McDonagh J, Fossel E T, Kradin R L, Dubinett S M, Laposata M, Hallaq Y A
Department of Pathology, Beth Israel Hospital, Massachusetts General Hospital, Boston, MA 02215.
Blood. 1992 Dec 15;80(12):3217-26.
Changes in the plasma lipid composition are observed in patients and animals with malignancy and certain other diseases that are consistent with peroxidation of plasma lipoprotein lipids. These changes can be observed with water-suppressed proton (H-1) and carbon-13 (C-13) nuclear magnetic resonance spectroscopy (NMR) and gas chromatography. Gas chromatography provides evidence of a decrease in polyunsaturated fatty acids relative to monounsaturated fatty acids. This evidence is consistent with that observed by C-13 NMR spectroscopy. Mediators for these effects were sought. Cytokines, known to be released in response to malignant tumor cells and to affect lipid metabolism, were injected into normal mice and their effects on the H-1 and C-13 NMR spectra of plasma lipids were observed. Mouse recombinant tumor necrosis factor-alpha (mr-TNF-alpha) significantly decreased the H-1 methyl and methylene lipid linewidths, and the C-13 spectra indicated a decrease in the relative concentration of polyunsaturated fatty acids. The same changes were directly confirmed by gas chromatographic analysis, showing decreases in the amount of linoleic and arachidonic acids and other polyunsaturated fatty acids relative to monounsaturated fatty acids and in the ratio of polyunsaturated to monounsaturated fatty acids. Serial plasma samples from volunteers receiving an infusion of endotoxin showed similar changes in their C-13 NMR spectroscopy at times when peak TNF-alpha values were measured. In addition, in these samples the C-13 NMR spectra showed direct evidence of lipid peroxidation products. These changes were similar to those observed commonly in the plasma of cancer patients. Other cytokines (human recombinant interleukin-1 alpha [hr-IL-1 alpha], hr-IL-2, mouse recombinant interferon-gamma) did not produce these effects. We conclude that TNF-alpha is a mediator (but not necessarily the only one) of changes in plasma lipoprotein lipid composition due to peroxidation and that this is a mechanism for the changes observed in the NMR spectra of plasma from cancer patients and from normal animals injected with TNF-alpha.
在患有恶性肿瘤及某些其他疾病的患者和动物中，可观察到血浆脂质成分的变化，这些变化与血浆脂蛋白脂质的过氧化作用相一致。利用水抑制质子（H-1）和碳-13（C-13）核磁共振波谱法（NMR）以及气相色谱法均可观察到这些变化。气相色谱法证实，相对于单不饱和脂肪酸，多不饱和脂肪酸有所减少。这一证据与C-13 NMR波谱法所观察到的结果一致。研究人员探寻了这些效应的介质。已知细胞因子会因恶性肿瘤细胞而释放，并影响脂质代谢，于是将其注入正常小鼠体内，观察其对血浆脂质H-1和C-13 NMR波谱的影响。小鼠重组肿瘤坏死因子-α（mr-TNF-α）显著降低了H-1甲基和亚甲基脂质线宽，C-13波谱显示多不饱和脂肪酸的相对浓度有所降低。气相色谱分析直接证实了相同的变化，结果表明，相对于单不饱和脂肪酸，亚油酸、花生四烯酸及其他多不饱和脂肪酸的含量减少，多不饱和脂肪酸与单不饱和脂肪酸的比例也降低。接受内毒素输注的志愿者的系列血浆样本，在测量到TNF-α峰值时，其C-13 NMR波谱也出现了类似变化。此外，在这些样本中，C-13 NMR波谱还直接显示了脂质过氧化产物的存在。这些变化与癌症患者血浆中常见的变化相似。其他细胞因子（人重组白细胞介素-1α [hr-IL-1α]、hr-IL-2、小鼠重组干扰素-γ）并未产生这些效应。我们得出结论，TNF-α是血浆脂蛋白脂质成分因过氧化作用而发生变化的介质（但不一定是唯一介质），这也是癌症患者血浆及注射TNF-α的正常动物血浆NMR波谱中所观察到的变化机制。
