A novel endotoxin-induced pathway:: upregulation of heme oxygenase 1, accumulation of free iron, and free iron-mediated mitochondrial dysfunction
A novel endotoxin-induced pathway:: upregulation of heme oxygenase 1, accumulation of free iron, and free iron-mediated mitochondrial dysfunction
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DOI：
10.1038/labinvest.3700691
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发表时间：
2008-01-01
影响因子：
5
通讯作者：
Kozlov, Andrey V.
中科院分区：
文献类型：
--
作者：
Duvigneau, J. Catharina;Piskernik, Christina;Kozlov, Andrey V.
线粒体参与重症监护疾病器官衰竭的发展。然而，线粒体功能障碍的机制尚不清楚。诱导型血氧合酶 (HO-1) 是热休克蛋白家族的成员，在重症监护疾病中表达上调，并被认为具有针对氧化应激的细胞保护作用。然而，HO-1 的产物之一是 Fe2+，它会增加活性氧催化芬顿反应的破坏潜力。本研究的目的是阐明游离铁代谢与内毒素休克中肝脏氧化损伤的相关性及其对线粒体功能的影响。通过注射 8 mg/kg（静脉注射）剂量的脂多糖（LPS）诱导大鼠内毒素休克。我们观察到血液中促炎细胞因子 TNF-α 和肝坏死标志物天冬氨酸转氨酶增加，分别证实了对 LPS 的炎症反应和对肝组织的损伤。内毒素休克发生后4和8小时，肝脏中游离铁的水平显着升高，这与血液中转铁蛋白铁水平的降低并不相符，而是与诱导型血红素加氧酶（HO-1）的表达有关。对隔离游离铁（铁蛋白）和将铁输出到细胞外（铁转运蛋白）很重要的蛋白质被下调，促进细胞中游离铁的积累。肝脏中游离铁浓度暂时升高与线粒体功能和组织 ATP 水平暂时受损相关。向从对照动物分离的线粒体中添加外源铁离子会导致线粒体呼吸受损，类似于体内内毒素休克中观察到的情况。我们的数据表明，HO-1 释放的游离铁在伴有内毒素休克的病理情况下导致线粒体功能障碍。
Mitochondria are involved in the development of organ failure in critical care diseases. However, the mechanisms underlying mitochondrial dysfunction are not clear yet. Inducible hemoxygenase (HO-1), a member of the heat shock protein family, is upregulated in critical care diseases and considered to confer cytoprotection against oxidative stress. However, one of the products of HO-1 is Fe2+ which multiplies the damaging potential of reactive oxygen species catalyzing Fenton reaction. The aim of this study was to clarify the relevance of free iron metabolism to the oxidative damage of the liver in endotoxic shock and its impact on mitochondrial function. Endotoxic shock in rats was induced by injection of lipopolysaccharide (LPS) at a dose of 8 mg/kg (i.v.). We observed that the pro-inflammatory cytokine TNF-alpha and the liver necrosis marker aspartate aminotransferase were increased in blood, confirming inflammatory response to LPS and damage to liver tissue, respectively. The levels of free iron in the liver were significantly increased at 4 and 8 h after onset of endotoxic shock, which did not coincide with the decrease of transferrin iron levels in the blood, but rather with expression of the inducible form of heme oxygenase (HO-1). The proteins important for sequestering free iron ( ferritin) and the export of iron out of the cells ( ferroportin) were downregulated facilitating the accumulation of free iron in cells. The temporarily increased concentration of free iron in the liver correlated with the temporary impairment of both mitochondrial function and tissue ATP levels. Addition of exogenous iron ions to mitochondria isolated from control animals resulted in an impairment of mitochondrial respiration similar to that observed in endotoxic shock in vivo. Our data suggest that free iron released by HO-1 causes mitochondrial dysfunction in pathological situations accompanied by endotoxic shock.