Department of Medicine, Division of Hematology, Oncology and Transplantation, Vascular Biology Center, University of Minnesota, Minneapolis, Minnesota, United States of America.
CSL Behring AG, Research and Development, Bern, Switzerland.
PLoS One. 2018 Apr 25;13(4):e0196455. doi: 10.1371/journal.pone.0196455. eCollection 2018.
During hemolysis, hemoglobin and heme released from red blood cells promote oxidative stress, inflammation and thrombosis. Plasma haptoglobin and hemopexin scavenge free hemoglobin and heme, respectively, but can be depleted in hemolytic states. Haptoglobin and hemopexin supplementation protect tissues, including the vasculature, liver and kidneys. It is widely assumed that these protective effects are due primarily to hemoglobin and heme clearance from the vasculature. However, this simple assumption does not account for the consequent cytoprotective adaptation seen in cells and organs. To further address the mechanism, we used a hyperhemolytic murine model (Townes-SS) of sickle cell disease to examine cellular responses to haptoglobin and hemopexin supplementation. A single infusion of haptoglobin or hemopexin (± equimolar hemoglobin) in SS-mice increased heme oxygenase-1 (HO-1) in the liver, kidney and skin several fold within 1 hour and decreased nuclear NF-ĸB phospho-p65, and vaso-occlusion for 48 hours after infusion. Plasma hemoglobin and heme levels were not significantly changed 1 hour after infusion of haptoglobin or hemopexin. Haptoglobin and hemopexin also inhibited hypoxia/reoxygenation and lipopolysaccharide-induced vaso-occlusion in SS-mice. Inhibition of HO-1 activity with tin protoporphyrin blocked the protections afforded by haptoglobin and hemopexin in SS-mice. The HO-1 reaction product carbon monoxide, fully restored the protection, in part by inhibiting Weibel-Palade body mobilization of P-selectin and von Willebrand factor to endothelial cell surfaces. Thus, the mechanism by which haptoglobin and hemopexin supplementation in hyperhemolytic SS-mice induces cytoprotective cellular responses is linked to increased HO-1 activity.
在溶血过程中，从红细胞中释放的血红蛋白和血红素会促进氧化应激、炎症和血栓形成。血浆触珠蛋白和血红素结合蛋白分别清除游离血红蛋白和血红素，但在溶血状态下可能会被耗尽。触珠蛋白和血红素结合蛋白的补充可以保护组织，包括血管、肝脏和肾脏。人们普遍认为，这些保护作用主要归因于从血管中清除血红蛋白和血红素。然而，这种简单的假设并不能解释细胞和器官中随后出现的细胞保护适应。为了进一步阐明机制，我们使用镰状细胞病的高溶血性小鼠模型（Townes-SS）来研究触珠蛋白和血红素结合蛋白补充对细胞的反应。在 SS 小鼠中单次输注触珠蛋白或血红素结合蛋白（±等摩尔血红蛋白）可在 1 小时内使肝脏、肾脏和皮肤中的血红素加氧酶-1（HO-1）增加数倍，并降低核 NF-ĸB 磷酸化 p65，以及输注后 48 小时内的血管阻塞。在输注触珠蛋白或血红素结合蛋白后 1 小时，血浆血红蛋白和血红素水平没有明显变化。触珠蛋白和血红素结合蛋白还抑制了 SS 小鼠的缺氧/复氧和脂多糖诱导的血管阻塞。用锡原卟啉抑制 HO-1 活性阻断了触珠蛋白和血红素结合蛋白在 SS 小鼠中提供的保护作用。HO-1 反应产物一氧化碳完全恢复了保护作用，部分通过抑制 Weibel-Palade 体向内皮细胞表面移动 P 选择素和血管性血友病因子。因此，触珠蛋白和血红素结合蛋白在高溶血性 SS 小鼠中的补充诱导细胞保护细胞反应的机制与 HO-1 活性的增加有关。
