Low-density lipoprotein receptor-deficient mice are protected against lethal endotoxemia and severe gram-negative infections
Low-density lipoprotein receptor-deficient mice are protected against lethal endotoxemia and severe gram-negative infections
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DOI：
10.1172/jci118556
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发表时间：
1996-03-15
影响因子：
15.9
通讯作者：
vanderMeer, JWM
中科院分区：
文献类型：
--
作者：
Netea, MG;Demacker, PNM;vanderMeer, JWM
脂蛋白可以结合脂多糖 (LPS) 并减少 LPS 刺激的促炎细胞因子的产生。我们研究了低密度脂蛋白 (LDL) 血浆浓度升高对 LDL 受体缺陷小鼠 (LDLR-/-) 的 LPS 或活革兰氏阴性菌致死攻击后的生存和细胞因子产生的影响。与野生型对照（C57BI/6J）相比，用LPS攻击的LDLR-/-小鼠的LD（50）增加了八倍，而肿瘤坏死因子α（TNFα）和白细胞介素-1α（IL-1α）血浆浓度降低了两倍。感染肺炎克雷伯菌后，LDLR-/- 小鼠的死亡率显着低于对照小鼠，并且死亡率延迟。两组之间器官中细菌的生长没有差异，而 LDLR-/- 小鼠的循环细胞因子浓度降低两倍。相反，与对照组相比，LPS刺激的LDLR-/-小鼠腹膜巨噬细胞在体外产生的细胞因子显着增加。这种增加与 LPS 与 LDLR-/- 小鼠巨噬细胞的特异性结合增强有关。总之，内源性低密度脂蛋白可以防止内毒素和革兰氏阴性菌感染的致命影响。尽管细胞因子的产生能力有所增加，但至少部分保护是通过减少体内促炎细胞因子的产生来实现的。
Lipoproteins can bind lipopolysaccharide (LPS) and decrease the LPS-stimulated production of pro-inflammatory cytokines. We investigated the effect of increased plasma concentrations of low-density-lipoproteins (LDL) on survival and cytokine production after a lethal challenge with either LPS or live Gram-negative bacteria in LDL receptor deficient mice (LDLR-/-). The LDLR-/- mice challenged with LPS had an eightfold increased LD(50) when compared with the wild type controls (C57BI/6J), while tumor necrosis factor alpha (TNF alpha) and interleukin-l alpha (IL-1 alpha) plasma concentrations were decreased twofold. LDLR-/- mice had significantly lower and delayed mortality than control mice after infection with Klebsiella pneumoniae. No differences in the outgrowth of bacteria in the organs were present between the two groups, while circulating cytokine concentrations were decreased twofold in LDLR-/- mice. In contrast, the LPS-stimulated in vitro production of cytokines by peritoneal macrophages of LDLR-/- mice was significantly increased compared with controls. This increase was associated with enhanced specific binding of LPS to the macrophages of LDLR-/- mice. In conclusion, endogenous LDL can protect against the lethal effects of endotoxin and Gram-negative infection. At least part of this protection is achieved through decreased in vivo production of pro-inflammatory cytokines, in spite of increased cytokine production capacity.