Losartan rescues inflammation-related mucociliary dysfunction in relevant models of cystic fibrosis

Michael D. Kim, Nathalie Baumlin, Makoto Yoshida, Deepika Polineni, Sebastian F. Salathe, Joseph K. David, Charles A. Peloquin, Adam Wanner, John S. Dennis, Juliette Sailland, Philip Whitney, Frank T. Horrigan, Juan R. Sabater, William M. Abraham, Matthias Salathe

Research output: Contribution to journalArticle

1 Scopus citations

Abstract

Rationale: Despite therapeutic progress in treating cysticfibrosis (CF) airway disease, airway inflammation with associated mucociliary dysfunction remains largely unaddressed. Inflammation reduces the activity of apically expressed large-conductance Ca2+-activated and voltage-dependentK+ (BK) channels, critical formucociliary function in the absence of CFTR (CF transmembrane conductance regulator). Objectives: To test losartan as an antiinflammatory therapy in CF using CF human bronchial epithelial cells and an ovine model of CFlike airway disease. Methods: Losartan's antiinflammatory effectiveness to rescue BK activity and thus mucociliary function was tested in vitro using primary, fully redifferentiated human airway epithelial cells homozygous for F508del and in vivo using a previously validated, now expanded pharmacologic sheep model of CF-like, inflammation-associated mucociliary dysfunction. Measurements and Main Results: Nasal scrapings from patients with CF showed that neutrophilic inflammation correlated with reduced expression of LRRC26 (leucine rich repeat containing 26), the γ subunit mandatory for BK function in the airways. TGF-β1 (transforming growth factor β1), downstream of neutrophil elastase, decreased mucociliary parameters in vitro. These were rescued by losartan at concentrations achieved by nebulization in the airway and oral application in the bloodstream: BK dysfunction recovered acutely and over time (the latter via an increase in LRRC26 expression), ciliary beat frequency and airway surface liquid volume improved, and mucus hyperconcentration and cellular inflammation decreased. These effects did not depend on angiotensin receptor blockade. Expanding on a validated and published nongenetic, CF-like sheep model, ewes inhaled CFTRinh172 and neutrophil elastase for 3 days, which resulted in prolonged tracheal mucus velocity reduction, mucus hyperconcentration, and increased TGFβ1. Nebulized losartan rescued both mucus transport and mucus hyperconcentration and reduced TGF-β1. Conclusions: Losartan effectively reversed CF- and inflammationassociated mucociliary dysfunction, independent of its angiotensin receptor blockade.

Original languageEnglish (US)
Pages (from-to)313-324
Number of pages12
JournalAmerican journal of respiratory and critical care medicine
Volume201
Issue number3
DOIs
StatePublished - Feb 1 2020

Keywords

  • Angiotensin receptor antagonists
  • Cilia
  • Human neutrophil elastase
  • Mucus
  • Transforming growth factor β

ASJC Scopus subject areas

  • Pulmonary and Respiratory Medicine
  • Critical Care and Intensive Care Medicine

Fingerprint Dive into the research topics of 'Losartan rescues inflammation-related mucociliary dysfunction in relevant models of cystic fibrosis'. Together they form a unique fingerprint.

  • Cite this

    Kim, M. D., Baumlin, N., Yoshida, M., Polineni, D., Salathe, S. F., David, J. K., Peloquin, C. A., Wanner, A., Dennis, J. S., Sailland, J., Whitney, P., Horrigan, F. T., Sabater, J. R., Abraham, W. M., & Salathe, M. (2020). Losartan rescues inflammation-related mucociliary dysfunction in relevant models of cystic fibrosis. American journal of respiratory and critical care medicine, 201(3), 313-324. https://doi.org/10.1164/rccm.201905-0990OC