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.
- Morrone, C.
- Smirnova, N. F.
- Jeridi, A.
- Kneidinger, N.
- Hollauer, C.
- Schupp, J. C.
- Kaminski, N.
- Jenne, D.
- Eickelberg, O.
- Yildirim, AÖ
Keywords
- Animals
- *Bronchiolitis Obliterans
- Bronchoalveolar Lavage Fluid
- Cathepsin B
- Humans
- Lung
- *Lung Transplantation
- Mice
- Smirnova has nothing to disclose. Conflict of interest: A. Jeridi has nothing to
- disclose. Conflict of interest: N. Kneidinger has nothing to disclose. Conflict of
- interest: C. Hollauer has nothing to disclose. Conflict of interest: J.C. Schupp has
- nothing to disclose. Conflict of interest: N. Kaminski reports personal fees for
- consultancy and/or advisory board work from Biogen Idec, Boehringer Ingelheim, Third
- Rock, Samumed, NuMedii, Indaloo, Theravance, LifeMax, Three Lake Partners, RohBar,
- Pliant and AstraZeneca
- non-financial support from Miragen, equity with Pliant and
- miRagen, and a grant from Veracyte, all outside the submitted work
- has patents on
- New Therapies in Pulmonary Fibrosis and on Peripheral Blood Gene Expression that
- have been licensed to Biotech
- and serves as deputy editor of Thorax. Conflict of
- interest: D. Jenne has nothing to disclose. Conflict of interest: O. Eickelberg has
- nothing to disclose. Conflict of interest: A.Ö. Yildirim has nothing to disclose.