Linked Life Data

18393301

Source:http://linkedlifedata.com/resource/pubmed/id/18393301

Statements in which the resource exists as a subject.
PredicateObject
rdf:type
lifeskim:mentions
pubmed:issue
5
pubmed:dateCreated
2008-5-1
pubmed:abstractText
Biliary atresia is a fibro-inflammatory cholangiopathy that obstructs the extrahepatic bile ducts in young infants. Although the pathogenesis of the disease is undefined, studies in livers from affected children and neonatal mice with experimental biliary atresia have shown increased expression of proapoptosis molecules. Therefore, we hypothesized that apoptosis is a significant mechanism of injury to duct epithelium. To test this hypothesis, we quantified apoptosis using terminal transferase dUTP nick end labeling and active caspase-3 staining in livers and extrahepatic bile ducts from Balb/c mice infected with Rhesus rotavirus (RRV) within 24 hours of birth. RRV induced a significant increase in labeled cells in the portal tracts and in epithelial and subepithelial compartments of extrahepatic bile ducts, with onset within 3 days and peaks at 5-10 days. Exploring mechanisms of injury, we found increased biliary expression of caspases 1 and 4 and of interferon-gamma (IFNgamma)-related and tumor necrosis factor-alpha (TNFalpha)-related genes. Using a cholangiocyte cell line, we found that neither IFNgamma nor TNFalpha alone affected cell viability; however, simultaneous exposure to IFNgamma and TNFalpha activated caspase-3 and decreased cell viability. Inhibition of caspase activity blocked apoptosis and restored viability to cultured cholangiocytes. In vivo, administration of the caspase inhibitor IDN-8050 decreased apoptosis in the duct epithelium and the extent of epithelial injury after RRV challenge. Conclusion: The biliary epithelium undergoes early activation of apoptosis in a mouse model of biliary atresia. The synergistic role of IFNgamma and TNFalpha in activating caspase-3 in cholangiocytes and the decreased apoptosis following pharmacologic inhibition of caspases support a prominent role for apoptosis in the pathogenesis of experimental biliary atresia.
pubmed:grant
pubmed:language
eng
pubmed:journal
pubmed:citationSubset
IM
pubmed:chemical
pubmed:status
MEDLINE
pubmed:month
May
pubmed:issn
1527-3350
pubmed:author
pubmed:issnType
Electronic
pubmed:volume
47
pubmed:owner
NLM
pubmed:authorsComplete
Y
pubmed:pagination
1567-77
pubmed:meshHeading
pubmed:year
2008
pubmed:articleTitle
Temporal-spatial activation of apoptosis and epithelial injury in murine experimental biliary atresia.
pubmed:affiliation
Cincinnati Children's Hospital Medical Center and Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH 45229-3039, USA.
pubmed:publicationType
Journal Article, Research Support, Non-U.S. Gov't, Research Support, N.I.H., Extramural