Platelet extracellular vesicles mediate transfusion-related acute lung injury by imbalancing the sphingolipid rheostat.
Platelet extracellular vesicles mediate transfusion-related acute lung injury by imbalancing the sphingolipid rheostat.
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DOI：
10.1182/blood.2020005985
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发表时间：
2021-02-04
期刊：
影响因子：
20.3
通讯作者：
Kuebler, Wolfgang M
中科院分区：
文献类型：
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作者：
McVey, Mark J;Weidenfeld, Sarah;Kuebler, Wolfgang M
输血相关急性肺损伤（TRALI）是一种危险的输血并发症，相关死亡率为5%至15%。我们以前的研究表明，储存（5天）而不是新鲜血小板（1天）通过神经酰胺介导的内皮屏障功能障碍引起TRALI。由于生物神经酰胺具有疏水性，因此可能需要细胞外囊泡（EV）将这些鞘脂从血小板运送到内皮细胞。更复杂的是，EV的形成反过来又需要神经酰胺。我们假设，从储存的血小板和EV依赖性鞘脂穿梭神经酰胺依赖性EV的形成诱导TRALI。对鼠血小板储存期间形成的EV进行计数，表征鞘脂，并应用于体内鼠TRALI模型和体外内皮屏障评估。与1天EV相比，5天EV更丰富，具有更高的长链神经酰胺（C16：0，C18：0，C20：0）和更低的鞘氨醇-1-磷酸（S1 P）含量。输注5天（而非1天）EV诱导体内肺损伤和体外内皮屏障破坏的特征性体征。抑制或补充神经酰胺形成鞘磷脂酶分别减少或增强EV的形成，但没有改变每个EV的伤害性。当EV富含或补充S1 P时，屏障失效减弱。储存人血小板4天的EV比2天的EV数量更多，含有更多的长链神经酰胺和更少的S1 P，并引起更多的内皮细胞屏障渗漏。因此，血小板衍生的EV在储存期间变得更多且更具伤害性（更多的长链神经酰胺，更少的S1 P）。在血小板储存期间阻断鞘磷脂酶、消除EV或补充S1 P可能是预防TRALI的有希望的策略。
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.