慢性病毒性肝病中的细胞凋亡及凋亡相关蛋白

Apoptosis and apoptosis related proteins in chronic viral liver disease.

作者信息

Papakyriakou P, Tzardi M, Valatas V, Kanavaros P, Karydi E, Notas G, Xidakis C, Kouroumalis E

机构信息

Department of Gastroenterology, Medical School, University of Crete, Heraklion, Greece.

出版信息

Apoptosis. 2002 Apr;7(2):133-41. doi: 10.1023/a:1014472430976.

DOI:10.1023/a:1014472430976

PMID:11865197

Abstract

BACKGROUND

Apoptosis may be an important mechanism of hepatocyte death in chronic viral liver disease.

METHODS

We studied apoptosis in liver biopsies from 30 patients with chronic viral hepatitis and 8 patients with viral cirrhosis by the TUNEL method. 12 cases of non-alcoholic steatohepatitis and 12 cases of primary biliary cirrhosis were used as non-viral disease controls. Immunohistochemical expression of p53, p21/waf1, bcl-2 and mdm-2 proteins was also studied in the same patients.

RESULTS

A statistically significant increase of apoptotic liver cells was found in severe chronic viral hepatitis (5.3 +/- 0.3%), cirrhosis (3.4 +/- 0.5%) and PBC (4.4 +/- 0.4%) cases compared to patients with non-alcoholic steatohepatitis (0.8 +/- 0.3%). The expression of p53 protein was increased in the cases of viral cirrhosis and in chronic severe viral hepatitis whereas in the cases of chronic mild hepatitis, PBC and non-alcoholic steatohepatitis we found no expression of p53. P21/waf1 expression was increased in severe chronic hepatitis, cirrhosis and PBC cases compared to mild hepatitis and non-alcoholic steatohepatitis cases. However no induction of mdm-2 was observed in the subgroups of chronic liver disease. Bcl-2 was expressed only in epithelium of bile ducts and mononuclear cells of the portal tracts and liver lobules. A weaker Bcl-2 expression was noted in the epithelium of bile ducts of 7/12 PBC cases.

CONCLUSION

Our results provide evidence of increased apoptosis in severe chronic viral liver disease, suggesting that apoptotic cell death might be involved in the pathogenesis of hepatocellular damage of viral hepatitis and cirrhosis. Furthermore we analysed part of the apoptotic pathways implicated in the above process and found an increased expression of p21/waf1, probably p53 mediated, without overexpression of the apoptosis inhibiting bcl-2 and mdm-2 proteins. By contrast p21/waf1 overexpression in PBC seems to be propagated by a p53 independent mechanism.

摘要

背景

细胞凋亡可能是慢性病毒性肝病中肝细胞死亡的重要机制。

方法

我们采用TUNEL法研究了30例慢性病毒性肝炎患者和8例病毒性肝硬化患者肝活检组织中的细胞凋亡情况。选取12例非酒精性脂肪性肝炎患者和12例原发性胆汁性肝硬化患者作为非病毒性疾病对照。同时研究了同一批患者中p53、p21/waf1、bcl-2和mdm-2蛋白的免疫组化表达。

结果

与非酒精性脂肪性肝炎患者（0.8±0.3%）相比，重度慢性病毒性肝炎（5.3±0.3%）、肝硬化（3.4±0.5%）和原发性胆汁性肝硬化（4.4±0.4%）患者肝组织中凋亡肝细胞数量有统计学意义的增加。p53蛋白在病毒性肝硬化和慢性重度病毒性肝炎患者中表达增加，而在慢性轻度肝炎、原发性胆汁性肝硬化和非酒精性脂肪性肝炎患者中未检测到p53表达。与轻度肝炎和非酒精性脂肪性肝炎患者相比，p21/waf1在重度慢性肝炎患者、肝硬化患者和原发性胆汁性肝硬化患者中表达增加。然而，在慢性肝病各亚组中均未观察到mdm-2的诱导表达。Bcl-2仅在胆管上皮细胞及门管区和肝小叶的单核细胞中表达。在12例原发性胆汁性肝硬化患者中的7例，胆管上皮细胞中Bcl-2表达较弱。

结论

我们的研究结果表明重度慢性病毒性肝病中细胞凋亡增加，提示凋亡性细胞死亡可能参与了病毒性肝炎和肝硬化肝细胞损伤的发病机制。此外，我们分析了上述过程中部分凋亡途径，发现p21/waf1表达增加，可能由p53介导，而凋亡抑制蛋白bcl-2和mdm-2未过表达。相比之下，原发性胆汁性肝硬化中p21/waf1的过表达似乎是通过一种不依赖p53的机制介导的。