Harris H W, Grunfeld C, Feingold K R, Read T E, Kane J P, Jones A L, Eichbaum E B, Bland G F, Rapp J H
Department of Surgery, University of California, San Francisco (UCSF).
J Clin Invest. 1993 Mar;91(3):1028-34. doi: 10.1172/JCI116259.
The hypertriglyceridemia of infection was traditionally thought to represent the mobilization of substrate to fuel the body's response to the infectious challenge. However, we have previously shown that triglyceride-rich lipoproteins can protect against endotoxin-induced lethality. The current studies examine the mechanism by which this protection occurs. Rats infused with a lethal dose of endotoxin preincubated with chylomicrons had a reduced mortality compared with rats infused with endotoxin alone (15 vs. 76%, P < 0.001). Preincubation with chylomicrons increased the rate of clearance of endotoxin from plasma and doubled the amount of endotoxin cleared by the liver (30 +/- 1 vs. 14 +/- 2% of the total infused radiolabel, P < 0.001). In addition, autoradiographic studies showed that chylomicrons directed more of the endotoxin to hepatocytes and away from hepatic macrophages. Rats infused with endotoxin plus chylomicrons also showed reduced peak serum levels of tumor necrosis factor as compared with controls (14.2 +/- 3.3 vs. 44.9 +/- 9.5 ng/ml, mean +/- SEM, P = 0.014). In separate experiments, chylomicrons (1,000 mg triglyceride/kg) or saline were infused 10 min before the infusion of endotoxin. Chylomicron pretreatment resulted in a reduced mortality compared with rats infused with endotoxin alone (22 vs. 78%, P < 0.005). Therefore, chylomicrons can protect against endotoxin-induced lethality with and without preincubation with endotoxin. The mechanism by which chylomicrons protect against endotoxin appears to involve the shunting of endotoxin to hepatocytes and away from macrophages, thereby decreasing macrophage activation and the secretion of cytokines.
感染性高甘油三酯血症传统上被认为是机体动员底物以应对感染挑战的表现。然而，我们之前已经表明富含甘油三酯的脂蛋白可以保护机体免受内毒素诱导的致死性影响。当前的研究探讨了这种保护作用发生的机制。与单独输注内毒素的大鼠相比，预先与乳糜微粒孵育后再输注致死剂量内毒素的大鼠死亡率降低（15% 对 76%，P < 0.001）。与乳糜微粒预先孵育可提高内毒素从血浆中的清除率，并使肝脏清除的内毒素量增加一倍（占总输注放射性标记物的 30 ± 1% 对 14 ± 2%，P < 0.001）。此外，放射自显影研究表明，乳糜微粒将更多的内毒素导向肝细胞，使其远离肝巨噬细胞。与对照组相比，输注内毒素加乳糜微粒的大鼠血清肿瘤坏死因子的峰值水平也降低（14.2 ± 3.3 对 44.9 ± 9.5 ng/ml，平均值 ± 标准误，P = 0.014）。在单独的实验中，在内毒素输注前 10 分钟输注乳糜微粒（1000 mg 甘油三酯/千克）或生理盐水。与单独输注内毒素的大鼠相比，乳糜微粒预处理导致死亡率降低（22% 对 78%，P < 0.005）。因此，无论是否与内毒素预先孵育，乳糜微粒都可以保护机体免受内毒素诱导的致死性影响。乳糜微粒保护机体免受内毒素影响的机制似乎涉及将内毒素从巨噬细胞分流至肝细胞，从而减少巨噬细胞激活和细胞因子分泌。
