Linked Life Data

16250054

Source:http://linkedlifedata.com/resource/pubmed/id/16250054

Statements in which the resource exists as a subject.
PredicateObject
rdf:type
lifeskim:mentions
pubmed:issue
5
pubmed:dateCreated
2005-11-1
pubmed:abstractText
Extrahepatic cholestasis leads to complex injury and repair processes that result in bile infarct formation, neutrophil infiltration, cholangiocyte and hepatocyte proliferation, extracellular matrix remodeling, and fibrosis. To identify early molecular mechanisms of injury and repair after bile duct obstruction, microarray analysis was performed on liver tissue 24 hours after bile duct ligation (BDL) or sham surgery. The most upregulated gene identified encodes plasminogen activator inhibitor 1 (PAI-1, Serpine 1), a protease inhibitor that blocks urokinase plasminogen activator (uPA) and tissue-type plasminogen activator (tPA) activity. Because PAI-1, uPA, and tPA influence growth factor and cytokine processing as well as extracellular matrix remodeling, we evaluated the role of PAI-1 in cholestatic liver injury by comparing the injury and repair processes in wild-type (WT) and PAI-1-deficient (PAI-1-/-) mice after BDL. PAI-1-/- mice had fewer and smaller bile infarcts, less neutrophil infiltration, and higher levels of cholangiocyte and hepatocyte proliferation than WT animals after BDL. Furthermore, PAI-1-/- mice had higher levels of tPA activation and mature hepatocyte growth factor (HGF) after BDL than WT mice, suggesting that PAI-1 effects on HGF activation critically influence cholestatic liver injury. This was further supported by elevated levels of c-Met and Akt phosphorylation in PAI-1-/- mice after BDL. In conclusion, PAI-1 deficiency reduces liver injury after BDL in mice. These data suggest that inhibiting PAI-1 might attenuate liver injury in cholestatic liver diseases.
pubmed:grant
pubmed:language
eng
pubmed:journal
pubmed:citationSubset
IM
pubmed:chemical
pubmed:status
MEDLINE
pubmed:month
Nov
pubmed:issn
0270-9139
pubmed:author
pubmed:issnType
Print
pubmed:volume
42
pubmed:owner
NLM
pubmed:authorsComplete
Y
pubmed:pagination
1099-108
pubmed:dateRevised
2008-11-21
pubmed:meshHeading
pubmed-meshheading:16250054-Animals, pubmed-meshheading:16250054-Bile Ducts, pubmed-meshheading:16250054-Cell Proliferation, pubmed-meshheading:16250054-Cholestasis, pubmed-meshheading:16250054-Gene Expression Profiling, pubmed-meshheading:16250054-Hepatitis, pubmed-meshheading:16250054-Hepatocytes, pubmed-meshheading:16250054-Incidence, pubmed-meshheading:16250054-Infarction, pubmed-meshheading:16250054-Interleukin-8, pubmed-meshheading:16250054-Ligation, pubmed-meshheading:16250054-Male, pubmed-meshheading:16250054-Mice, pubmed-meshheading:16250054-Mice, Inbred C57BL, pubmed-meshheading:16250054-Mice, Knockout, pubmed-meshheading:16250054-Oligonucleotide Array Sequence Analysis, pubmed-meshheading:16250054-Plasminogen Activator Inhibitor 1, pubmed-meshheading:16250054-RNA, Messenger, pubmed-meshheading:16250054-Tissue Plasminogen Activator, pubmed-meshheading:16250054-Transcription, Genetic, pubmed-meshheading:16250054-Urokinase-Type Plasminogen Activator
pubmed:year
2005
pubmed:articleTitle
Transcriptional profiling after bile duct ligation identifies PAI-1 as a contributor to cholestatic injury in mice.
pubmed:affiliation
Division of Gastroenterology and Nutrition, Department of Pediatrics, Washington University School of Medicine, St. Louis, MO 63110, USA.
pubmed:publicationType
Journal Article, Research Support, U.S. Gov't, P.H.S., Research Support, Non-U.S. Gov't, Research Support, N.I.H., Extramural