Centro Cardiologico Monzino, IRCCS, Milan, Italy.
Centro Cardiologico Monzino, IRCCS, Milan, Italy; Dipartimento di Scienze Cliniche e di Comunità, University of Milan, Milan, Italy.
Pharmacol Res. 2016 May;107:415-425. doi: 10.1016/j.phrs.2016.04.001. Epub 2016 Apr 5.
Recent trials suggest that Aspirin (ASA) reduces the incidence of venous thromboembolism in human. However, the molecular mechanisms underlying this effect are still unclear. In this study we assessed the effects of ASA in venous thrombosis mouse model induced by inferior vena cava (IVC) ligation and we investigated the mechanisms responsible for this effect. ASA (3mg/kg daily for 2 days) treatment decreased the thrombus size, the amounts of tissue factor activity in plasma microvesicles (TF-MP) and the levels of 2,3-dinor Thromboxane B2 (TXB-M) in urine compared to control mice. Interestingly, the thrombus size positively correlated with both TF-MP activity and TXB-M. In addition, positive correlation was observed between TF-MP activity and TXB-M. A reduced number of neutrophils and monocytes, and of TF-positive cells accompanied to a lower amount of fibrin and neutrophil extracellular traps (NETs) were also found in thrombi of ASA-treated mice. Similar results were obtained when mice were treated 24h before IVC ligation with SQ29548 (1mg/kg), a selective thromboxane receptor antagonist. In addition, transfusion of platelets in SQ29548 treated-mice excluded the likelihood of a redundant role of platelet-TP receptor in this context. Finally, incubation of macrophages and neutrophils with SQ29548 prevented TF activity and/or NETs formation induced by supernatant of activated platelets or by IBOP, a selective thromboxane analogue. In conclusion, ASA, suppressing TXA2, prevents macrophages and neutrophils activation and markedly reduces thrombus size with a mechanism most likely dependent of the inhibition of TF activity and NETs formation. These results provide a new link between platelet-produced thromboxane and the occurrence of venous thrombosis.
最近的试验表明，阿司匹林（ASA）可降低人类静脉血栓栓塞的发生率。然而，其作用的分子机制仍不清楚。在这项研究中，我们评估了 ASA 对腔静脉结扎诱导的静脉血栓形成小鼠模型的影响，并研究了其作用机制。ASA（每天 3mg/kg，连续 2 天）治疗可降低血栓大小、血浆微泡中组织因子活性（TF-MP）和尿中 2,3-二去甲血栓烷 B2（TXB-M）的水平与对照组相比。有趣的是，血栓大小与 TF-MP 活性和 TXB-M 呈正相关。此外，TF-MP 活性与 TXB-M 之间也存在正相关。ASA 治疗小鼠的血栓中还发现中性粒细胞和单核细胞数量减少，TF 阳性细胞减少，纤维蛋白和中性粒细胞胞外陷阱（NETs）的量也减少。在 IVC 结扎前 24 小时用 SQ29548（1mg/kg）治疗的小鼠中也得到了类似的结果，这是一种选择性血栓素受体拮抗剂。此外，在 SQ29548 治疗的小鼠中输注血小板排除了血小板-TP 受体在这种情况下冗余作用的可能性。最后，用 SQ29548 孵育巨噬细胞和中性粒细胞可防止由激活的血小板上清液或选择性血栓烷类似物 IBOP 诱导的 TF 活性和/或 NETs 形成。总之，ASA 通过抑制 TXA2 来抑制巨噬细胞和中性粒细胞的激活，并显著降低血栓大小，其机制很可能依赖于抑制 TF 活性和 NETs 形成。这些结果为血小板产生的血栓烷与静脉血栓形成的发生之间提供了新的联系。
