Losartan Rescues Inflammation-related Mucociliary Dysfunction in Relevant Models of Cystic Fibrosis

Area of Science:

• Pulmonary Medicine
• Cellular Biology
• Pharmacology

Background:

• Cystic fibrosis (CF) airway disease involves inflammation and mucociliary dysfunction, impacting large-conductance Ca2+-activated and voltage-dependent K+ (BK) channels critical for mucociliary function.
• Inflammation reduces BK channel activity, essential for airway clearance in the absence of functional CFTR (cystic fibrosis transmembrane conductance regulator).

Purpose of the Study:

• To evaluate losartan as an anti-inflammatory therapy for CF-related airway disease.
• To assess losartan's ability to restore BK channel activity and mucociliary function in CF models.

Main Methods:

• In vitro studies used primary human bronchial epithelial cells from CF patients (F508del homozygous).
• In vivo studies utilized a pharmacologic ovine model of CF-like airway inflammation and mucociliary dysfunction.
• Losartan's effects on BK activity, LRRC26 expression, ciliary beat frequency, airway surface liquid, mucus, and inflammation were measured.

Main Results:

• Neutrophilic inflammation in CF airways correlated with reduced LRRC26, a key BK channel subunit.
• Losartan treatment in vitro and in vivo rescued BK channel dysfunction and improved mucociliary parameters.
• Nebulized losartan restored mucus transport, reduced mucus hyperconcentration, and decreased TGF-β1 levels in the ovine model.
• Observed benefits were independent of angiotensin receptor blockade.

Conclusions:

• Losartan effectively reverses inflammation-associated mucociliary dysfunction in cystic fibrosis.
• The therapeutic effects of losartan are mediated through mechanisms other than angiotensin receptor blockade, potentially involving LRRC26 restoration.
• Losartan presents a promising therapeutic strategy for managing airway inflammation and improving mucociliary clearance in CF.