Walker R M, McElligott T F
J Pathol. 1981 Dec;135(4):301-14. doi: 10.1002/path.1711350407.
Furosemide-induced (400mg/kg ip) hepatotoxicity progressing to centrilobular necrosis was studied by light and electron microscopy in Swiss white mice. Centrilobular glycogen depletion and cytoplasmic foaminess, usually accompanied by extensive vacuolation, were detectable by light microscopy 1 1/2 hr after furosemide. Centrilobular congestion and hydropic single cell necrosis developed after 3 hr. Electron microscopy revealed disaggregation of polyribosomes, vesiculation of endoplasmic reticulum, an endocytic origin for the vacuolation, and a definite sequence in the development of congestion. Vacuolation coincided with loss of microvilli and resulted in detachment of sinusoidal lining cells from hepatocytes. Small vacuoles apparently formed at the sinusoidal margin of hepatocytes by fusion of microvilli. Congestion and occlusion of sinusoidal lumens developed as a consequence of erythrocytes entering the enlarged Disse space, possibly through pores in the lining cells, and thence entering endocytic vacuoles. The vacuolation, loss of microvilli and terminal hydropic degeneration suggest an important role for the plasma membrane in the development of furosemide-induced hepatotoxicity. Comparisons with known membrane toxins support this concept.
通过光学显微镜和电子显微镜研究了速尿（400mg/kg腹腔注射）诱导的瑞士小白鼠肝毒性进展至小叶中心坏死的情况。速尿给药1.5小时后，光学显微镜下可检测到小叶中心糖原耗竭和细胞质泡沫化，通常伴有广泛的空泡形成。3小时后出现小叶中心充血和水样单细胞坏死。电子显微镜显示多核糖体解聚、内质网囊泡化、空泡形成的内吞起源以及充血发展的明确顺序。空泡形成与微绒毛丧失同时发生，并导致肝血窦衬里细胞与肝细胞分离。小空泡显然是由微绒毛融合在肝细胞的肝血窦边缘形成的。由于红细胞进入扩大的狄氏间隙（可能通过衬里细胞的孔隙），进而进入内吞空泡，导致肝血窦腔充血和阻塞。空泡形成、微绒毛丧失和终末期水样变性表明质膜在速尿诱导的肝毒性发展中起重要作用。与已知膜毒素的比较支持这一概念。
