p38 mitogen-activated protein kinase activation during platelet storage: consequences for platelet recovery and hemostatic function in vivo
p38 mitogen-activated protein kinase activation during platelet storage: consequences for platelet recovery and hemostatic function in vivo
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DOI：
10.1182/blood-2009-03-211706
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发表时间：
2010-03-04
期刊：
影响因子：
20.3
通讯作者：
Wagner, Denisa D.
中科院分区：
文献类型：
--
作者：
Canault, Matthias;Duerschmied, Daniel;Wagner, Denisa D.
血小板在储存过程中经历了几次改变，降低了其输血后的存活率和功能。这些变化的一个重要特征是表面糖蛋白GPIb-α和GPV的脱落，称为血小板储存损伤。我们最近证明，肿瘤坏死因子-α转换酶（TACE/ADAM 17）介导的线粒体损伤诱导脱落的粘附受体和TACE活性与减少输血后这些细胞的生存。我们现在证实TACE介导受体脱落和在37 ℃或22 ℃下储存16小时的血小板的清除。我们进一步证明，储存和线粒体损伤导致血小板中p38丝裂原活化激酶（MAPK）的磷酸化，并且小鼠和人血小板的TACE介导的受体脱落需要p38 MAP激酶信号传导。蛋白激酶C、细胞外调节信号激酶MAPK和半胱天冬酶不参与TACE激活。在血小板保存过程中，抑制p38 MAPK和灭活TACE均能显著改善小鼠血小板输注后的恢复和止血功能。p38 MAPK抑制剂在体外静态或流动条件下对新鲜血小板的聚集只有轻微的影响。总之，我们的数据表明，在储存过程中抑制p38 MAPK或TACE可显著改善储存血小板的质量。（血。2010;115：1835-1842）
Platelets undergo several modifications during storage that reduce their post-transfusion survival and functionality. One important feature of these changes, which are known as platelet storage lesion, is the shedding of the surface glycoproteins GPIb-alpha and GPV. We recently demonstrated that tumor necrosis factor-alpha converting enzyme (TACE/ADAM17) mediates mitochondrial injury-induced shedding of adhesion receptors and that TACE activity correlates with reduced posttransfusion survival of these cells. We now confirm that TACE mediates receptor shedding and clearance of platelets stored for 16 hours at 37 degrees C or 22 degrees C. We further demonstrate that both storage and mitochondrial injury lead to the phosphorylation of p38 mitogen-activated kinase (MAPK) in platelets and that TACE-mediated receptor shedding from mouse and human platelets requires p38 MAP kinase signaling. Protein kinase C, extracellular regulated-signal kinase MAPK, and caspases were not involved in TACE activation. Both inhibition of p38 MAPK and inactivation of TACE during platelet storage led to a markedly improved posttransfusion recovery and hemostatic function of platelets in mice. p38 MAPK inhibitors had only minor effects on the aggregation of fresh platelets under static or flow conditions in vitro. In summary, our data suggest that inhibition of p38 MAPK or TACE during storage may significantly improve the quality of stored platelets. (Blood. 2010;115:1835-1842)