HIF-1alpha-pathway activation in cholangiocytes of patients with biliary atresia : an immunohistochemical/molecular exploratory study

• Autor(a) principal: Quelhas, Patrícia
• Data de Publicação: 2023
• Outros Autores: Breton, Michèle Claire, Oliveira, Rui Caetano, Cipriano, Maria Augusta, Teixeira, Paulo, Cerski, Carlos Thadeu Schmidt, Shivakumar, Pranavkumar, Vieira, Sandra Maria Gonçalves, Kieling, Carlos Oscar, Verde, Ignacio, Santos, Jorge Luiz dos
• Tipo de documento: Artigo
• Idioma: eng
• Título da fonte: Repositório Institucional da UFRGS
• Texto Completo: http://hdl.handle.net/10183/267279
• topic: Estresse oxidativo; Atresia biliar; Colestase; Recém-nascido; Isquemia; Ischemic cholangiopathy; Biliary atresia; Neonatal cholestasis; Oxidative stress

Background: Biliary atresia is a neonatal disease characterized by choledochal obstruction and progressive cholangiopathy requiring liver transplantation in most patients. Hypoxia-ischemia affecting the biliary epithelium may lead to biliary obstruction. We hypothesized that ischemic cholangiopathy involving disruption of the peribiliary vascular plexus could act as a triggering event in biliary atresia pathogenesis. Methods: Liver and porta hepatis paraffin-embedded samples of patients with biliary atresia or intrahepatic neonatal cholestasis (controls) were immunohistochemically evaluated for HIF-1alpha-nuclear signals. Frozen histological samples were analyzed for gene expression in molecular profiles associated with hypoxia-ischemia. Prospective clinical-laboratory and histopathological data of biliary atresia patients and controls were reviewed. Results: Immunohistochemical HIF-1alpha signals localized to cholangiocytes were detected exclusively in liver specimens from biliary atresia patients. In 37.5% of liver specimens, HIF-1alpha signals were observed in biliary structures involving progenitor cell niches and peribiliary vascular plexus. HIF-1alpha signals were also detected in biliary remnants of 81.8% of porta hepatis specimens. Increased gene expression of molecules linked to REDOX status, biliary proliferation, and angiogenesis was identified in biliary atresia liver specimens. In addition, there was a trend towards decreased GSR expression levels in the HIF-1alpha-positive group compared to the HIF-1alpha-negative group. Conclusion: Activation of the HIF-1alpha pathway may be associated with the pathogenesis of biliary atresia, and additional studies are necessary to confirm the significance of this finding. Ischemic cholangiopathy and REDOX status disturbance are putative explanations for HIF-1alpha activation. These findings may give rise to novel lines of clinical and therapeutic investigation in the BA field.