Validation of AMP-Activated Protein Kinase as a Therapeutic Target in Bronchiectasis

Introduction: Neutrophilic inflammation, ineffective bacterial clearance and mucociliary dysfunction are defined features of bronchiectasis (BE). The mechanisms linking these phenomena are not known, and there is a need to identify new therapies that can target multiple components of the vicious cycle. AMP-activated protein kinase is a master regulator of cellular metabolism which may represent a therapeutic target in BE. Methods: Sputum was collected from patients participating in the multicentre BRIDGE study (NCT03791086) for airway metabolite analysis. Airway epithelial cells and peripheral neutrophils were treated with AMPK inhibitors (compound C and resistin) and AMPK activators (A769662). Results: N=296 patients were analysed. Glucose was highly variable in sputum but was not related to BE severity. Lactate associated with increased neutrophil elastase (r=0.16,p=0.04), resistin (r=0.49,p Confocal microscopy showed AMPK expression in nasal cilia. AMPK inhibition transiently reduced ciliary beat frequency (CBF) (15.80%,p=0.0161) by compound C and (20.34%,p Resistin potentiated the effect of the NET inducer PMA to promote NET formation in-vitro (p=0.0304) Conclusions: Our data suggests that the BE airway contains factors such as resistin and high glucose levels that promote AMPK inhibition. This is associated with reduced CBF and increased NETosis, which are central features of BE pathophysiology. Targeting AMPK has therapeutic potential in BE.