Effect of Rotavirus Strain on the Murine Model of Biliary Atresia

ABSTRACT Biliary atresia is a devastating disorder of the newborn in which afflicted infants develop inflammation and fibrosis of the extrahepatic biliary tract, resulting in cirrhosis and end-stage liver disease. Infection with a virus is thought to be a contributing factor in the etiology of biliary atresia. In the murine model of biliary atresia, perinatal exposure to rhesus rotavirus (RRV) results in biliary epithelial cell infection causing bile duct obstruction. The purpose of this study was to determine if tropism for the biliary epithelial cell was unique to RRV. Newborn mice underwent intraperitoneal injection with five strains of rotavirus: RRV (simian), SA11-FM (simian/bovine), SA11-SM (simian), EDIM (murine), and Wa (human). RRV and SA11-FM caused clinical manifestations of bile duct obstruction and high mortality. SA11-SM caused clinical signs of hepatobiliary injury but the mortality was markedly reduced. EDIM and Wa caused no sign of hepatobiliary disease. The systemic and temporal distribution of viral protein and live virus varied according to the injected strain. Immunohistochemistry revealed that RRV and SA11-FM targeted the biliary epithelial cells. In contrast, SA11-SM was found in the liver but in not in the biliary epithelium. These results indicate that strain-specific characteristics dictate tropism for cells of hepatobiliary origin which in turn impact the ability to induce the murine model of biliary atresia.

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Biliary Epithelial Cell Proliferation Following α-Naphthylisothiocyanate (ANIT) Treatment: Relationship to Bile Duct Obstruction

Fundamental and Applied Toxicology ◽

10.1006/faat.1995.1074 ◽

1995 ◽

Vol 26 (1) ◽

pp. 51-62 ◽

Cited By ~ 33

Author(s):

D Kossor

Keyword(s):

Cell Proliferation ◽

Bile Duct ◽

Epithelial Cell ◽

Bile Duct Obstruction ◽

Epithelial Cell Proliferation ◽

Biliary Epithelial Cell ◽

Duct Obstruction ◽

Treatment Relationship

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Biliary Epithelial Cell Proliferation Following α-Naphthylisothiocyanate (ANIT) Treatment: Relationship to Bile Duct Obstruction

Toxicological Sciences ◽

10.1093/toxsci/26.1.51 ◽

1995 ◽

Vol 26 (1) ◽

pp. 51-62

Author(s):

DAVID C. KOSSOR ◽

ROBIN S. GOLDSTEIN ◽

WINNIE NGO ◽

DENNIS B. DENICOLA ◽

THOMAS B. LEONARD ◽

...

Keyword(s):

Cell Proliferation ◽

Bile Duct ◽

Epithelial Cell ◽

Bile Duct Obstruction ◽

Epithelial Cell Proliferation ◽

Biliary Epithelial Cell ◽

Duct Obstruction ◽

Treatment Relationship

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Bile Duct Obstruction Is not a Prerequisite for Type I Biliary Epithelial Cell Hyperplasia

Toxicology and Applied Pharmacology ◽

10.1006/taap.1998.8507 ◽

1998 ◽

Vol 152 (2) ◽

pp. 327-338 ◽

Cited By ~ 9

Author(s):

David C. Kossor ◽

Paul C. Meunier ◽

Deanne M. Dulik ◽

Thomas B. Leonard ◽

Robin S. Goldstein

Keyword(s):

Bile Duct ◽

Epithelial Cell ◽

Bile Duct Obstruction ◽

Type I ◽

Biliary Epithelial Cell ◽

Cell Hyperplasia ◽

Duct Obstruction

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

Cellular Physiology and Biochemistry ◽

10.1159/000493290 ◽

2018 ◽

Vol 49 (3) ◽

pp. 1115-1123 ◽

Cited By ~ 2

Author(s):

Yongzhong Mao ◽

Shaotao Tang ◽

Li Yang ◽

Kang Li

Keyword(s):

Bile Duct ◽

Biliary Atresia ◽

Progenitor Cells ◽

Notch Pathway ◽

Bile Duct Obstruction ◽

Hepatic Progenitor Cells ◽

Newborn Mice ◽

Duct Obstruction

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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