State-of-the-Art-Review : The Antithrombotic Factor Singlet Oxygen/Light (1O2/hv)

Abstract

Activated phagocytes (especially polymorpho nuclear granulocytes (PMNs)) by respiratory oxidative/ photonic burst (activation of NADPH-oxidase and myeloper oxidase) generate large amounts of oxidants of the hypochlo rite-/chloramine-type, which are physiologic sources for singlet oxygen (¹O₂), a nonradical-excited (photon (hυ) emitting) oxy gen species [Weiss SJ, NEJM 1989;320:365-376]. In vitro ex periments show that ¹O₂ (1) inhibits coagulation by inactiva tion 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/hυ acts antithrombotically, induc ing selective thrombolysis in vivo (i.e., thrombolysis induced by 0.1 to 0.5 mmol/l chloramine within 30 to 60 minutes with out changes of the plasmatic hemostasis system). ¹O₂ might activate flowing to (on the endothelium) rolling PMN, increas ing 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, physi ologic) 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 in volved in the pathogenesis of atherothrombosis. Consequently, it is suggested that activated PMNs modulate hemostasis, shift ing it into an antithrombotic state; this cellular part of fibrino lysis 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 com plications. Light is the only signal whose origin can be imme diately recognized by a fast moving cell in the (dark) blood stream. The cell signal action of ¹O₂/hυ (e.g., released by chlo ramines such as taurine-chloramine or vancomycin, by fiber- optic, 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 athero thrombosis.