Tracy T F, Goerke M E, Bailey P V, Sotelo-Avila C, Weber T R
Pediatric Research Institute, Cardinal Glennon Children's Hospital, St. Louis, Mo.
Surgery. 1993 Sep;114(3):532-7.
Extrahepatic biliary obstruction initiates cholestasis, bile duct proliferation, periportal fibrosis, and, eventually, lethal biliary cirrhosis. Little is known about the genetic regulation of the cellular proliferation and differentiation that begins with the onset of bile duct obstruction. To focus this and future gene expression studies, we sought to determine the time frame for growth-related gene expression and questioned whether the in vivo expression of the protooncogenes H-ras and c-myc was altered after bile duct obstruction.
Female Fisher rats underwent ligation and division of the common bile duct or sham laparotomy.
After obstruction, serum bilirubin and gamma-glutamyl transpeptidase rose to 24% and 30%, respectively, of maximum levels by 10 days after ligation. Morphologic evidence of proliferation of bile duct epithelial cells was first evident after 3 days. After hybridization to c-DNA probes, densitometry for H-ras and beta-actin revealed an immediate and parallel increase in steady-state levels of expression after 24 hours of cholestasis. Levels of c-myc messenger RNA were elevated during the first 3 days of cholestasis; however, at 7 and 10 days c-myc expression was depressed 16% and 60%, respectively.
These profiles of expression show an oncogene response induced by early cholestasis. These data showed that elevations in H-ras and c-myc steady-state expression accompany the proliferative response of bile duct epithelial cells. Decreased levels of c-myc after initial elevation infer that ductal proliferation may continue independently of its steady-state expression, a response usually seen in vitro rather than in in vivo proliferation.
肝外胆管梗阻引发胆汁淤积、胆管增生、门周纤维化，并最终导致致命性胆汁性肝硬化。关于胆管梗阻开始时细胞增殖和分化的基因调控知之甚少。为了聚焦此次及未来的基因表达研究，我们试图确定生长相关基因表达的时间框架，并质疑胆管梗阻后原癌基因H-ras和c-myc的体内表达是否发生改变。
对雌性Fisher大鼠进行胆总管结扎和切断或假手术剖腹术。
梗阻后，血清胆红素和γ-谷氨酰转肽酶在结扎后10天分别升至最高水平的24%和30%。胆管上皮细胞增殖的形态学证据在3天后首次明显。与c-DNA探针杂交后，对H-ras和β-肌动蛋白进行光密度测定，结果显示胆汁淤积24小时后，表达的稳态水平立即平行升高。在胆汁淤积的前3天，c-myc信使核糖核酸水平升高；然而，在7天和10天时，c-myc表达分别下降了16%和60%。
这些表达谱显示了早期胆汁淤积诱导的癌基因反应。这些数据表明，H-ras和c-myc稳态表达的升高伴随着胆管上皮细胞的增殖反应。最初升高后c-myc水平降低表明，导管增殖可能独立于其稳态表达而继续，这种反应通常在体外而非体内增殖中出现。
