Acquired resistance to acute oxidative stress. Possible role of heme oxygenase and ferritin.
Acquired resistance to acute oxidative stress. Possible role of heme oxygenase and ferritin.
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发表时间：
1995
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通讯作者：
B. Vogt;J. Alam;A. J. Croatt;G. Vercellotti;K. Nath
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作者：
B. Vogt;J. Alam;A. J. Croatt;G. Vercellotti;K. Nath
背景在许多器官损伤模型中，内毒素的预先给药已经赋予了对组织损伤的抗性。赋予这种抵抗力的机制是神秘的。认识到增强的组织氧化应激可能是内毒素相关损伤的一个特征，并且存在于许多组织损伤模型中，我们质疑内毒素赋予的有益作用是否依赖于抗氧化防御的上调。实验设计我们采用甘油急性肾衰竭模型（Gly-ARF），在该模型中，由于横纹肌溶解和溶血，在肾脏和其他器官中发生氧化损伤。在Gly-ARF诱导前24小时或诱导时，用内毒素预处理大鼠。进行肾功能研究和肾脏抗氧化状态评估。还在高铁血红蛋白诱导的和缺血性ARF模型中检查了内毒素预先治疗的效果。结果内毒素预处理组大鼠肾功能明显改善，Gly-ARF与内毒素联合处理组大鼠肾功能明显恶化。内毒素诱导血红素加氧酶活性和铁蛋白含量在肾脏中，但不诱导其他抗氧化系统，如过氧化氢酶和谷胱甘肽过氧化物酶。血红素加氧酶的竞争性抑制剂的治疗阻断内毒素诱导的保护在第2天和第3天，而在第1天的保护作用显着减弱。内毒素预处理可减少高铁血红蛋白引起的肾损伤，但不能减少缺血。结论：Gly-ARF对内毒素损伤的抵抗涉及诱导抗氧化反应，包括血红素加氧酶和铁蛋白合成的增加。这种耦合反应允许血红素的降解以及铁的螯合，从而减少氧化剂介导的组织损伤。这种内毒素诱导的抵抗的新机制可能不仅适用于Gly-ARF，而且适用于其他涉及氧化应激增强的组织损伤模型。
BACKGROUND Prior administration of endotoxin has conferred resistance to tissue damage in a number of models of organ injury. The mechanisms by which this resistance is conferred are enigmatic. Recognizing that enhanced tissue oxidative stress may be a feature of endotoxin-associated injury and is present in many models of tissue injury, we questioned whether the beneficial effect conferred by endotoxin is dependent on the up-regulation of antioxidant defenses. EXPERIMENTAL DESIGN We employed the glycerol model of acute renal failure (Gly-ARF), a model in which oxidant damage occurs in the kidney and other organs as a result of rhabdomyolysis and hemolysis. Rats were pretreated with endotoxin 24 hours before, or at the time of, induction of Gly-ARF. Renal functional studies and assessment of renal antioxidant status were performed. The effect of prior treatment with endotoxin was also examined in models of methemoglobin-induced and ischemic ARF. RESULTS Renal function was improved in rats pretreated with endotoxin but worsened in rats subjected to Gly-ARF and endotoxin simultaneously. Endotoxin induced heme oxygenase activity and ferritin content in the kidney but did not induce other antioxidant systems such as catalase and glutathione peroxidase. Treatment with a competitive inhibitor of heme oxygenase blocked endotoxin-induced protection on days 2 and 3, while markedly attenuating the protective effect on day 1. Pretreatment with endotoxin reduced renal injury induced by methemoglobin, but not ischemia. CONCLUSIONS The resistance to injury conferred by endotoxin in Gly-ARF involves induction of an antioxidant response, consisting of increased heme oxygenase and ferritin synthesis. This coupled response allows degradation of heme as well as chelation of iron, thus decreasing oxidant-mediated tissue injury. This novel mechanism of endotoxin-induced resistance may be applicable not only to Gly-ARF but also to other models of tissue injury in which enhanced oxidative stress is implicated.