Critical Illness Research, Lawson Health Research Institute, London, Ontario, Canada.
Microcirculation. 2011 Feb;18(2):152-62. doi: 10.1111/j.1549-8719.2010.00080.x.
Sepsis is a complex multifaceted response to a local infectious insult. One important facet is the circulatory system dysfunction, which includes capillary bed plugging. This review addresses the mechanisms of capillary plugging and highlights our recent discoveries on the roles of NO, ROS, and activated coagulation in platelet adhesion and blood flow stoppage in septic mouse capillaries. We show that sepsis increases platelet adhesion, fibrin deposition and flow stoppage in capillaries, and that NADPH oxidase-derived ROS, rather than NO, play a detrimental role in this adhesion/stoppage. P-selectin and activated coagulation are required for adhesion/stoppage. Further, platelet adhesion in capillaries (i) strongly predicts capillary flow stoppage, and (ii) may explain why severe sepsis is associated with a drop in platelet count in systemic blood. Significantly, we also show that a single bolus of the antioxidant ascorbate (injected intravenously at clinically relevant dose of 10 mg/kg) inhibits adhesion/stoppage. Our data suggest that eNOS-derived NO at the platelet-endothelial interface is anti-adhesive and required for the inhibitory effect of ascorbate. Because of the critical role of ROS in capillary plugging, ascorbate bolus administration may be beneficial to septic patients whose survival depends on restoring microvascular perfusion.
脓毒症是机体对局部感染性损伤的一种复杂的、多方面的反应。其中一个重要方面是循环系统功能障碍，包括毛细血管床堵塞。这篇综述探讨了毛细血管堵塞的机制，并强调了我们最近在一氧化氮（NO）、活性氧（ROS）和激活的凝血在脓毒症小鼠毛细血管中血小板黏附和血流停止中的作用方面的发现。我们表明，脓毒症增加了血小板在毛细血管中的黏附、纤维蛋白沉积和血流停止，而来源于 NADPH 氧化酶的 ROS 而不是 NO 在这种黏附/停止中起着有害的作用。P 选择素和激活的凝血因子对于黏附/停止是必需的。此外，毛细血管中的血小板黏附（i）强烈预测毛细血管血流停止，并且（ii）可能解释为什么严重脓毒症与全身血液中血小板计数下降有关。重要的是，我们还表明，静脉内注射单剂量的抗氧化剂抗坏血酸（以临床相关剂量 10mg/kg 静脉注射）可抑制黏附/停止。我们的数据表明，血小板-内皮界面处的 eNOS 衍生的 NO 具有抗黏附作用，并且是抗坏血酸抑制作用所必需的。由于 ROS 在毛细血管堵塞中的关键作用，抗坏血酸的单次推注给药可能对依赖恢复微血管灌注的脓毒症患者有益。
