Research ArticleLung Disease

Oxidation increases mucin polymer cross-links to stiffen airway mucus gels

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Science Translational Medicine  25 Feb 2015:
Vol. 7, Issue 276, pp. 276ra27
DOI: 10.1126/scitranslmed.3010525

Mucus: Quality counts

Sniffing, sneezing, coughing—from allergies to the common cold, too much mucus can cause misery. Yet, the ability to get mucus up and out is critical to its function. In patients with cystic fibrosis (CF) or other lung diseases, airway mucus can be highly elastic and much more difficult to clear, leading to airflow obstruction and lung infection. Now, Yuan et al. find that the biophysical properties of mucus from CF patients are altered because of neutrophilic oxidative stress. On the basis of these properties, they then targeted mucin disulfide cross-links with a thiol-modified carbohydrate, and found fast-acting mucolytic activity in CF sputum. Their findings support the use of mucolytics as a therapeutic strategy for CF and related inflammatory lung diseases.


Airway mucus in cystic fibrosis (CF) is highly elastic, but the mechanism behind this pathology is unclear. We hypothesized that the biophysical properties of CF mucus are altered because of neutrophilic oxidative stress. Using confocal imaging, rheology, and biochemical measures of inflammation and oxidation, we found that CF airway mucus gels have a molecular architecture characterized by a core of mucin covered by a web of DNA and a rheological profile characterized by high elasticity that can be normalized by chemical reduction. We also found that high levels of reactive oxygen species in CF mucus correlated positively and significantly with high concentrations of the oxidized products of cysteine (disulfide cross-links). To directly determine whether oxidation can cross-link mucins to increase mucus elasticity, we exposed induced sputum from healthy subjects to oxidizing stimuli and found a marked and thiol-dependent increase in sputum elasticity. Targeting mucin disulfide cross-links using current thiol-amino structures such as N-acetylcysteine (NAC) requires high drug concentrations to have mucolytic effects. We therefore synthesized a thiol-carbohydrate structure (methyl 6-thio-6-deoxy-α-d-galactopyranoside) and found that it had stronger reducing activity than NAC and more potent and fast-acting mucolytic activity in CF sputum. Thus, oxidation arising from airway inflammation or environmental exposure contributes to pathologic mucus gel formation in the lung, which suggests that it can be targeted by thiol-modified carbohydrates.

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