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Platelet extracellular vesicles mediate transfusion-related acute lung injury by imbalancing the sphingolipid rheostat

McVey, Mark J. ; Weidenfeld, Sarah ; Maishan, Mazharul ; Spring, Chris ; Kim, Michael ; Tabuchi, Arata ; Srbely, Victoria ; Takabe-French, Alisa ; Simmons, Szandor and Arenz, Christoph , et al. (2021) In Blood 137(5). p.690-701
Abstract

Transfusion-related acute lung injury (TRALI) is a hazardous transfusion complication with an associated mortality of 5% to 15%. We previously showed that stored (5 days) but not fresh platelets (1 day) cause TRALI via ceramide-mediated endothelial barrier dysfunction. As biological ceramides are hydrophobic, extracellular vesicles (EVs) may be required to shuttle these sphingolipids from platelets to endothelial cells. Adding to complexity, EV formation in turn requires ceramide. We hypothesized that ceramide-dependent EV formation from stored platelets and EV-dependent sphingolipid shuttling induces TRALI. EVs formed during storage of murine platelets were enumerated, characterized for sphingolipids, and applied in a murine TRALI... (More)

Transfusion-related acute lung injury (TRALI) is a hazardous transfusion complication with an associated mortality of 5% to 15%. We previously showed that stored (5 days) but not fresh platelets (1 day) cause TRALI via ceramide-mediated endothelial barrier dysfunction. As biological ceramides are hydrophobic, extracellular vesicles (EVs) may be required to shuttle these sphingolipids from platelets to endothelial cells. Adding to complexity, EV formation in turn requires ceramide. We hypothesized that ceramide-dependent EV formation from stored platelets and EV-dependent sphingolipid shuttling induces TRALI. EVs formed during storage of murine platelets were enumerated, characterized for sphingolipids, and applied in a murine TRALI model in vivo and for endothelial barrier assessment in vitro. Five-day EVs were more abundant, had higher long-chain ceramide (C16:0, C18:0, C20:0), and lower sphingosine-1-phosphate (S1P) content than 1-day EVs. Transfusion of 5-day, but not 1-day, EVs induced characteristic signs of lung injury in vivo and endothelial barrier disruption in vitro. Inhibition or supplementation of ceramide-forming sphingomyelinase reduced or enhanced the formation of EVs, respectively, but did not alter the injuriousness per individual EV. Barrier failure was attenuated when EVs were abundant in or supplemented with S1P. Stored human platelet 4-day EVs were more numerous compared with 2-day EVs, contained more long-chain ceramide and less S1P, and caused more endothelial cell barrier leak. Hence, platelet-derived EVs become more numerous and more injurious (more long-chain ceramide, less S1P) during storage. Blockade of sphingomyelinase, EV elimination, or supplementation of S1P during platelet storage may present promising strategies for TRALI prevention. Key Points: • EVs derived from stored platelets cause TRALI as a function of their elevated ceramide and decreased S1P content. • Inhibiting ceramide formation, supplementing S1P, or washing stored platelets could potentially reduce TRALI incidence and severity.

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published
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Blood
volume
137
issue
5
pages
12 pages
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American Society of Hematology
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  • pmid:33232973
  • scopus:85100385520
ISSN
0006-4971
DOI
10.1182/blood.2020005985
language
English
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Funding Information: This work was supported by a grant from the Canadian Blood Services (CBS) in partnership with the Canadian Institutes of Health Research (CIHR; CIHR-TRA201403-WK-325399) (W.M.K.) and a Health Canada/CBS Priority Grant (2013JS-N-317899) (J.W.S. and W.M.K.). M.J.M. was supported by a CIHR Vanier scholarship. Publisher Copyright: © 2021 American Society of Hematology Copyright: Copyright 2021 Elsevier B.V., All rights reserved.
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20d8fb60-7092-431e-8e99-537c859265d0
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2021-02-18 09:21:02
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2021-06-08 03:36:15
@article{20d8fb60-7092-431e-8e99-537c859265d0,
  abstract     = {<p>Transfusion-related acute lung injury (TRALI) is a hazardous transfusion complication with an associated mortality of 5% to 15%. We previously showed that stored (5 days) but not fresh platelets (1 day) cause TRALI via ceramide-mediated endothelial barrier dysfunction. As biological ceramides are hydrophobic, extracellular vesicles (EVs) may be required to shuttle these sphingolipids from platelets to endothelial cells. Adding to complexity, EV formation in turn requires ceramide. We hypothesized that ceramide-dependent EV formation from stored platelets and EV-dependent sphingolipid shuttling induces TRALI. EVs formed during storage of murine platelets were enumerated, characterized for sphingolipids, and applied in a murine TRALI model in vivo and for endothelial barrier assessment in vitro. Five-day EVs were more abundant, had higher long-chain ceramide (C16:0, C18:0, C20:0), and lower sphingosine-1-phosphate (S1P) content than 1-day EVs. Transfusion of 5-day, but not 1-day, EVs induced characteristic signs of lung injury in vivo and endothelial barrier disruption in vitro. Inhibition or supplementation of ceramide-forming sphingomyelinase reduced or enhanced the formation of EVs, respectively, but did not alter the injuriousness per individual EV. Barrier failure was attenuated when EVs were abundant in or supplemented with S1P. Stored human platelet 4-day EVs were more numerous compared with 2-day EVs, contained more long-chain ceramide and less S1P, and caused more endothelial cell barrier leak. Hence, platelet-derived EVs become more numerous and more injurious (more long-chain ceramide, less S1P) during storage. Blockade of sphingomyelinase, EV elimination, or supplementation of S1P during platelet storage may present promising strategies for TRALI prevention. Key Points: • EVs derived from stored platelets cause TRALI as a function of their elevated ceramide and decreased S1P content. • Inhibiting ceramide formation, supplementing S1P, or washing stored platelets could potentially reduce TRALI incidence and severity.</p>},
  author       = {McVey, Mark J. and Weidenfeld, Sarah and Maishan, Mazharul and Spring, Chris and Kim, Michael and Tabuchi, Arata and Srbely, Victoria and Takabe-French, Alisa and Simmons, Szandor and Arenz, Christoph and Semple, John W. and Kuebler, Wolfgang M.},
  issn         = {0006-4971},
  language     = {eng},
  number       = {5},
  pages        = {690--701},
  publisher    = {American Society of Hematology},
  series       = {Blood},
  title        = {Platelet extracellular vesicles mediate transfusion-related acute lung injury by imbalancing the sphingolipid rheostat},
  url          = {http://dx.doi.org/10.1182/blood.2020005985},
  doi          = {10.1182/blood.2020005985},
  volume       = {137},
  year         = {2021},
}