Department of Clinical Pharmacy, Key Laboratory of Clinical Cancer Pharmacology and Toxicology Research of Zhejiang Province, Affiliated Hangzhou First People's Hospital, Zhejiang University School of Medicine, Hangzhou 310006, China.
Zhejiang Provincial People's Hospital, Hangzhou Medical College, Hangzhou 310006, China.
Int Immunopharmacol. 2020 Jul;84:106521. doi: 10.1016/j.intimp.2020.106521. Epub 2020 Apr 18.
Platelets have been proved to exacerbate influenza infection and its complications. Inhibition of platelet activation may be a feasible method for preventing severe infection and secondary acute lung injury (ALI). Isofraxidin (IFD) is a natural coumarin isolated from the plants Sarcandra glabra and Siberian ginseng, and exerts anticancer, antioxidant and antiinflammatory effects. In the present study, we examined the therapeutic effects of IFD in ADP- or arachidonic acid (AA)-induced platelet aggregation model and in influenza A virus (IAV)-induced ALI mouse model. The results showed that IFD significantly inhibited platelet aggregation induced by ADP and AA in vitro in a concentration-dependent manner as well as the release of soluble P-selectin and platelet factor 4. Moreover, IFD significantly relieved IAV-induced lung inflammation, reduced the expressions of platelet activation biomarkers (P-selectin and CD61), decreased the serum levels of TNF-α, IL-1β, IL-6 and MIP-2, suppressed peripheral platelet aggregation and prolonged the survival time of infected mice. The western blotting results also demonstrated that IFD reduced the phosphorylation levels of PI3K, AKT and p38 in the activated platelets stimulated by ADP and IAV infection. But IFD did not have any effects on IAV replication. It indicated that IFD ameliorated IAV-induced severe lung damage and lethal infection by suppressing platelet aggregation via regulating PI3K/AKT and MAPK pathways.
血小板已被证实可加重流感感染及其并发症。抑制血小板活化可能是预防严重感染和继发性急性肺损伤（ALI）的一种可行方法。异甘草素（IFD）是一种从穿心莲和西伯利亚人参植物中分离出来的天然香豆素，具有抗癌、抗氧化和抗炎作用。在本研究中，我们研究了 IFD 在 ADP 或花生四烯酸（AA）诱导的血小板聚集模型和流感 A 病毒（IAV）诱导的 ALI 小鼠模型中的治疗作用。结果表明，IFD 可显著抑制体外 ADP 和 AA 诱导的血小板聚集及可溶性 P-选择素和血小板因子 4 的释放，呈浓度依赖性。此外，IFD 可显著缓解 IAV 诱导的肺部炎症，降低血小板活化生物标志物（P-选择素和 CD61）的表达，降低血清 TNF-α、IL-1β、IL-6 和 MIP-2 水平，抑制外周血小板聚集，延长感染小鼠的生存时间。Western blot 结果还表明，IFD 降低了 ADP 和 IAV 感染刺激的活化血小板中 PI3K、AKT 和 p38 的磷酸化水平。但 IFD 对 IAV 复制没有任何影响。这表明 IFD 通过调节 PI3K/AKT 和 MAPK 通路抑制血小板聚集，改善了 IAV 诱导的严重肺损伤和致死性感染。
