肺微生物组与慢性阻塞性肺疾病的研究进展

摘要：慢性阻塞性肺疾病（COPD）是一种慢性炎症性呼吸道疾病,其特征是持续气流受限和肺部炎症反应异常。气道内微生物是COPD恶化的主要原因,并且使气道中的炎症反应持续存在而促成COPD进展,这导致肺功能的进一步损害和巨大的医疗保健成本。近年来随着高通量测序技术的发展和运用,人类肺微生物组的研究逐渐成为热点。大量研究表明,COPD患者肺内存在明显不同的微生物群落,而且与COPD的疾病严重程度及恶化状态有关。肺微生物组学的研究有助于人们更全面地理解COPD患者肺内的微生态系统及其在该病恶化和进展中的作用。本文就肺微生物组在COPD中的研究进展作一综述,并探讨未来的研究前景。     

COPD的下呼吸道微生态研究进展

新一代测序技术的发展,拓展了人类对肺微生物组的认识,下呼吸道微生物组与呼吸系统疾病的关系日益受到关注。下呼吸道微生物组包含平衡的共生菌群和致病菌群,在慢性阻塞性肺疾病(chronic obstructive pulmonary disease, COPD)中,其疾病的严重性、炎症程度或抗生素等治疗因素均会影响肺部微生物群稳态,下呼吸道微生物群落的改变又可能通过操纵炎症或免疫过程,对COPD的病程产生影响。据此,本文通过回顾近年来对COPD下呼吸道微生态的研究,总结了COPD患者的下呼吸道微生态特征及菌群定植情况,探讨下呼吸道微生态与COPD发病机制之间的相关性和治疗对策,希望为COPD的诊断和治疗提供新思路。     

巨噬细胞极化及其在慢性阻塞性肺疾病中的作用

巨噬细胞具有高度可塑性,在炎症因子的诱导和多种信息分子的调控下可极化为经典活化巨噬细胞(M1)和替代活化巨噬细胞(M2)。慢性肺部炎症反应和肺实质损伤是慢性阻塞性肺疾病(chronic obstructive pulmonary disease, COPD)的主要病理表现。M1促进肺部炎症反应;M2抑制炎症反应,参与肺组织损伤与修复,并吞噬和清除病原微生物和凋亡细胞。靶向干预巨噬细胞极化方向有可能成为COPD治疗的新策略。     

肺微生物组在慢性阻塞性肺疾病中的研究进展CSCD

慢性阻塞性肺疾病（chronic obstructive pulmonary disease,COPD）是一种以持续的呼吸道症状和气流受限为主要特征的异质性疾病。新一代基因测序技术已经证明健康肺部存在庞大的微生物群落。越来越多的研究表明,肺微生物群失调与COPD的发生、急性加重次数及病死率有关。肺微生物可能通过调控炎症或免疫过程参与COPD的发病机制。全面了解肺微生物群在COPD不同阶段的动态变化和微生物与宿主的相互作用,有助于进一步揭示其在COPD发病机制中的作用。本文综述了肺微生物组在COPD中的研究进展,探讨其与COPD进展之间的关系及潜在的机制,以期开发有针对性的治疗方法。     

运动介导腺苷酸活化蛋白激酶防治慢性阻塞性肺疾病的作用机制

慢性阻塞性肺疾病(chronic obstructive pulmonary disease, COPD)是一种以持续存在的呼吸道症状和气流受限为主要特征的、常见的、可预防和治疗的慢性气道疾病。目前，我国COPD的患病率仍呈不断增长的趋势，已成为仅次于高血压、糖尿病的中国第三大常见慢性病，给患者家庭和国家卫生系统带来巨大的负担。研究证实，肺部炎症、肺细胞衰老、肺线粒体功能障碍和肺代谢失调是COPD发生与发展的主要病理原因，腺苷酸活化蛋白激酶(AMP-activated protein kinase, AMPK)可以改善肺部炎症反应、延缓肺细胞衰老、纠正肺线粒体功能障碍及调节肺细胞代谢紊乱。但就目前而言，通过运动手段上调AMPK的表达防治COPD的潜在机制仍不清楚。因此，通过中国知网(CNKI)、PubMed、Web of Science、WHO等官网与数据库，检索并梳理相关文献资料，综述COPD的发病机制、运动对AMPK表达的影响及运动介导AMPK防治COPD的可能机制，以期为COPD提供新的治疗靶点。     

