Corticosteroid treatment in biliary atresia: Tonic or toast?

Sokol, Ronald J.

doi:10.1002/hep.22001

Cited by 11 publications

(11 citation statements)

References 26 publications

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“…Biliary atresia (BA) is a disease of infants characterized by progressive, fibroinflammatory obliteration of the extrahepatic biliary tree and rapidly progressing intrahepatic biliary fibrosis. BA is the most common cause of pediatric end‐stage liver disease and, if untreated, is inevitably fatal within the first 2 years of life . Primary treatment, which involves surgical drainage of bile, is successful only half of the time .…”

mentioning

confidence: 99%

“…Primary treatment, which involves surgical drainage of bile, is successful only half of the time . Even with successful surgical drainage, the majority of patients with BA still experience progression of intrahepatic biliary fibrosis toward cirrhosis . Importantly, transplant‐free survival with one's native liver inversely correlates with extent of intrahepatic fibrosis at the time of surgery .…”

mentioning

confidence: 99%

“…Even with successful surgical drainage, the majority of patients with BA still experience progression of intrahepatic biliary fibrosis toward cirrhosis . Importantly, transplant‐free survival with one's native liver inversely correlates with extent of intrahepatic fibrosis at the time of surgery . Unfortunately, the mechanism of BA‐associated fibrosis remains poorly understood.…”

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confidence: 99%

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Expansion of prominin-1-expressing cells in association with fibrosis of biliary atresia

et al. 2014

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Biliary atresia (BA), the most common cause of end-stage liver disease and the leading indication for pediatric liver transplantation, is associated with intrahepatic ductular reactions within regions of rapidly expanding periportal biliary fibrosis. While the extent of such biliary fibrosis is a negative predictor of long-term transplant-free survival, the cellular phenotypes involved in the fibrosis are not well established. Using a Rhesus rotavirus (RRV)-induced mouse model of BA, we demonstrate significant expansion of a cell population expressing the putative stem/progenitor cell marker PROMININ-1 (PROM1) adjacent to ductular reactions within regions of periportal fibrosis. PROM1positive (pos) cells express Collagen-1α1. Subsets of PROM1pos cells co-express progenitor cell marker CD49f, epithelial marker E-CADHERIN, biliary marker CYTOKERATIN-19, and mesenchymal markers VIMENTIN and α-SMOOTH MUSCLE ACTIN. Expansion of the PROM1pos cell population is associated with activation of Fibroblast Growth Factor (FGF) and Transforming Growth Factor-β (TGFβ) signaling. In vitro co-treatment of PROM1-expressing Mat1a−/− hepatic progenitor cells with recombinant human FGF10 and TGFβ1 promotes morphologic transformation toward a myofibroblastic cell phenotype with increased expression of myofibroblastic genes Collagen-1α1, Fibronectin, and α–Smooth muscle actin. Infants with BA demonstrate similar expansion of periportal PROM1pos cells with activated SMAD3 signaling in association with increased hepatic expression of FGF10, FGFR1, and FGFR2 as well as mesenchymal genes SLUG and SNAIL. Infants with perinatal subtype of BA have higher tissue levels of PROM1 expression than those with embryonic subtype. Conclusion Expansion of collagen-producing PROM1pos cells within the regions of periportal fibrosis is associated with activated FGF and TGFβ pathways in both experimental and human BA. PROM1pos cells may, therefore, play an important role in the biliary fibrosis of BA.

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Expansion of prominin-1-expressing cells in association with fibrosis of biliary atresia

et al. 2014

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“…of treatment, it is inevitably fatal within the first 2 years of life [2]. Although there have been reports that viral infections, immune-mediated injury, and other factors are related to BA, the pathogenesis of BA is still not understood completely.…”

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confidence: 99%

Inhibition of the Notch Signaling Pathway Reduces the Differentiation of Hepatic Progenitor Cells into Cholangiocytes in Biliary Atresia

Mao

Tang

Yang

et al. 2018

Cell Physiol Biochem

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Background/Aims: Viral infections, especially with rotavirus, are often considered an initiator of the pathogenesis of biliary atresia (BA). However, the mechanism by which rotavirus induces BA is still unclear. Methods: A BA mouse model was induced in newborn mice by i.p. inoculation with rhesus rotavirus within 6 h of birth. The expression of Notch pathway-associated molecules (JAG1, JAG2, Notch1, Notch2, Notch3, Notch4, DII1, DII3, and DII4) was measured by quantitative PCR and western blot analysis. Bile duct obstruction was detected by hematoxylin and eosin staining and CK-19 immunohistochemical staining. DAPT was used to inhibit the Notch pathway in vivo and in vitro. Results: In the livers of patients with BA and rotavirus-induced BA mice, the expression of JAG1 and Notch2 was significantly increased. Inhibition of the Notch pathway by DAPT in vivo ameliorated bile duct obstruction and delayed BA-induced mortality. The serum levels of inflammation cytokines (TNF-α, IL-2, IL-8, and IL-18) were reduced by inhibiting the Notch pathway. The expression of CK19, Sox9, and EpCAM was significantly increased in BA liver, while DAPT treatment decreased the expression of CK19, Sox9, and EpCAM. Conclusion: Notch activation is involved in the pathogenesis of BA by promoting the differentiation of hepatic progenitor cells into cholangiocytes.

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“…Perhaps PPARgamma or LXR agonists may be suitable agents to explore. Interestingly, glucocorticoids have often been used in the treatment of BA, but only after the primary surgical intervention, i.e., Kasai portoenterostomy, with the underlying thoughts that glucocorticoids will enhance bile formation and reduce inflammation, and thus increase the chances of establishing permanent post-Kasai bile drainage (Sokol (268)).…”

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confidence: 99%

Nuclear receptors: mediators and modifiers of inflammation-induced cholestasis

et al. 2009

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Inflammation-induced cholestasis (IIC) is a frequently occurring phenomenon. A central role in its pathogenesis is played by nuclear receptors (NRs). These ligand-activated transcription factors not only regulate basal expression of hepatobiliary transport systems, but also mediate adaptive responses and possess anti-inflammatory characteristics. The latter two functions may be exploited in the search for new treatments for IIC and likely for cholestasis in general as well. Current knowledge of the pathogenesis of IIC and the dual role NRs in this process are reviewed. Special interest is given to the use of NRs as potential targets for intervention.

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Corticosteroid treatment in biliary atresia: Tonic or toast?

Cited by 11 publications

References 26 publications

Expansion of prominin-1-expressing cells in association with fibrosis of biliary atresia

Expansion of prominin-1-expressing cells in association with fibrosis of biliary atresia

Inhibition of the Notch Signaling Pathway Reduces the Differentiation of Hepatic Progenitor Cells into Cholangiocytes in Biliary Atresia

Nuclear receptors: mediators and modifiers of inflammation-induced cholestasis

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