction with antibiotics to combat bacterial infections and to minimize toxin-induced tissue damage that occurs during bacterial clearance.
Y1  - 2015
U6  - https://doi.org/10.1038/nbt.3037
SN  - 1087-0156
SN  - 1546-1696
VL  - 33
IS  - 1
SP  - 81
EP  - U295
PB  - Nature Publ. Group
CY  - New York
ER  - 
TY  - JOUR
A1  - Carpinteiro, Alexander
A1  - Becker, Katrin Anne
A1  - Japtok, Lukasz
A1  - Hessler, Gabriele
A1  - Keitsch, Simone
A1  - Pozgajova, Miroslava
A1  - Schmid, Kurt W.
A1  - Adams, Constantin
A1  - Müller, Stefan
A1  - Kleuser, Burkhard
A1  - Edwards, Michael J.
A1  - Grassme, Heike
A1  - Helfrich, Iris
A1  - Gulbins, Erich
T1  - Regulation of hematogenous tumor metastasis by acid sphingomyelinase
JF  - EMBO molecular medicine
N2  - Metastatic dissemination of cancer cells is the ultimate hallmark of malignancy and accounts for approximately 90% of human cancer deaths. We investigated the role of acid sphingomyelinase (Asm) in the hematogenous metastasis of melanoma cells. Intravenous injection of B16F10 melanoma cells into wild-type mice resulted in multiple lung metastases, while Asm-deficient mice (Smpd1(-/-) mice) were protected from pulmonary tumor spread. Transplanting wild-type platelets into Asm-deficient mice reinstated tumor metastasis. Likewise, Asm-deficient mice were protected from hematogenous MT/ret melanoma metastasis to the spleen in a mouse model of spontaneous tumor metastasis. Human and mouse melanoma cells triggered activation and release of platelet secretory Asm, in turn leading to ceramide formation, clustering, and activation of 51 integrins on melanoma cells finally leading to adhesion of the tumor cells. Clustering of integrins by applying purified Asm or C-16 ceramide to B16F10 melanoma cells before intravenous injection restored trapping of tumor cells in the lung in Asm-deficient mice. This effect was revertable by arginine-glycine-aspartic acid peptides, which are known inhibitors of integrins, and by antibodies neutralizing 1 integrins. These findings indicate that melanoma cells employ platelet-derived Asm for adhesion and metastasis.
KW  - acid sphingomyelinase
KW  - ceramide
KW  - integrins
KW  - platelets
KW  - tumor-metastasis
Y1  - 2015
SN  - 1757-4676
SN  - 1757-4684
VL  - 7
IS  - 6
SP  - 714
EP  - 734
PB  - Wiley-Blackwell
CY  - Hoboken
ER  - 
TY  - JOUR
A1  - Pewzner-Jung, Yael
A1  - Tabazavareh, Shaghayegh Tavakoli
A1  - Grassme, Heike
A1  - Becker, Katrin Anne
A1  - Japtok, Lukasz
A1  - Steinmann, Joerg
A1  - Joseph, Tammar
A1  - Lang, Stephan
A1  - Tuemmler, Burkhard
A1  - Schuchman, Edward H.
A1  - Lentsch, Alex B.
A1  - Kleuser, Burkhard
A1  - Edwards, Michael J.
A1  - Futerman, Anthony H.
A1  - Gulbins, Erich
T1  - Sphingoid long chain bases prevent lung infection by Pseudomonas aeruginosa
JF  - EMBO molecular medicine
N2  - Cystic fibrosis patients and patients with chronic obstructive pulmonary disease, trauma, burn wound, or patients requiring ventilation are susceptible to severe pulmonary infection by Pseudomonas aeruginosa. Physiological innate defense mechanisms against this pathogen, and their alterations in lung diseases, are for the most part unknown. We now demonstrate a role for the sphingoid long chain base, sphingosine, in determining susceptibility to lung infection by P.aeruginosa. Tracheal and bronchial sphingosine levels were significantly reduced in tissues from cystic fibrosis patients and from cystic fibrosis mouse models due to reduced activity of acid ceramidase, which generates sphingosine from ceramide. Inhalation of mice with sphingosine, with a sphingosine analog, FTY720, or with acid ceramidase rescued susceptible mice from infection. Our data suggest that luminal sphingosine in tracheal and bronchial epithelial cells prevents pulmonary P.aeruginosa infection in normal individuals, paving the way for novel therapeutic paradigms based on inhalation of acid ceramidase or of sphingoid long chain bases in lung infection.
KW  - cystic fibrosis
KW  - long chain base
KW  - lung infection
KW  - Pseudomonas aeruginosa
KW  - sphingosine
Y1  - 2014
U6  - https://doi.org/10.15252/emmm.201404075
SN  - 1757-4676
SN  - 1757-4684
VL  - 6
IS  - 9
SP  - 1205
EP  - 1214
PB  - Wiley-Blackwell
CY  - Hoboken
ER  -