COPD is a highly prevalent disorder with rising mordibity and mortality and there are limited therapeutic options to alter disease course. Patients with a predominance of cough and sputum production are felt to be a distinct phenotypic group with greater airway inflammation;however, the factors underlying persistent inflammation in COPD remain unresolved. The parent study of this proposal examines the effect of roflumilast (a potent and specific PDE4 inhibitor) versus placebo on airway inflammation. This ancillary study provides an unparalled opportunity to examine longitudinal changes in airway microbial structure and function, relating these to inflammation, changes in epithelial gene expression and mucin production. The central hypothesis of this proposal is that changes in the indigenous pulmonary microbiome of COPD patients (either a change in overall community structure or through domination/colonization of the pulmonary mucosa by a single species or limited bacterial consortia) causes changes in epithelial cell gene expression, including activation of the EGFR pathway and mucin induction, thereby contributing to airway obstruction and symptoms of chronic bronchitis in COPD patients. This process will be ameliorated by a PDE4 inhibitor. Specifically, we will 1) define the microbial communities from airway samples in COPD patients;2) identify bacterial determinants of airway epithelial mucin dysregulation in COPD and whether roflumilast exerts its beneficial effects through reduction in airway mucin production;3) determine the relationship between localized changes in the bacterial microbiome and epithelial gene expression of pattern recognition receptors (PRRs), anti-microbial peptides and host stress-response pathways and;4) investigate the interrelationship between changes in the bacterial microbiome (longitudinal &via roflumilast) with epithelial mucin regulation, epithelial gene expression, airway inflammation and clinical phenotype, using mathematical models to identify potential interactions. This proposal will leverage a large, industry sponsored investigation with state of the art methodologies to examine complex microbial communities, epithelial mucin production and airway inflammation in a highly characterized group of COPD subjects with chronic bronchitis. The data generated by these novel experiments will provide novel insight into the contribution of changes in the lung microbiota to changes in disease in highly characterized COPD subjects, utilizing high throughput technologies and systems science approaches.

Public Health Relevance

COPD is a highly prevalent disorder with rising mordibity, mortality and limited therapeutic options. This ancillary study provides an unparalleled opportunity to examine longitudinal changes in airway microbial composition and identify relationships between inflammation and mucus production that may lead to improved diagnostics and/or therapeutics.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL114447-02
Application #
8509021
Study Section
Special Emphasis Panel (ZHL1-CSR-B (F1))
Program Officer
Punturieri, Antonello
Project Start
2012-07-10
Project End
2016-05-31
Budget Start
2013-06-01
Budget End
2014-05-31
Support Year
2
Fiscal Year
2013
Total Cost
$369,372
Indirect Cost
$92,260
Name
University of Michigan Ann Arbor
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
073133571
City
Ann Arbor
State
MI
Country
United States
Zip Code
48109
Camargo Jr, Carlos A; Budinger, G R Scott; Escobar, Gabriel J et al. (2014) Promotion of lung health: NHLBI Workshop on the Primary Prevention of Chronic Lung Diseases. Ann Am Thorac Soc 11 Suppl 3:S125-38
Dickson, Robert P; Martinez, Fernando J; Huffnagle, Gary B (2014) The role of the microbiome in exacerbations of chronic lung diseases. Lancet 384:691-702
Scales, Brittan S; Dickson, Robert P; LiPuma, John J et al. (2014) Microbiology, genomics, and clinical significance of the Pseudomonas fluorescens species complex, an unappreciated colonizer of humans. Clin Microbiol Rev 27:927-48
Dickson, Robert P; Erb-Downward, John R; Huffnagle, Gary B (2014) Towards an ecology of the lung: new conceptual models of pulmonary microbiology and pneumonia pathogenesis. Lancet Respir Med 2:238-46
Dickson, Robert P; Erb-Downward, John R; Prescott, Hallie C et al. (2014) Cell-associated bacteria in the human lung microbiome. Microbiome 2:28
Dickson, Robert P; Erb-Downward, John R; Freeman, Christine M et al. (2014) Changes in the lung microbiome following lung transplantation include the emergence of two distinct Pseudomonas species with distinct clinical associations. PLoS One 9:e97214
Dickson, Robert P; Erb-Downward, John R; Prescott, Hallie C et al. (2014) Analysis of culture-dependent versus culture-independent techniques for identification of bacteria in clinically obtained bronchoalveolar lavage fluid. J Clin Microbiol 52:3605-13
Dickson, Robert P; Erb-Downward, John R; Huffnagle, Gary B (2013) The role of the bacterial microbiome in lung disease. Expert Rev Respir Med 7:245-57
Scales, Brittan S; Huffnagle, Gary B (2013) The microbiome in wound repair and tissue fibrosis. J Pathol 229:323-31