Immune Disease Institute, Boston, MA, USA.
Blood. 2010 Mar 4;115(9):1835-42. doi: 10.1182/blood-2009-03-211706. Epub 2009 Nov 30.
Platelets undergo several modifications during storage that reduce their posttransfusion 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.
血小板在储存过程中会发生多种变化，从而降低其输注后的存活和功能。这些变化的一个重要特征是表面糖蛋白 GPIb-α和 GPV 的脱落。我们最近证明肿瘤坏死因子-α转换酶（TACE/ADAM17）介导了线粒体损伤诱导的粘附受体脱落，并且 TACE 活性与这些细胞输注后的存活降低相关。我们现在证实 TACE 介导了储存 16 小时的血小板在 37°C 或 22°C 下的受体脱落和清除。我们进一步证明，储存和线粒体损伤都会导致血小板中 p38 丝裂原活化激酶（MAPK）的磷酸化，并且 TACE 介导的小鼠和人类血小板受体脱落需要 p38 MAP 激酶信号。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 的激活。在血小板储存过程中抑制 p38 MAPK 和失活 TACE 均可显著改善小鼠输注后血小板的恢复和止血功能。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仅有轻微影响。总之，我们的数据表明，在储存过程中抑制 p38 MAPK 或 TACE 可能会显著改善储存血小板的质量。
