Cathepsin B inactivation attenuates hepatic injury and fibrosis during cholestasis

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

Research output: Contribution to journalArticle

164 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)152-159
Number of pages8
JournalJournal of Clinical Investigation
Volume112
Issue number2
DOIs
StatePublished - Jul 2003

ASJC Scopus subject areas

  • Medicine(all)

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    Canbay, A., Guicciardi, M. E., Higuchi, H., Feldstein, A., Bronk, S. F., Rydzewski, R., Taniai, M., & Gores, G. J. (2003). Cathepsin B inactivation attenuates hepatic injury and fibrosis during cholestasis. Journal of Clinical Investigation, 112(2), 152-159. https://doi.org/10.1172/JCI200317740