Dipeptidyl peptidase-1 inhibitors in bronchiectasis

Abstract

Dipeptidyl peptidase (DPP)-1 (also known as cathepsin C) inhibitors are the first disease-specific therapy shown to be effective in bronchiectasis. The mechanism of action of DPP-1 inhibitors is suppression of activity of neutrophil serine proteases (NSPs) by preventing them from being activated during neutrophil maturation in the bone marrow. NSPs exert multiple directly damaging effects and contribute to ongoing dysregulated airway inflammation. High airway levels of NSPs are linked to bronchiectasis disease severity. Several phase 2 and one phase 3 trial have now confirmed that DPP-1 inhibitors reduce activity of the NSPs in the airways and have clinical benefits in bronchiectasis including reducing exacerbations and improving other clinical end-points such as quality of life and slowing lung function decline. DPP-1 inhibition may also be a promising treatment avenue in other diseases where neutrophilic inflammation is implicated. Future directions include establishing direct and downstream effects of DPP-1 inhibitors in humans and seeking biomarkers to guide clinical application.

FIGURE 1

Inflammatory changes on chest high-resolution computed tomography in patients with bronchiectasis including: mucus plugging, bronchial wall thickening and inflammatory nodules. a) A patient with idiopathic bronchiectasis showing focal right lower lobe mucus plugging (A). b) A patient with bronchiectasis due to non-tuberculous mycobacteria showing bronchial wall thickening in the right lower lobe (A) and ground-glass change and inflammatory nodules (B). c) A patient with bronchiectasis due to primary ciliary dyskinesia with chronic Pseudomonas aeruginosa infection showing bronchial wall thickening (A), mucus plugging (B) and inflammatory nodules (C).

FIGURE 2

Actions of neutrophil serine proteases (NSPs) throughout the inflammatory cascade (with direct actions marked with black arrows and secondary downstream effects marked with grey arrows). ICAM: intracellular adhesion molecule; IL: interleukin; MMP: matrix metalloproteinase; NE: neutrophil elastase; NET: neutrophil extracellular trap; PR3: proteinase 3; SLPI: secretory leukoproteinase inhibitor; TGF: transforming growth factor; TNF: tumour necrosis factor.