Feingold K R, Funk J L, Moser A H, Shigenaga J K, Rapp J H, Grunfeld C
Department of Medicine, University of California, San Francisco, USA.
Infect Immun. 1995 May;63(5):2041-6. doi: 10.1128/iai.63.5.2041-2046.1995.
Previous studies have shown that endotoxin (lipopolysaccharide [LPS])-induced death can be prevented by preincubating LPS with lipoproteins in vitro or by infusing large quantities of lipids into animals prior to LPS administration. In the present study we determined whether physiological levels of lipids also provide protection. Serum lipid levels were decreased by two different mechanisms: administration of 4-aminopyrolo-(3,4-D)pyrimide, which prevents the hepatic secretion of lipoproteins, and administration of pharmacological doses of estradiol, which increases the number of hepatic low-density lipoprotein receptors, leading to increased lipoprotein clearance. In both hypolipidemic models, LPS-induced mortality is markedly increased compared with that of controls with normal serum lipid levels. In both hypolipidemic models, administration of exogenous lipoproteins, which increase levels of serum lipids into the physiological range, reduces the increased mortality to levels similar to that seen in normal animals. In normal lipidemic animals, 63% of 125I-LPS in plasma is associated with lipoproteins, where it would not be capable of stimulating cytokine production. In contrast, in hypolipidemic animals, very little LPS (12 to 17%) is associated with lipoproteins. Rather, more LPS is in the lipoprotein-free plasma compartment, where it could exert biological effects. In both hypolipidemic models, LPS produces a greater increase in serum tumor necrosis factor levels than it does in controls (three- to fivefold increase), and administration of exogenous lipoproteins prevents this increase. Cytokines, in particular tumor necrosis factor, are responsible for most of the toxic effects of LPS. These data provide evidence that physiological levels of serum lipids protect animals from LPS toxicity. Thus, lipoproteins, in addition to playing a role in lipid transport, may have protective functions. Moreover, as part of the immune response, cytokine-induced increases in serum lipid levels may play a role in host defense by decreasing the toxicities of biological and chemical agents.
先前的研究表明，通过在体外将内毒素（脂多糖[LPS]）与脂蛋白预孵育，或在给予LPS之前向动物输注大量脂质，可预防LPS诱导的死亡。在本研究中，我们确定生理水平的脂质是否也具有保护作用。通过两种不同机制降低血清脂质水平：给予4-氨基吡咯并-(3,4-D)嘧啶，其可阻止肝脏分泌脂蛋白；给予药理剂量的雌二醇，其可增加肝脏低密度脂蛋白受体数量，导致脂蛋白清除增加。在两种低脂血症模型中，与血清脂质水平正常的对照组相比，LPS诱导的死亡率显著增加。在两种低脂血症模型中，给予外源性脂蛋白可将血清脂质水平提高到生理范围，从而将增加的死亡率降低至与正常动物相似的水平。在血脂正常的动物中，血浆中63%的125I-LPS与脂蛋白结合，在此情况下其无法刺激细胞因子产生。相比之下，在低脂血症动物中，只有极少的LPS（12%至17%）与脂蛋白结合。相反，更多的LPS存在于无脂蛋白的血浆部分，在那里它可以发挥生物学作用。在两种低脂血症模型中，LPS导致血清肿瘤坏死因子水平的升高幅度均大于对照组（增加三至五倍），给予外源性脂蛋白可阻止这种升高。细胞因子，尤其是肿瘤坏死因子，是LPS大部分毒性作用的原因。这些数据表明生理水平的血清脂质可保护动物免受LPS毒性。因此，脂蛋白除了在脂质转运中发挥作用外，可能还具有保护功能。此外，作为免疫反应的一部分，细胞因子诱导的血清脂质水平升高可能通过降低生物和化学制剂的毒性在宿主防御中发挥作用。
