Hypophysectomy, high tumor necrosis factor levels, and hemoglobinemia in lethal endotoxemic shock
Hypophysectomy, high tumor necrosis factor levels, and hemoglobinemia in lethal endotoxemic shock
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DOI：
10.1097/00024382-199812000-00003
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发表时间：
1998-12-01
期刊：
影响因子：
3.1
通讯作者：
Tracey, KJ
中科院分区：
文献类型：
--
作者：
Bloom, O;Wang, HC;Tracey, KJ
啮齿类动物致死性内毒素血症的实验模型被广泛用于描述炎症、脓毒症和脓毒性休克的致病机制。一个长期存在但知之甚少的观察结果是，切除脑垂体（垂体切除术）使实验动物对脂多糖（LPS）的致命后遗症敏感1,000倍。以前对这种现象的解释集中在垂体切除术诱导的皮质类固醇缺乏，因为糖皮质激素有效地抑制肿瘤坏死因子（TNF）的合成，这是LPS致死的主要介质。我们测量了LPS刺激的巨噬细胞TNF释放的存在下，血清从垂体切除大鼠检测诱导的65 kDa蛋白，增强TNF释放的外观。令人惊讶的是，分离纯化的蛋白质的N-末端氨基酸序列分析揭示了其与血红蛋白的同一性。垂体切除术显著增加血清血红蛋白水平（对照血红蛋白= 103 +/-18 μ g/mL对比垂体切除的血清血红蛋白= 279 +/-13 μ g/mL; p <0.05）。纯化的血红蛋白使LPS刺激的巨噬细胞中的TNF合成增强至少1，000倍，其被抗血红蛋白抗体特异性抑制。因此，血红蛋白介导内毒素血症，垂体切除大鼠TNF合成增加。这种TNF释放增加的机制对输血、手术、损伤、感染或其他可能与内毒素血症和脓毒症相关的血红蛋白血症患者具有潜在意义。
Experimental models of lethal endotoxemia in rodents are widely used to delineate pathogenic mechanisms of inflammation, sepsis, and septic shock. One long-standing but poorly understood observation is that removal of the pituitary gland (hypophysectomy) renders experimental animals 1,000-fold more sensitive to the lethal sequelae of lipopolysaccharide (LPS). Previous explanations for this phenomenon focused on hypophysectomy-induced deficiencies of corticosteroids, because glucocorticoids effectively suppress the synthesis of tumor necrosis factor (TNF), which is a primary mediator of LPS lethality. We measured LPS-stimutated macrophage TNF release in the presence of serum from hypophysectomized rats to detect the appearance of an inducible 65 kDa protein that enhances TNF release. Surprisingly, the N-terminal amino acid sequence analysis of the isolated, purified protein revealed its identity as hemoglobin. Hypophysectomy significantly increases serum hemoglobin levels (control hemoglobin = 103 +/- 18 mu g/mL versus hypophysectomized serum hemoglobin = 279 +/- 13 mu g/mL; p < .05). Purified hemoglobin enhances TNF synthesis in LPS-stimulated macrophages by at least 1,000-fold, which is specifically inhibited by antihemoglobin antibodies. Thus, hemoglobin mediates increased TNF synthesis in endotoxemic, hypophysectomized rats. This mechanism of increased TNF release has potential implications for patients with hemoglobinemia following blood transfusion, surgery, injury, infection, or other conditions that can be associated with endotoxemia and sepsis.