Journal of hepato-biliary-pancreatic sciences · 2015
Hypoxic-ischemic gene expression profile in the isolated variant of biliary atresia.
СтатьяПоддержка исследования: вне правительства СШАНазвание и аннотация: Перевод в очереди
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Fratta Leila Xavier Sinigaglia, Hoss Giovana Regina Weber, Longo Larisse, Uribe-Cruz Carolina, da Silveira Themis Reverbel, Vieira Sandra Maria Gonçalves, Kieling Carlos Oscar, Dos Santos Jorge Luiz
Аннотация
BACKGROUND: Biliary atresia (BA) includes a sclerosing cholangiopathy whose nature is not fully deciphered. Aiming to evaluate the role of an arteriopathy as an etiologic factor in BA, we investigated hypoxia and the correlated angiogenic response in livers from affected patients.
METHODS: Gene expression of the molecular axis: hypoxia-inducible factor (HIF)1a, HIF2a and vascular endothelial growth factor A (VEGFA)/VEGFR1, VEGFR2. Liver biopsy specimens collected at exploratory laparotomy of age-matched patients with isolated, cytomegalovirus IgM-negative BA (n = 32) and intrahepatic cholestasis (IHC, n = 9) were evaluated.
RESULTS: We observed higher HIF1a and HIF2a expression in BA than in IHC. Paradoxically, VEGFR2, the main target of VEGFA-induced angiogenesis, was underexpressed in BA, and VEGFA was decreased in most BA patients. Patients with the highest expression of HIFs and the lowest VEGFA and VEGFR2 were essentially the same, indicating hypoxia without the necessary angiogenesis. This group included most BA patients and, except for HIF2a, they were older and presented increased bilirubin serum levels. In the highest HIF2a/lowest VEGFR2 subsets, gene expression of the cytokeratin 19, marker of cholangiocyte phenotype, was decreased.
CONCLUSION: This study suggests that hypoxia-ischemia is present in the livers of patients with BA, progresses over time and leads to a decreased cholangiocyte mass.
METHODS: Gene expression of the molecular axis: hypoxia-inducible factor (HIF)1a, HIF2a and vascular endothelial growth factor A (VEGFA)/VEGFR1, VEGFR2. Liver biopsy specimens collected at exploratory laparotomy of age-matched patients with isolated, cytomegalovirus IgM-negative BA (n = 32) and intrahepatic cholestasis (IHC, n = 9) were evaluated.
RESULTS: We observed higher HIF1a and HIF2a expression in BA than in IHC. Paradoxically, VEGFR2, the main target of VEGFA-induced angiogenesis, was underexpressed in BA, and VEGFA was decreased in most BA patients. Patients with the highest expression of HIFs and the lowest VEGFA and VEGFR2 were essentially the same, indicating hypoxia without the necessary angiogenesis. This group included most BA patients and, except for HIF2a, they were older and presented increased bilirubin serum levels. In the highest HIF2a/lowest VEGFR2 subsets, gene expression of the cytokeratin 19, marker of cholangiocyte phenotype, was decreased.
CONCLUSION: This study suggests that hypoxia-ischemia is present in the livers of patients with BA, progresses over time and leads to a decreased cholangiocyte mass.
Предметные рубрики MeSH
Basic Helix-Loop-Helix ProteinsBiliary AtresiaDisease ProgressionFemaleGene Expression ProfilingHumansHypoxiaHypoxia-Inducible Factor 1, alpha SubunitInfantIschemiaMalePolymerase Chain ReactionVascular Endothelial Growth Factor AVascular Endothelial Growth Factor Receptor-1Vascular Endothelial Growth Factor Receptor-2Endothelial PAS Domain-Containing Protein 1