Vogt B A, Alam J, Croatt A J, Vercellotti G M, Nath K A
Department of Pediatrics and Medicine, University of Minnesota, Minneapolis, USA.
Lab Invest. 1995 Apr;72(4):474-83.
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.
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.
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.
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.
在内毒素预先给药的情况下，许多器官损伤模型中都出现了对组织损伤的抗性。赋予这种抗性的机制尚不明确。鉴于增强的组织氧化应激可能是内毒素相关损伤的一个特征，并且在许多组织损伤模型中都存在，我们不禁要问，内毒素赋予的有益作用是否依赖于抗氧化防御的上调。
我们采用了急性肾衰竭的甘油模型（Gly-ARF），在这个模型中，由于横纹肌溶解和溶血，肾脏和其他器官会发生氧化损伤。大鼠在诱导Gly-ARF前24小时或诱导时用内毒素进行预处理。进行了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急性肾衰竭和缺血性急性肾衰竭模型中研究了内毒素预先治疗的效果。
内毒素预处理的大鼠肾功能得到改善，但同时接受Gly-ARF和内毒素的大鼠肾功能恶化。内毒素诱导了肾脏中的血红素加氧酶活性和铁蛋白含量，但未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。用血红素加氧酶的竞争性抑制剂处理在第2天和第3天阻断了内毒素诱导的保护作用，同时在第1天显著减弱了保护作用。内毒素预处理可减轻高铁血红蛋白诱导的肾损伤，但对缺血性肾损伤无效。
内毒素在Gly-ARF中赋予的抗损伤作用涉及诱导抗氧化反应，包括血红素加氧酶和铁蛋白合成增加。这种联合反应使血红素降解以及铁螯合，从而减少氧化介导的组织损伤。内毒素诱导抗性的这种新机制可能不仅适用于Gly-ARF，也适用于其他涉及氧化应激增强的组织损伤模型。
