The pathogenesis of the chronic bronchitis component of pulmonary diseases, defined by chronic cough and sputum production, is not well understood. Despite the bronchitic features of CF, PCD, COPD, and asthma, there has been a general inability to relate changes in mucus properties to disease pathogenesis. The absence of an adequate formulation to describe mucus transport and health, and predict the failure of mucus transport in disease, has limited our knowledge in this area. A novel topographical description of airway mucus the (?gel on brush? model), coupled with a novel application of polymer physics concepts, has been applied to the local biophysical processes that govern mucus flow in health and the failure to flow in disease. However, a full description of the mucus clearance system and health and disease requires a more global/multi-scaled description of mucin/mucus biology in the lung. At one length scale, we need to understand the integration of mucin secretion and flow in different regions of the lung and how secretions from glands and superficial epithelia are admixed in proximal airways to maintain basal flow and respond to irritants by cough. At another length scale, we need to know why mucins require their gigantic size and how these very large molecules are released and integrated into the local airway surface liquid environment. We have selected four key gaps in our understanding of the mucociliary system for investigation. These gaps constitute our four specific aims.
Specific Aim 1 How is mucin secretion organized intraregionally in superficial epithelia and proximally with submucosal gland secretion? This aim will test the hypothesis that a new paradigm for mucin secretion in the lung is required, focusing on the role of basal MUC5B secretion in the distal airways (rather than proximal airway glands) in the lung.
Specific Aim 2 : Are there functional differences in mucus secreted by superficial epithelia vs glands? This aim will test the hypothesis that the mucins secreted by superficial epithelial constitute a ?reversible? gel that dissolves into the local ASL environment whereas mucin secreted from glands constitute a ?permanent? gel configured for plug-like flow/coughability.
Specific Aim 3 : How are mucins released from granules onto the airway surface? This aim will attempt to distinguish between the hypotheses that are mucins are released in response to an electrostatic Na+ for Ca2+ entropic exchange mechanism vs a HCO-3/pH +/- protease dependent mechanism.
Specific Aim 4 : Why are mucins organized into gigantic (>100MD) higher-order multimers? The hypotheses tested are that gigantic molecules are required to generate mucus gels with biophysical properties commensurate with transport in dilute solutions and that such large molecules impose unique cell biologic packaging constraints on the cell. Importantly, resolution of the questions/hypotheses generated by this analysis of ?gaps? in knowledge of the MCC system may lead to paradigm shifts in our understanding of normal MCC and how to approach novel therapies for bronchitic diseases.
The syndrome of chronic-bronchitis associated with major pulmonary diseases, e.g., COPD, CF, PCD, and asthma, constitutes a major public health problem. Presently, we have no specific therapies designed to therapeutically better the health of patients with these diseases. In part, this failure represents the absence of an adequate understanding/description of the mucus transport system in health vs disease. Resolution of the gaps in knowledge identified in this proposal may lead to novel therapies to treat patients in need with bronchitis.
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