Cathepsin B inactivation attenuates hepatic injury and fibrosis during cholestasis.
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.
Canbay
Ali
A
Division of Gastroenterology and Hepatology, Mayo Medical School, Clinic, and Foundation, Rochester, Minnesota 55905, USA. gores.gregory@mayo.edu
Guicciardi
Maria Eugenia
ME
Higuchi
Hajime
H
Feldstein
Ariel
A
Bronk
Steven F
SF
Rydzewski
Robert
R
Taniai
Makiko
M
Gores
Gregory J
GJ
D000410:Alanine Transaminase / Q000097:blood / Q000378:metabolism; D000818:Animals; D017209:Apoptosis; D001647:Bile Acids and Salts / Q000378:metabolism; D001663:Bilirubin / Q000097:blood; D002401:Cathepsin B / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D002779:Cholestasis / Q000378:metabolism*; D003574:Cytochrome c Group / Q000378:metabolism; D005355:Fibrosis; D022781:Hepatocytes / Q000473:pathology; D015151:Immunoblotting; D020287:In Situ Nick-End Labeling; D007249:Inflammation; D008099:Liver / Q000293:injuries* / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008928:Mitochondria / Q000378:metabolism; D009504:Neutrophils / Q000473:pathology; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013997:Time Factors
D001647:Bile Acids and Salts; D003574:Cytochrome c Group; D000410:Alanine Transaminase; D002401:Cathepsin B; D001663:Bilirubin