Cathepsin B promotes collagen biosynthesis, which drives bronchiolitis obliterans syndrome

Morrone, Carmela; Smirnova, Natalia F.; Jeridi, Aicha; Kneidinger, Nikolaus; Hollauer, Christine; Schupp, Jonas Christian; Kaminski, Naftali; Jenne, Dieter; Eickelberg, Oliver und Yildirim, Ali Onder (2021): Cathepsin B promotes collagen biosynthesis, which drives bronchiolitis obliterans syndrome. In: European Respiratory Journal, Bd. 57, Nr. 5, 2001416

Abstract

Bronchiolitis obliterans syndrome (BOS) is a major complication after lung transplantation (LTx). BOS is characterised by massive peribronchial fibrosis, leading to air trapping-induced pulmonary dysfunction. Cathepsin B, a lysosomal cysteine protease, has been shown to enforce fibrotic pathways in several diseases. However, the relevance of cathepsin B in BOS progression has not yet been addressed. The aim of the study was to elucidate the function of cathepsin B in BOS pathogenesis. We determined cathepsin B levels in bronchoalveolar lavage fluid (BALF) and lung tissue from healthy donors (HD) and BOS LTx patients. Cathepsin B activity was assessed via a fluorescence resonance energy transfer-based assay and protein expression was determined using Western blotting, ELISA and immunostaining. To investigate the impact of cathepsin B in the pathophysiology of BOS, we used an in vivo orthotopic left LTx mouse model. Mechanistic studies were performed in vitro using macrophage and fibroblast cell lines. We found a significant increase of cathepsin B activity in BALF and lung tissue from BOS patients, as well as in our murine model of lymphocytic bronchiolitis. Moreover, cathepsin B activity was associated with increased biosynthesis of collagen and had a negative effect on lung function. We observed that cathepsin B was mainly expressed in macrophages that infiltrated areas characterised by a massive accumulation of collagen deposition. Mechanistically, macrophage-derived cathepsin B contributed to transforming growth factor-beta 1-dependent activation of fibroblasts, and its inhibition reversed the phenotype. Infiltrating macrophages release active cathepsin B, thereby promoting fibroblast activation and subsequent collagen deposition, which drive BOS. Cathepsin B represents a promising therapeutic target to prevent the progression of BOS.

• Dokumententyp: Zeitschriftenartikel
• Fakultät: Medizin
• Themengebiete: 600 Technik, Medizin, angewandte Wissenschaften > 610 Medizin und Gesundheit
• ISSN: 0903-1936
• Sprache: Englisch