Ticagrelor potentiates adenosine-induced stimulation of neutrophil chemotaxis and phagocytosis.
Ticagrelor potentiates adenosine-induced stimulation of neutrophil chemotaxis and phagocytosis.
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DOI：
10.1016/j.vph.2015.02.006
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发表时间：
2015-08
影响因子：
4
通讯作者：
Storey RF
中科院分区：
文献类型：
--
作者：
Alsharif KF;Thomas MR;Judge HM;Khan H;Prince LR;Sabroe I;Ridger VC;Storey RF
在PLATO研究中，替格瑞洛与氯吡格雷相比，肺部感染和随后的死亡更少。中性粒细胞是抵御细菌性肺部感染的第一道防线；替格瑞洛抑制腺苷的细胞摄取，腺苷是一种已知的中性粒细胞趋化和吞噬的调节因子。我们评估了替格瑞洛对腺苷摄取的抑制是否影响中性粒细胞趋化和吞噬。从健康志愿者中分离出中性粒细胞和红细胞。研究了腺苷对il -8诱导的中性粒细胞趋化作用的浓度依赖性，并使用腺苷受体拮抗剂鉴定了相关受体。在红细胞的存在下，测定替格瑞洛对腺苷介导的中性粒细胞趋化性和肺炎链球菌吞噬变化的调节作用，以复制细胞腺苷摄取的生理条件。低浓度腺苷（10 ~ 8 M）通过作用于高亲和力A1受体，显著提高il -8诱导的中性粒细胞趋化性（中性粒细胞趋化率：腺苷28.7%±4.4比对照组22.6%±2.4,p < 0.01）。红细胞减弱了腺苷的作用，虽然替格瑞洛和双嘧达莫（另一种腺苷摄取抑制剂）保留了这种作用，但对照组或康格瑞洛没有。同样，在红细胞存在的情况下，与对照组相比，当替格瑞洛存在时，低浓度腺苷（10 - 8 M）显著增加中性粒细胞吞噬指数（37.6±6.6 vs 28.0±6.6;p = 0.028），但在没有替格瑞洛的情况下没有影响。因此，我们得出结论，替格瑞洛对细胞腺苷再摄取的抑制增强了纳摩尔浓度腺苷对中性粒细胞趋化和吞噬的影响。这代表了替格瑞洛影响宿主抵抗细菌性肺部感染的潜在机制。
In the PLATO study, ticagrelor was associated with fewer pulmonary infections and subsequent deaths than clopidogrel. Neutrophils are a first-line defence against bacterial lung infection; ticagrelor inhibits cellular uptake of adenosine, a known regulator of neutrophil chemotaxis and phagocytosis. We assessed whether the inhibition of adenosine uptake by ticagrelor influences neutrophil chemotaxis and phagocytosis. Neutrophils and erythrocytes were isolated from healthy volunteers. Concentration-dependent effects of adenosine on IL-8-induced neutrophil chemotaxis were investigated and the involved receptors identified using adenosine receptor antagonists. The modulatory effects of ticagrelor on adenosine-mediated changes in neutrophil chemotaxis and phagocytosis of Streptococcus pneumoniae were determined in the presence of erythrocytes to replicate physiological conditions of cellular adenosine uptake. Low-concentration adenosine (10− 8 M) significantly increased IL-8-induced neutrophil chemotaxis (% neutrophil chemotaxis: adenosine 28.7% ± 4.4 vs. control 22.6% ± 2.4; p < 0.01) by acting on the high-affinity A1 receptor. Erythrocytes attenuated the effect of adenosine, although this was preserved by ticagrelor and dipyridamole (another inhibitor of adenosine uptake) but not by control or by cangrelor. Similarly, in the presence of erythrocytes, a low concentration of adenosine (10− 8 M) significantly increased neutrophil phagocytic index compared to control when ticagrelor was present (37.6 ± 6.6 vs. 28.0 ± 6.6; p = 0.028) but had no effect in the absence of ticagrelor. We therefore conclude that the inhibition of cellular adenosine reuptake by ticagrelor potentiates the effects of a nanomolar concentration of adenosine on neutrophil chemotaxis and phagocytosis. This represents a potential mechanism by which ticagrelor could influence host defence against bacterial lung infection.