毒理性
炎症介质协调宿主对急性细菌感染的免疫和代谢反应，并介导导致败血症休克的事件。肿瘤坏死因子（TNF）长期以来一直被认为是内毒素作用近端介质之一。最近的研究表明，过氧化物酶体增殖激活受体alpha（PPARalpha）可能是调节免疫反应的潜在靶标。由于PPARalpha激活剂（一种降血脂药物）正在被大量老年患者使用，因此确定这些药物对宿主对急性炎症反应的影响非常重要。因此，我们检查了PPARalpha激活剂在小鼠内毒素血症模型中对TNF表达调节的作用。经饮食处理的fenofibrate或Wy-14,643的CD-1小鼠，其LPS诱导的TNF血浆水平比LPS处理的对照饲养动物高出五倍。药物饲养动物中较高的LPS诱导的TNF水平在生理上反映为血浆中的葡萄糖水平显著降低，以及50%致死剂量显著低于LPS处理的对照饲养动物。使用PPARalpha野生型（WT）和敲除（KO）小鼠，我们证明了fenofibrate对LPS诱导的TNF表达的作用确实是由PPARalpha介导的。服用fenofibrate的PPARalpha WT小鼠的LPS诱导的TNF水平也较对照饲养动物增加了五倍。然而，服用fenofibrate的PPARalpha KO小鼠的LPS诱导的TNF水平显著降低，血浆中的葡萄糖水平显著升高，与对照饲养动物相比。来自腹膜巨噬细胞研究的资料显示，Wy-14,643在体外适度降低了TNF表达。类似地，293T细胞中PPARalpha的过表达降低了人类TNF启动子-荧光素酶构建体的活性。这些研究的结果表明，PPARalpha在体内的任何抗炎活性都可能被PPARalpha激活剂的其它系统性效果所掩盖。
Inflammatory mediators orchestrate the host immune and metabolic response to acute bacterial infections and mediate the events leading to septic shock. Tumor necrosis factor (TNF) has long been identified as one of the proximal mediators of endotoxin action. Recent studies have implicated peroxisome proliferator-activated receptor alpha (PPARalpha) as a potential target to modulate regulation of the immune response. Since PPARalpha activators, which are hypolipidemic drugs, are being prescribed for a significant population of older patients, it is important to determine the impact of these drugs on the host response to acute inflammation. Therefore, we examined the role of PPARalpha activators on the regulation of TNF expression in a mouse model of endotoxemia. CD-1 mice treated with dietary fenofibrate or Wy-14,643 had fivefold-higher lipopolysaccharide (LPS)-induced TNF plasma levels than LPS-treated control-fed animals. Higher LPS-induced TNF levels in drug-fed animals were reflected physiologically in significantly lower glucose levels in plasma and a significantly lower 50% lethal dose than those in LPS-treated control-fed animals. Utilizing PPARalpha wild-type (WT) and knockout (KO) mice, we showed that the effect of fenofibrate on LPS-induced TNF expression was indeed mediated by PPARalpha. PPARalpha WT mice fed fenofibrate also had a fivefold increase in LPS-induced TNF levels in plasma compared to control-fed animals. However, LPS-induced TNF levels were significantly decreased and glucose levels in plasma were significantly increased in PPARalpha KO mice fed fenofibrate compared to those in control-fed animals. Data from peritoneal macrophage studies indicate that Wy-14,643 modestly decreased TNF expression in vitro. Similarly, overexpression of PPARalpha in 293T cells decreased activity of a human TNF promoter-luciferase construct. The results from these studies suggest that any anti-inflammatory activity of PPARalpha in vivo can be masked by other systemic effects of PPARalpha activators.
来源:Hazardous Substances Data Bank (HSDB)
