TY  - JOUR
A1  - McVey, Mark J.
A1  - Kim, Michael
A1  - Tabuchi, Arata
A1  - Srbely, Victoria
A1  - Japtok, Lukasz
A1  - Arenz, Christoph
A1  - Rotstein, Ori
A1  - Kleuser, Burkhard
A1  - Semple, John W.
A1  - Kuebler, Wolfgang M.
T1  - Acid sphingomyelinase mediates murine acute lung injury following transfusion of aged platelets
T2  - American journal of physiology : Lung cellular and molecular physiology
N2  - 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.
KW  - transfusion-related acute lung injury
KW  - ceramide
KW  - acid sphingomyelinase
KW  - platelets
KW  - storage
Y1  - 2017
UR  - https://publishup.uni-potsdam.de/frontdoor/index/index/docId/55080
SN  - 1040-0605
SN  - 1522-1504
VL  - 312
IS  - 5
SP  - 625
EP  - 637
PB  - American Physiological Society
CY  - Bethesda
ER  -