The Role Of HMGB1in Pathogenesis Of Biliary Atresia

PART ONEThe expression of HMGB1,RAGE,NF-кB in livers ofpatients with biliatry atresia【Objective】To study the expressions of HMGB1,RAGE,NF-к B in biliaryatresia(BA) liver tissues and to explore the relationship between them andBA.【Methods】Liver tissues were taken from11cases of BA and6cases of CBD.The expressions of HMGB1,RAGE,NF-к B were detected by means ofimmunohistochemical,RT-PCR and western blot.【Results】The expressions of HMGB1,RAGE,NF-к B were significantly higherin hepatic cells and bile ducts epithelium cells from BA than those from CBD.In patients with BA,the increased expression of RAGE were positivelycorrelated with the HMGB1expression (r=0.7602,P<O.05,OR=2.1172,respectively), the increased expression of NF-к B were positively correlatedwith the RAGE expression (r=0.7219,P<O.05,OR=1.9082,respectively). However，there was no correlation of the expression of HMGB1, NF-к B and RAGE in patientswith CBD.【Conclusions】The abnormal expressions of HMGB1,RAGE,NF-к B in the BAliver tissue may play important roles in the inflammation and destruction ofthe bile duct in patients with BA. PART TWOHMGB1in Biliary Duct Destruction by RRV Infection【Objective】To establish a murine model of biliary duct destruction dueto RRV infection and probe into the role of HMGB1and its downstreaminflammatory factors in the pathogenesis of biliary duct destruction.【Methods】 After overnight mating， the pregnant mice(BALB/c) wereseparately bred. The newborn pups were randomly divided into three groups:RRV-infected group(group A)， Anti-HMBG1antibody blocking after virusinfection Group(group B), and experimental control group(group C).Ggroup Awas injected with virus suspension in the first24hours after birth, groupB was injected with virus suspension and anti-HMBG1antibody, and group C wasinjected with sterile0.9%sodium chloride of equal volume at same time. Thegrowth and survival of pups were recorded. And the biliary duct tissues were gained.The biliary duct pathological changes were analyzed after HE staining, andHMGB1,RAGE and NF-к B protein expressions in bile duct epithelial cells wereshown by immunohistochemical techniques.【Result】Four in the20pups of group A survived with notable anomaly2weeks after birth，and14in the18pups of group B, while all the pups ofgroup C normally grew up. The survival rate of group A was significantly lowerthan that in the latter two groups. However, group A of biliary atresia wassignificantly higher than the latter two groups, the difference wasstatistically significant. HMGB1,RAGE and NF-к B protein expressions ofbiliary epithelial cells in A group were significantly stronger than that inthe latter two groups.【Conclusion】The murine model of biliary atresia by RRV was successfullyestablished. The HMGB1-RAGE-NF-к B pathway might play an important role inthe pathogenesis biliary atresia caused by RRV infection. The anti-HMGB1antibody can effectively prevent pup mortality and bile duct injury caused by the RRV infection.