期刊名称：Proceedings of the National Academy of Sciences
印刷版ISSN：0027-8424
电子版ISSN：1091-6490
出版年度：2022
卷号：119
期号：13
DOI：10.1073/pnas.2121731119
语种：English
出版社：The National Academy of Sciences of the United States of America
摘要：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.
Defective mucociliary transport contributes to infections and inflammation that destroy cystic fibrosis (CF) lungs. To better understand mechanisms that impair mucociliary transport, we tracked insufflated microdisks with X-ray computed tomography in spontaneously breathing CF pigs. Aerosolized saline increased microdisk movement toward the larynx. Surprisingly, forward progression was repeatedly interrupted as microdisks abruptly recoiled. Thus, although saline increased motion, it had minimal effects on microdisk clearance. To test if abnormally elastic mucus strands were responsible, we aerosolized Tris-carboxyethyl phosphine (TCEP), a reducing agent that breaks disulfide bonds linking mucins. TCEP largely eliminated retrograde movement and increased microdisk clearance. Ex vivo studies confirmed that TCEP broke CF mucus strands, unleashing them from submucosal gland ducts, and cilia carried them rostrally. These findings emphasize the role of abnormally elastic submucosal gland mucus strands in impairing CF mucociliary clearance and suggest that disrupting mucus strands may improve mucociliary clearance in CF.
