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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)
Verlagsversion DOI PMC
Free by publisher
Open Access Green möglich sobald Postprint bei der ZB eingereicht worden ist.
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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Publikationstyp Artikel: Journalartikel
Dokumenttyp Wissenschaftlicher Artikel
Korrespondenzautor
Schlagwörter Cystatin-c; Mesenchymal Transition; Bronchoalveolar Lavage; Tgf-beta; Lung; Macrophages; Model
ISSN (print) / ISBN 0903-1936
e-ISSN 1399-3003
Zeitschrift European Respiratory Journal
Quellenangaben Band: 57, Heft: 5 Seiten: , Artikelnummer: , Supplement: ,
Verlag European Respiratory Society
Verlagsort Sheffield
Nichtpatentliteratur Publikationen
Begutachtungsstatus Peer reviewed
Institut(e) Institute of Lung Health and Immunity (LHI)
Förderungen Max Planck Society
European Union's Horizon 2020 research and innovation program
German Center for Lung Research (DZL)