title: Acid sphingomyelinase mediates murine acute lung injury following transfusion of aged platelets.
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.
authors.affiliation: Keenan Research Centre for Biomedical Science, St. Michael's Hospital, Toronto, Ontario, Canada.|Departments of Anesthesia and Physiology, University of Toronto, and Department of Anesthesia and Pain Medicine Sickkids Hospital, Toronto, Ontario, Canada.
authors.forename: Mark J
authors.initials: MJ
authors.lastname: McVey
authors.affiliation: Keenan Research Centre for Biomedical Science, St. Michael's Hospital, Toronto, Ontario, Canada.
authors.forename: Michael
authors.initials: M
authors.lastname: Kim
authors.affiliation: Keenan Research Centre for Biomedical Science, St. Michael's Hospital, Toronto, Ontario, Canada.
authors.forename: Arata
authors.initials: A
authors.lastname: Tabuchi
authors.affiliation: Keenan Research Centre for Biomedical Science, St. Michael's Hospital, Toronto, Ontario, Canada.
authors.forename: Victoria
authors.initials: V
authors.lastname: Srbely
authors.affiliation: Institute of Nutritional Science, University of Potsdam, Potsdam, Germany.
authors.forename: Lukasz
authors.initials: L
authors.lastname: Japtok
authors.affiliation: Institute for Chemistry, Humboldt University, Berlin, Germany.
authors.forename: Christoph
authors.initials: C
authors.lastname: Arenz
authors.affiliation: Keenan Research Centre for Biomedical Science, St. Michael's Hospital, Toronto, Ontario, Canada.|Department of Surgery University of Toronto, Toronto, Ontario, Canada.
authors.forename: Ori
authors.initials: O
authors.lastname: Rotstein
authors.affiliation: Institute of Nutritional Science, University of Potsdam, Potsdam, Germany.
authors.forename: Burkhard
authors.initials: B
authors.lastname: Kleuser
authors.affiliation: Keenan Research Centre for Biomedical Science, St. Michael's Hospital, Toronto, Ontario, Canada.|Departments of Pharmacology, Medicine, and Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada.
authors.forename: John W
authors.initials: JW
authors.lastname: Semple
authors.affiliation: Keenan Research Centre for Biomedical Science, St. Michael's Hospital, Toronto, Ontario, Canada; kueblerw@smh.ca.|Department of Surgery University of Toronto, Toronto, Ontario, Canada.|Department of Physiology University of Toronto, Toronto, Ontario, Canada.|Institute of Physiology, Charité-Univcersitätsmedizin Berlin, Germany; and.|German Heart Institute, Berlin, Germany.
authors.forename: Wolfgang M
authors.initials: WM
authors.lastname: Kuebler
mesh_terms: D055371:Acute Lung Injury / Q000201:enzymology* / Q000209:etiology* / Q000473:pathology; D000818:Animals; D001792:Blood Platelets / Q000187:drug effects / Q000378:metabolism*; D016922:Cellular Senescence; D002518:Ceramides / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology; D017353:Gene Deletion; D006801:Humans; D007249:Inflammation / Q000473:pathology; D008070:Lipopolysaccharides / Q000494:pharmacology; D008264:Macrophages / Q000473:pathology; D008297:Male; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D017713:Platelet Transfusion / Q000009:adverse effects*; D013108:Sphingomyelin Phosphodiesterase / Q000037:antagonists & inhibitors / Q000172:deficiency / Q000378:metabolism*; D013997:Time Factors
chemical_list: D002518:Ceramides; D004791:Enzyme Inhibitors; D008070:Lipopolysaccharides; D013108:Sphingomyelin Phosphodiesterase
keywords: acid sphingomyelinase; ceramide; platelets; storage; transfusion-related acute lung injury