CHYLOMICRONS ALTER THE FATE OF ENDOTOXIN, DECREASING TUMOR-NECROSIS-FACTOR RELEASE AND PREVENTING DEATH
CHYLOMICRONS ALTER THE FATE OF ENDOTOXIN, DECREASING TUMOR-NECROSIS-FACTOR RELEASE AND PREVENTING DEATH
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DOI：
10.1172/jci116259
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发表时间：
1993-03-01
影响因子：
15.9
通讯作者：
RAPP, JH
中科院分区：
文献类型：
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作者：
HARRIS, HW;GRUNFELD, C;RAPP, JH
感染的高甘油三酯血症传统上被认为代表着底物的动员，以刺激身体对感染挑战的反应。然而，我们之前已经证明，富含甘油三酯的脂蛋白可以保护内毒素诱导的致死性。目前的研究考察了这种保护发生的机制。与单独注射内毒素的大鼠相比，注射致死剂量的内毒素与乳糜粒预先孵育的大鼠相比，死亡率降低了15%(P<；0.001)。用乳胶粒预先孵育可提高血浆内毒素的清除率，并使肝脏清除内毒素的量增加一倍(30+/-1比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，而不是肝巨噬细胞。与对照组相比，注入内毒素+乳糜粒的大鼠血清肿瘤坏死因子峰值水平也降低(14.2+/-3.3vs.44.9+/-9.5 ng/ml，平均+/-扫描电子显微镜，P=0.014)。在单独的实验中，在注入内毒素前10分钟，注入乳糜微粒(1,000毫克甘油三酯/公斤)或生理盐水。与单独输注内毒素的大鼠相比，乳糜米隆预处理导致死亡率降低(22vs.78%，P<；0.005)。因此，无论是否预先与内毒素孵育，乳胶粒都可以预防内毒素诱导的致死。乳胶粒保护内毒素的机制似乎涉及内毒素分流到肝细胞而远离巨噬细胞，从而减少巨噬细胞的激活和细胞因子的分泌。
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.