Patients with muco-obstructive lung diseases (CF, COPD, and asthma) suffer from reduced mucus clearability due to accumulation of sticky, adherent, mucus in their airways. In order to understand the pathogenesis of these diseases, it is necessary to understand both the mechanisms that mediate efficient mucus clearance in health and how alterations in this system leads to failed mucus clearance in each of these disorders. Our overarching hypothesis is that reduced mucus clearance in disease is a result of multiple alterations in the composition and physical properties of the airway mucus. Based on our preliminary data, such changes in mucus properties come as a result of: 1) disease-related increases in mucus concentration, 2) alteration in the ratio of MUC5AC (the dominant asthma mucin) vs. MUC5B (the dominant CF/COPD mucin), and/or 3) oxidation of mucins resulting in additional cross-links. We hypothesize that such alterations in the mucus layer will produce a more ?sticky? (more viscous, adherent, tear-resistant) mucus that will be harder to be cleared by the action of cilia beating and coughing. There is currently a lack of knowledge of how such changes in the mucus alter the biophysics properties of the mucus and how such changes lead to reduced mucus clearance. To answer these questions, studies in Aim 1 are designed to test the effect of altering mucus concentration and MUC5AC:MUC5B ratio on mucus biophysical properties (rheology, adhesion and cohesion strength, and friction) and how such alterations affect the rate of mucus clearance by cough and cilia beating. Once it has been established how disease alters mucus clearance, our goal, in support of the tPPG clinical projects 3 & 4 is to determine how best to restore mucus clearance in patients with mucus obstructions. We hypothesize that there are two separate, but complementary, approaches to clear adherent mucus from the airways. The simplest is to reduce the mucus concentration, via hydration. The second is by breaking down the structure of mucus through reduction in mucin molecular weight using reducing agents. Importantly, we hypothesize that such approaches may be additive/synergistic.
In Aim 2 we will test these hypotheses by correlating reducing agent-mediated changes in mucin molecular weight/size combined with hydration-mediated changes in mucus concentration on changes in mucus biophysical properties and assess the impact of these changes on stimulating both cilia- and cough-mediated mucus clearance.
In Aim 3, we will assess the role of inflammation- mediated oxidation of mucus in the formation of a permeant, non-swellable, mucus gel, which can severely limit clearance from the airways. We will test the hypothesis that hydration method alone is not sufficient, but a combination of hydrator plus a reducing agent is required to restore the mucus clearance. Overall, the studies in Project 1 are expected to support other tPPG Projects by advancing our understanding of the mechanism(s) of defective mucus clearance in disease and identifying the most effective therapeutic combination of hydrating and reducing agents to maximally restore mucus clearance in patients with CF, COPD, and asthma.
Mucus obstruction and reduced mucus clearance are associated with a number of life-threatening lung diseases, including CF, COPD, and asthma, constituting a major public health problem. In order to treat these diseases, it is necessary to understand how alterations in mucus properties, associated with these diseases, affect the mucus clearance system. The studies conducted in Project 1 are designed not only to advance our understanding the mechanism(s) of defective mucus clearance in disease but to identify a, effective therapeutic regimen to maximally restore mucus clearance in patients with CF, COPD, and asthma.
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