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| Status |
Public on Jun 09, 2011 |
| Title |
Transcriptional profiling after bile duct ligation identifies PAI-1 as a contributor to cholestatic injury in mice. |
| Organism |
Mus musculus |
| Experiment type |
Expression profiling by array
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| Summary |
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.
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| Overall design |
Total RNA isolated using TRI Reagent (Sigma, St. Louis, MO) was purified with an RNeasy mini kit (Qiagen, Valencia, CA). Twenty micrograms cRNA was hybridized to a mouse GeneChip (U74Av2, Affymetrix, Santa Clara, CA) at the Siteman Cancer Center GeneChip facility as described by the manufacturer. Analyses used one mouse per chip. Gene expression changes were analyzed using Affymetrix MicroArray Suite 4.0 and GeneChip 3.1 Expression Analysis and Statistical Algorithms (Affymetrix). The complete methodology and full data sets for all 6 analyzed chips are available at http://bioinformatics.wustl.edu.beckerproxy.wustl.edu
This study compares the injury and repair processed in wild-type mice after BDL.
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| Contributor(s) |
Wang H, Vohra BP, Zhang Y, Heuckeroth RO |
| Citation(s) |
16250054 |
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| Submission date |
Jun 07, 2011 |
| Last update date |
Feb 18, 2018 |
| Contact name |
Rekha Meyer |
| E-mail(s) |
[email protected]
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| Phone |
314 362 8853
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| Organization name |
Washington University School of Medicine
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| Street address |
4320 Forest Park Av
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| City |
St Louis |
| State/province |
MO |
| ZIP/Postal code |
63128 |
| Country |
USA |
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| Platforms (1) |
| GPL81 |
[MG_U74Av2] Affymetrix Murine Genome U74A Version 2 Array |
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| Samples (6)
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| Relations |
| BioProject |
PRJNA141049 |
| Supplementary file |
Size |
Download |
File type/resource |
| GSE29776_RAW.tar |
17.1 Mb |
(http)(custom) |
TAR (of CEL) |
| Processed data included within Sample table |
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