Potential Role of Bcl-2 and Bax mRNA and Protein Expression in Chronic Hepatitis Type B and C: A Clinicopathologic Study

Abstract

Bcl-2 oncoprotein regulates programmed cell death by providing a survival advantage to rapidly proliferating cells, and bax protein promotes apoptosis by enchanting cell susceptibility to apoptotic stimuli. In this study, we assessed the expression of bcl-2 and bax in liver biopsies from patients with chronic hepatitis (CH) Type B (HBV) and C (HCV). The study comprised 65 liver biopsies from 65 patients with HBV (n = 37) and HCV (n = 28) and 10 normal liver biopsies as controls. The HAI score ranged from 3/18-13/18, and the fibrosis Stage, from 1-6 (7 HBV/10 HCV). Pathologic examination included the following: (1) immunohistochemical stains in paraffin sections for bcl-2 and bax protein expression, (2) Western blot analysis (bcl-2 and bax protein levels evaluation), (3) ISH (detection of bcl-2 and bax mRNA), and (4) ISH (TUNEL-ABI [apoptotic body index]). In CH cases, both bcl-2 and bax protein and mRNA were detected in portal and intralobular lymphocytes and in cholangiolar epithelial cells in interface areas and fibrous bands. Bax protein and mRNA was expressed within hepatocytes and epithelial cells of interlobular ducts in portal tracts. Bcl-2 mRNA was present in periportal hepatocytes only in cases with Stage 5-6 fibrosis. Western blot analysis showed a decreased bcl-2 and an increased bax expression toward advanced fibrotic stages. In CH cases, ABI was reverse correlated with the percentage of bcl-2 expression and was correlated directly with the percentage of bax expression (P <.001). The results of this study suggest that in cases of chronic HBV or HCV infection, bax may be involved in the hepatocyte cycle regulation during infection, whereas its expression in intraportal bile duct epithelium implies that this protein enhances susceptibility of these particular cells to apoptosis. The increased bax expression and ABI in fibrosis Stages 1-5, imply that they are responsible for hepatocytes depletion through apoptosis, during progress of liver fibrosis and fibrous tissue accumulation, until cirrhosis is established. Bcl-2 mRNA expression in periportal hepatocytes only in Stages 5 and 6 suggests that this oncogene is involved in the late stages of progressive liver fibrosis and failure and furthermore that periportal hepatocytes are resistant to apoptosis. Bcl-2 expression, in cholangioles of interface area, suggests that this oncoprotein may be involved in growth regulation of these epithelial cells. Further research is warranted to specify the exact role of apoptosis and apoptotic genes involved in liver fibrosis process in cases of chronic HBV and HCV infection. This may lead to new strategies in the management of human liver disease to prevent the progression to chronic liver failure.

Punicalagin alleviates hepatotoxicity in rats challenged with cyclophosphamide

“…The mitochondrial outer membrane integrity is maintained by Bcl-2, while increased membrane permeability by Bax releases apoptogenic factors in the cytosol, which activate caspase-9 and caspase-3 (Tsamandas et al, 2003). Caspase-3, the main apoptotic executioner, causes chromatin condensation, protein breakdown, and DNA fragmentation (D'Amelio et al, 2010).…”

The role of Bcl-2 family proteins in pulmonary fibrosis

“…Therefore changes of apoptosis and Bcl-2 family members should be studied according to the stages of disorder. Although the Bcl-2 expression has been investigated in different stages of some fibrotic diseases such as liver fibrosis (Tsamandas et al, 2003), unfortunately there is no study about the changes of Bcl-2 family proteins in various stages of pulmonary fibrosis to explore their correlation with the severity of this disease. More studies are needed in future to exactly clarify the importance of bcl-2 family in diagnosis, grading and treatment of pulmonary fibrosis.…”

Deficient Stat3 DNA-binding is associated with high Pias3 expression and a positive anti-apoptotic balance in human end-stage alcoholic and hepatitis C cirrhosis

“…Conflicting data have been reported to whether evolution of chronic liver disease towards cirrhosis is a consequence of increased apoptosis, reduced proliferation or a combination of both [15][16][17][18][19]. In HCV infection but also in primary biliary cirrhosis (PBC), both pro-and anti-apoptotic effects have been observed [20][21][22][23][24][25] and expression patterns may be different according to the stage of fibrosis progression [25]. We previously reported that Stat3 activity is disturbed in human end-stage ALD [26].…”