@article{HoehnJerniganJaptoketal.2017, author = {Hoehn, Richard S. and Jernigan, Peter L. and Japtok, Lukasz and Chang, Alex L. and Midura, Emily F. and Caldwell, Charles C. and Kleuser, Burkhard and Lentsch, Alex B. and Edwards, Michael J. and Gulbins, Erich and Pritts, Timothy A.}, title = {Acid sphingomyelinase inhibition in stored erythrocytes reduces transfusion-associated lung inflammation}, series = {Annals of surgery : a monthly review of surgical science and practice}, volume = {265}, journal = {Annals of surgery : a monthly review of surgical science and practice}, number = {1}, publisher = {Lippincott Williams \& Wilkins}, address = {Philadelphia}, issn = {0003-4932}, doi = {10.1097/SLA.0000000000001648}, pages = {218 -- 226}, year = {2017}, abstract = {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.}, language = {en} } @misc{NojimaKonishiFreemanetal.2016, author = {Nojima, Hiroyuki and Konishi, Takanori and Freeman, Christopher M. and Schuster, Rebecca M. and Japtok, Lukasz and Kleuser, Burkhard and Edwards, Michael J. and Gulbins, Erich and Lentsch, Alex B.}, title = {Chemokine receptors, CXCR1 and CXCR2, differentially regulate exosome release in hepatocytes}, series = {Postprints der Universit{\"a}t Potsdam : Mathematisch-Naturwissenschaftliche Reihe}, journal = {Postprints der Universit{\"a}t Potsdam : Mathematisch-Naturwissenschaftliche Reihe}, number = {538}, issn = {1866-8372}, doi = {10.25932/publishup-41088}, url = {http://nbn-resolving.de/urn:nbn:de:kobv:517-opus4-410885}, pages = {15}, year = {2016}, abstract = {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.}, language = {en} } @article{NojimaKonishiFreemanetal.2016, author = {Nojima, Hiroyuki and Konishi, Takanori and Freeman, Christopher M. and Schuster, Rebecca M. and Japtok, Lukasz and Kleuser, Burkhard and Edwards, Michael J. and Gulbins, Erich and Lentsch, Alex B.}, title = {Chemokine Receptors, CXCR1 and CXCR2, Differentially Regulate Exosome Release in Hepatocytes}, series = {PLoS one}, volume = {11}, journal = {PLoS one}, publisher = {PLoS}, address = {San Fransisco}, issn = {1932-6203}, doi = {10.1371/journal.pone.0161443}, pages = {6900 -- +}, year = {2016}, abstract = {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.}, language = {en} } @misc{NojimaKonishiJaptoketal.2016, author = {Nojima, Hiroyuki and Konishi, Takanori and Japtok, Lukasz and Kleuser, Burkhard and Edwards, Michael J. and Gulbins, Erich and Lentsch, Alex B.}, title = {Chemokine receptors, CXCR1 and CXCR2, differentially regulate exosome release in hepatocytes}, series = {Hepatology : official journal of the American Association for the Study of Liver Diseases}, volume = {64}, journal = {Hepatology : official journal of the American Association for the Study of Liver Diseases}, publisher = {Wiley-Blackwell}, address = {Hoboken}, issn = {0270-9139}, pages = {165A -- 165A}, year = {2016}, language = {en} } @article{NojimaFreemanSchusteretal.2016, author = {Nojima, Hiroyuki and Freeman, Christopher M. and Schuster, Rebecca M. and Japtok, Lukasz and Kleuser, Burkhard and Edwards, Michael J. and Gulbins, Erich and Lentsch, Alex B.}, title = {Hepatocyte exosomes mediate liver repair and regeneration via sphingosine-1-phosphate}, series = {Journal of hepatology}, volume = {64}, journal = {Journal of hepatology}, publisher = {Elsevier}, address = {Amsterdam}, issn = {0168-8278}, doi = {10.1016/j.jhep.2015.07.030}, pages = {60 -- 68}, year = {2016}, abstract = {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.}, language = {en} } @article{PewznerJungTabazavarehGrassmeetal.2014, author = {Pewzner-Jung, Yael and Tabazavareh, Shaghayegh Tavakoli and Grassme, Heike and Becker, Katrin Anne and Japtok, Lukasz and Steinmann, Joerg and Joseph, Tammar and Lang, Stephan and Tuemmler, Burkhard and Schuchman, Edward H. and Lentsch, Alex B. and Kleuser, Burkhard and Edwards, Michael J. and Futerman, Anthony H. and Gulbins, Erich}, title = {Sphingoid long chain bases prevent lung infection by Pseudomonas aeruginosa}, series = {EMBO molecular medicine}, volume = {6}, journal = {EMBO molecular medicine}, number = {9}, publisher = {Wiley-Blackwell}, address = {Hoboken}, issn = {1757-4676}, doi = {10.15252/emmm.201404075}, pages = {1205 -- 1214}, year = {2014}, abstract = {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.}, language = {en} }