Bacterial colonization/infection is ubiquitous in Chronic Obstructive Pulmonary Disease (COPD) patients and has been felt to be biologically relevant in disease. The quantity of airway mucus can be altered in COPD and contribute to chronic and acute airway obstruction, symptoms of chronic bronchitis and bacterial colonization. Correlations have been reported between the identification of bacteria and the intensity of the inflammatory/immune response, increased cough and sputum and increased rates of acute exacerbations of COPD. It is now appreciated that the COPD lung harbors a microbiome, distinct from that in healthy individuals, which is not captured by standard culture techniques. Unlike studies of the gastrointestinal tract, culture-independent analyses of the airways have not identified significant numbers of routinely unculturable bacteria. Rather, these studies implicate the existence of culturable bacterial species, such as Pseudomonas spp. that may go through cycles of culturability and unculturability during disease. These likely reflect changes in the nutritional environment of the lungs, adaptation to host defenses and changes in the metabolic activity of the bacteria. More recently, studies have begun to support the concept that host-derived factors during inflammation may be a driving force for adaptation and metabolic shifts in many respiratory bacteria. Our hypothesis in this proposal is that the inflammatory response (i.e. IL-17 driven inflammation, interferon (IFN)-mediated inducible nitric oxide synthase (iNOS) induction and activation of catecholamine-producing inflammatory macrophages) may also drive Pseudomonas infection, creating a self-reinforcing cycle of inflammation. P. aeruginosa has long been held to be an obligate aerobic bacterium; however, recent studies have highlighted that this is not true, providing a bacteriologic mechanism for its growth in mucus-rich regions of diseased lungs in the presence of ongoing inflammation. In support of this hypothesis, inflammatory macrophages can produce reactive nitrogen species and catecholamines, both of which have the potential to directly promote Pseudomonas colonization and virulence. In turn, this activates airway epithelial pathways involved in mucus over-production in the airways that, altogether, perpetuate airway disease by creating nitrate-rich micro-aerophilic or anaerobic niches that promote Pseudomonas colonization.

Public Health Relevance

COPD is a highly prevalent disorder with rising mordibity, mortality and limited therapeutic options. This study investigates a pathway that links inflammation, Gram negative bacterial overgrowth, mucus production and chronic bacterial colonization in COPD, with the ultimate goal of improved diagnostics and/or therapeutics.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL121774-03
Application #
9615017
Study Section
Lung Cellular, Molecular, and Immunobiology Study Section (LCMI)
Program Officer
Caler, Elisabet V
Project Start
2017-01-01
Project End
2020-12-31
Budget Start
2019-01-01
Budget End
2019-12-31
Support Year
3
Fiscal Year
2019
Total Cost
Indirect Cost
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
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