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

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 shuttle these sphingolipids from cells. Adding complexity, EV formation in turn requires ceramide. hypothesized ceramide-dependent and EV-dependent sphingolipid shuttling induces TRALI. EVs formed during storage murine were enumerated, characterized for sphingolipids, applied model vivo assessment vitro. Five-day more abundant, had higher long-chain ceramide (C16:0, C18:0, C20:0), lower sphingosine-1-phosphate (S1P) content than 1-day EVs. Transfusion 5-day, 1-day, induced characteristic signs disruption Inhibition or supplementation ceramide-forming sphingomyelinase reduced enhanced the EVs, respectively, did alter injuriousness per individual EV. Barrier failure was attenuated when abundant supplemented S1P. Stored human platelet 4-day numerous compared 2-day contained less S1P, caused cell leak. Hence, platelet-derived become injurious (more ceramide, S1P) storage. Blockade sphingomyelinase, elimination, S1P present promising strategies prevention.