Hyperconcentrated mucus in small airways: a mechanistic model for the pathogenesis of paediatric bronchiectasis

This is the authors' abstract. We don't add key points for this paper.

BACKGROUND: Childhood bronchiectasis is an under-recognised and increasingly prevalent lung disease with a poorly understood pathogenesis. Traditional models focus on the damage in the large airways and the resultant microbial colonisation; however, the initiating events remain unclear. OBJECTIVE: We propose a unified, evidence-based model in which injury to the small airway epithelium leads to the formation of hyperconcentrated, stagnant mucus. This initiates a muco-inflammatory positive feedback loop that causes small airway wall thickening. The development of bronchiectasis in the large airways represents the final stage of this process. CONTENT: This review synthesises emerging clinical, histological and experimental data suggesting that small airway obstruction from hyperconcentrated mucus leads to localised hypoxia. In turn, hypoxic epithelial cells and stagnant mucus promote the release of alarmins, driving neutrophilic infiltration in the absence of infection. This process establishes a self-perpetuating muco-inflammatory loop characterised by excessive mucin production and immune dysregulation, which results in progressive thickening of the small airway walls through the formation of lymphoid follicles. Neutrophil recruitment into the major airways follows, marking the next step in the pathophysiology cascade. These events precede microbial colonisation and the characteristic radiological features of bronchiectasis. CONCLUSION: By redefining hyperconcentrated mucus and small airway dysfunction as the initial events in the bronchiectasis cascade, our model offers novel mechanistic insight. Targeted interventions at various stages of this cascade are clearly needed. If validated, this model could shift therapeutic focus in paediatric bronchiectasis, from antibiotics toward muco-regulatory or anti-inflammatory agents, especially during the early, often asymptomatic stages of the disease.