Dipeptidyl peptidase 1 inhibitors and neutrophilic inflammation in bronchiectasis: a narrative review

Abstract

Background and objective: Bronchiectasis is a chronic respiratory disease characterized by predominantly neutrophilic inflammation, recurrent infection and pathological dilatation of the airways. Current therapeutic strategies primarily target infections and improving mucus clearance. However, no current treatment can directly ameliorate neutrophilic inflammation. Recently, dipeptidyl peptidase 1 (DPP-1) inhibitors effectively abrogated neutrophilic inflammation in bronchiectasis. This narrative review aimed to analyze the structural characteristics and functional effects of DPP-1, explore the mechanism of DPP-1 inhibitors in bronchiectasis, and highlight major clinical trial findings.

Methods: We performed an online electronic search for relevant English literature on PubMed and Web of Science databases, with the keywords of "dipeptidyl peptidase 1", "cathepsin C", "cathepsin C structure", "cathepsin C maturation", "cathepsin C loss-of-function", "neutrophil serine proteases and bronchiectasis", "neutrophil serine proteases and cathepsin C", "neutrophil serine proteases and DPP-1", "DPP-1 inhibitors", "cathepsin C inhibitors", "DPP-1 inhibitors and bronchiectasis", "cathepsin C inhibitors and bronchiectasis". Two authors (R.D.T. and J.Q.Y.) independently searched and reviewed the articles.

Key content and findings: Excessive and uncontrolled release of neutrophil serine proteases (NSPs) can lead to airway inflammatory responses and structural damage in bronchiectasis. Elevated levels of neutrophil elastase (NE) and other neutrophil markers in the airway are associated with exacerbations and lung function decline. In light of the pivotal role of DPP-1 in eliciting neutrophilic inflammation, several DPP-1 inhibitors have been developed and entered clinical trials for safety and efficacy assessment in bronchiectasis. Of these, brensocatib markedly prolonged the time to the first exacerbation and decreased the exacerbation frequency via decreasing the activity of NSPs. The phase III ASPEN trial has been completed and confirms reduced exacerbations and slower lung function decline with DPP-1 inhibitor treatment. Treatment with BI 1291583 reduced the risk of bronchiectasis exacerbations in the phase II Airleaf^® trial. HSK31858 significantly decreased the exacerbation frequency and prolonged the time to the first exacerbation in the latest phase II trial among the Chinese population.

Conclusions: DPP-1 inhibitors have exhibited promising effects in improving several major clinical outcomes in bronchiectasis via suppressing the activity of NSPs.

Keywords: Dipeptidyl peptidase 1 inhibitors (DPP-1 inhibitors); bronchiectasis; neutrophilic inflammation.

Figure 1

NSPs processing and their role in bronchiectasis. (A) NSPs are activated by DPP-1 in the bone marrow and stored in neutrophil granules. (B) NSPs which are released by activated neutrophils can impair mucociliary clearance, exacerbate airway inflammation and structural destruction in bronchiectasis. CatG, cathepsin G; DPP-1, dipeptidyl peptidase 1; MMP, matrix metalloproteinase; NE, neutrophil elastase; NSP, neutrophil serine protease; PR3, proteinase 3; SLPI, secretory leucoprotease inhibitor.