作者@article {Morrone2001416 ={莫龙,卡la and Smirnova, Natalia F. and Jeridi, Aicha and Kneidinger, Nikolaus and Hollauer, Christine and Schupp, Jonas Christian and Kaminski, Naftali and Jenne, Dieter and Eickelberg, Oliver and Yildirim, Ali {\"O}nder}, title = {Cathepsin B promotes collagen biosynthesis, which drives bronchiolitis obliterans syndrome}, volume = {57}, number = {5}, elocation-id = {2001416}, year = {2021}, doi = {10.1183/13993003.01416-2020}, publisher = {European Respiratory Society}, 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-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.CatB is a new biomarker and therapeutic target for early bronchiolitis obliterans syndrome after lung transplantation https://bit.ly/36vOXHc}, issn = {0903-1936}, URL = {//www.qdcxjkg.com/content/57/5/2001416}, eprint = {//www.qdcxjkg.com/content/57/5/2001416.full.pdf}, journal = {European Respiratory Journal} }