Bile ductular cells undergoing cellular senescence increase in chronic liver diseases along with fibrous progression

Abstract

We investigated the pathologic significance of ductular reactions in chronic liver diseases with respect to cellular senescence. The expression of senescence-associated markers (p16(INK4a) and p21(WAF1/Cip1)), cell proliferation, cell cycle markers (cyclin D and cyclin A), and neural cell adhesion molecule (NCAM) was examined immunohistochemically in primary biliary cirrhosis (PBC, n = 37), chronic viral hepatitis (n = 39), nonalcoholic steatohepatitis (n = 25), and control normal livers (n = 12). The expression of p16(INK4a) and p21(WAF1/Cip1) was frequently found in ductular cells in the advanced stage of chronic liver diseases, especially in PBC (P < .05). Double immunostaining disclosed that most senescent cells expressed cyclin D (G(1)-phase marker). NCAM was frequently coexpressed in ductular cells showing senescence-associated markers. Some ductular cells in ductular reactions in chronic liver diseases were at G(1) arrest and undergoing cellular senescence. Such senescent cells may be involved in the progression of fibrosis of these diseases, particularly in PBC.