Role of JNK and p38 MAPK signaling pathways in the initiation of polyploidization in cholestatic liver

Abstract Background Cholestasis-induced liver injury is a major factor contributing to the development of hepatic pathologies. Ligation of the common bile duct induces proliferation of epithelial cells and cholangiocytes, as well as activation of portal fibroblasts and hepatic myofibroblasts. These processes promote inflammation, formation of fibrotic scar tissue, and ultimately the development of liver fibrosis and cirrhosis. At the same time, under cholestatic conditions, the liver exhibits adaptive responses to increased functional load. One such process is hepatocyte polyploidization, manifested by an increase in the number of high ploidy cells. Although JNK1/2 and p38 are known to be activated in hepatocytes during cholestasis. However, their role in the initiation of the polyploidization process has not been fully elucidated. The aim of the present study was to determine whether the JNK1/2 and p38 MAPK signaling pathways participate in the initiation of polyploidization as an adaptive response in the cholestatic liver. Materials and methods Experiments were carried out on adult white rats using a cholestatic liver model induced by common bile duct ligation (CBDL). Experiment was performed by using JNK1/2 inhibitor - SP600125 and p38 inhibitor - SB203580. Proliferative activity was evaluated using the colchicine mitotic index, while alterations in hepatocyte ploidy were analyzed using Feulgen staining and ImageJ software. Results Inhibition of JNK1/2 altered neither hepatocyte mitotic activity nor the quantitative distribution of polyploid hepatocytes, indicating that JNK1/2 is not involved in the initiation of polyploidization at the early stage of cholestasis. In contrast, p38 inhibition significantly reduced ( p < 0.05) the high ploidy hepatocytes induced by CBDL, without affecting mitotic activity. Conclusion Under conditions of increased functional load caused by common bile duct ligation, at the initial stage of cholestatic liver, the increase number of high ploidy cells is dependent on the activation of the p38 MAPK cascade.