Le Couteur D G, Cogger V C, Markus A M, Harvey P J, Yin Z L, Ansselin A D, McLean A J
The Canberra Clinical School of the University of Sydney, Garran, Australia.
Hepatology. 2001 Mar;33(3):537-43. doi: 10.1053/jhep.2001.22754.
Age-related impairment of drug metabolism by the liver is consistent with hepatocyte hypoxia, suggestive of the development of a diffusional barrier to oxygen supply. Because the effects of aging on the diffusional pathway (sinusoidal endothelium and space of Disse) have not been described, we performed comparative studies on the livers of Fischer F344 rats aged 4 to 7, 12 to 15, and 24 to 27 months. Light-microscopic examination revealed no evidence of fibrosis, cirrhosis, or other specific pathology. In contrast, scanning and transmission electron-microscopic examination revealed that aging is associated with pseudocapillarization of the sinusoidal endothelium, indicated by defenestration with reduced porosity, thickening of the endothelium, infrequent development of basal lamina, and only minor collagen deposits in the space of Disse. Furthermore, immunohistochemistry studies showed strong expression of collagen IV, moderate expression of factor VIII-related antigen, and weak expression of collagen I along the sinusoids of livers from old rats (P <.0001). In vitro (31)P magnetic resonance spectroscopy analysis showed that aging is associated with changes in high-energy phosphate and other metabolites, consistent with hepatocyte hypoxia. Aging in the liver is associated with changes in the sinusoidal endothelium and space of Disse that may restrict the availability of oxygen and other substrates.
肝脏中与年龄相关的药物代谢受损与肝细胞缺氧一致，提示存在对氧气供应的扩散屏障。由于衰老对扩散途径（窦状内皮和狄氏间隙）的影响尚未见报道，我们对4至7个月、12至15个月和24至27个月的Fischer F344大鼠肝脏进行了比较研究。光学显微镜检查未发现纤维化、肝硬化或其他特定病理改变的证据。相比之下，扫描电镜和透射电镜检查显示，衰老与窦状内皮的假毛细血管化有关，表现为窗孔消失、孔隙率降低、内皮增厚、基底膜形成不常见以及狄氏间隙中仅有少量胶原沉积。此外，免疫组织化学研究显示，老年大鼠肝脏窦状隙周围IV型胶原表达强烈、VIII因子相关抗原表达中等、I型胶原表达较弱（P <.0001）。体外磷磁共振波谱分析显示，衰老与高能磷酸酯和其他代谢物的变化有关，与肝细胞缺氧一致。肝脏衰老与窦状内皮和狄氏间隙的变化有关，这些变化可能会限制氧气和其他底物的供应。
