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Morrone, C. ; Smirnova, N.F.* ; Jeridi, A. ; Kneidinger, N.* ; Hollauer, C. ; Schupp, J.C.* ; Kaminski, N.* ; Jenne, D. ; Eickelberg, O.* ; Yildirim, A.Ö.

Cathepsin B promotes collagen biosynthesis driving Bronchiolitis Obliterans Syndrome.

Eur. Respir. J. 57, DOI: 10.1183/13993003.01416-2020 (2020)
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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, was 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 BAL fluid and lung tissue from healthy donors (HD) and BOS LTx patients. Furthermore, Cathepsin B activity was assessed via a FRET-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 (LB). Moreover, Cathepsin B activity was associated with an increased biosynthesis of collagen, and negatively affected lung function. Interestingly, 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 TGF-β1-dependent activation of fibroblasts, and its inhibition reversed the phenotype.Infiltrating macrophages release active Cathepsin B promoting fibroblast-activation and subsequent collagen deposition, driving BOS. Cathepsin B represents a promising therapeutic target to prevent the progression of BOS.
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Publication type Article: Journal article
Document type Scientific Article
Keywords Cystatin-c; Mesenchymal Transition; Bronchoalveolar Lavage; Tgf-beta; Lung; Macrophages; Model
Language english
Publication Year 2020
HGF-reported in Year 2020
ISSN (print) / ISBN 0903-1936
e-ISSN 1399-3003
Journal European Respiratory Journal
Quellenangaben Volume: 57, Issue: 5 Pages: , Article Number: , Supplement: ,
Publisher European Respiratory Society
Publishing Place Sheffield
Reviewing status Peer reviewed
Institute(s) Institute of Lung Health and Immunity (LHI)
POF-Topic(s) 30202 - Environmental Health
Research field(s) Lung Research
PSP Element(s) G-505000-007
G-501600-001
Grants Max Planck Society
European Union's Horizon 2020 research and innovation program
German Center for Lung Research (DZL)
DOI 10.1183/13993003.01416-2020
WOS ID WOS:000663123900013
PubMed ID 33303550
Erfassungsdatum 2020-12-16
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