@article {Kim00394-2020, author = {Michael D. Kim and Nathalie Baumlin and John S. Dennis and Makoto Yoshida and Adrian Kis and Carolina Aguiar and Andreas Schmid and Eliana Mendes and Matthias Salathe}, title = {Losartan reduces cigarette smoke-induced airway inflammation and mucus hypersecretion}, volume = {7}, number = {1}, elocation-id = {00394-2020}, year = {2021}, doi = {10.1183/23120541.00394-2020}, publisher = {European Respiratory Society}, abstract = {The aim was to determine whether losartan reduces cigarette smoke (CS)-induced airway inflammation and mucus hypersecretion in an in vitro model and a small clinical trial.Primary human bronchial epithelial cells (HBECs) were differentiated at the air{\textendash}liquid interface (ALI) and exposed to CS. Expression of transforming growth factor (TGF)-β1 and the mucin MUC5AC, and expression or activity of matrix metalloproteinase (MMP)-9 were measured after CS exposure. Parameters of mucociliary clearance were evaluated by measuring airway surface liquid volumes, mucus concentrations, and conductance of cystic fibrosis transmembrane conductance regulator (CFTR) and large conductance, Ca2+-activated and voltage-dependent potassium (BK) channels. Nasal cells were collected from study participants and expression of MUC5AC, TGF-β1, and MMP-9 mRNAs was measured before and after losartan treatment.In vitro, CS exposure of HBECs caused a significant increase in mRNA expression of MUC5AC and TGF-β1 and MMP-9 activity and decreased CFTR and BK channel activities, thereby reducing airway surface liquid volumes and increasing mucus concentrations. Treatment of HBECs with losartan rescued CS-induced CFTR and BK dysfunction and caused a significant decrease in MUC5AC expression and mucus concentrations, partially by inhibiting TGF-β signalling. In a prospective clinical study, cigarette smokers showed significantly reduced mRNA expression levels of MUC5AC, TGF-β1, and MMP-9 in the upper airways after 2 months of losartan treatment.Our findings suggest that losartan may be an effective therapy to reduce inflammation and mucus hypersecretion in CS-induced chronic airway diseases.Inflammation and mucus hypersecretion, associated with cigarette smoke-induced chronic airway diseases, is ameliorated by losartan in human airway epithelial cells in vitro and in the upper airways of human subjects in a small clinical trial https://bit.ly/2G0aM8j}, URL = {https://openres.ersjournals.com/content/7/1/00394-2020}, eprint = {https://openres.ersjournals.com/content/7/1/00394-2020.full.pdf}, journal = {ERJ Open Research} }