Graw Jan A, Yu Binglan, Rezoagli Emanuele, Warren H Shaw, Buys Emmanuel S, Bloch Donald B, Zapol Warren M
Anesthesia Center for Critical Care Research, Department of Anesthesia, Critical Care, and Pain Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts.
Infectious Disease Unit, Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts; and.
Am J Physiol Heart Circ Physiol. 2017 Jun 1;312(6):H1120-H1127. doi: 10.1152/ajpheart.00851.2016. Epub 2017 Mar 17.
Intravascular hemolysis produces injury in a variety of human diseases including hemoglobinopathies, malaria, and sepsis. The adverse effects of increased plasma hemoglobin are partly mediated by depletion of nitric oxide (NO) and result in vasoconstriction. Circulating plasma proteins haptoglobin and hemopexin scavenge extracellular hemoglobin and cell-free heme, respectively. The ability of human haptoglobin or hemopexin to inhibit the adverse effects of NO scavenging by circulating murine hemoglobin was tested in C57Bl/6 mice. In healthy awake mice, the systemic hemodynamic effects of intravenous coinfusion of cell-free hemoglobin and exogenous haptoglobin or of cell-free hemoglobin and hemopexin were compared with the hemodynamic effects of infusion of cell-free hemoglobin or control protein (albumin) alone. We also studied the hemodynamic effects of infusing hemoglobin and haptoglobin as well as injecting either hemoglobin or albumin alone in mice fed a high-fat diet (HFD) and in diabetic (/) mice. Coinfusion of a 1:1 weight ratio of haptoglobin but not hemopexin with cell-free hemoglobin prevented hemoglobin-induced systemic hypertension in healthy awake mice. In mice fed a HFD and in diabetic mice, coinfusion of haptoglobin mixed with an equal mass of cell-free hemoglobin did not reverse hemoglobin-induced hypertension. Haptoglobin retained cell-free hemoglobin in plasma, but neither haptoglobin nor hemopexin affected the ability of hemoglobin to scavenge NO ex vivo. In conclusion, in healthy C57Bl/6 mice with normal endothelium, coadministration of haptoglobin but not hemopexin with cell-free hemoglobin prevents acute hemoglobin-induced systemic hypertension by compartmentalizing cell-free hemoglobin in plasma. In murine diseases associated with endothelial dysfunction, haptoglobin therapy appears to be insufficient to prevent hemoglobin-induced vasoconstriction. Coadministraton of haptoglobin but not hemopexin with cell-free hemoglobin prevents hemoglobin-induced systemic hypertension in mice with a normal endothelium. In contrast, treatment with the same amount of haptoglobin is unable to prevent hemoglobin-induced vasoconstriction in mice with hyperlipidemia or diabetes mellitus, disorders that are associated with endothelial dysfunction.
血管内溶血在包括血红蛋白病、疟疾和败血症在内的多种人类疾病中都会造成损伤。血浆血红蛋白增加所产生的不良影响部分是由一氧化氮（NO）耗竭介导的，并导致血管收缩。循环血浆蛋白结合珠蛋白和血红素结合蛋白分别清除细胞外血红蛋白和游离血红素。在C57Bl/6小鼠中测试了人结合珠蛋白或血红素结合蛋白抑制循环鼠血红蛋白清除NO的不良影响的能力。在健康清醒小鼠中，将无细胞血红蛋白与外源性结合珠蛋白或无细胞血红蛋白与血红素结合蛋白静脉联合输注的全身血流动力学效应与单独输注无细胞血红蛋白或对照蛋白（白蛋白）的血流动力学效应进行了比较。我们还研究了在高脂饮食（HFD）喂养的小鼠和糖尿病（/）小鼠中输注血红蛋白和结合珠蛋白以及单独注射血红蛋白或白蛋白的血流动力学效应。结合珠蛋白与无细胞血红蛋白以1:1重量比联合输注可预防健康清醒小鼠中血红蛋白诱导的全身性高血压，而血红素结合蛋白则不能。在HFD喂养的小鼠和糖尿病小鼠中，结合珠蛋白与等量无细胞血红蛋白混合联合输注并不能逆转血红蛋白诱导的高血压。结合珠蛋白将无细胞血红蛋白保留在血浆中，但结合珠蛋白和血红素结合蛋白均不影响血红蛋白在体外清除NO的能力。总之，在具有正常内皮的健康C57Bl/6小鼠中，结合珠蛋白而非血红素结合蛋白与无细胞血红蛋白共同给药可通过将无细胞血红蛋白隔离在血浆中来预防急性血红蛋白诱导的全身性高血压。在与内皮功能障碍相关的小鼠疾病中，结合珠蛋白治疗似乎不足以预防血红蛋白诱导的血管收缩。结合珠蛋白而非血红素结合蛋白与无细胞血红蛋白共同给药可预防具有正常内皮的小鼠中血红蛋白诱导的全身性高血压。相比之下，等量结合珠蛋白治疗无法预防高脂血症或糖尿病小鼠中血红蛋白诱导的血管收缩，这些疾病与内皮功能障碍有关。
