Cathepsin B inactivation attenuates hepatic injury and fibrosis during cholestasis
Ali Canbay, … , Makiko Taniai, Gregory J. Gores
Ali Canbay, … , Makiko Taniai, Gregory J. Gores
Published July 15, 2003
Citation Information: J Clin Invest. 2003;112(2):152-159. https://doi.org/10.1172/JCI17740.
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Article Hepatology

Cathepsin B inactivation attenuates hepatic injury and fibrosis during cholestasis

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.

Authors

Ali Canbay, Maria Eugenia Guicciardi, Hajime Higuchi, Ariel Feldstein, Steven F. Bronk, Robert Rydzewski, Makiko Taniai, Gregory J. Gores

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Figure 5

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Hepatic fibrosis is increased in Ctsb+/+ BDL compared with Ctsb–/– BDL m...
Hepatic fibrosis is increased in Ctsb+/+ BDL compared with Ctsb–/– BDL mice. (a) Two weeks after the surgical procedure, liver tissue was obtained from BDL and sham-operated Ctsb+/+, Ctsb–/–, and R-3032–treated Ctsb+/+ BDL mice, and collagen fibers were stained with sirius red as described in Methods. (b) The surface area stained with sirius red was quantitated using digital image analysis. Sirius red staining was quantitatively greater in Ctsb+/+ BDL than in Ctsb–/– and R-3032–treated Ctsb+/+ BDL mice (P < 0.001, n = 4 for each group). Only minimal sirius red staining was observed in sham-operated mice from the three groups of animals. (Original magnification ×20.)