Cathepsin B promotes collagen biosynthesis driving 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, 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 assessedÂ viaÂ 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 anÂ in-vivoÂ orthotopic left-LTx mouse model. Mechanistic studies were performedÂ in-vitroÂ 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-Î²1-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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Conflict of interest: Dr. Morrone has nothing to disclose.
Conflict of interest: Dr. Smirnova has nothing to disclose.
Conflict of interest: Dr. Jeridi has nothing to disclose.
Conflict of interest: Dr. Kneidinger has nothing to disclose.
Conflict of interest: Dr. Hollauer has nothing to disclose.
Conflict of interest: Dr. Schupp has nothing to disclose.
Conflict of interest: Dr. Kaminski reports personal fees from Biogen Idec, Boehringer Ingelheim, Third Rock, Samumed, NuMedii, Indaloo, Theravance, LifeMax, Three Lake Partners, RohBar, Pliant, Atra Zeneca. ReportsÂ non-financial support from Miragen, equity with Pliant and miRagen, and aÂ grant from Veracyte. All outside the submitted work; In addition, Dr. Kaminski has patents on New Therapies in Pulmonary Fibrosis and on Peripheral Blood Gene Expression that have been licensed to Biotech.Dr. Kaminski reports personal fees from Biogen Idec, personal fees from Boehringer Ingelheim, personal fees from Third Rock, personal fees from MMI, non-financial support from Miragen, personal fees from Pliant, personal fees from Samumed, personal fees from NuMedii, personal fees from Indaloo, outside the submitted work; In addition, Dr. Kaminski has a patent New Threapies in Pulmonary Fibrosis with royalties paid to Biotech, and a patent Peripheral Blood Gene Expression issued and Serves as Deputy Editor of Thorax, BMJ.
Conflict of interest: Dr. Jenne has nothing to disclose.
Conflict of interest: Dr. Eickelberg has nothing to disclose.
Conflict of interest: Dr. Yildirim has nothing to disclose.
- ReceivedÂ April 26, 2020.
- AcceptedÂ November 8, 2020.
- Copyright Â©ERS 2020