Reduced sialylation of mucin impairs mucus transport in lungs

BIRMINGHAM, Ala. – With each breath, a human may inhale thousands of harmful microbes into the lungs. Mucus, the gel-like moist substance coating the airways, is one of the first lines of defense and aids in removal these microbes. It entraps bacteria, viruses, dust and pollen to protect the lungs, and the mucus is moved up and out of the airways by the beating of tiny hair-like projections called cilia.

But what happens when the body produces too much mucus that is too thick, viscous and dehydrated to move and clear properly? Overly thick and sticky mucus over time can obstruct the airway, overwhelming mucus clearance mechanisms, resulting in a breeding ground for entrapped microbes. These pathophysiological processes contribute to the development of muco-obstructive diseases including cystic fibrosis, or CF.

A research team at the University of Alabama at Birmingham led by Jarrod W. Barnes, Ph.D., an associate professor in the UAB Department of Medicine, and Steven M. Rowe, M.D., a professor in the UAB Department of Medicine Division of Pulmonary, Allergy and Critical Care Medicine, has investigated defective mucus formation. They show in the journal Scientific Reports how a single sugar modification on mucus affects its expansion and transport.

Mucus is a hydrogel composed primarily of water and solid matter, including large sugar-coated protein molecules called mucins, the principal component of mucus. The research focused on the addition and removal of a terminal negatively charged sugar modification, called sialic acid, of MUC5B, one of the major mucin proteins found in the airway. A high anionic density of MUC5B helps the polymerization and packaging of mucus, yet previous reports have shown a less negative “low” charged form of the mucin in CF and asthma. The UAB researchers found that reducing the sialic acid levels of MUC5B was sufficient to generate this low-charged, potentially pathologic form.

When the researchers reduced sialic acid on MUC5B, they observed a change in the electrophoretic mobility for the protein indicative of a lower charged form. Transmission electron microscope imaging showed reducing sialylation contributed to entangled (more compact) MUC5B polymers when compared to normal levels of mucin sialylation that facilitate linearization and expansion.

The reduction in negative charge, by blocking α-2,3 sialylation specifically, influenced the mucus structure and affected its transport in human bronchial epithelial cells and on rat trachea models of an intact airway. Thus, the authors report that “the mucin charge may bear pathological significance in muco-obstructive diseases through increased mucus compaction and transport impairment.”

The study also found that patients with CF have a reduced expression of an enzyme called ST3Gal1, which adds α-2,3 sialic acid to mucin proteins. However, treatment with cystic fibrosis transmembrane conductance regulator protein correctors Elexacaftor, Tezacaftor and Ivacaftor partially recovered the expression of ST3Gal1.

By showing a crucial role for mucin sialylation on mucus properties and transport, the study identified a possible therapeutic strategy for the treatment of cystic fibrosis and potentially other debilitating muco-obstructive diseases, such as chronic obstructive pulmonary disease, or COPD, primary ciliary dyskinesia and non-cystic fibrosis bronchiectasis.

Besides Rowe and Barnes, authors of this study, “Reduced sialylation of airway mucin impairs mucus transport by altering the biophysical properties of mucin,” published in Scientific Reports, are Elex S. Harris, Hannah J. McIntire, Marina Mazur and Stefanie Krick, the UAB Gregory Fleming James Cystic Fibrosis Research Center; and Hinnerk Schulz-Hildebrandt, Hui Min Leung and Guillermo J. Tearney, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts.

Support for this study came from National Institutes of Health grants HL164005-02, HL135816-01, HL152246 and DK072482 and a CF Foundation grant.

At UAB, Medicine is a department in the Marnix E. Heersink School of Medicine.