Abstract

Persistent exposure of biliary epithelial cells (i.e., cholangiocytes) to diverse factors such as disordered immunity, genetic alterations, ischemia, toxic compounds and/or infectious agents leads to a chronic portal inflammatory response which eventually progresses to biliary fibrosis. This stage is characterized by increased production and deposition of scar-forming extracellular matrix proteins (ECM), in particular fibrillar collagen types I and III, but including other ECM constituents such as elastin and fibrillin-1, both components of elastic fibers. The major cellular mediators responsible for collagen deposition are activated hepatic stellate cells (HSCs) and to a lesser extent, portal myofibroblasts, which are activated by soluble inflammatory mediators (i.e., cytokines, growth factors) and extracellular matrix components. Unless the underlying cause of biliary injury can be effectively treated, these processes may ultimately lead to decompensated cirrhosis and can also provide ideal microenvironments for the development and growth of primary tumors. Recent evidence indicates that fibrosis is a dynamic and potentially reversible process. As the curative options for most chronic biliary diseases remain limited to transplantation, there is an urgent need to clarify the molecular pathways involved in the development of biliary fibrosis and identify new therapeutic targets. In this review we describe the cellular and molecular regulators that orchestrate the cholangiocyte /myofibroblast cross-talk and identify the signaling processes that are most promising for therapeutic targeting.

Keywords: Biliary fibrosis, ductular reaction, myofibroblast, reactive cholangiocyte, therapeutic targets.

Graphical Abstract