Activation of ATM signaling pathway is involved in oxidative stress-induced expression of mito-inhibitory p21 WAF1/Cip1 in chronic non-suppurative destructive cholangitis in primary biliary cirrhosis: An immunohistochemical study

Abstract

Biliary epithelial cells (BECs) of chronic non-suppurative destructive cholangitis (CNSDC) in primary biliary cirrhosis (PBC) reportedly express p21 WAF1/Cip1 and p16 INK4a, which may induce cell cycle arrest and are related to progressive loss of BECs of PBC. Given that the ATM pathway plays a role in the induction of p21 WAF1/Cip1, we examined its possible involvement in bile duct damage of PBC. The expression of phosphorylated-ATM (p-ATM) reflecting the activation of ATM, p21 WAF1/Cip1 and 8-hydroxy-deoxyguanosine (8-OHdG), an oxidative stress marker, was examined immunohistochemically in the liver tissues of 20 cases of stage 1/2 PBC, 9 extrahepatic biliary obstruction (EBO), 35 chronic viral hepatitis (CVH), 17 nonalcoholic steatohepatitis (NASH), and 18 histologically normal liver. p21 WAF1/Cip1, p-ATM and 8-OHdG were frequently and extensively co-expressed in the nuclei of CNSDC in PBC, and their expressions were correlated. In contrast, the expression of these three molecules was absent or faint in small bile ducts in normal livers, CVH, and EBO, and these molecules were clearly expressed in the nuclei of hepatocytes of NASH, in which oxidative stress is involved in hepatocellular damage. In conclusion, oxidative stress-induced p21 WAF1/Cip1 expression in BECs in PBC is closely associated with activation of the ATM pathway and the resultant reduced regeneration or cell cycle arrest of BECs may be related to the progressive loss of small bile ducts of PBC.