Smith J S, Tian J, Muller J, Byrnes A P
Division of Cellular and Gene Therapies, Center for Biologics Evaluation and Research, Food and Drug Administration, Bethesda, MD, USA.
Gene Ther. 2004 Mar;11(5):431-8. doi: 10.1038/sj.gt.3302149.
When adenovirus vectors are injected intravenously, most of the virions are quickly taken up by the reticuloendothelial system, primarily by the liver macrophages known as Kupffer cells. However, little is known about the behavior of adenovirus vectors when there is pre-existing liver disease. To study this, we examined the biodistribution of intravenously injected vector in a rat model of cirrhosis induced by bile duct ligation. Using quantitative PCR and fluorescently tagged adenovirus vectors, we observed a significant reduction in vector uptake by the cirrhotic liver and increased accumulation in the lungs. Immunocytochemistry and electron microscopy demonstrated that this was due to changes in the reticuloendothelial system, with the vector being taken up by large numbers of pulmonary intravascular macrophages in the lungs of cirrhotic rats. Interestingly, expression of vector-encoded luciferase was significantly reduced in the livers of cirrhotic rats, but was not increased in the lungs. These data demonstrate that the biodistribution of adenovirus vectors in rats is altered by cirrhosis, which suggests the possibility that these vectors might behave unexpectedly in patients with pre-existing liver conditions, particularly since pulmonary reticuloendothelial changes are known to occur in human disease.
当静脉注射腺病毒载体时，大多数病毒粒子会迅速被网状内皮系统摄取，主要是被称为库普弗细胞的肝巨噬细胞摄取。然而，对于存在肝脏疾病时腺病毒载体的行为知之甚少。为了研究这一点，我们在胆管结扎诱导的肝硬化大鼠模型中检查了静脉注射载体的生物分布。使用定量PCR和荧光标记的腺病毒载体，我们观察到肝硬化肝脏对载体的摄取显著减少，而在肺部的积累增加。免疫细胞化学和电子显微镜表明，这是由于网状内皮系统的变化，载体被肝硬化大鼠肺部的大量肺血管内巨噬细胞摄取。有趣的是，载体编码的荧光素酶在肝硬化大鼠肝脏中的表达显著降低，但在肺部并未增加。这些数据表明，肝硬化会改变大鼠体内腺病毒载体的生物分布，这表明这些载体在已有肝脏疾病的患者中可能会出现意想不到的行为，特别是因为已知在人类疾病中会发生肺网状内皮系统的变化。
