Belcher John D, Nath Karl A, Vercellotti Gregory M
Division of Hematology, Oncology and Transplantation, Vascular Biology Center, Department of Medicine, University of Minnesota Medical School, 420 Delaware Street SE, Minneapolis, MN 55455, USA.
Division of Nephrology and Hypertension, Mayo Clinic, Rochester, MN, USA.
ISRN Oxidative Med. 2013;2013. doi: 10.1155/2013/831596.
The proinfammatory vasculotoxic effects of intravascular hemolysis are modulated by plasma hemoglobin and heme clearance via the haptoglobin/CD163 system and the hemopexin/CD91 system, respectively, and detoxification through the heme oxygenase/ferritin system. However, sudden or excessive hemolysis can overwhelm these protective systems leading to heme interacting with cells of the vasculature. Heme presents a damage-associated molecular pattern to the innate immune system. Heme is an extracellular inflammatory signaling molecule with strict binding specificity for TLR4 on monocyte/macrophages, endothelial, and other cells. The resulting TLR4 signaling cascade rapidly leads to intracellular oxidative stress and an inflammatory response. Heme also induces a cytoprotective response that includes Nrf2 responsive genes such as heme oxygenase-1, ferritin, haptoglobin, hemopexin, and other antioxidant response genes. It is the balance between the pro-inflammatory/vasculotoxic effects of plasma hemoglobin/heme and the cytoprotective responses that ultimately determines the pathophysiologic outcome in patients.
血管内溶血的促炎血管毒性作用分别通过触珠蛋白/CD163系统和血红素结合蛋白/CD91系统对血浆血红蛋白和血红素的清除作用以及通过血红素加氧酶/铁蛋白系统的解毒作用进行调节。然而，突然或过度的溶血会使这些保护系统不堪重负，导致血红素与脉管系统的细胞相互作用。血红素向先天免疫系统呈现一种损伤相关分子模式。血红素是一种细胞外炎症信号分子，对单核细胞/巨噬细胞、内皮细胞和其他细胞上的TLR4具有严格的结合特异性。由此产生的TLR4信号级联反应迅速导致细胞内氧化应激和炎症反应。血红素还诱导一种细胞保护反应，包括Nrf2反应性基因，如血红素加氧酶-1、铁蛋白、触珠蛋白、血红素结合蛋白和其他抗氧化反应基因。血浆血红蛋白/血红素的促炎/血管毒性作用与细胞保护反应之间的平衡最终决定了患者的病理生理结果。
