Exposure to cigarette smoke triggers proteolytic cleavage of occludin, a tight junction protein, by cathepsin S and impairs the pulmonary epithelial barrier during COPD - 17/02/23
, S. Chesseron 1, A. Saidi 1, D. Sizaret 2, A. Petit-Courty 1, Y. Courty 1, F. Lecaille 1, G. Lalmanach 1
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Resumen |
Introduction |
Smoking is accountable for more than 80% of chronic obstructive pulmonary disease (COPD, 3rd cause of death worldwide), which is characterized by emphysema, chronic bronchitis associated to an impaired epithelial permeability. Exposure of the lung to cigarette smoke elicits the expression of elastinolytic cathepsin S (CatS), a cysteine protease, which remains active despite an oxidizing environment [1]. Recently, junctional and/or adhesion molecules were pinpointed as putative CatS targets, suggesting that CatS could proteolytically alter epithelial integrity during COPD.
Methods |
Clinical features: immunochemical analysis of human COPD and non-COPD lung biopsies revealed a decreased expression level of tight junction occludin for smokers (vs. non-smokers). Statistical analysis demonstrated that occludin level correlates negatively with the smoking history (number of pack-years), COPD grades as well with proteolytic activity of CatS.
Results |
Molecular mechanisms: exposure of macrophages to cigarette smoke extract (CSE) or nicotine, a major CSE component, triggered expression of secreted and catalytically active CatS through the mTOR/TFEB signaling pathway. Incubation of lung epithelial cells (grown in submerge or air–liquid interface culture) with CatS was associated with an increased proteolysis of occludin (observed by western blotting and confocal microscopy), a decreased trans-epithelial electrical resistance (TEER) and an amplified epithelial permeability. In a model of co-cultured macrophages/epithelial cells, an increase of epithelial permeability was observed following exposure to CSE. Conversely, both pharmacological inhibition of CatS as well its transient transcriptional inhibition by siRNAs restored the basal permeability of lung epithelial cells.
Conclusions |
Altogether with its deleterious elastinolytic activity favoring emphysema, the uncontrolled enzymatic activity of CatS displays detrimental effects on the integrity of lung epithelial barriers, therefore strengthening the therapeutic relevance of targeting CatS in COPD [2].
El texto completo de este artículo está disponible en PDF.Keywords : Cysteine protease, Chronic obstructive pulmonary disease (COPD), Epithelial barrier, Inflammation, Tight junction protein
Esquema
Vol 40 - N° 2
P. 117 - février 2023 Regresar al número
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