Elastic mucus strands impair mucociliary clearance in cystic fibrosis pigs

Abstract

Significance In many lung diseases, increased amounts of and/or abnormal mucus impair mucociliary clearance, a key defense against inhaled and aspirated material. Submucosal glands lining cartilaginous airways secrete mucus strands that are pulled by cilia until they break free from the duct and sweep upward toward the larynx, carrying particulates. In cystic fibrosis (CF) pigs, progressive clearance of insufflated microdisks was repeatedly interrupted as microdisks abruptly recoiled. Aerosolizing a reducing agent to break disulfide bonds linking mucins ruptured mucus strands, freeing them from submucosal gland ducts and allowing cilia to propel them up the airways. These findings highlight the abnormally increased elasticity of CF mucus and suggest that agents that break disulfide bonds might have value in lung diseases with increased mucus.

Tromethamine improves mucociliary clearance in cystic fibrosis pigs

“…Interestingly, there was no difference in the mean speed of moving particles between alkaline Tham and acidic Tham (Figure 2c). Although the average speed of these microdisks is high in comparison to what is reported in the literature (Cooper et al, 2013;Liu et al, 2013), the values are comparable to the increased microdisk speed that we have seen with cholinergic stimulation (Hoegger et al, 2014a,b,c, Fischer et al, 2019, Pino-Argumedo et al, 2022.…”

“…After 6.3 min, microdisk clearance averaged 18 ± 7% (Figure 4a). These values were lower than what we reported previously with inhaled isotonic saline in non-CF airways with mean of 74% [95% Confidence Interval: 50, 98] (yellow band) and lower than with inhaled isotonic saline in CF airways with mean of 42% [confidence interval: 20, 63] (green band) (Figure 4a) (Fischer et al, 2019, Pino-Argumedo et al, 2022.…”

“…In a flooded trachea, excessive increase in ASL depth may inhibit MCT. However, in submerged preparations of airways, cilia was still able to generate the transport of mucus (Fischer et al, 2019; Hoegger et al, 2014c; Pino‐Argumedo et al, 2022). Second, HS is an irritant and may induce MCT by provoking cough reflexes (Robinson et al, 1996).…”

“…How to cite this article: Ash, J. J., Hilkin, B. M., Gansemer, N. D., Hoffman, E. A., Zabner, J., Stoltz, D. A., & Abou Alaiwa, M. H. (2022). Tromethamine improves mucociliary clearance in cystic fibrosis pigs.…”

“…In CF airways, mucus strands failed to detach from their anchor point at the level of the SMG duct opening (Hoegger et al, 2014c). Instead, they were stretched by the action of cilia and repetitively snapped backward due to abnormal elastic recoil forces (Pino‐Argumedo et al, 2022). Both “failure to detach” and “backward recoil” impaired the movement of particles (Hoegger et al, 2014c; Pino‐Argumedo et al, 2022).…”