Swain M G, Meddings J B
Liver Unit, University of Calgary, Alberta, Canada.
Life Sci. 1996;59(24):2093-8. doi: 10.1016/s0024-3205(96)00563-2.
We have recently described impaired IL-1 beta-induced activation of the hypothalamic-pituitary-adrenal (HPA) axis in cholestatic rats and have implicated defective IL-1 beta-mediated hypothalamic generation of PGE2 in this finding. Since patients with obstructive cholestasis have decreased levels of PGE2 precursor fatty acids in their red blood cell membranes (arachidonic acid) we speculated that a similar deficiency of membrane prostaglandin percursor fatty acids in the hypothalamus of cholestatic rats may contribute to the defective cytokine-mediated PGE2 generation we have previously described. Therefore, in this study we determined red blood cell and hypothalamic membrane fatty acid composition in rats with obstructive cholestasis due to bile duct resection and in non-cholestatic sham resected controls 5 days after operation. To do this red blood cell membrane and hypothalamic membrane fatty acids were extracted, methyl esterified and quantified by gas liquid chromatography. Similar to results found in patients with obstructive cholestasis, bile duct resected rats had significantly reduced levels of red blood cell membrane arachidonic acid compared to levels in sham resected controls (p < or = 0.02). However, bile duct resected and sham resected rats had similar levels of hypothalamic membrane arachidonic acid. Therefore, these results suggest that the impaired IL-1 beta-induced HPA axis activation in cholestatic rats cannot be explained by lower hypothalamic membrane levels of the PGE2 substrate arachidonic acid in these animals. Furthermore, our results suggest that the brain in cholestasis appears to be protected from membrane fatty acid composition alterations which are seen outside the blood-brain-barrier.
我们最近描述了胆汁淤积大鼠中白细胞介素-1β（IL-1β）诱导的下丘脑-垂体-肾上腺（HPA）轴激活受损，并认为这一发现与IL-1β介导的下丘脑前列腺素E2（PGE2）生成缺陷有关。由于阻塞性胆汁淤积患者红细胞膜中PGE2前体脂肪酸（花生四烯酸）水平降低，我们推测胆汁淤积大鼠下丘脑中类似的膜前列腺素前体脂肪酸缺乏可能导致了我们之前描述的细胞因子介导的PGE2生成缺陷。因此，在本研究中，我们测定了胆管切除所致阻塞性胆汁淤积大鼠及假手术切除对照大鼠术后5天的红细胞和下丘脑膜脂肪酸组成。为此，提取红细胞膜和下丘脑膜脂肪酸，进行甲酯化处理，并通过气相色谱法定量。与阻塞性胆汁淤积患者的结果相似，与假手术切除对照大鼠相比，胆管切除大鼠红细胞膜花生四烯酸水平显著降低（p≤0.02）。然而，胆管切除大鼠和假手术切除大鼠下丘脑膜花生四烯酸水平相似。因此，这些结果表明，胆汁淤积大鼠中IL-1β诱导的HPA轴激活受损不能用这些动物下丘脑中PGE2底物花生四烯酸的膜水平降低来解释。此外，我们的结果表明，胆汁淤积时大脑似乎受到保护，免受血脑屏障外所见的膜脂肪酸组成改变的影响。
