Haptoglobin and hemopexin inhibit vaso-occlusion and inflammation in murine sickle cell disease: Role of heme oxygenase-1 induction
Haptoglobin and hemopexin inhibit vaso-occlusion and inflammation in murine sickle cell disease: Role of heme oxygenase-1 induction
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DOI：
10.1371/journal.pone.0196455
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发表时间：
2018-04-25
期刊：
影响因子：
3.7
通讯作者：
Vercellotti, Gregory M.
中科院分区：
文献类型：
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作者：
Belcher, John D.;Chen, Chunsheng;Vercellotti, Gregory M.
在溶血过程中，从红细胞释放的血红蛋白和血红素促进氧化应激、炎症和血栓形成。血浆结合珠蛋白和血红素结合蛋白分别不含血红蛋白和血红素，但在溶血状态下可被耗尽。结合珠蛋白和血红素结合蛋白补充剂保护组织，包括脉管系统、肝脏和肾脏。人们普遍认为，这些保护作用主要是由于血红蛋白和血红素从血管系统中清除。然而，这种简单的假设并不能解释细胞和器官中所见的细胞保护性适应。为了进一步阐明该机制，我们使用镰状细胞病的高溶血性小鼠模型（Townes-SS）来检查细胞对触珠蛋白和血红素结合蛋白补充的反应。在SS-小鼠中单次输注结合珠蛋白或血红素结合蛋白（+/-等摩尔血红蛋白）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，并在输注后48小时降低核NF-κ B磷酸化p65和血管闭塞。血浆血红蛋白和血红素水平没有显着变化后1小时输注结合珠蛋白或血红素结合素。结合珠蛋白和血红素结合蛋白也抑制缺氧/复氧和脂多糖诱导的SS小鼠血管闭塞。用锡原卟啉抑制HO-1活性阻断了结合珠蛋白和血红素结合蛋白在SS小鼠中提供的保护。HO-1反应产物一氧化碳完全恢复了保护作用，部分是通过抑制P-选择素和血管性血友病因子向内皮细胞表面的韦伯-帕拉德体动员。因此，在高溶血性SS小鼠中补充触珠蛋白和血红素结合蛋白诱导细胞保护性细胞应答的机制与HO-1活性增加有关。
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-kappa B 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.