Mucus hypersecretion and airway hyperreactivity (AHR) are significant features of asthma, cystic fibrosis (CF), and chronic obstructive pulmonary disease (COPD). In spite of these well-recognized pathological associations, the mechanisms by which AHR is mediated by the chief glycoprotein components of respiratory mucus, the secreted polymeric mucins, are unknown. Autopsy studies show that 98% of the airways of patients who die from fatal asthma have extensive mucus plugging. MUC5AC and MUC5B are the major secreted airway mucins. Their production (especially that of MUC5AC) increases significantly in asthma, CF, and COPD, and in animal models of these diseases. Furthermore, blockade of mucus secretion reduces AHR by ~80%. These findings provide the basis for the overall goal of this proposal, which is to assess the functional consequences of mucus secretion on lung function. The central hypothesis of this proposal is that secreted Muc5ac and Muc5b play essential roles in the development of airway hyperreactivity by promoting mucus thickening, airway lumen occlusion, and distal airway closure. Studies will be conducted in human airway epithelial cell cultures and knockout mice in order to achieve the following specific aims:
Aim 1 : Determine the role of polymeric mucin secretion in mucus layer thickening.
Aim 2 : Determine the functional consequences of polymeric mucin secretion on AHR.

Public Health Relevance

Mucus overproduction and hypersecretion are cardinal features that are strongly associated with morbidity and mortality in asthma, cystic fibrosis (CF), and chronic obstructive pulmonary disease (COPD). Our studies are aimed at understanding how mucus is secreted, how it is altered in lung disease, and what the functional consequences of these are, using genetically engineered mice and cells grown in culture. Achievement of these goals will provide insights into novel treatments of obstructive lung diseases.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
3R01HL080396-04S1
Application #
8432315
Study Section
Lung Cellular, Molecular, and Immunobiology Study Section (LCMI)
Program Officer
Banks-Schlegel, Susan P
Project Start
2009-08-01
Project End
2014-07-31
Budget Start
2012-03-08
Budget End
2012-07-31
Support Year
4
Fiscal Year
2012
Total Cost
$28,511
Indirect Cost
$9,901
Name
University of Colorado Denver
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
041096314
City
Aurora
State
CO
Country
United States
Zip Code
80045
Janssen, William J; Stefanski, Adrianne L; Bochner, Bruce S et al. (2016) Control of lung defence by mucins and macrophages: ancient defence mechanisms with modern functions. Eur Respir J 48:1201-1214
Livraghi-Butrico, A; Grubb, B R; Wilkinson, K J et al. (2016) Contribution of mucus concentration and secreted mucins Muc5ac and Muc5b to the pathogenesis of muco-obstructive lung disease. Mucosal Immunol :
Nakano, Yasushi; Yang, Ivana V; Walts, Avram D et al. (2016) MUC5B Promoter Variant rs35705950 Affects MUC5B Expression in the Distal Airways in Idiopathic Pulmonary Fibrosis. Am J Respir Crit Care Med 193:464-6
Evans, Christopher M; Fingerlin, Tasha E; Schwarz, Marvin I et al. (2016) Idiopathic Pulmonary Fibrosis: A Genetic Disease That Involves Mucociliary Dysfunction of the Peripheral Airways. Physiol Rev 96:1567-91
Raclawska, Dorota S; Ttofali, Fani; Fletcher, Ashley A et al. (2016) Mucins and Their Sugars. Critical Mediators of Hyperreactivity and Inflammation. Ann Am Thorac Soc 13 Suppl 1:S98-9
Ren, Binhui; Azzegagh, Zoulikha; Jaramillo, Ana M et al. (2015) SNAP23 is selectively expressed in airway secretory cells and mediates baseline and stimulated mucin secretion. Biosci Rep 35:
Kiwamoto, Takumi; Katoh, Toshihiko; Evans, Christopher M et al. (2015) Endogenous airway mucins carry glycans that bind Siglec-F and induce eosinophil apoptosis. J Allergy Clin Immunol 135:1329-40.e1-9
Aherne, C M; Saeedi, B; Collins, C B et al. (2015) Epithelial-specific A2B adenosine receptor signaling protects the colonic epithelial barrier during acute colitis. Mucosal Immunol 8:1324-38
Evans, Christopher M; Raclawska, Dorota S; Ttofali, Fani et al. (2015) The polymeric mucin Muc5ac is required for allergic airway hyperreactivity. Nat Commun 6:6281
Liptzin, Deborah R; Watson, Alan M; Murphy, Elissa et al. (2015) MUC5B expression and location in surfactant protein C mutations in children. Pediatr Pulmonol 50:1270-6

Showing the most recent 10 out of 19 publications