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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

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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 3

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Neutrophilic infiltration and chemokine expression are increased in Ctsb...
Neutrophilic infiltration and chemokine expression are increased in Ctsb+/+ compared with Ctsb–/– and R-3032–treated Ctsb+/+ BDL mice. Fixed liver specimens from mice were stained for MPO, a neutrophil marker. Neutrophil infiltration was present only in Ctsb+/+ BDL mice (a) (original magnification ×20). Three days after the surgical procedure, liver tissue was procured and total hepatic RNA was isolated as described in Methods. (b and c) MIP-2 and KC expression was quantitated by real-time PCR. The expression was normalized as a ratio using GAPDH mRNA as a housekeeping gene. A value of 1 for this ratio was arbitrarily assigned to the data obtained from sham-operated Ctsb+/+ mice. KC mRNA expression in Ctsb+/+ BDL was higher than in Ctsb–/– (P < 0.0001) and R-3032–treated Ctsb+/+ BDL mice (P < 0.0001, n = 4 for each group). The expression of MIP-2 mRNA was greater in Ctsb+/+ than in Ctsb–/– (P < 0.0001) and R-3032–treated Ctsb+/+ BDL mice (P < 0.0001, n = 4 for each group).

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ISSN: 0021-9738 (print), 1558-8238 (online)

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