Protective role of phospholipid oxidation products in endotoxin-induced tissue damage
Protective role of phospholipid oxidation products in endotoxin-induced tissue damage
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DOI：
10.1038/nature01023
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发表时间：
2002-09-05
期刊：
影响因子：
64.8
通讯作者：
Leitinger, N
中科院分区：
文献类型：
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作者：
Bochkov, VN;Kadl, A;Leitinger, N
脂多糖（LPS）是革兰氏阴性菌的外膜组分，与LPS结合蛋白和CD 14相互作用，后者将LPS呈递给toll样受体4（参考文献1，2），后者通过核因子κ B（NF κ B）和丝裂原活化蛋白激酶信号传导激活炎症基因表达（3，4）。抗菌防御涉及中性粒细胞的活化，其产生能够杀死细菌的活性氧物质（5）;因此宿主脂质过氧化发生，由NADPH氧化酶和髓过氧化物酶等酶引发（6）。氧化磷脂是促进动脉粥样硬化慢性炎症的促炎激动剂（7）;然而，最近的数据表明，它们可以抑制炎症粘附分子的表达（8）。我们发现氧化磷脂通过阻断LPS与LPS结合蛋白和CD 14的相互作用，抑制LPS诱导的炎症基因上调，但不抑制肿瘤坏死因子α诱导的或白细胞介素1 β诱导的NF κ B介导的炎症基因上调。此外，在注射LPS的小鼠中，氧化磷脂抑制炎症并保护小鼠免受致命的内毒素休克。因此，在严重的革兰氏阴性细菌感染中，内源性形成的氧化磷脂可作为负反馈来减弱先天免疫应答。此外，鉴定的能够抑制内毒素如LPS的作用的化学结构可用于开发用于治疗脓毒症的新药。
Lipopolysaccharide (LPS), an outer-membrane component of Gram-negative bacteria, interacts with LPS-binding protein and CD14, which present LPS to toll-like receptor 4 (refs 1, 2), which activates inflammatory gene expression through nuclear factor kappaB (NFkappaB) and mitogen-activated protein-kinase signalling(3,4). Antibacterial defence involves activation of neutrophils that generate reactive oxygen species capable of killing bacteria(5); therefore host lipid peroxidation occurs, initiated by enzymes such as NADPH oxidase and myeloperoxidase(6). Oxidized phospholipids are pro-inflammatory agonists promoting chronic inflammation in atherosclerosis(7); however, recent data suggest that they can inhibit expression of inflammatory adhesion molecules(8). Here we show that oxidized phospholipids inhibit LPS-induced but not tumour-necrosis factor-alpha-induced or interleukin-1beta-induced NFkappaB-mediated upregulation of inflammatory genes, by blocking the interaction of LPS with LPS-binding protein and CD14. Moreover, in LPS-injected mice, oxidized phospholipids inhibited inflammation and protected mice from lethal endotoxin shock. Thus, in severe Gram-negative bacterial infection, endogenously formed oxidized phospholipids may function as a negative feedback to blunt innate immune responses. Furthermore, identified chemical structures capable of inhibiting the effects of endotoxins such as LPS could be used for the development of new drugs for treatment of sepsis.