PuSH - Publikationsserver des Helmholtz Zentrums München

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., DOI: 10.1183/13993003.01416-2020 (2020)
DOI Verlagsversion bestellen
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.
Altmetric
Weitere Metriken?
Zusatzinfos bearbeiten [➜Einloggen]
Publikationstyp Artikel: Journalartikel
Dokumenttyp Wissenschaftlicher Artikel
ISSN (print) / ISBN 0903-1936
e-ISSN 1399-3003
Verlag European Respiratory Society
Verlagsort Sheffield
Begutachtungsstatus Peer reviewed