Nitric oxide scavenging by red blood cell microparticles and cell-free hemoglobin as a mechanism for the red cell storage lesion.
Nitric oxide scavenging by red blood cell microparticles and cell-free hemoglobin as a mechanism for the red cell storage lesion.
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DOI：
10.1161/circulationaha.110.008698
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发表时间：
2011-07-26
期刊：
影响因子：
37.8
通讯作者：
Gladwin MT
中科院分区：
文献类型：
--
作者：
Donadee C;Raat NJ;Kanias T;Tejero J;Lee JS;Kelley EE;Zhao X;Liu C;Reynolds H;Azarov I;Frizzell S;Meyer EM;Donnenberg AD;Qu L;Triulzi D;Kim-Shapiro DB;Gladwin MT
血管内红细胞溶血损害no -氧化还原稳态，产生内皮功能障碍、血小板活化和血管病变。标准条件下的红细胞储存导致红细胞膜完整性降低，形成胞外微泡或“微颗粒”和溶血，我们假设这可能损害血管功能，并导致假定的血液“储存损伤”。我们现在发现，在标准血库条件下储存人类红细胞会导致无细胞和微颗粒包裹的血红蛋白的积累，尽管储存了39天，这些血红蛋白仍处于还原铁氧血红蛋白氧化还原状态，并与血管舒张剂一氧化氮（NO）发生化学计量反应并清除它们。通过停止流动光谱和激光触发一氧化氮释放，我们发现游离血红蛋白和微粒与一氧化氮的反应速度比与完整红细胞的反应速度快1000倍。在补充的体内研究中，我们发现血红蛋白，即使浓度低于10 μM（血红素），在注入大鼠循环时也会产生有效的血管收缩，而控制高铁血红蛋白和氰高铁血红蛋白的输注，不消耗NO，大大降低了血管收缩作用。将储存的人红细胞单位的血浆输注到大鼠循环中，会产生与储存相关的溶血强度相关的显著血管收缩。这些研究的结果提示内皮损伤和血管功能受损的新机制与最基本的储存病变，溶血有关。
Intravascular red cell hemolysis impairs NO-redox homeostasis, producing endothelial dysfunction, platelet activation and vasculopathy. Red blood cell storage under standard conditions results in reduced integrity of the erythrocyte membrane, with formation of exocytic microvesicles or “microparticles” and hemolysis, which we hypothesized could impair vascular function and contribute to the putative “storage lesion” of banked blood. We now find that storage of human red blood cells under standard blood banking conditions results in the accumulation of cell free and microparticle-encapsulated hemoglobin which, despite 39 days of storage, remains in the reduced ferrous oxyhemoglobin redox state and stoichiometrically reacts with and scavenges the vasodilator nitric oxide (NO). Using stopped-flow spectroscopy and laser triggered NO release from a caged NO compound we found that both free hemoglobin and microparticles react with NO about 1000 times faster than with intact erythrocytes. In complementary in vivo studies we show that hemoglobin, even at concentrations below 10 μM (in heme), produces potent vasoconstriction when infused into the rat circulation, while controlled infusions of methemoglobin and cyanomethemoglobin, which do not consume NO, have substantially reduced vasoconstrictor effects. Infusion of the plasma from stored human red cell units into the rat circulation produces significant vasoconstriction related to the magnitude of storage related hemolysis. The results of these studies suggest new mechanisms for endothelial injury and impaired vascular function associated with the most fundamental of storage lesions, hemolysis.