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

Abstract

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.

• Authors: Shaopeng Yuan, Martin Hollinger, Marrah E Lachowicz-Scroggins, Sheena C Kerr, Eleanor M Dunican, Brian M Daniel, Sudakshina Ghosh, Serpel C Erzurum, Belinda Willard, Stanley L Hazen, Xiaozhu Huang, Stephen D Carrington, Stefan Oscarson, John V Fahy
• Journal: Science translational medicine (Sci Transl Med) Vol. 7 Issue 276 Pg. 276ra27 (Feb 25 2015) ISSN: 1946-6242 [Electronic] United States
• PMID: 25717100 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2015, American Association for the Advancement of Science.

Chemical References

• Cross-Linking Reagents
• Disulfides
• Expectorants
• Gels
• Mucins
• Polymers
• Reducing Agents
• Sulfhydryl Compounds
• DNA
• Acetylcysteine
• Galactose

Topics

• Acetylcysteine (pharmacology)
• Animals
• Biomechanical Phenomena (drug effects)
• Cross-Linking Reagents (metabolism)
• Cystic Fibrosis (pathology, physiopathology)
• DNA (metabolism)
• Disulfides (metabolism)
• Elasticity (drug effects)
• Expectorants (pharmacology)
• Galactose (chemistry, pharmacology)
• Gels (metabolism)
• Humans
• Lung (drug effects, physiology)
• Mice, Inbred C57BL
• Mucins (metabolism)
• Mucus (metabolism)
• Oxidation-Reduction (drug effects)
• Oxidative Stress (drug effects)
• Polymers (metabolism)
• Reducing Agents (pharmacology)
• Sputum (drug effects)
• Sulfhydryl Compounds (chemistry, pharmacology)