J Immunol:坏死性肠炎引发肺部炎症的分子机制

正坏死性小肠结肠炎(NEC)是高发于新生儿的致死性肠道疾病。随着疾病的恶化,会有严重的肺部炎症的出现。针对NEC介导的肺炎的发生机制,来自约翰霍普金斯大学的David J.Hackam课题组进行了深入研究,发现NEC引发的肺部炎症依赖于局部的TLR4信号,且肠道微生物分泌的HMGB1是引发肺脏炎症反应的关键配体物质,HMGB1能够促进肺脏中性粒细胞的分泌以     

肺癌合并呼吸道感染患者肺部病原菌分布及其对凋亡相关蛋白的影响

目的 探讨肺癌合并呼吸道感染患者肺部病原菌分布及其对凋亡相关蛋白的影响,为该病的治疗提供参考.方法 选择2017年3月至2019年3月我院收治的肺癌合并呼吸道感染患者62例为观察组,再选取同期我院收治的肺癌未合并呼吸道感染患者60例为对照组.分析观察组患者病原微生物分布情况,比较两组患者炎症因子[白细胞介素-6(IL-...     

肠道菌群对慢性阻塞性肺疾病的影响研究

慢性阻塞性肺疾病(chronic obstructive pulmonary disease,COPD)是肺部常见疾病,肺部炎症作为COPD的一贯特征,其炎症反应多为中性粒细胞型。近年的流行病学调查表明,COPD在我国的防治现状并不理想,表现出高致死率、致残率及高隐匿性的特点。目前COPD的有效治疗措施匮乏,寻找新的治疗突破口迫在眉睫。现有的研究显示,肠道菌群及其代谢产物与多种疾病的发生发展有着密切关联,其与肺系疾病的联系称为“肺—肠轴”。在COPD中,这可能是通过改变肠道屏障完整性、产生抗炎性代谢产物和调节骨髓造血免疫功能来实现的。但现有的研究尚不能明确特定的肠道菌群对COPD的作用机制,这也是未来研究的方向及COPD治疗可能的突破口。     

脂蛋白受体激动剂调节COPD小鼠炎症反应机制研究

目的:探究脂蛋白受体激动剂BML-111调节COPD小鼠炎症反应的机制。方法:构建COPD小鼠模型,通过HE染色检测小鼠肺组织和血管周围炎性细胞侵润程度;通过ELISA检测小鼠支气管肺泡灌洗液(BALF)中TGF-β、TNF-α、IL-1β和IL-10的含量;通过Western blot检测小鼠肺组织中NLRP3、Cleaved-IL-1β、Cleaved-caspase-1和Nrf-2的表达。结果:番红染色结果显示,与对照组相比,COPD模型组显示出严重的炎症反应,炎症细胞侵润程度增加,肺泡囊和间隙增大,支气管壁增厚。与模型组相比,低BML、高BML和Dex组的肺组织和血管周围的炎性细胞浸润程度明显降低(P0.05)。ELISA检测结果显示,COPD模型组中TGF-β、TNF-α、IL-10和IL-1β的表达均明显高于对照组(P0.05);在高BML组中,TGF-β、TNF-α、IL-10和IL-1β的表达明显低于COPD模型组中的表达(P0.05)。与COPD模型组相比,Dex组的TNF-α、IL-10和IL-1β的表达显著下调(P0.05),TGF-β的表达无显著差异(P0.05)。Western blot检测结果显示,与对照组相比,COPD模型组中NLRP3、cleaved-IL-1β和cleaved-caspase-1的表达显著上调(P0.05);与COPD模型组相比,低剂量BML组、高剂量BML组和Dex组中NLRP3、cleaved-IL-1β和cleaved-caspase-1的表达显著下调(P0.05)。活性检测结果显示,与对照组相比,COPD模型组的SOD活性显著降低(P0.05),MDA活性显著增强(P0.05)。BML-111处理后,与模型组相比,10 mg/kg的BML-111和2 mg/kg的Dex显著提高SOD活性,并显著降低MDA活性(P0.05)。与对照组相比,COPD模型组的Nrf-2的表达显著下调;而低剂量BML组,高剂量BML组和Dex组中Nrf-2的表达明显高于COPD模型组(P0.05)。结论:BML-111对COPD小鼠的抗炎作用可能是通过调节NLRP3炎症小体激活和ROS的产生来介导。     

