Cellular Senescence in Cholestatic Liver Injury

Abstract

Cholestatic liver diseases such as primary biliary cholangitis and primary sclerosing cholangitis are characterized by bile duct inflammation and damage followed by obstruction or impaired bile flow leading to liver fibrosis. Cholangiocytes are the target of therapies of cholangiopathies. Although bile duct hyperplasia caused by elevated cholangiocyte proliferation is characteristic during cholestatic liver injury, accumulating evidence shows that enhanced cellular senescence in cholangiocytes is an important factor for pathophysiology of cholangiopathies. Senescent cholangiocytes secrete elevated levels of proinflammatory cytokines and chemokines that activate hepatic stellate cells or myofibroblasts leading to fibrogenesis in the liver. Previous studies suggest that endotoxin or lipopolysaccharide derived from gut bacteria may be a key factor for cholangiocyte senescence in cholangiopathies. This review summarizes current understandings for functional roles of cellular senescence in cholangiocytes during cholestatic liver injury.