Functional Analysis of the Pulmonary Microbiome during COPD

摘要 细菌定植/感染在慢性阻塞性肺疾病(COPD)患者中普遍存在 已经被认为在生物学上与疾病有关。慢性阻塞性肺疾病和慢性阻塞性肺疾病患者的呼吸道粘液量均有改变。 导致慢性和急性呼吸道阻塞、慢性支气管炎症状和细菌定植。 据报道，细菌的鉴定和细菌感染的强度之间存在相关性。 炎症/免疫反应，咳嗽和痰增加，急性加重率增加 慢性阻塞性肺疾病（慢阻肺）。现在人们认识到，慢性阻塞性肺疾病的肺中有一个微生物群，与健康人的不同。 个体，这不是标准的培养技术所能捕捉到的。与胃肠道的研究不同， 对呼吸道的独立于培养的分析没有发现大量常规不可培养的 细菌。相反，这些研究表明存在可培养的细菌物种，如假单胞菌 SPP.这可能会在疾病期间经历可培养和不可培养的循环。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 细菌的活性。最近，研究开始支持这样一个概念，即宿主衍生因子 炎症过程中可能是许多呼吸道细菌适应和代谢变化的驱动力。 我们在这个建议中的假设是炎症反应(即IL-17驱动的炎症、干扰素 干扰素介导诱导型一氧化氮合酶诱导和激活儿茶酚胺的产生 炎性巨噬细胞)也可能推动假单胞菌感染，创造一个自我强化的循环 发炎。铜绿假单胞菌一直被认为是一种必需的需氧细菌；然而，最近的研究 强调这不是真的，为它在粘液丰富的区域生长提供了细菌学机制 在存在持续炎症的情况下，病变肺的存在。为了支持这一假设，炎症性的 巨噬细胞可以产生活性氮和儿茶酚胺，这两种物质都有可能 直接促进假单胞菌的定植和毒力。反过来，这激活了呼吸道上皮细胞通路 参与了呼吸道粘液的过度产生，这些粘液总共通过产生 富含硝酸盐的微好氧或厌氧生态位，可促进假单胞菌的定植。

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.