ASL Height, Decreased leads to Mucus Viscosity, Increased

At least one study in primary cultures of human bronchial epithelial cells grown at the air-liquid interface found mucus viscosity to be higher in cultures from cystic fibrosis donors compared to those from healthy donors, but did not observe differences in ASL height (Derichs et al., 2011). In asthmatics, airway mucus is very viscous, and its viscosity increases even more in acute exacerbations (Innes et al., 2009). However, unlike in individuals with cystic fibrosis or chronic bronchitis, changes in ASL height because of impaired anion transport might not be the primary cause for increased mucus viscosity in patients with asthma. Instead a more acidic ASL may lead to improper unpacking of secreted mucins and tethering of mucins to the epithelial surface, where they form protein tangles that result in mucus airway plugs (Abdullah et al., 2017; Bonser and Erle, 2017; Bonser et al., 2016; Evans et al., 2015; Shimura et al., 1988; Tang et al., 2016). Alternatively, the composition of mucus may be altered by production of more acidic mucins thereby skewing the pH balance of mucus itself (Gearhart and Schlesinger, 1989; Holma, 1989; Kim et al., 2014). In addition, mucus viscosity is also affected by the presence of DNA, lipids and proteins other than mucins, such as lactoferrin, albumin and immunoglobulins, all of which may be present in higher amounts in the presence of airway inflammation (Puchelle et al., 2002; Rogers, 2004). 

In primary human bronchial epithelial cultures grown at the air-liquid interface, the ASL depth of cystic fibrosis cells was significantly lower than that of non-cystic fibrosis cells (2.4±0.6 µm vs. 6.7±0.2 µm) and mucus viscosity was significantly higher (80.6±26.5 cP vs. 12.0±3.6 mm/min) by particle-tracking microrheology. FRAP indicated an increased half-life of fluorescence recovery (evidence of increased viscosity) of approx. 16 s in cystic fibrosis cultures vs ca. 11 s in non-cystic fibrosis cultures (Birket et al., 2014).

ASL height in the tracheas of ^-/^- CFTR piglets was significantly lower than in wild-type littermates (3.2±0.8 µm vs. 6.5±0.2 µm) and mucus viscosity was significantly higher by FRAP, which indicated an increased half-life of approx. 13 s in CFTR-deficient tracheas vs ca. 9.5 s in wild-type controls (Birket et al., 2014). Treatment of normal adult pig trachea with 100 µM bumetanide to block HCO3^– transport reduced ASL height from 7.8±0.5 µm (untreated) to 6.4±0.4 µm and mucus viscosity from approx. 600 cP (untreated) to 2000 cP at frequencies between 0.5 and 10 Hz (Birket et al., 2014).

In tracheas of Cftr-deficient rats, ASL depths were diminished in both basal and stimulated conditions, from weaning until at least 6 months of age (WT 1 month 22.9 ± 4.6 μm, 6 months 43.6 ± 12.5 μm vs. KO 1 month 6.9 ± 0.7 μm, 6 month 19.5 ± 4.8 μm). Under baseline conditions at 1 month of age, effective viscosity was no different in KO tracheae compared with WT tracheae (1.76 ± 1.0 cP WT vs. 1.90 ± 1.7 cP KO). At 3 months, effective viscosity of KO airway mucus increased slightly but was still no different than that of WT airway mucus (5.12 ± 1.0 cP WT vs. 10.72 ± 2.7 cP KO). By 6 months of age, KO tracheal mucus was 20-fold more viscous compared with WT littermates (2.91 ± 0.9 cP WT vs. 65.09 ± 3.6 cP KO) (Birket et al., 2018).

Treatment of primary bronchial epithelial cell monolayer cultures from G551D/F508del cystic fibrosis patients with ivacaftor, a CFTR potentiator, at concentrations ≥ 100 nM for 24 h increased ASL height from ca. 6 to 17.5 µm, which was similar to the ASL height of non-cystic fibrosis cultures (18.03 ± 1.6 µm). The half-life of time to recovery measured by FRAP shortened from 12.39 ± 1.3 to 7.57 ± 0.8 s, indicative of decreased mucus viscosity. Effective viscosity of cells treated with ivacaftor (600 cP) was significantly lower than control (2,600 cP) at the physiological frequency of 0.9 Hz (Birket et al., 2016).

Treatment of primary bronchial epithelial cell monolayer cultures from homozygous F508del cystic fibrosis patients with the combination of 10 µM ivacaftor and 3 µM C18 (a ivacaftor homolog) with 20 µM forskolin significantly increased ASL height (23.4 ±  2.6 vs. 9.01 ± 1.4 µm C18 + forskolin, 10.99 ± 1.7 µm ivacaftor + forskolin; 13.03 ± 2.8 µm forskolin alone, and 12.53 ± 2.3 µm vehicle). Effective mucus viscosity effective in situ was reduced from ca. 1200 cP (vehicle) to ca. 100 cP by 48-h treatment only with the combination of ivacaftor and C18 (Birket et al., 2016).

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