When Neutrophils Go Rogue: Dysregulated Inflammation in Airway Diseases and Implications for Therapy

Failure to resolve the neutrophilic inflammation during the innate immune response results in neutrophil accumulation in the airways. These cells exhibit prolonged survival, increased necrosis, and impaired phagocytic capacity. Paradoxically, despite reduced pathogen-clearing ability, neutrophils release serine proteases that drive the destruction of airway tissue. Their persistence in the lung chronically promotes a cycle of tissue damage, remodeling, and inflammation, leading to progressive pulmonary dysfunction. Recent discoveries in neutrophil dysregulation open up the possibility of developing more targeted, disease-specific therapies, potentially revolutionizing the treatment of diseases like cystic fibrosis, chronic obstructive pulmonary disease, bronchiectasis, and asthma, where current treatments remain largely generalized and ineffective. This review explores the complex relationship between neutrophil dysregulation and disease progression, highlighting the different roles that neutrophils play across various lung diseases, and will summarize current strategies to target key pathways. Understanding these pathways could inform the development of therapeutic strategies to effectively mitigate neutrophil-driven inflammation to improve the clinical outcome.