Functional Analysis of the Pulmonary Microbiome during COPD

总结 细菌定植/感染在慢性阻塞性肺病（COPD）患者中普遍存在， 被认为与疾病有生物学相关性。COPD患者的气道粘液量会发生变化， 导致慢性和急性气道阻塞、慢性支气管炎症状和细菌定植。 已经报道了细菌的鉴定和细菌的强度之间的相关性。 炎症/免疫反应，咳嗽和咳痰增加， 慢性阻塞性肺病现在认识到，COPD肺含有与健康肺不同的微生物组。 这是标准培养技术无法捕捉到的。与胃肠道的研究不同， 对气道的非培养分析没有发现大量的常规不可培养的 细菌相反，这些研究暗示存在可培养的细菌物种，如假单胞菌 spp.在疾病期间可能会经历可培养性和“不可培养性”的循环。这些可能反映了 肺的营养环境的变化，对宿主防御的适应和代谢的变化 细菌的活动。最近，研究开始支持宿主衍生因子 在炎症过程中可能是许多呼吸道细菌适应和代谢转变的驱动力。 我们的假设是，炎症反应（即IL-17驱动的炎症，干扰素 干扰素介导的诱导型一氧化氮合酶（iNOS）诱导和激活的儿茶酚胺产生 炎症性巨噬细胞）也可能驱动假单胞菌感染，创造一个自我强化的循环， 炎症铜绿假单胞菌长期以来一直被认为是专性好氧细菌;然而，最近的研究表明， 已经强调这是不正确的，提供了一个细菌学机制，其生长在粘液丰富的地区 在存在持续炎症的情况下，对患病肺部的影响。为了支持这一假设， 巨噬细胞可以产生活性氮物质和儿茶酚胺，这两者都有潜力， 直接促进假单胞菌的定殖和毒力。反过来，这会激活气道上皮通路， 参与气道中粘液的过度产生，总的来说，通过创造 促进假单胞菌定植的富含硝酸盐的微需氧或厌氧小生境。

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.