Platelet Activation and Aggregation Promote Lung Inflammation and Influenza Virus Pathogenesis
Platelet Activation and Aggregation Promote Lung Inflammation and Influenza Virus Pathogenesis
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DOI：
10.1164/rccm.201406-1031oc
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发表时间：
2015-04-01
影响因子：
24.7
通讯作者：
Riteau, Beatrice
中科院分区：
文献类型：
--
作者：
Vuong Ba Le;Schneider, Jochen G.;Riteau, Beatrice
理论基础：严重流感病毒感染的特征是肺部过度炎症。流感期间血小板被激活，但其在流感病毒致病和炎症反应中的作用尚不清楚。目的：确定血小板在甲型流感病毒感染过程中的作用，并提出针对流感病毒的新的治疗方法。方法：采用靶向基因缺失和药物干预的方法，研究血小板在流感病毒感染小鼠中的作用。血小板活化促进了甲型流感病毒的发病。激活的蛋白酶激活受体4是一种凝血酶的血小板受体，对血小板激活至关重要，它加剧了流感引起的急性肺损伤和死亡。相反，缺乏主要的血小板受体糖蛋白IIIa可以保护小鼠免受流感病毒引起的死亡，而用一种特定的糖蛋白IIb/IIIa拮抗剂Etifiatide治疗小鼠也有同样的效果。有趣的是，其他抗血小板化合物(蛋白酶激活受体4、MRS 2179和氯吡格雷的拮抗剂)也能保护小鼠免受几种流感病毒株诱导的严重肺损伤和致死性感染。结论：止血和炎症之间复杂的关系在流感病毒的发病机制中具有重要后果，抗血小板药物可能被探索用于开发新的抗炎药物来对抗流感病毒感染。
Rationale: The hallmark of Severe influenza virus infection is excessive inflammation of the lungs. Platelets are activated during influenza, but their role in influenza virus pathogenesis and inflammatory responses is unknown.Objectives: To determine the role of platelets during influenza A virus infections and propose new therapeutics against influenza.Methods: We used targeted gene deletion approaches and pharmacologic interventions to investigate the role of platelets during influenza virus infection in mice.Measurements and Main Results: Lungs of infected mice were Massively infiltrated by aggregates of activated platelets. Platelet activation promoted influenza A virus pathogenesis. Activating protease-activated receptor 4, a platelet receptor for thrombin that is crucial for platelet activation, exacerbated influenza-induced acute lung injury and death. In contrast, deficiency in the major platelet receptor glycoprotein IIIa protected mice from death caused by influenza viruses, and treating the mice with a specific glycoprotein IIb/IIIa antagonist, eptifibatide, had the same effect. Interestingly, mice treated with other antiplatelet compounds (antagonists of protease-activated receptor 4, MRS 2179, and clopidogrel) were also protected from severe lung injury and lethal infections induced by several influenza strains.Conclusions: The intricate relationship between hemostasis and inflammation has major consequences in influenza virus pathogenesis, and antiplatelet drugs might be explored to develop new antiinflammatory treatment against influenza virus infections.