Airway Surface Liquid Volume Regulation Determines Different Airway Phenotypes in Liddle Compared with βENaC-overexpressing Mice

Abstract

Studies in cystic fibrosis

Hypertonic Saline Is Effective in the Prevention and Treatment of Mucus Obstruction, but Not Airway Inflammation, in Mice with Chronic Obstructive Lung Disease

“…Because increased mucus concentration cannot only result from reduced amounts of airway surface fluid due to primary defects in epithelial ion transport as in CF (1,2,6), but also from an increased amount of secreted mucins triggered by airway inflammation and infection (11,12,45), the study by Button and colleagues (7) supports the concept that insufficient hydration of airway surfaces is a common disease mechanism contributing to mucociliary dysfunction and mucus obstruction in a broad spectrum of obstructive lung diseases (44). This concept is supported by the airway phenotype of the bENaC-overexpressing mouse, which develops spontaneous mucus obstruction caused by constitutive hyperabsorption of airway surface fluid due to an increased activity of ENaC (9,26,27). The concept is also supported by the phenotype of mice lacking the SLC26A9 Cl 2 channel, which show normal ion transport and airway morphology under physiological conditions, but develop airway mucus obstruction due to a reduced capacity to increase Cl 2 and fluid secretion in parallel to mucin hypersecretion in allergic airway disease (8,46).…”

“…Recent results suggest that relative dehydration of airway surfaces, either caused by reduced availability of airway surface liquid due to dysregulated epithelial ion transport, or increased mucin secretion triggered by airway inflammation, generates an abnormally concentrated mucus that impairs mucus clearance and produces airway mucus obstruction in a spectrum of other acute and chronic obstructive lung diseases, including asthma and chronic obstructive pulmonary disease (COPD) (7)(8)(9)(10)(11)(12).…”

International Union of Basic and Clinical Pharmacology. XCI. Structure, Function, and Pharmacology of Acid-Sensing Ion Channels and the Epithelial Na+Channel

“…aENaC KO mice die shortly after birth, due at least in part to a massive lung edema at birth, leading to a respiratory distress syndrome (Hummler et al, 1996). In contrast, an increase in Na + absorption by ENaC overexpression in a genetic mouse model leads to a cystic fibrosis lung phenotype (Mall et al, 2010). In airway epithelia of cystic fibrosis patients, the loss of cystic fibrosis transmembrane conductance regulator (CFTR) activity is accompanied by an increased ENaC activity resulting in Na + hyperabsorption, suggesting that ENaC upregulation may contribute to the cystic fibrosis lung phenotype (Mall et al, 2010;Hobbs et al, 2013).…”

Acute Effects of Cigarette Smoke Extract on Alveolar Epithelial Sodium Channel Activity and Lung Fluid Clearance

“…As such, vectorial transport of salt and water out of the airspace by normal ENaC activity is critical in maintaining the appropriate amount of fluid on the airway surface. Hyperactive sodium reabsorption can lead to airway drying, infection, inflammation, and cell death (2,13). Therefore, it is important to study the signal transduction pathways that regulate lung ENaC.…”