Asthma is a complex disease, whose principal characteristics include reversible airflow obstruction, airway hyperresponsiveness (AHR), airway inflammation, airway remodeling and mucus hypersecretion. Airway mucus hypersecretion specifically is an important and dangerous pathophysiological manifestation of asthma.
Mucus, composed predominantly of polymeric mucin glycoproteins, is essential for normal functioning of respiratory airways. However, excessive mucin secretion has been associated with fatal disease conditions. and can be targeted via therapies that target genetic production, synthesis or secretion of mucin (MUC) genes.
Dr. Christopher Evans, Ph.D., and his team from the University of Colorado, investigated a targeted technique for the reversal of mucus (MUC5AC & MUC5B) hypersecretion by targeting the mucin glycoprotein polymers without affecting healthy functions of mucus. This is based on the hypothesis that MUC5AC was a major contributor to AHR in conditions of bronchoconstriction. Dr. Evan’s team tested a reducing agent, tris(2-carboxyethyl) phosphine (TCEP) to essentially disrupt the mucin disulfides by depolymerizing them; reducing the size of the MUC5AC and MUC5B polymers and rendering mucus less viscoelastic.
The SCIREQ flexiVent was used to measure precise lung mechanics and airway hyperreactivity (AHR) measurements in an Aspergillus oryzae extract (AOE) exposure model of allergic asthma with and without TCEP treatment. AOE mice with vehicle demonstrated severe responses to bronchoconstrictive AHR challenges, with an exaggerated increase in total lung resistance, airway resistance, tissue resistance and tissue elastance. Interestingly, mucolytic treatment TCEP showed protective effects as demonstrated by improved allergic AHR in response to bronchoconstictive challenges.
The results validated that TCEP mucolytic treatment was effective in the protection against AHR by reversing the mucus dysfunction. Interfering with mucin depolymerization could therefore be an important therapeutic target to not only reduce airway mucous obstruction, but as well enhance the deposition of complementary asthma therapeutics.
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