TY - JOUR T1 - Losartan reduces cigarette smoke-induced airway inflammation and mucus hypersecretion JF - ERJ Open Research JO - erjor DO - 10.1183/23120541.00394-2020 SP - 00394-2020 AU - Michael D. Kim AU - Nathalie Baumlin AU - John S. Dennis AU - Makoto Yoshida AU - Adrian Kis AU - Carolina Aguiar AU - Andreas Schmid AU - Eliana Mendes AU - Matthias Salathe Y1 - 2020/01/01 UR - http://openres.ersjournals.com/content/early/2020/09/17/23120541.00394-2020.abstract N2 - 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-liquid interface (ALI) and exposed to CS. Expression of transforming growth factor beta 1 (TGF-β1) and the mucin MUC5AC, and expression or activity of matrix metalloproteinase-9 (MMP-9) was measured after CS exposure. Parameters of mucociliary clearance were evaluated by measuring airway surface liquid (ASL) 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 ASL 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.FootnotesThis manuscript has recently been accepted for publication in the ERJ Open Research. It is published here in its accepted form prior to copyediting and typesetting by our production team. After these production processes are complete and the authors have approved the resulting proofs, the article will move to the latest issue of the ERJOR online. Please open or download the PDF to view this article.Conflict of interest: Dr. Kim reports grants from NIH, grants from Cystic Fibrosis Foundation, grants from Flight Attendant Medical Research Institute, grants from James and Esther King Florida Biomedical Research Program, during the conduct of the study.Conflict of interest: Nathalie Baumlin reports grants from NIH, grants from Cystic Fibrosis Foundation, grants from Flight Attendant Medical Research Institute, grants from James and Esther King Florida Biomedical Research Program, during the conduct of the study.Conflict of interest: John S. Dennis has nothing to disclose.Conflict of interest: Makoto Yoshida has nothing to disclose.Conflict of interest: Dr. Kis has nothing to disclose.Conflict of interest: Carolina Aguiar has nothing to disclose.Conflict of interest: Dr. Schmid has nothing to disclose.Conflict of interest: Dr. Mendes reports grants from Florida Department of Health, during the conduct of the study; grants from Florida Department of Health, outside the submitted work.Conflict of interest: M. Salathe reports grants and personal fees for grant review from the NIH and the Flight Attendant Medical Research Institute; grants from the James and Esther King Florida Biomedical Research Program; grants, and personal fees for grant review and committee work from the Cystic Fibrosis Foundation; and grants from the COPD Foundation, all during the conduct of the study; and grants and personal fees from Arrowhead Pharmaceuticals outside the submitted work. ER -