COPD大鼠模型在不同时期细胞转录因子NF-kB变化及意义(英文)

目的:建立分别由吸烟以及气管内滴注脂多糖导致慢性阻塞性肺病小鼠模型,并研究核因子-κB在(COPD)的作用。方法:我们将50只wistar鼠随机分成2组,1组为正常对照组,2组为COPD进展组。COPD进展组又进一步分为暴露香烟烟雾及气管内滴注脂多糖1周、2周、3周、4周、5周。预备好的小鼠被解剖观察,肉眼观察小鼠外形及肺组织标本,显微镜下观察肺脏的病理改变。分析PH、氧分压、二氧化碳分压,NF-kB的活性被测量。结果:COPD小鼠模型肺组织的病理改变如同COPD患者,不同暴露组的实验小鼠细胞总数结果表明,实验小鼠COPD肺组织的病理改变和人类COPD的病理改变是一致的。动脉血气分析结果显示暴露与烟雾及气管内滴注脂多糖4周的小鼠与正常对照组比较血PH、氧分压是降低的,而二氧化碳分压是升高的。结论:NF-kB在促进肺部炎症反应中起着重要的作用,通过活化肿瘤坏死因子及肺泡巨噬细胞。     

The Lung Microbiome in Moderate and Severe Chronic Obstructive Pulmonary Disease

Chronic obstructive pulmonary disease (COPD) is an inflammatory disorder characterized by incompletely reversible airflow obstruction. Bacterial infection of the lower respiratory tract contributes to approximately 50% of COPD exacerbations. Even during periods of stable lung function, the lung harbors a community of bacteria, termed the microbiome. The role of the lung microbiome in the pathogenesis of COPD remains unknown. The COPD lung microbiome, like the healthy lung microbiome, appears to reflect microaspiration of oral microflora. Here we describe the COPD lung microbiome of 22 patients with Moderate or Severe COPD compared to 10 healthy control patients. The composition of the lung microbiomes was determined using 454 pyrosequencing of 16S rDNA found in bronchoalveolar lavage fluid. Sequences were analyzed using mothur, Ribosomal Database Project, Fast UniFrac, and Metastats. Our results showed a significant increase in microbial diversity with the development of COPD. The main phyla in all samples were Actinobacteria, Firmicutes, and Proteobacteria. Principal coordinate analyses demonstrated separation of control and COPD samples, but samples did not cluster based on disease severity. However, samples did cluster based on the use of inhaled corticosteroids and inhaled bronchodilators. Metastats analyses demonstrated an increased abundance of several oral bacteria in COPD samples.     

Unexpected guests in the tumor microenvironment:microbiome in cancer

Although intestinal microbiome have been established as an important biomarker and regulator of cancer development and therapeutic response,less is known about the role of microbiome at other body sites in cancer.Emerging evidence has revealed that the local microbiota make up an important part of the tumor microenvironment across many types of cancer,espe-cially in cancers arising from mucosal sites,including the lung,skin and gastrointestinal tract.The populations of bacteria that reside specifically within tumors have been found to be tumor-type specific,and mechanistic studies have demonstrated that tumor-associated microbiota may directly regulate cancer initiation,pro-gression and responses to chemo-or immuno-thera-pies.This review aims to provide a comprehensive review of the important literature on the microbiota in the cancerous tissue,and their function and mechanism of action in cancer development and treatment.     

Defective Lung Macrophage Function in Lung Cancer±Chronic Obstructive Pulmonary Disease (COPD/Emphysema)-Mediated by Cancer Cell Production of PGE2?

In chronic obstructive pulmonary disease (COPD/emphysema) we have shown a reduced ability of lung and alveolar (AM) macrophages to phagocytose apoptotic cells (defective ‘efferocytosis’), associated with evidence of secondary cellular necrosis and a resultant inflammatory response in the airway. It is unknown whether this defect is present in cancer (no COPD) and if so, whether this results from soluble mediators produced by cancer cells.We investigated efferocytosis in AM (26 controls, 15 healthy smokers, 37 COPD, 20 COPD+ non small cell lung cancer (NSCLC) and 8 patients with NSCLC without COPD) and tumor and tumor-free lung tissue macrophages (21 NSCLC with/13 without COPD). To investigate the effects of soluble mediators produced by lung cancer cells we then treated AM or U937 macrophages with cancer cell line supernatant and assessed their efferocytosis ability. We qualitatively identified Arachidonic Acid (AA) metabolites in cancer cells by LC-ESI-MSMS, and assessed the effects of COX inhibition (using indomethacin) on efferocytosis.Decreased efferocytosis was noted in all cancer/COPD groups in all compartments. Conditioned media from cancer cell cultures decreased the efferocytosis ability of both AM and U937 macrophages with the most pronounced effects occurring with supernatant from SCLC (an aggressive lung cancer type). AA metabolites identified in cancer cells included PGE2. The inhibitory effect of PGE2 on efferocytosis, and the involvement of the COX-2 pathway were shown.Efferocytosis is decreased in COPD/emphysema and lung cancer; the latter at least partially a result of inhibition by soluble mediators produced by cancer cells that include PGE2.     

