Disulfide disruption reverses mucus dysfunction in allergic airway disease

Abstract

Airway mucus is essential for healthy lung defense 1 , but excessive mucus in asthma obstructs airflow, leading to severe and potentially fatal outcomes 2-5 . Current asthma therapies reduce allergic inflammation and relax airway smooth muscle, but treatments are often inadequate due to their minimal effects on mucus obstruction 6,7 . The lack of efficacious mucus-targeted treatments stems from a poor understanding of healthy mucus function and pathological mucus dysfunction at a molecular level. The chief macromolecules in mucus, polymeric mucins, are massive glycoproteins whose sizes and biophysical properties are dictated in part by covalent disulfide bonds that link mucin molecules into assemblies of 10 or more subunits 8 . Once secreted, mucin glycopolymers can aggregate to form plugs that block airflow. Here we show that reducing mucin disulfide bonds depolymerizes mucus in human asthma and reverses pathological effects of mucus hypersecretion in a mouse allergic asthma model. In mice challenged with a fungal allergen, inhaled mucolytic treatment acutely loosened mucus mesh, enhanced mucociliary clearance (MCC), and abolished airway hyperreactivity (AHR) to the bronchoprovocative agent methacholine. AHR reversal was directly related to reduced mucus plugging. Furthermore, protection in mucolytic treated mice was identical to prevention observed in mice lacking Muc5ac, the polymeric mucin required for allergic AHR in murine models 9 . These findings establish grounds for developing novel fast-acting agents to treat mucus hypersecretion in asthma 10,11 . Efficacious mucolytic therapies could be used to directly improve airflow, help resolve inflammation, and enhance the effects of inhaled treatments for asthma and other respiratory conditions 11,12 .With daily exposures to >8,000 liters of air containing billions of particles and potential pathogens, respiratory tissues embody the need for robust host defense. Airway mucus is critical for protection, but poor control of mucus function is central to numerous lung diseases. In patients who die during asthma exacerbations, mucus obstruction is a feature long-recognized by pathologists 13 , with plugging observed in >90% of cases and thus considered a major cause of fatal obstruction 5 . Mucus obstruction is also prominent in non-fatal cases of severe asthma 2 , but effective mucolytic therapies are lacking.

The Combination of Bromelain and Acetylcysteine (BromAc) Synergistically Inactivates SARS-CoV-2

“…This property has been widely exploited in the development of several therapies (chronic obstructive pulmonary disease, allergic airways diseases, cystic fibrosis, pseudomyxoma peritonei, etc.) [ 20 , 23 , 24 , 25 , 26 , 27 ]. More recently, Acetylcysteine has been used in the development of therapies for respiratory infections such as influenza and COVID-19 [ 28 , 29 , 30 ], where the integrity of the spike protein is vital for infection [ 12 , 13 ].…”