Stief T W, Fareed J
Department of Clinical Chemistry, Philipps University, Marburg, Germany.
Clin Appl Thromb Hemost. 2000 Jan;6(1):22-30. doi: 10.1177/107602960000600104.
Activated phagocytes (especially polymorphonuclear granulocytes (PMNs)) by respiratory oxidative/photonic burst (activation of NADPH-oxidase and myeloper-oxidase) generate large amounts of oxidants of the hypochlorite-/chloramine-type, which are physiologic sources for singlet oxygen (1O2), a nonradical-excited (photon (h nu) emitting) oxygen species [Weiss SJ, NEJM 1989;320:365-376]. In vitro experiments show that 1O2 (1) inhibits coagulation by inactivation of thrombocytes, fibrinogen, factor V, factor VIII, and factor X and (2) activates fibrinolysis by inactivation of the main fibrinolysis inhibitors plasminogen activator inhibitor (PAI)-1 and alpha-2-antiplasmin, and by activation of single-chain urokinase by plasmin and oxidized fibrin. Additionally, this work suggests that 1O2/h nu acts antithrombotically, inducing selective thrombolysis in vivo (i.e., thrombolysis induced by 0.1 to 0.5 mmol/l chloramine within 30 to 60 minutes without changes of the plasmatic hemostasis system). 1O2 might activate flowing to (on the endothelium) rolling PMN, increasing their chance to get in contact with fibrin/platelet aggregates deposited on the endothelial layer. Via 1O2 generation, the thrombus-activated phagocytes might call for (acute, physiologic) inflammation/fibrinolysis amplification, resulting in the "moving front" of PMN, which infiltrates and destroys the thrombus. 1O2 seems to (partially) participate in the reactivity of nitric oxide, another prooxidative agent. The inhibition of physiologic amounts of 1O2 by blood cholesterol might be involved in the pathogenesis of atherothrombosis. Consequently, it is suggested that activated PMNs modulate hemostasis, shifting it into an antithrombotic state; this cellular part of fibrinolysis seems to be of greater physiologic importance than the plasmatic one. Impaired PMN function (e.g., as occurring in patients with antineutrophil cytoplasmic antibodies or under cytostatic treatments) often results in serious thrombotic complications. Light is the only signal whose origin can be immediately recognized by a fast moving cell in the (dark) blood stream. The cell signal action of 1O2/h nu (e.g., released by chloramines such as taurine-chloramine or vancomycin, by fiberoptic, by photodynamic therapy, or by so-called redox-cycling drugs such as quinones or tetracyclines) might be a new and physiologic principle for pharmacologic intervention in atherothrombosis.
通过呼吸氧化/光爆发（烟酰胺腺嘌呤二核苷酸磷酸氧化酶和髓过氧化物酶的激活）激活的吞噬细胞（尤其是多形核粒细胞（PMN））会产生大量次氯酸盐/氯胺类氧化剂，这些氧化剂是单线态氧（1O2）的生理来源，单线态氧是一种非自由基激发（发射光子（h ν））的氧物种[魏斯·SJ，《新英格兰医学杂志》1989年；320:365 - 376]。体外实验表明，1O2（1）通过使血小板、纤维蛋白原、因子V、因子VIII和因子X失活来抑制凝血，（2）通过使主要的纤溶酶原激活物抑制剂（PAI）-1和α-2-抗纤溶酶失活，以及通过纤溶酶和氧化纤维蛋白激活单链尿激酶来激活纤维蛋白溶解。此外，这项研究表明1O2/h ν具有抗血栓形成作用，可在体内诱导选择性溶栓（即由0.1至0.5 mmol/l氯胺在30至60分钟内诱导的溶栓，而血浆止血系统无变化）。1O2可能激活流向（在内皮上）滚动的PMN，增加它们与沉积在内皮层上的纤维蛋白/血小板聚集体接触的机会。通过产生1O2，血栓激活的吞噬细胞可能引发（急性、生理性）炎症/纤维蛋白溶解放大，导致PMN的“移动前沿”，其浸润并破坏血栓。1O2似乎（部分）参与了另一种促氧化剂一氧化氮的反应性。血液胆固醇对生理量1O2的抑制可能参与动脉粥样硬化血栓形成的发病机制。因此，有人提出激活的PMN调节止血，使其转变为抗血栓状态；这种纤维蛋白溶解的细胞部分似乎比血浆部分具有更大的生理重要性。PMN功能受损（例如，在抗中性粒细胞胞浆抗体患者或细胞毒性治疗下发生）常导致严重的血栓并发症。光是以（黑暗的）血流中快速移动的细胞能够立即识别其来源唯一信号。1O2/h ν的细胞信号作用（例如，由牛磺酸氯胺或万古霉素等氯胺释放，通过光纤，通过光动力疗法，或通过醌或四环素等所谓的氧化还原循环药物释放）可能是动脉粥样硬化血栓形成药物干预的一种新的生理原理。
