Project V (Mucus Dehydration and Evolution of COPD Lung Disease; R. Boucher, P.I.) will test thehypothesis that a significant component of the chronic bronchitic phenotype of COPD reflects the relativedehydration of airway mucus (secretions), which produces mucus adhesion to airway surfaces, infection ofmucus with bacterial communities, inflammation, and airflow obstruction. Sp.
Aim 1 will test this hypothesisdirectly in cross-sectional cohorts of Gold 0/1,2, and 3 subjects, measuring: 1) COPD mucociliary (MCC)and cough clearance (CC); 2) mucus hydration (water content/activity); 3) the concentrations of the dominantregulators of airway hydration, i.e., purine nucleotides (ATP) and nucleosides (ADO); and 4) theconsequences of mucus dehydration on mucus biophysical properties and bacterial infection. Sp.
Aim 2 tests the hypotheses that: 1) COPD acute exacerbations (AEs) reflect a transient worsening/failure of themucus clearance (ciliary/cough-dependent) mechanism; 2) the COPD patient is vulnerable to triggers of AEsbecause mucus clearance is chronically compromised by cigarette smoke-induced mucus dehydration; and3) respiratory viruses trigger many COPD AEs via direct infection of the lower airway epithelium andderangement of the extracellular ATP/adenosine and cytokine pathways that regulate salt/water transportand mucin secretion rates. Finally, we hypothesize that we can do little to acutely downregulate mucinsecretion during an AE. In Sp.
Aim 3, we test whether we can rehydrate the abnormal (dehydrated) mucusthat we speculate is characteristic of an AE via inhalation of hypertonic saline (HS), and whether it is safe todeliver HS to a COPD patient with an AE. Thus, we will test this hypothesis by exposing COPD subjectsbefore (to assess safety) and during an AE to inhaled 7% HS and test acute (surrogate) efficacy viameasures of mucus clearance and spirometry. This project depends heavily on Project IV (D. Peden) andProject VI (S. Donaldson) for comparative normal and CF data describing mucus composition (hydration,nucleotides+nucleosides, and mucin molecules). The ultimate goals articulated in this Project for the U.S.COPD patient population are to generate a mechanistic understanding of the failure in host defense thatproduces COPD and test novel approaches to restore host defense aimed at rehydrating the surface of theCOPD lung.
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|Livraghi-Butrico, A; Grubb, B R; Wilkinson, K J et al. (2017) Contribution of mucus concentration and secreted mucins Muc5ac and Muc5b to the pathogenesis of muco-obstructive lung disease. Mucosal Immunol 10:829|
|Livraghi-Butrico, Alessandra; Grubb, Barbara R; Wilkinson, Kristen J et al. (2017) Contribution of mucus concentration and secreted mucins Muc5ac and Muc5b to the pathogenesis of muco-obstructive lung disease. Mucosal Immunol 10:395-407|
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|Button, Brian; Anderson, Wayne H; Boucher, Richard C (2016) Mucus Hyperconcentration as a Unifying Aspect of the Chronic Bronchitic Phenotype. Ann Am Thorac Soc 13 Suppl 2:S156-62|
|Sesma, Juliana I; Weitzer, Clarissa D; Livraghi-Butrico, Alessandra et al. (2016) UDP-glucose promotes neutrophil recruitment in the lung. Purinergic Signal 12:627-635|
|Sherrard, Laura J; McGrath, Stef J; McIlreavey, Leanne et al. (2016) Production of extended-spectrum ?-lactamases and the potential indirect pathogenic role of Prevotella isolates from the cystic fibrosis respiratory microbiota. Int J Antimicrob Agents 47:140-5|
|Davis, Stephanie D; Ratjen, Felix; Brumback, Lyndia C et al. (2016) Infant lung function tests as endpoints in the ISIS multicenter clinical trial in cystic fibrosis. J Cyst Fibros 15:386-91|
|Bennett, William D; Xie, Miao; Zeman, Kirby et al. (2015) Heterogeneity of Particle Deposition by Pixel Analysis of 2D Gamma Scintigraphy Images. J Aerosol Med Pulm Drug Deliv 28:211-8|
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