@article{McVeyKimTabuchietal.2017,
  author    = {McVey, Mark J. and Kim, Michael and Tabuchi, Arata and Srbely, Victoria and Japtok, Lukasz and Arenz, Christoph and Rotstein, Ori and Kleuser, Burkhard and Semple, John W. and Kuebler, Wolfgang M.},
  title     = {Acid sphingomyelinase mediates murine acute lung injury following transfusion of aged platelets},
  series = {American journal of physiology : Lung cellular and molecular physiology},
  volume    = {312},
  journal   = {American journal of physiology : Lung cellular and molecular physiology},
  number    = {5},
  publisher = {American Physiological Society},
  address   = {Bethesda},
  issn      = {1040-0605},
  doi       = {10.1152/ajplung.00317.2016},
  pages     = {625 -- 637},
  year      = {2017},
  abstract  = {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.},
  language  = {en}
}
@article{CarpinteiroBeckerJaptoketal.2015,
  author    = {Carpinteiro, Alexander and Becker, Katrin Anne and Japtok, Lukasz and Hessler, Gabriele and Keitsch, Simone and Pozgajova, Miroslava and Schmid, Kurt W. and Adams, Constantin and M{\"u}ller, Stefan and Kleuser, Burkhard and Edwards, Michael J. and Grassme, Heike and Helfrich, Iris and Gulbins, Erich},
  title     = {Regulation of hematogenous tumor metastasis by acid sphingomyelinase},
  series = {EMBO molecular medicine},
  volume    = {7},
  journal   = {EMBO molecular medicine},
  number    = {6},
  publisher = {Wiley-Blackwell},
  address   = {Hoboken},
  issn      = {1757-4676},
  pages     = {714 -- 734},
  year      = {2015},
  abstract  = {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.},
  language  = {en}
}