Science and Research

Cathepsin B promotes collagen biosynthesis, which drives bronchiolitis obliterans syndrome

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.
Publication details
DOI: 10.1183/13993003.01416-2020
Journal: Eur Respir J
Number: 5
Work Type: Original
Location: CPC-M
Disease Area: ROR
Partner / Member: HMGU, KUM
Access-Number: 33303550

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