MicroRNAs in inflammatory lung disease - master regulators or target practice?

MicroRNAs (miRNAs) have emerged as a class of regulatory RNAs with immense significance in numerous biological processes. When aberrantly expressed miRNAs have been shown to play a role in the pathogenesis of several disease states. Extensive research has explored miRNA involvement in the development and fate of immune cells and in both the innate and adaptive immune responses whereby strong evidence links miRNA expression to signalling pathways and receptors with critical roles in the inflammatory response such as NF-κB and the toll-like receptors, respectively. Recent studies have revealed that unique miRNA expression profiles exist in inflammatory lung diseases such as cystic fibrosis, chronic obstructive pulmonary disease, asthma, idiopathic pulmonary fibrosis and lung cancer. Evaluation of the global expression of miRNAs provides a unique opportunity to identify important target gene sets regulating susceptibility and response to infection and treatment, and control of inflammation in chronic airway disorders. Over 800 human miRNAs have been discovered to date, however the biological function of the majority remains to be uncovered. Understanding the role that miRNAs play in the modulation of gene expression leading to sustained chronic pulmonary inflammation is important for the development of new therapies which focus on prevention of disease progression rather than symptom relief. Here we discuss the current understanding of miRNA involvement in innate immunity, specifically in LPS/TLR4 signalling and in the progression of the chronic inflammatory lung diseases cystic fibrosis, COPD and asthma. miRNA in lung cancer and IPF are also reviewed.     

Mesenchymal stem cells protect cigarette smoke‐damaged lung and pulmonary function partly via VEGF–VEGF receptors

Progressive pulmonary inflammation and emphysema have been implicated in the progression of chronic obstructive pulmonary disease (COPD), while current pharmacological treatments are not effective. Transplantation of bone marrow mesenchymal stem cells (MSCs) has been identified as one such possible strategy for treatment of lung diseases including acute lung injury (ALI) and pulmonary fibrosis. However, their role in COPD still requires further investigation. The aim of this study is to test the effect of administration of rat MSCs (rMSCs) on emphysema and pulmonary function. To accomplish this study, the rats were exposed to cigarette smoke (CS) for 11 weeks, followed by administration of rMSCs into the lungs. Here we show that rMSCs infusion mediates a down‐regulation of pro‐inflammatory mediators (TNF‐α, IL‐1β, MCP‐1, and IL‐6) and proteases (MMP9 and MMP12) in lung, an up‐regulation of vascular endothelial growth factor (VEGF), VEGF receptor 2, and transforming growth factor (TGFβ‐1), while reducing pulmonary cell apoptosis. More importantly, rMSCs administration improves emphysema and destructive pulmonary function induced by CS exposure. In vitro co‐culture system study of human umbilical endothelial vein cells (EA.hy926) and human MSCs (hMSCs) provides the evidence that hMSCs mediates an anti‐apoptosis effect, which partly depends on an up‐regulation of VEGF. These findings suggest that MSCs have a therapeutic potential in emphysematous rats by suppressing the inflammatory response, excessive protease expression, and cell apoptosis, as well as up‐regulating VEGF, VEGF receptor 2, and TGFβ‐1. J. Cell. Biochem. 114: 323–335, 2013. © 2012 Wiley Periodicals, Inc.     

