Acidic Submucosal Gland pH and Elevated Protein Concentration Produce Abnormal Cystic Fibrosis Mucus

• Published in: Developmental cell Vol. 54; no. 4; pp. 488 - 500.e5
• Main Authors: Xie, Yuliang, Lu, Lin, Tang, Xiao Xiao, Moninger, Thomas O., Huang, Tony Jun, Stoltz, David A., Welsh, Michael J.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 24.08.2020
• Subjects: acidic pH; Animals; Ariolimax columbianus; Biological Transport; cystic fibrosis; Cystic Fibrosis - genetics; Cystic Fibrosis - metabolism; Cystic Fibrosis - pathology; Cystic Fibrosis Transmembrane Conductance Regulator - genetics; Humans; Lung - metabolism; Lung - pathology; mucus; Mucus - metabolism; pig; Respiratory Mucosa - metabolism; Respiratory Mucosa - pathology; Serum Albumin, Bovine - pharmacology; submucosal gland; Swine; Trachea - metabolism; Trachea - pathology; acidic pH; Ariolimax columbianus; cystic fibrosis; submucosal gland; mucus; pig
• ISSN: 1534-5807; 1878-1551
• DOI: 10.1016/j.devcel.2020.07.002

In response to respiratory insults, airway submucosal glands secrete copious mucus strands to increase mucociliary clearance and protect the lung. However, in cystic fibrosis, stimulating submucosal glands has the opposite effect, disrupting mucociliary transport. In cystic fibrosis (CF) pigs, loss of cystic fibrosis transmembrane conductance regulator (CFTR) anion channels produced submucosal gland mucus that was abnormally acidic with an increased protein concentration. To test whether these variables alter mucus, we produced a microfluidic model of submucosal glands using mucus vesicles from banana slugs. Acidic pH and increased protein concentration decreased mucus gel volume and increased mucus strand elasticity and tensile strength. However, once mucus strands were formed, changing pH or protein concentration largely failed to alter the biophysical properties. Likewise, raising pH or apical perfusion did not improve clearance of mucus strands from CF airways. These findings reveal mechanisms responsible for impaired mucociliary transport in CF and have important implications for potential treatments. [Display omitted] •Cystic fibrosis submucosal glands produce abnormally acidic and concentrated mucus•A microfluidic model using banana slug mucus produced strands of mucus•Acidic, concentrated mucus formed strands with high elasticity and tensile strength•After mucus strands formed, their biophysical properties resisted further change In cystic fibrosis, airway submucosal glands produce mucus that disrupts mucociliary transport. Using pigs, which have lungs like humans, and a microfluidic model of glands, Xie et al. show that acidic pH and increased protein concentration increase the elasticity and tensile strength of mucus strands, thereby preventing normal mucociliary transport.