Cathepsin B promotes collagen biosynthesis, which drives bronchiolitis obliterans syndrome
Carmela Morrone, Natalia F. Smirnova, Aicha Jeridi, Nikolaus Kneidinger, Christine Hollauer, Jonas Christian Schupp, Naftali Kaminski, Dieter Jenne, Oliver Eickelberg, Ali Önder Yildirim
Source: Eur Respir J, 57 (5) 2001416; 10.1183/13993003.01416-2020
Abstract
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-ß1-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.
Rating:
You must login to grade this presentation.
Share or cite this content
Citations should be made in the following way:
Carmela Morrone, Natalia F. Smirnova, Aicha Jeridi, Nikolaus Kneidinger, Christine Hollauer, Jonas Christian Schupp, Naftali Kaminski, Dieter Jenne, Oliver Eickelberg, Ali Önder Yildirim. Cathepsin B promotes collagen biosynthesis, which drives bronchiolitis obliterans syndrome. Eur Respir J, 57 (5) 2001416; 10.1183/13993003.01416-2020
You must login to share this Presentation/Article on Twitter, Facebook, LinkedIn or by email.
Member's Comments
Related content which might interest you:
Related content which might interest you:
Neutrophil mediated matrixmetalloproteinase activity is increased in bronchiolitis obliterans syndrome after lung transplantation Source: Eur Respir J 2004; 24: Suppl. 48, 179s Year: 2004
Pseudomonas aeruginosa accentuates epithelial-to-mesenchymal transition in the airway Source: Eur Respir J 2011; 37: 1237-1247 Year: 2011
Matrix metalloproteinase-9 in bronchiolitis obliterans syndrome after lung transplantation Source: Eur Respir J 2005; 25: 494-501 Year: 2005
In vitro model to study the correlation between neutrophils and miR21 expression: a role in Bronchiolitis obliterans syndrome Source: International Congress 2019 – Lung transplantation: from basic science to clinical outcomes Year: 2019
Balance of matrix metalloproteinase-9 and tissue inhibitor of metalloproteinase-1 in the development of bronchiolitis obliterans syndrome after lung transplantation Source: Eur Respir J 2003; 22: Suppl. 45, 327s Year: 2003
Antimicrobial peptides in lung transplant recipients with bronchiolitis obliterans syndrome Source: Eur Respir J 2008; 32: 670-677 Year: 2008
Genetic polymorphism in the MMP7 gene correlates with the development of bronchiolitis obliterans syndrome Source: Annual Congress 2009 - Bronchiolitis obliterans syndrome after lung transplantation: pathophysiology and treatment options Year: 2009
Macrolides inhibit cytokine production by alveolar macrophages in bronchiolitis obliterans organizing pneumonia Source: Annual Congress 2012 - Diffuse parenchymal lung disease II Year: 2012
Calcineurin inhibitors in bronchiolitis obliterans syndrome following stem cell transplantation Source: Eur Respir J 2014; 43: 221-232 Year: 2004
Immunohistochemical characterization of inflammatory cells in childhood bronchiolitis obliterans Source: Eur Respir J 2001; 18: Suppl. 33, 292s Year: 2001
Bronchiolitis obliterans syndrome and bronchiolitis obliterans in lung transplantation: will a pathologist and a physician ever meet? Source: ISSN=1025-448x, ISBN=1-904097-33-2, page=55 Year: 2004
Mediators produced by apoptotic endothelial cells activates Twist and Snail; role in bronchiolitis obliterans Source: Annual Congress 2010 - Lung cell biology and immunology Year: 2010
Bronchiolitis obliterans syndrome after lung transplantation: diagnosis and treatment Source: ISSN=1025-448x, ISBN=1-904097-33-2, page=19 Year: 2004
Calprotectin as new sensitive marker of neutrophilic inflammation in patients with bronchiolitis obliterans Source: International Congress 2018 – Paediatric respiratory infections: mechanistic insights and clinical outcomes Year: 2018
Bronchiolitis obliterans (BO) treatment with collagen with collagen type V and corticoid by nasal-drop in Balb-c mice (BM) Source: Eur Respir J 2005; 26: Suppl. 49, 732s Year: 2005
Chronic lung allograft rejection: prevalence, pathology, risk factors and pathophysiology Source: ISSN=1025-448x, ISBN=1-904097-33-2, page=1 Year: 2004
Validation of a bronchiolitis obliterans rat lung transplant model: the role of MMP-9 Source: Eur Respir J 2006; 28: Suppl. 50, 778s Year: 2006
The role of cytomegalovirus in the development of bronchiolitis obliterans syndrome Source: International Congress 2015 – Pathogenic mechanisms of lung transplant complications: a focus on CLAD Year: 2015
The mononuclear phagocyte system contributes to fibrosis in post-transplant obliterans bronchiolitis Source: Eur Respir J, 57 (3) 2000344; 10.1183/13993003.00344-2020 Year: 2021
Putting the spotlight on macrophage-derived cathepsin in the pathophysiology of obliterative bronchiolitis Source: Eur Respir J, 57 (5) 2004607; 10.1183/13993003.04607-2020 Year: 2021