Biliary atresia--translational research on key molecular processes regulating biliary injury and obstruction

Biliary atresia is the most common cause of pathologic jaundice in young infants and results from the obstruction of the extrahepatic bile ducts by an inflammatory and fibro-obliterative process. Although the pathogenesis of the disease is multifactorial, recent patient- and animal-based studies began deciphering the molecular pathways involved in biliary injury and duct obstruction. Using large-scale genomics and immunostaining of livers from children with biliary atresia, investigators have discovered unique molecular signatures of dominant proinflammatory cytokines at the time of diagnosis. To study hypotheses generated from these patient-based studies, the anatomical and inflammatory profiles of a mouse model of rotavirus-induced biliary atresia were analyzed and found to share striking similarities with the human profiles. Then, using these mice in mechanistic studies, interferon-gamma (IFNgamma) has been shown to regulate the biliary tropism of lymphocytes to the biliary system, and to play a critical role in the inflammatory obstruction of extrahepatic bile ducts. The ability to combine human studies with a laboratory model of neonatal biliary injury and obstruction opens a new era of opportunities to advance the field of biliary atresia, and to develop new therapeutic strategies to improve long-term outcome with the native liver of children with biliary atresia.