Biliary Atresia: Will Blocking Inflammation Tame the Disease?

Bessho, Kazuhiko; Bezerra, Jorge A.

doi:10.1146/annurev-med-042909-093734

Cited by 85 publications

(76 citation statements)

References 64 publications

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“…The immune system plays a major role in the progressive fibrosis and obliteration of bile ducts in BA [21]. Release of proinflammatory cytokines from activated immune cells permanently damages bile ducts and causes biliary destruction, followed by fibrosis, producing the atresia phenotype [22].…”

Section: Inhibition Of Notch Signaling Reduces Inflammatory Cytokinesmentioning

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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Section: Inhibition Of Notch Signaling Reduces Inflammatory Cytokinesmentioning

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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“…Although the etiology is largely undefined, patient-and animal-based experiments point to a key role of the innate and adaptive immune responses in the pathogenesis of bile duct injury and obstruction (1). Studies using an experimental model of rhesus rotavirus-induced (RRV-induced) biliary atresia in newborn BALB/c mice have shown that the mechanisms of bile duct injury begins with the activation of DCs and NK cells, which target the bile duct epithelium (2,3).…”

Section: Introductionmentioning

confidence: 99%

Preferential TNFα signaling via TNFR2 regulates epithelial injury and duct obstruction in experimental biliary atresia

Shivakumar¹,

Mizuochi²,

Mourya³

et al. 2017

JCI Insight

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“…In terms of etiology, biliary atresia seems to be a heterogeneous condition in which environmental factors can act both in the early intrauterine period (embryonic form) and in the perinatal period (isolated form) [13][14][15][16] . This study showed that the conception of a patient with BA was 84% less likely if this condition was diagnosed in winter, suggesting a seasonal influence on BA etiology, although season at birth was not associated with the occurrence of BA.…”

Section: Discussionmentioning

confidence: 99%

Environmental Risk Factors Associated With Biliary Atresia in Rio Grande Do Sul, Brazil

Longo¹,

Ferrari²,

Hoss³

et al. 2017

Clin. Biomed. Res.

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Biliary atresia (BA) seems to be a multifactorial disorder in which environmental factors interact with the patient's genetic constitution. This study aimed to analyze information concerning environmental risk factors associated with BA in southern Brazil. A case-control study with mothers of patients with BA and mothers of patients with cystic fibrosis (CF) was conducted. Inquiry included questions related to exposition to environmental risk factors during the periconceptional and gestational (second and third trimesters) periods. Mothers of BA patients had smoked during pregnancy more frequently in comparison with the mothers of CF patients, but no significant difference was found in a multivariate analysis. There was no between group difference in terms of seasonality, but the multivariate analysis showed a significant difference within the BA group between date of conception in winter compared to other seasons. In conclusion, smoking during pregnancy seemed to increase the risk of BA while date of conception in winter decreased it.Keywords: Biliary atresia; environmental risk factor; etiology; seasonality; smoking Biliary atresia (BA) is a disease that begins exclusively in infancy and consists in the complete obstruction of extrahepatic and intrahepatic bile ducts 1,2 . Regardless of a timely surgical treatment, BA induces cirrhosis and cholangiopathy and constitutes the leading cause of pediatric liver transplantation 3,4 . The etiology of biliary obstruction and chronic cholangiopathy is not fully understood, and their association with genetic/chromosomal alterations, immune and immunogenetic abnormalities, environmental factors and maternal diseases, such as gestational diabetes, has been proposed 1,[5][6][7] . An immune disorder induced by viral infection seems to be part of BA etiology 8 . Distinct variants of the disease, such as BA splenic malformation (BASM), isolated BA, cystic BA, and cytomegalovirus IgM-positive BA, suggest distinct patterns of acquisition 3,7 . BA seems to be a multifactorial disorder in which environmental factors interact with the patient's genetic constitution. Environmental risk factors associated with the development of BA have been seldom investigated 5,[9][10][11][12] . In the present study, we collected and analyzed information concerning family history and environmental risk factors in the gestational and periconceptional periods associated with the occurrence of BA in the state of Rio Grande do Sul, southern Brazil, aiming to elucidate the etiology of this disease. METHODSThis was a case-control study in which the evaluated sample included mothers of patients with the isolated form of BA. The investigation was conducted during the first weeks after birth or at different points during outpatient follow-up. Mothers of infants, children and adolescents (up to 18 years old) St. Hill), and use of medications, condoms and skin creams. Additional topics were parents' age, pregnancy planning, season at conception and at birth, and diagnosis of infections. To control a...

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Biliary Atresia: Will Blocking Inflammation Tame the Disease?

Cited by 85 publications

References 64 publications

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

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

Preferential TNFα signaling via TNFR2 regulates epithelial injury and duct obstruction in experimental biliary atresia

Environmental Risk Factors Associated With Biliary Atresia in Rio Grande Do Sul, Brazil

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