Pathogenetic Significance of Lipid Peroxidation in Various Cell Injuries, with a Special Reference to the Investigation on Cell Biological Characteristics of Glutathione Peroxidase-an Anti-lipoperoxidative Agent.

通过对肝细胞和巨噬细胞脂质过氧化损伤或脂质过氧化增强的一系列实验，证明一定程度的脂质过氧化可引起这些细胞内有效的脂质过氧化清除剂谷胱甘肽过氧化物酶(GSH-PO)的增加。另一方面，某些细胞中GSH-PO合成的增加强烈地表明这些细胞中可能已经诱导了脂质过氧化的增加。在此基础上，利用本实验室制备的抗人GSH-PO，经免疫印迹试验验证其免疫组织化学有效性后，对GSH-PO在动脉粥样硬化病变中的免疫组织化学定位进行了研究。结果表明，谷胱甘肽过氧化物酶定位于“泡沫细胞”，推测泡沫细胞来源于浸润性肌炎S和血管内膜平滑肌细胞。作为“泡沫细胞”前体的变性和/或变形的SMC也显示GSH-PO的免疫过氧化物酶染色。非动脉粥样硬化性动脉的GSH-PO免疫过氧化物酶活性较弱，而非动脉粥样硬化性动脉中膜细胞GSH-PO免疫过氧化物酶活性较弱。为了研究上述变化的过程和原因刺激，给兔喂高胆固醇饲料(Oriental-Kohbo Co.LED)，该饲料确实能在动脉中引起典型的动脉粥样硬化改变。在单层内皮细胞正下方排列的泡沫M S中观察到了最初的谷胱甘肽-PO现象。饮食开始后2周。随后，这些GSH-PO阳性细胞的数量增加，GSH阳性的SMC在第4~8周首次出现。总结这些结果，强调了这些泡沫细胞中发生的脂质过氧化在动脉粥样硬化中的发病意义。

Through a series of the experiments on lipoperoxidative cell injury or the enhanced lipid peroxidation in hepatocytes and peritoneal macrophages (M ), it was proved that the lipid peroxidation of certain degree elicited the increase of the glutathione peroxidase (GSH-PO), the effective lipid peroxides scavenger, in those cells. The other way around, the increase of GSH-PO synthesis in certain cell would strongly suggest that the increased lipid peroxidation may have been induced in those cells. On the basis of this notion, the immunohistochemical localization of GSH-PO in the atherosclerotic lesions of human arteries was investigated utilizing the anti human GSH-PO prepared in our laboratory after its immunohistochemical validity was checked by "Western" immunoblotting test. As a results, GSH-PO was specifically localized in "foamy cells" which are supposed to be originated from both the infiltrating M s and the intimal smooth muscle cells (SMC). Degenerated and/or deformed SMCs which are precursor to the "foamy cell" also showed the intense immunoperoxidase staining for the GSH-PO. Non-atherosclerotic arteries did not show such GSH-PO immunoperoxidase staining except the very weak staining shown in SMCs in their media.In order to examine the course and the causative stimulation of the above changes, rabbits were fed with the high cholesterol diet (Oriental-Kohbo Co. Led) which was proved to induce typical atherosclerotic changes in their arteries for sure. The initial GSH-PO appeorance was observed in the foamy M s lined just beneath the endothelial cells in a monolayer. 2 weeks after the initiation of the diet. Sequentially, such GSH-PO positive cells increased their number, and GSH-positive SMCs gave their first appearance at 4th to 8th week.Summerizing these results, the pathogenetic significance of the lipid peroxidation taking place in those "foamy cells" for atherosclerosis was stressed.