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Cathepsin B inactivation attenuates hepatic injury and fibrosis during cholestasis
- Source :
- Journal of Clinical Investigation. 112:152-159
- Publication Year :
- 2003
- Publisher :
- American Society for Clinical Investigation, 2003.
-
Abstract
- Although a lysosomal, cathepsin B-dependent (Ctsb-dependent) pathway of apoptosis has been described, the contribution of this pathway to tissue damage remains unclear. Our aim was to ascertain if Ctsb inactivation attenuates liver injury, inflammation, and fibrogenesis after bile duct ligation (BDL). In 3-day BDL mice, hepatocyte apoptosis, mitochondrial cytochrome c release, and serum alanine aminotransferase (ALT) values were reduced in Ctsb-/- versus Ctsb+/+ animals. Likewise, R-3032 (a Ctsb inhibitor) also reduced these parameters in BDL WT mice. Both genetic and pharmacologic inhibition of Ctsb in the BDL mouse reduced (a). hepatic inflammation, as assessed by transcripts for CXC chemokines and neutrophil infiltration, and (b). fibrogenesis, as assessed by transcripts for stellate cell activation and sirius red staining for hepatic collagen deposition. These differences could not be ascribed to alterations in cholestasis. These findings support a prominent role for the lysosomal pathway of apoptosis in tissue injury and link apoptosis to inflammation and fibrogenesis. Ctsb inhibition may be therapeutic in liver diseases.
- Subjects :
- Pathology
medicine.medical_specialty
Time Factors
Neutrophils
Immunoblotting
Apoptosis
Cytochrome c Group
digestive system
Cathepsin B
Article
Bile Acids and Salts
Mice
Cholestasis
Fibrosis
Clinical investigation
In Situ Nick-End Labeling
Medicine
Animals
Inflammation
Mice, Knockout
business.industry
Reverse Transcriptase Polymerase Chain Reaction
Alanine Transaminase
Bilirubin
General Medicine
medicine.disease
Mitochondria
Mice, Inbred C57BL
Liver
Hepatocytes
business
Corrigendum
Subjects
Details
- ISSN :
- 00219738
- Volume :
- 112
- Database :
- OpenAIRE
- Journal :
- Journal of Clinical Investigation
- Accession number :
- edsair.doi.dedup.....c7f1d49c2cc149fc8566845b257fca33