Saperstein L A, Jirtle R L, Farouk M, Thompson H J, Chung K S, Meyers W C
Department of Surgery, Duke University Medical Center, Durham, North Carolina 27710.
Hepatology. 1994 Feb;19(2):412-7.
These studies investigate the role of transforming growth factor-beta 1, a potent inhibitor of epithelial cell proliferation and stimulator of extracellular matrix biosynthesis, during intrahepatic bile duct hyperplasia and biliary fibrosis. These pathogenic responses were induced in rats by common bile duct ligation. Bile duct cell replication, measured by the bromodeoxyuridine labeling index, was significantly increased 24 hr after common bile duct ligation. This response diminished to baseline by 1 wk. Liver collagen content, determined by quantification of hydroxyproline, was increased significantly after 1 wk of common bile duct ligation, and by 4 wk was increased by a factor of 4. Immunohistochemistry revealed low levels of TGF-beta 1 in normal intrahepatic bile duct epithelium. In contrast, the bile duct epithelium in bile duct-ligated rats stained strongly positive for transforming growth factor-beta 1 at 1 and 4 wk after ligation. These results suggest that transforming growth factor-beta 1 may play a role in both the termination of the bile duct epithelial cell proliferative response and the induction of fibrogenesis after common bile duct ligation. In addition, the mannose 6-phosphate/insulin-like growth factor II receptor was up-regulated in hyperplastic bile duct epithelium 1 and 4 wk after ligation. Because the mannose 6-phosphate/insulin-like growth factor-II receptor has been shown to facilitate the proteolytic activation of transforming growth factor-beta 1, these results suggest that the bile duct epithelium may also be involved in the activation of transforming growth factor-beta 1.
这些研究调查了转化生长因子β1在肝内胆管增生和胆管纤维化过程中的作用，转化生长因子β1是上皮细胞增殖的强效抑制剂和细胞外基质生物合成的刺激剂。这些致病反应是通过胆总管结扎在大鼠中诱导产生的。通过溴脱氧尿苷标记指数测量的胆管细胞复制在胆总管结扎后24小时显著增加。这种反应在1周后降至基线水平。通过羟脯氨酸定量测定的肝脏胶原含量在胆总管结扎1周后显著增加，到4周时增加了4倍。免疫组织化学显示正常肝内胆管上皮中转化生长因子β1水平较低。相比之下，在结扎后1周和4周，胆总管结扎大鼠的胆管上皮转化生长因子β1染色呈强阳性。这些结果表明，转化生长因子β1可能在胆总管结扎后胆管上皮细胞增殖反应的终止和纤维化形成的诱导中均发挥作用。此外，在结扎后1周和4周，增生胆管上皮中的甘露糖6-磷酸/胰岛素样生长因子II受体上调。由于甘露糖6-磷酸/胰岛素样生长因子II受体已被证明有助于转化生长因子β1的蛋白水解激活，这些结果表明胆管上皮也可能参与转化生长因子β1的激活。
