Tracy T F, Bailey P V, Goerke M E, Sotelo-Avila C, Weber T R
Pediatric Research Institute, Cardinal Glennon Children's Hospital, St. Louis, Mo.
Surgery. 1991 Aug;110(2):176-82; discussion 182-3.
Partial hepatectomy (PH) initiates cellular signals for regeneration. Sequential expression of nuclear and cytosolic protooncogenes accompanies the restoration of normal liver function and architecture. Although cirrhosis is known to inhibit liver regeneration, the effects of noncirrhotic cholestasis on hepatocellular proliferation, differentiation, and regulatory gene expression are unknown. To examine this, 25 male Fisher rats underwent common bile duct ligation and division. A 47% +/- 5% PH was performed 10 days after common bile duct ligation and division when histologic analysis revealed cholestasis without cirrhosis. Despite early elevations of total hepatic DNA and RNA values, cholestatic livers demonstrated a significant threefold suppression of expected hepatocyte mitotic indexes 48 and 72 hours after PH, compared with livers after PH alone. Weight restoration in cholestatic livers was 11% +/- 5.2% compared with 40% +/- 4.3% in control livers (+/- SEM; p less than 0.001) 5 days after PH. Analysis of regenerating liver messenger RNA with complementary DNA probes revealed an abnormal, sustained elevation of K-ras expression in cholestatic livers through all time points. Cholestasis blunted but did not obliterate normal sequential elevations in H-ras found in control livers. The expression of c-myc was inhibited threefold with cholestasis 72 hours after PH. These results are the first indication that cholestasis alone inhibits hepatocyte proliferation and the expression of c-myc that normally precedes the first wave of mitosis. This implies that cholestasis without cirrhosis may alter programmed liver gene expression, inhibiting normal hepatic regeneration.
部分肝切除术（PH）启动细胞再生信号。随着正常肝功能和结构的恢复，核内和胞质原癌基因会依次表达。虽然已知肝硬化会抑制肝脏再生，但非肝硬化性胆汁淤积对肝细胞增殖、分化及调节基因表达的影响尚不清楚。为研究此问题，对25只雄性Fisher大鼠进行胆总管结扎和切断术。在胆总管结扎和切断术后10天进行47%±5%的部分肝切除术，此时组织学分析显示存在无肝硬化的胆汁淤积。尽管肝总DNA和RNA值早期升高，但与单纯部分肝切除术后的肝脏相比，胆汁淤积性肝脏在部分肝切除术后48小时和72小时的预期肝细胞有丝分裂指数显著受到三倍抑制。部分肝切除术后第5天，胆汁淤积性肝脏的体重恢复率为11%±5.2%，而对照肝脏为40%±4.3%（±标准误；P<0.001）。用互补DNA探针分析再生肝脏信使RNA显示，在所有时间点胆汁淤积性肝脏中K-ras表达异常持续升高。胆汁淤积使对照肝脏中正常依次升高的H-ras变钝但未消除。部分肝切除术后72小时，胆汁淤积使c-myc的表达受到三倍抑制。这些结果首次表明，单纯胆汁淤积会抑制肝细胞增殖以及正常情况下先于第一波有丝分裂的c-myc的表达。这意味着无肝硬化的胆汁淤积可能会改变肝脏程序性基因表达，抑制正常肝脏再生。
