Laurén D J, Teh S J, Hinton D E
Department of Medicine, School of Veterinary Medicine, University of California, Davis 95616.
Cancer Res. 1990 Sep 1;50(17):5504-14.
Adult Oryzias latipes were exposed to 50 mg of diethylnitrosamine per liter of water for 5 wk and then transferred to clean water for an additional 15 wk. Response of the liver during the first 6 wk were analyzed by enzyme histochemistry and by high-resolution light and transmission electron microscopy. After 1 wk, cytotoxicity was apparent at the light microscopic level by piecemeal necrosis and phagocytosis apoptosis by adjacent hepatocytes and resident macrophages. Spongiosis hepatis and inflammation, found as early as wk 3, were not widespread until wk 6. Glycogen depletion and multifocal increases in gamma-glutamyl transpeptidase were found as early as 3 wk. At 5 wk, macrophage infiltration and aggregation and hepatocyte lysosome proliferation were revealed by an increase in cells staining for acid phosphatase. In addition, a subpopulation of macrophages stained positively for glucose-6-phosphate dehydrogenase during wk 6. Other histochemical biomarkers (Mg2(+)-ATPase, DT-diaphorase, uridine diphosphoglucuronyl dehydrogenase) were not altered. Mitotic figures were rare for the entire 6-wk period. At the ultrastructural level, necrotic alterations of some hepatocytes were seen within 24 h. Within 48 h, an apparent reduction of hepatocyte glycogen and cell volume characterized the majority of hepatocytes; this was accompanied by an increase in interhepatocytic space and the length and complexity of the hepatocyte microvillous projections found in the space of Disse. Lipid vacuolar inclusions inhabited space previously occupied by glycogen. Margins of hepatocyte nuclei were irregular, and mitochondria were condensed and their shape altered so that crescentric and elongated profiles were abundant. Lysosomes and residual bodies were increased after 1 wk. The cytoplasmic processes delineating spongiotic lesions were identified as originating from Ito cells. After 4 wk, apparent proliferation of smooth endoplasmic reticulum and retention of transport lipid within its cisternae were seen. The toxic depletion of hepatocytes and the attendant altered cellular environment are discussed in relation to cell-to-cell interactions and the possible contribution of stromal and extracellular matrix changes to liver regeneration and neoplasia.
将成年日本青鳉暴露于每升含50毫克二乙基亚硝胺的水中5周，然后再转移至清洁水中15周。在前6周期间，通过酶组织化学以及高分辨率光学显微镜和透射电子显微镜分析肝脏的反应。1周后，在光学显微镜水平上，可见散在性坏死以及相邻肝细胞和驻留巨噬细胞的吞噬性凋亡，提示细胞毒性。肝海绵样变和炎症最早在第3周出现，但直到第6周才广泛存在。早在第3周就发现糖原耗竭和γ-谷氨酰转肽酶多灶性增加。在第5周，酸性磷酸酶染色细胞增多，提示巨噬细胞浸润和聚集以及肝细胞溶酶体增殖。此外，在第6周期间，有一部分巨噬细胞葡萄糖-6-磷酸脱氢酶染色呈阳性。其他组织化学生物标志物（Mg2(+)-ATP酶、DT-黄递酶、尿苷二磷酸葡糖醛酸脱氢酶）未发生改变。在整个6周期间，有丝分裂象罕见。在超微结构水平上，在24小时内可见一些肝细胞出现坏死改变。48小时内，大多数肝细胞表现为肝细胞糖原明显减少和细胞体积减小；同时，肝血窦内肝细胞间隙增宽，肝细胞微绒毛突起的长度和复杂性增加。脂滴空泡占据了以前糖原所在的空间。肝细胞核边缘不规则，线粒体浓缩且形态改变，出现大量新月形和细长形轮廓。1周后溶酶体和残余体增多。界定海绵样病变的细胞质突起被确定源自伊托细胞。4周后，可见滑面内质网明显增殖，其池内有运输脂质潴留。本文讨论了肝细胞的毒性耗竭以及随之改变的细胞环境与细胞间相互作用的关系，以及基质和细胞外基质变化对肝脏再生和肿瘤形成的可能作用。
