Mucus Viscosity, Increased leads to CBF, Decreased

Mucus viscoelastic properties, whether altered by airway dehydration or mucus hypersecretion, directly influence MCC. In fact, there is an inverse relationship between mucus viscosity and CBF and mucus transport/MCC, as demonstrated in several in vivo and ex vivo studies. A large proportion of these studies have employed (bio)polymers or other large organic molecules to mimic the mucus layer in the airways and the increase in its viscosity. In addition, some of these studies have shown that decreased mucus viscosity may also result in impairment of MCC. Therefore, a causal link is only tentatively supported. Because cilia function, ASL height, and mucus properties are intricately linked to each other as evidenced by cystic fibrosis studies, we consider the plausibility as moderate.

Exposure of primary cultures of hamster oviductal ciliated cells to increased viscous loading reduced the CBF (Andrade et al., 2005).

The tracheal samples from mice were used to measure ciliary beat frequencies and beat amplitudes of ciliary motion in viscous culture media over the range of η= 0.9–303.8 mPa.s. The CBF decreased with increasing viscosity, up to about 32.0 mPa.s, while it was nearly constant above 32.0 mPa.s (Kikuchi et al., 2017). In tracheal samples from mice, CBF decreased with increasing viscosity, up to about 32.0 mPa.s, while it was nearly constant above 32.0 mPa.s. CBF were calculated from the averaged cycles of beat velocity, with 14.8 ± 3.0 Hz and 9.0 ± 2.4 Hz  at η = 0.9 (0% methylcellulose solution) and 32.0 mPa.s (0.3% methylcellulose solution), respectively (Kikuchi et al., 2017).

When the viscosity of medium 199 was increased from 7.8 to 58 mP by adding polyvinylpyrrolidone, CBF of bronchial epithelial cell explants was decreased by ca. 10% from the control value. Medium viscosity of 87 millipoises decreased CBF to 25% from the control value (Luk and Dulfano, 1983).

Treatment of primary bronchial epithelial cell monolayer cultures from G551D/F508del cystic fibrosis patients with 10 µM ivacaftor, a CFTR potentiator, at concentrations ≥ 100 nM for 24 hr and 10 µM forskolin decreased mucus viscosity from 2600 cP to 600 cP at the physiological frequency of 0.9 Hz and increased CBF from ca. 3 Hz to ca. 5 Hz (Birket et al., 2016).

Epithelial cell monolayers from explants of pediatric adenoid tissues were used to assess the impact of viscosity on CBF. A decrease in CBF was observed immediately after the viscosity of the medium was increased, with a greater decrease in CBF in cultures exposed to 20% dextran (González et al., 2016).  

Studies interrogating the link between CBF and/or mucus viscosity and MCC found the optimal range of viscoelastic mucus properties to be between 10 and 30 cP and 11 to 25 dyn/cm2 (Chen and Dulfano, 1978; King, 1979; King, 2006; King et al., 1997). These studies also documented that both increases and decreases in mucus viscosity beyond that optimal range impact CBF and decrease and increases, respectively, MCC. A large proportion of these studies utilize (bio)polymers or other large organic molecules to mimic the mucus layer in the airways and increases in its viscosity. Therefore, there may be limitations to the translatability of these findings. 

There is at least one study showing that increased mucus viscosity not only slows CBF, but also alters cilia beat metachrony, with medium viscosities in the range of 30–1500 cP increasing metachronal wave velocities by up to 50% and changes in wave direction in cultured frog esophagus (Gheber et al., 1998; Stafanger et al., 1987). CBF also appears to be, at least in part, autoregulated by ciliated respiratory cells, which adjust cilia beating to differences in viscous load via a mechanosensory mechanism (Johnson et al., 1991).  

Exposure of primary cultures of hamster oviductal ciliated cells to increased viscous loading reduced the CBF (Andrade et al., 2005).

The tracheal samples from mice were used to measure ciliary beat frequencies and beat amplitudes of ciliary motion in viscous culture media over the range of η= 0.9–303.8 mPa.s. The CBF decreased with increasing viscosity, up to about 32.0 mPa.s, while it was nearly constant above 32.0 mPa.s (Kikuchi et al., 2017).

When the viscosity of medium 199 was increased from 7.8 to 58 millipoises (by adding polyvinylpyrrolidone), CBF of bronchial epithelial cell explants was decreased by ca. 10% from the control value. Medium viscosity of 87 millipoises decreased CBF to 25% from the control value (Luk and Dulfano, 1983).

Treatment of primary bronchial epithelial cell monolayer cultures from G551D/F508del cystic fibrosis patients with 10 µM ivacaftor, a CFTR potentiator, at concentrations ≥ 100 nM for 24 hr and 10 µM forskolin decreased mucus viscosity (from 2600 cP to 600 cP) at the physiological frequency of 0.9 Hz and increased CBF (from ca. 3 Hz to ca. 5 Hz) (Birket et al., 2016).

Epithelial cell monolayers from explants of pediatric adenoid tissues were used to assess the impact of viscosity on CBF. A decrease in CBF was observed immediately after the viscosity of the medium was increased, with a greater decrease in CBF in cultures exposed to 20% dextran (González et al., 2016).  

Within the first 10 min, the CBF of human oviductal cells dropped ~35% within the range of 2–37 cP (2–15% dextran solutions), but no further decrease was observed at higher viscosities in the range of 37–200 cP (15–30% dextran solutions) (Andrade et al., 2005).

The CBF decreased with increasing viscosity, up to about 32.0 mPa.s, while it was nearly constant above 32.0 mPa.s. The beat frequencies were calculated from the averaged cycles of beat velocity, 14.8 ± 3.0 Hz and 9.0 ± 2.4 Hz (0% methylcellulose solution) and 32.0 mPa.s (0.3% methylcellulose solution), respectively (Kikuchi et al., 2017).

In epithelial cell monolayers from explants of pediatric adenoid tissues , a decrease in CBF was observed immediately after the viscosity of the medium was increased, with a greater decrease in CBF in cultures exposed to 20% dextran. When cultures, prior to viscosity change, were treated with TNFa, CBF decreased furthermore only in culture exposed to 10% dextran. This effect of TNFa occurs in the first 10 min of viscous load, then TNFa-treated cells seem to adjust the CBF to control values (González et al., 2016).

Unknown