Nath K A, Balla G, Vercellotti G M, Balla J, Jacob H S, Levitt M D, Rosenberg M E
Department of Medicine, University of Minnesota, Minneapolis 55455.
J Clin Invest. 1992 Jul;90(1):267-70. doi: 10.1172/JCI115847.
Heme proteins such as myoglobin or hemoglobin, when released into the extracellular space, can instigate tissue toxicity. Myoglobin is directly implicated in the pathogenesis of renal failure in rhabdomyolysis. In the glycerol model of this syndrome, we demonstrate that the kidney responds to such inordinate amounts of heme proteins by inducing the heme-degradative enzyme, heme oxygenase, as well as increasing the synthesis of ferritin, the major cellular repository for iron. Prior recruitment of this response with a single preinfusion of hemoglobin prevents kidney failure and drastically reduces mortality (from 100% to 14%). Conversely, ablating this response with a competitive inhibitor of heme oxygenase exacerbates kidney dysfunction. We provide the first in vivo evidence that induction of heme oxygenase coupled to ferritin synthesis is a rapid, protective antioxidant response. Our findings suggest a therapeutic strategy for populations at a high risk for rhabdomyolysis.
血红素蛋白，如肌红蛋白或血红蛋白，一旦释放到细胞外空间，就会引发组织毒性。肌红蛋白直接与横纹肌溶解症中肾衰竭的发病机制相关。在该综合征的甘油模型中，我们证明肾脏通过诱导血红素降解酶血红素加氧酶以及增加铁蛋白（细胞内主要的铁储存库）的合成来应对过量的血红素蛋白。预先单次输注血红蛋白引发这种反应可预防肾衰竭并大幅降低死亡率（从100%降至14%）。相反，用血红素加氧酶的竞争性抑制剂消除这种反应会加剧肾功能障碍。我们提供了首个体内证据，表明血红素加氧酶的诱导与铁蛋白合成相结合是一种快速的保护性抗氧化反应。我们的研究结果为横纹肌溶解症高危人群提出了一种治疗策略。
