Cathepsin G-dependent modulation of platelet thrombus formation in vivo by blood neutrophils.
Cathepsin G-dependent modulation of platelet thrombus formation in vivo by blood neutrophils.
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DOI：
10.1371/journal.pone.0071447
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发表时间：
2013
期刊：
影响因子：
3.7
通讯作者：
Dore S
中科院分区：
文献类型：
--
作者：
Faraday N;Schunke K;Saleem S;Fu J;Wang B;Zhang J;Morrell C;Dore S
在人类临床研究中，中性粒细胞始终与动脉血栓形成发病率相关，但这种相关性的因果关系尚不清楚。我们检验了中性粒细胞以组织蛋白酶G依赖性方式调节体内血小板活化和血栓形成的假设。中性粒细胞在体外以剂量依赖性方式增强人血小板的聚集，并且这种作用通过药理学抑制组织蛋白酶G活性和敲低组织蛋白酶G表达而减弱。组织蛋白酶G抑制剂延长了小鼠和组织蛋白酶G敲除小鼠的尾部出血时间，并且在不存在组织蛋白酶G的情况下，从横断尾部流出的血液中嗜血小板-血小板缀合物的形成减少。出血时间与野生型小鼠的血液中性粒细胞计数高度相关，但与组织蛋白酶G缺陷小鼠无关。在血液中性粒细胞计数升高的情况下，组织蛋白酶G抑制剂的抗血栓形成作用大于阿司匹林，并且在联合给药时与阿司匹林相加。组织蛋白酶G的药理学抑制及其先天性缺失均延长了氯化铁损伤小鼠肠系膜小动脉中血小板血栓形成的时间。在缺血性卒中的血管闭塞模型中，抑制组织蛋白酶G及其先天性缺失可改善脑血流量，减少组织学脑损伤，并改善神经行为结局。这些实验表明，中性粒细胞组织蛋白酶G是体内血小板血栓形成的生理调节剂，并有潜力作为新的抗血栓治疗的目标。
Neutrophils are consistently associated with arterial thrombotic morbidity in human clinical studies but the causal basis for this association is unclear. We tested the hypothesis that neutrophils modulate platelet activation and thrombus formation in vivo in a cathepsin G-dependent manner. Neutrophils enhanced aggregation of human platelets in vitro in dose-dependent fashion and this effect was diminished by pharmacologic inhibition of cathepsin G activity and knockdown of cathepsin G expression. Tail bleeding time in the mouse was prolonged by a cathepsin G inhibitor and in cathepsin G knockout mice, and formation of neutrophil-platelet conjugates in blood that was shed from transected tails was reduced in the absence of cathepsin G. Bleeding time was highly correlated with blood neutrophil count in wildtype but not cathepsin G deficient mice. In the presence of elevated blood neutrophil counts, the anti-thrombotic effect of cathepsin G inhibition was greater than that of aspirin and additive to it when administered in combination. Both pharmacologic inhibition of cathepsin G and its congenital absence prolonged the time for platelet thrombus to form in ferric chloride-injured mouse mesenteric arterioles. In a vaso-occlusive model of ischemic stroke, inhibition of cathepsin G and its congenital absence improved cerebral blood flow, reduced histologic brain injury, and improved neurobehavioral outcome. These experiments demonstrate that neutrophil cathepsin G is a physiologic modulator of platelet thrombus formation in vivo and has potential as a target for novel anti-thrombotic therapies.
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影响因子：
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作者：
Bruehl, Hilke;Cihak, Josef;Mack, Matthias
通讯作者：
Mack, Matthias
影响因子：
20.3
作者：
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作者：
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Cerletti, C
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8.3
作者：
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通讯作者：
Hacke, W