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Functional Analysis of the Pulmonary Microbiome during COPD

Functional Analysis of the Pulmonary Microbiome during COPD
COPD 期间肺部微生物组的功能分析
批准号:
9542530
负责人:
Gary B Huffnagle
金额:
$22.32万
依托单位国家:
美国
项目类别:
财政年份:
2017
资助国家:
美国
项目状态:
已结题
起止时间:
2017-09-18 至 2017-12-31

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英文摘要
Summary 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.
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