Mucus accumulation in the lungs precedes structural changes and infection in children with cystic fibrosis

Abstract

Although destructive airways disease is evident in young children with cystic fibrosis (CF), little is known about the nature of the early CF lung environment triggering the disease. To elucidate early CF pulmonary pathophysiology, we performed mucus, inflammation, metabolomic, and microbiome analyses on bronchoalveolar lavage fluid (BALF) from 46 preschool children with CF enrolled in the Australian Respiratory Early Surveillance Team for Cystic Fibrosis (AREST CF) program and 16 non-CF disease controls. Total airway mucins were elevated in CF compared to non-CF BALF irrespective of infection, and higher densities of mucus flakes containing Mucin 5B (MUC5B) and Mucin 5AC (MUC5AC) were observed in samples from CF patients. Total mucins and mucus flakes correlated with inflammation, hypoxia, and oxidative stress. Many CF BALFs appeared sterile by culture and molecular analyses, whereas other samples exhibiting bacterial taxa associated with the oral cavity. Children without computed tomography (CT)-defined structural lung disease exhibited elevated BALF mucus flakes and neutrophils, but little/no bacterial infection. Although CF mucus flakes appeared “permanent” since they did not dissolve in dilute BALF matrix, they could be solubilized by a novel reducing agent (P2062), but not N-acetylcysteine (NAC) or DNase. These findings indicate that early CF lung disease is characterized by an increased mucus burden and inflammatory markers without infection or structural lung disease and suggest that mucolytics and anti-inflammatory agents should be explored as preventive therapy.

Acid exposure impairs mucus secretion and disrupts mucus transport in neonatal piglet airways

“…Combined, these studies highlight the submucosal gland as a key node in CF pathogenesis (9), and suggest that abnormal mucus might precede infection and inflammation. Consistent with this, a recent study in preschool children with CF suggested that mucus accumulates in the airways prior to infection and airway remodeling (10).…”

“…In early CF pathogenesis, the airway is acidic (7,18,19). Although mucus abnormalities precede airway infection and inflammation (6,7,10), how and whether transient airway acidification impacts the development of mucus abnormalities is unknown. To characterize the significance of acute and transient early life airway acidification on mucus properties, we challenged neonatal piglets with intra-airway acid or saline control.…”

“…However, it is possible that with time, acid-challenged piglets might exhibit increased mucin abundance. It is also possible that inflammation on top of acidification might be required to increase mucin abundance (10).…”

Durable Changes to Airway Mucus and Fluid Secretion Following Cholinergic Challenge

“…The presence of mucus sheets in the airways of pigs challenged with bethanechol suggested MUC5AC and MUC5B abundance might be increased. Because abnormal mucin protein concentrations have been implicated in chronic airway disease [33], we stained tracheal crosssections using antibody-specific labeling and performed signal intensity analyses [18,34]. No significant differences were found in MUC5AC or MUC5B signal intensity within and on the tracheal surface between treatment groups (Figure 2A, 2B).…”

Revealing the molecular signaling pathways of mucus stasis in cystic fibrosis

“…More recent data suggests that the mucoobstructive phenotype that results in bronchiectasis and pulmonary function decline is present and damaging even in the absence of overt infection (3). Patients at the earliest stages of the disease have evidence of neutrophil influx, neutrophil elastase, and increased mucin concentrations (4). In a ferret model of CF, these events occur despite aggressive bacterial eradication (5), suggesting that infection control alone will not prevent progression of lung disease.…”