Allen T M, Smuckler E A
Res Commun Chem Pathol Pharmacol. 1985 Nov;50(2):281-90.
Particulate drug carriers have a pronounced tendency to localize in the mononuclear phagocyte system and chronic administration of such carriers can result in reticuloendothelial (RE) blockade. In a previous study (Allen et al., J. Pharmacol. Exp. Therap., 229, 267, 1984) we have examined the ability of chronic i.v. administration of liposomes of a variety of compositions to cause RE blockade in mice. In this communication we report on the time course of histological changes in liver accompanying chronic liposome administration in samples collected at the time of our previous studies. The predominant histological feature was the appearance of a granulomatous reaction in liver. Granulomas were frequent in liver tissue of mice receiving 2 or more injections of sphingomyelin:phosphatidylcholine, 4:1 or distearoylphosphatidylcholine:cholesterol, 1:1 liposomes, but disappeared shortly after termination of liposome injections. In mice receiving phosphatidylcholine:cholesterol, 2:1 liposomes no granulomas in liver were apparent during the injection course (10 injections of 2 mg phospholipid each over 25 days) but granulomatous inflammation of the liver became apparent 2 weeks after the last injection and had not resolved by 9 weeks post-injection. The appearance of granulomas was correlated with depression of phagocytic index and their disappearance was correlated with normalization or stimulation of reticuloendothelial function. These observations may be related to the rate of phospholipid metabolism for the various phospholipid types or to the nature of phospholipid metabolites.
微粒药物载体有明显的倾向定位于单核吞噬细胞系统，长期给予此类载体可导致网状内皮（RE）阻滞。在之前的一项研究中（Allen等人，《药理学与实验治疗学杂志》，229, 267, 1984），我们研究了长期静脉注射多种组成的脂质体在小鼠中引起RE阻滞的能力。在本通讯中，我们报告了在我们之前研究时收集的样本中，伴随长期脂质体给药肝脏组织学变化的时间进程。主要的组织学特征是肝脏中出现肉芽肿反应。在接受2次或更多次鞘磷脂：磷脂酰胆碱（4:1）或二硬脂酰磷脂酰胆碱：胆固醇（1:1）脂质体注射的小鼠肝脏组织中肉芽肿很常见，但在脂质体注射终止后不久就消失了。在接受磷脂酰胆碱：胆固醇（2:1）脂质体注射的小鼠中，在注射过程中（25天内每次注射2 mg磷脂，共注射10次）肝脏中未出现明显的肉芽肿，但在最后一次注射后2周肝脏出现肉芽肿性炎症，且在注射后9周仍未消退。肉芽肿的出现与吞噬指数降低相关，其消失与网状内皮功能恢复正常或增强相关。这些观察结果可能与不同磷脂类型的磷脂代谢速率或磷脂代谢产物的性质有关。
