Acid sphingomyelinase mediates murine acute lung injury following transfusion of aged platelets.

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  • Additional Information
    • Source:
      Publisher: American Physiological Society Country of Publication: United States NLM ID: 100901229 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1522-1504 (Electronic) Linking ISSN: 10400605 NLM ISO Abbreviation: Am J Physiol Lung Cell Mol Physiol Subsets: MEDLINE
    • Publication Information:
      Original Publication: Bethesda, MD : American Physiological Society, c1989-
    • Subject Terms:
      Cellular Senescence*; Acute Lung Injury/*enzymology ; Acute Lung Injury/*etiology ; Blood Platelets/*metabolism ; Platelet Transfusion/*adverse effects ; Sphingomyelin Phosphodiesterase/*metabolism; Acute Lung Injury/pathology ; Animals ; Blood Platelets/drug effects ; Ceramides/metabolism ; Enzyme Inhibitors/pharmacology ; Gene Deletion ; Humans ; Inflammation/pathology ; Lipopolysaccharides/pharmacology ; Macrophages/pathology ; Male ; Mice, Inbred BALB C ; Mice, Inbred C57BL ; Sphingomyelin Phosphodiesterase/antagonists & inhibitors ; Sphingomyelin Phosphodiesterase/deficiency ; Time Factors
    • 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.
      (Copyright © 2017 the American Physiological Society.)
    • Grant Information:
      Canada CIHR
    • Contributed Indexing:
      Keywords: acid sphingomyelinase; ceramide; platelets; storage; transfusion-related acute lung injury
    • Accession Number:
      0 (Ceramides)
      0 (Enzyme Inhibitors)
      0 (Lipopolysaccharides)
      EC 3.1.4.12 (Sphingomyelin Phosphodiesterase)
    • Publication Date:
      Date Created: 20170312 Date Completed: 20170731 Latest Revision: 20200930
    • Publication Date:
      20240829
    • Accession Number:
      10.1152/ajplung.00317.2016
    • Accession Number:
      28283474