title: Natural killer cells promote long-term hepatobiliary inflammation in a low-dose rotavirus model of experimental biliary atresia.
abstract: Biliary atresia is a rapidly progressive obstructive cholangiopathy of infants. Mechanistic studies in the mouse model of Rhesus rotavirus (RRV)-induced biliary atresia have linked the importance of effector lymphocytes to the pathogenesis of extrahepatic bile duct (EHBD) injury and obstruction in experimental biliary atresia; however, studies of the progressive liver injury have been limited by early death of newborn mice. Here, we aimed to determine 1) if a lower inoculum of RRV induces obstruction of EHBDs while allowing for ongoing liver inflammation, and 2) if NK cells regulate intrahepatic injury. The administration of 0.25 x 10(6) fluorescence forming units of RRV induced an obstructive extrahepatic cholangiopathy, but allowed for restoration of the duct epithelium, increased survival, and the development of a progressive intrahepatic inflammatory injury with molecular and cellular signatures equivalent to the traditional infectious model. Investigating the mechanisms of liver injury, we found that NK cell depletion at the onset of jaundice decreased liver inflammation, suppressed the expression of fibrosis and inflammation/immunity genes, lowered plasma ALT and bilirubin and improved survival.
  
  
  CONCLUSIONS
  Lower inoculation of RRV-induced progressive liver injury and fibrosis via NK cells. These findings point to the potential use of NK cell-depleting strategies to block progression of liver disease in biliary atresia.
authors.affiliation: Department of Pediatrics of the University of Cincinnati College of Medicine, the Division of Gastroenterology, Hepatology and Nutrition and the Pediatric Liver Care Center of Cincinnati Children's Hospital Medical Center; Cincinnati, Ohio, United States of America.
authors.forename: James E
authors.initials: JE
authors.lastname: Squires
authors.affiliation: Department of Pediatrics of the University of Cincinnati College of Medicine, the Division of Gastroenterology, Hepatology and Nutrition and the Pediatric Liver Care Center of Cincinnati Children's Hospital Medical Center; Cincinnati, Ohio, United States of America.
authors.forename: Pranavkumar
authors.initials: P
authors.lastname: Shivakumar
authors.affiliation: Department of Pediatrics of the University of Cincinnati College of Medicine, the Division of Gastroenterology, Hepatology and Nutrition and the Pediatric Liver Care Center of Cincinnati Children's Hospital Medical Center; Cincinnati, Ohio, United States of America.
authors.forename: Reena
authors.initials: R
authors.lastname: Mourya
authors.affiliation: Division of Pediatrics, Osaka University, Osaka, Japan.
authors.forename: Kazuhiko
authors.initials: K
authors.lastname: Bessho
authors.affiliation: Department of Pediatrics of the University of Cincinnati College of Medicine, the Division of Gastroenterology, Hepatology and Nutrition and the Pediatric Liver Care Center of Cincinnati Children's Hospital Medical Center; Cincinnati, Ohio, United States of America.
authors.forename: Stephanie
authors.initials: S
authors.lastname: Walters
authors.affiliation: Department of Pediatrics of the University of Cincinnati College of Medicine, the Division of Gastroenterology, Hepatology and Nutrition and the Pediatric Liver Care Center of Cincinnati Children's Hospital Medical Center; Cincinnati, Ohio, United States of America.
authors.forename: Jorge A
authors.initials: JA
authors.lastname: Bezerra
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D001656:Biliary Atresia / Q000276:immunology*; D004195:Disease Models, Animal; D007694:Killer Cells, Natural / Q000276:immunology*; D051379:Mice; D012400:Rotavirus Infections / Q000276:immunology*