Neutrophil dysfunction in bronchiectasis: Pathophysiological insights and emerging targeted therapies

Bronchiectasis is a heterogeneous, chronic airway disease characterized by irreversible bronchial dilation, persistent infection, and neutrophilic inflammation. As traditional treatments often fail to address the underlying pathophysiology, particularly the central role of dysfunctional neutrophils, this review explores recent advances in the understanding of neutrophil-driven mechanisms in bronchiectasis and highlights emerging targeted therapies for this condition. A comprehensive literature review of studies published between 2020 and 2025 focusing on neutrophil activity, biomarkers, and clinical trials evaluating novel anti-inflammatory agents for the treatment of bronchiectasis was conducted. Data were synthesized from experimental models, randomized controlled trials (WILLOW and ASPEN), and expert consensus guidelines (ERS 2023-2024). These results indicate that neutrophils contribute to tissue destruction in bronchiectasis via serine proteases and excessive neutrophil extracellular trap (NET) formation. Key emerging therapies include DPP-1 inhibitors (e.g., brensocatib), CXCR2 antagonists, PI3K inhibitors, and NET-targeting therapies. Biomarkers, such as neutrophil elastase activity, sputum procalcitonin, and NMR-derived metabolic phenotypes, may help personalize therapy, and combination treatment strategies alongside precision medicine are reshaping the therapeutic landscape of ABPA. Although targeting neutrophil dysfunction offers a promising avenue for advancing bronchiectasis care, balancing immunomodulation and infection control remains a challenge. The integration of novel therapies with biomarker-guided treatment and treatable trait approaches is essential to improve the outcomes of this complex disease.