Laboratory for Biologics Development, International Institute for Zoonosis Control, Hokkaido University, Kita 20 Nishi 10, Kita-ku, Sapporo, 001-0020, Japan.
Department of Molecular Pathophysiology, School of Medicine, Shinshu University, Matsumoto, Japan.
Sci Rep. 2021 Aug 3;11(1):15675. doi: 10.1038/s41598-021-95046-y.
Although coagulation abnormalities, including microvascular thrombosis, are thought to contribute to tissue injury and single- or multiple-organ dysfunction in severe influenza, the detailed mechanisms have yet been clarified. This study evaluated influenza-associated abnormal blood coagulation utilizing a severe influenza mouse model. After infecting C57BL/6 male mice with intranasal applications of 500 plaque-forming units of influenza virus A/Puerto Rico/8/34 (H1N1; PR8), an elevated serum level of prothrombin fragment 1 + 2, an indicator for activated thrombin generation, was observed. Also, an increased gene expression of oxidized low-density lipoprotein (LDL) receptor-1 (Olr1), a key molecule in endothelial dysfunction in the progression of atherosclerosis, was detected in the aorta of infected mice. Body weight decrease, serum levels of cytokines and chemokines, viral load, and inflammation in the lungs of infected animals were similar between wild-type and Olr1 knockout (KO) mice. In contrast, the elevation of prothrombin fragment 1 + 2 levels in the sera and intravascular thrombosis in the lungs by PR8 virus infection were not induced in KO mice. Collectively, the results indicated that OLR1 is a critical host factor in intravascular thrombosis as a pathogeny of severe influenza. Thus, OLR1 is a promising novel therapeutic target for thrombosis during severe influenza.
虽然凝血异常，包括微血管血栓形成，被认为导致严重流感中的组织损伤和单一或多器官功能障碍，但详细的机制尚未阐明。本研究利用严重流感小鼠模型评估了与流感相关的异常凝血。通过鼻内应用 500 噬菌斑形成单位的流感病毒 A/Puerto Rico/8/34（H1N1；PR8）感染 C57BL/6 雄性小鼠后，观察到凝血酶生成激活的指标凝血酶原片段 1+2 的血清水平升高。此外，还检测到感染小鼠主动脉中氧化型低密度脂蛋白（LDL）受体-1（Olr1）的基因表达增加，Olr1 是动脉粥样硬化进展中内皮功能障碍的关键分子。野生型和 Olr1 敲除（KO）小鼠之间感染动物的体重减轻、细胞因子和趋化因子的血清水平、病毒载量和肺部炎症无明显差异。相比之下，PR8 病毒感染引起的 KO 小鼠血清中凝血酶原片段 1+2 水平升高和肺部血管内血栓形成并未诱导。总的来说，这些结果表明 Olr1 是严重流感中血管内血栓形成的关键宿主因素。因此，OLR1 是严重流感期间血栓形成的有前途的新型治疗靶点。
