Cathepsin B promotes collagen biosynthesis, which drives bronchiolitis obliterans syndrome.
Carmela MorroneNatalia F SmirnovaAicha JeridiNikolaus KneidingerChristine HollauerJonas Christian SchuppNaftali KaminskiDieter E JenneOliver EickelbergAli Oender YildirimPublished in: The European respiratory journal (2021)
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-β1-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.
Keyphrases
- energy transfer
- end stage renal disease
- mouse model
- transforming growth factor
- chronic kidney disease
- lung function
- newly diagnosed
- ejection fraction
- adipose tissue
- chronic obstructive pulmonary disease
- prognostic factors
- wound healing
- epithelial mesenchymal transition
- south africa
- pulmonary hypertension
- air pollution
- case report
- single cell
- signaling pathway
- extracorporeal membrane oxygenation
- drug induced