慢性呼吸道疾病患者呼吸道微生物群研究进展

过去认为健康人肺部是无菌的,对疾病状态下呼吸道菌群的研究依赖传统培养技术。近年来,DNA测序技术应用于呼吸道标本的微生物检测,发现健康肺部存在复杂的微生物群。越来越多的证据表明,呼吸道微生物群在多种慢性呼吸道疾病发生和发展过程中扮演重要角色,与哮喘、慢性阻塞性肺病等疾病的临床表现、急性加重及预后相关。通过比较急性加重期与稳定期患者的呼吸道标本微生物群,形成了新的疾病假说,阐释了慢性呼吸道疾病急性加重的微生物学基础。未来对微生物测序数据的深度挖掘及基于临床问题的研究,有望为慢性呼吸道疾病的治疗提供新的靶点。     

Immunohistochemical analysis of the ubiquitin-conjugating enzyme UbcH10 in lung cancer: a useful tool for diagnosis and therapy

The ubiquitin-conjugating enzyme (UbcH10) plays important roles in the regulation of cell cycle progression. Recently, UbcH10 expression has been demonstrated in several human and experimental tumors, and proteasome inhibitors have been tested in trials for pulmonary neoplasms; however, the underlying mechanisms as well as the clinicopathological relevance of UbcH10 in the genesis and progression of lung cancer remain largely unknown. Therefore, the authors evaluated the expression of UbcH10 in human lung cancer and evaluated its possible diagnostic and prognostic use. They found that most cases of lung adenocarcinoma, squamous cell carcinoma, and large cell and small cell carcinoma were positive for UbcH10. The expression levels of UbcH10 progressively increased with decreasing degree of tumor differentiation. There was a statistically significant difference of UbcH10 positivity between grade I/III of lung adenocarcinoma (p=0.013) and squamous cell carcinoma (p=0.002). No significant differences were found between histological types (p=0.072). In the case of cell blocks prepared from pleural effusions, inflammatory and reactive mesothelial elements did not show appreciable UbcH10 expression, whereas neoplastic cells exhibited clear UbcH10 positivity. The results suggest that UbcH10 might represent a new and promising diagnostic and prognostic marker in both histologic and cytologic specimens of lung cancer.     

New aspects on the role of lipoxygenases in cancer progression

The Lipoxygenases (LOXs) are a class of enzymes that convert arachidonic, linoleic, and other polyunsaturated fatty acid into biologically active metabolites involved in the inflammatory and immune responses. Recent evidences indicate that LOXs and the signaling pathways that are involved in their activation are also important for carcinogenesis and tumor progression. LOXs should therefore receive as much attention from cancer researchers as it has already from immunologists. In this article, we will review some evidence that the LOXs pathways affect several aspects of lung, pancreatic and prostate cancer progression. Moreover, we discuss how this new perspective on the roles of LOXs and their metabolites can have important implications to cancer therapy.     

Inhibition of ceramide de novo synthesis by myriocin produces the double effect of reducing pathological inflammation and exerting antifungal activity against A. fumigatus airways infection

BackgroundFungal infections develop in pulmonary chronic inflammatory diseases such as asthma, Chronic Obstructive Pulmonary Disease (COPD) and Cystic Fibrosis (CF). The available antifungal drugs may fail to eradicate fungal pathogens, that can invade the lungs and vessels and spread by systemic circulation taking advantage of defective lung immunity. An increased rate of sphingolipid de novo synthesis, leading to ceramide accumulation, was demonstrated in CF and COPD inflamed lungs. The inhibitor of sphingolipid synthesis myriocin reduces inflammation and ameliorates the response against bacterial airway infection in CF mice. Myriocin also inhibits sphingolipid synthesis in fungi and exerts a powerful fungistatic effect.MethodsWe treated Aspergillus fumigatus infected airway epithelial cells with myriocin and we administered myriocin-loaded nanocarriers to A. fumigatus infected mice lung.ResultsWe demonstrate here that de novo synthesized ceramide mediates the inflammatory response induced by A. fumigatus infection in airway epithelia. CF epithelial cells are chronically inflamed and defective in killing internalized conidia. Myriocin treatment reduced ceramide increase and inflammatory mediator release whereas it upregulated HO1 and NOD2, allowing the recovery of a functional killing of conidia in these cells. Myriocin-loaded nanocarriers, intratracheally administered to mice, significantly reduced both the inflammatory response induced by A. fumigatus pulmonary challenge and fungal lung invasion.ConclusionsWe conclude that inhibition of sphingolipid synthesis can be envisaged as a dual anti-inflammatory and anti-fungal therapy in patients suffering from chronic lung inflammation with compromised immunity.General significanceMyriocin represents a powerful agent for inflammatory diseases and fungal infection.