P-selectin-mediated platelet-neutrophil aggregate formation activates neutrophils in mouse and human sickle cell disease.
P-selectin-mediated platelet-neutrophil aggregate formation activates neutrophils in mouse and human sickle cell disease.
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P-选择蛋白介导的血小板中性基质骨料形成激活小鼠和人类镰状细胞病中的中性粒细胞。
DOI：
10.1161/atvbaha.110.211615
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发表时间：
2010-12
期刊：
影响因子：
--
通讯作者：
Linden J
中科院分区：
文献类型：
--
作者：
Polanowska-Grabowska R;Wallace K;Field JJ;Chen L;Marshall MA;Figler R;Gear AR;Linden J
镰状细胞病（SCD）发生血小板和中性粒细胞活化，但这些事件的相互依赖性尚不清楚。本研究的目的是确定血小板在刺激小鼠和人中性粒细胞活化和SCD肺损伤中的作用。在对照组、SCD小鼠和患者中测量血小板活化和与白细胞的结合。与对照组相比，从SCD小鼠或患者获得的血液中含有显著升高的血小板-中性粒细胞聚集体（PNAs）。在镰状PNAs中发现的血小板和中性粒细胞都被激活。多光谱成像（ImageStream）和常规流式细胞术显示，与单个中性粒细胞相比，具有多个粘附血小板的活化中性粒细胞亚群表达了更多的CD11b，并表现出更强的氧化活性。平均而言，野生型和镰状PNAs每个中性粒细胞分别含有1.1和2.6个血小板。缺氧/再氧化诱导SCD小鼠血小板-中性粒细胞聚集进一步增加，血小板和中性粒细胞进一步活化。用氯吡格雷或p -选择素抗体预处理SCD小鼠，可减少PNAs的形成和中性粒细胞的活化，降低肺血管通透性。总之，我们的研究结果表明，血小板结合激活中性粒细胞，并有助于慢性炎症状态和SCD的肺功能障碍。抑制血小板活化可能有助于减少SCD的组织损伤，特别是在血管闭塞危象的早期阶段。
Both platelet and neutrophil activation occur in sickle cell disease (SCD) but the interdependence of these events is unknown. The goal of this study was to determine the role of platelets in stimulating mouse and human neutrophil activation and pulmonary injury in SCD. Platelet activation and binding to leukocytes was measured in control and SCD mice and patients. Relative to controls, blood obtained from SCD mice or patients contained significantly elevated platelet-neutrophil aggregates (PNAs). Both platelets and neutrophils found in sickle PNAs were activated. Multi-spectral imaging (ImageStream) and conventional flow cytometry revealed a subpopulation of activated neutrophils with multiple adhered platelets that expressed significantly more CD11b and exhibited greater oxidative activity than single neutrophils. On average, wild type and sickle PNAs contained 1.1 and 2.6 platelets per neutrophil, respectively. Hypoxia/reoxygenation induced a further increase in platelet-neutrophil aggregates in SCD mice and additional activation of both platelets and neutrophils. Pretreatment of SCD mice with clopidogrel or P-selectin antibody reduced the formation of PNAs and neutrophil activation and decreased lung vascular permeability. In sum, our findings suggest that platelet binding activates neutrophils and contributes to a chronic inflammatory state and pulmonary dysfunction in SCD. Inhibition of platelet activation may be useful to decrease tissue injury in SCD, particularly during the early stages of vaso-occlusive crises.