Although culture-independent techniques have shown that the lungs are not sterile, little is known about the lung microbiome in chronic obstructive pulmonary disease (COPD). We used pyrosequencing of ...16S amplicons to analyze the lung microbiome in two ways: first, using bronchoalveolar lavage (BAL) to sample the distal bronchi and air-spaces; and second, by examining multiple discrete tissue sites in the lungs of six subjects removed at the time of transplantation. We performed BAL on three never-smokers (NS) with normal spirometry, seven smokers with normal spirometry ("healthy smokers", HS), and four subjects with COPD (CS). Bacterial 16 s sequences were found in all subjects, without significant quantitative differences between groups. Both taxonomy-based and taxonomy-independent approaches disclosed heterogeneity in the bacterial communities between HS subjects that was similar to that seen in healthy NS and two mild COPD patients. The moderate and severe COPD patients had very limited community diversity, which was also noted in 28% of the healthy subjects. Both approaches revealed extensive membership overlap between the bacterial communities of the three study groups. No genera were common within a group but unique across groups. Our data suggests the existence of a core pulmonary bacterial microbiome that includes Pseudomonas, Streptococcus, Prevotella, Fusobacterium, Haemophilus, Veillonella, and Porphyromonas. Most strikingly, there were significant micro-anatomic differences in bacterial communities within the same lung of subjects with advanced COPD. These studies are further demonstration of the pulmonary microbiome and highlight global and micro-anatomic changes in these bacterial communities in severe COPD patients.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
COPD, one of the leading worldwide health problems, currently lacks truly disease-modifying medical therapies applicable to most patients. Developing such novel therapies has been hampered by the ...marked heterogeneity of phenotypes between individuals with COPD. Such heterogeneity suggests that, rather than a single cause (particularly just direct inhalation of tobacco products), development and progression of COPD likely involve both complex gene-by-environment interactions to multiple inhalational exposures and a variety of molecular pathways. However, there has been considerable recent progress toward understanding how specific pathological processes can lead to discrete COPD phenotypes, particularly that of small airways disease. Advances in imaging techniques that correlate to specific types of histological damage, and in the immunological mechanisms of lung damage in COPD, hold promise for development of personalized therapies. At the same time, there is growing recognition that the current diagnostic criteria for COPD, based solely on spirometry, exclude large numbers of individuals with very similar disease manifestations. This concise review summarizes current understanding of the etiology and pathophysiology of COPD and provides background explaining the increasing calls to expand the diagnostic criteria used to diagnose COPD and some challenges in doing so.
Although culture-independent techniques have refuted lung sterility in health, controversy about contamination during bronchoscope passage through the upper respiratory tract (URT) has impeded ...research progress. We sought to establish whether bronchoscopic sampling accurately reflects the lung microbiome in health and to distinguish between two proposed routes of authentic microbial immigration, (i) dispersion along contiguous respiratory mucosa and (ii) subclinical microaspiration. During bronchoscopy of eight adult volunteers without lung disease, we performed seven protected specimen brushings (PSB) and bilateral bronchoalveolar lavages (BALs) per subject. We amplified, sequenced, and analyzed the bacterial 16S rRNA gene V4 regions by using the Illumina MiSeq platform. Rigorous attention was paid to eliminate potential sources of error or contamination, including a randomized processing order and the inclusion and analysis of exhaustive procedural and sequencing control specimens. Indices of mouth-lung immigration (mouth-lung community similarity, bacterial burden, and community richness) were all significantly greater in airway and alveolar specimens than in bronchoscope contamination control specimens, indicating minimal evidence of pharyngeal contamination. Ecological indices of mouth-lung immigration peaked at or near the carina, as predicted for a primary immigration route of microaspiration. Bacterial burden, diversity, and mouth-lung similarity were greater in BAL than PSB samples, reflecting differences in the sampled surface areas. (This study has been registered at ClinicalTrials.gov under registration no. NCT02392182.)
This study defines the bacterial topography of the healthy human respiratory tract and provides ecological evidence that bacteria enter the lungs in health primarily by microaspiration, with potential contribution in some subjects by direct dispersal along contiguous mucosa. By demonstrating that contamination contributes negligibly to microbial communities in bronchoscopically acquired specimens, we validate the use of bronchoscopy to investigate the lung microbiome.
IL-21 has opposite effects on two types of T regulatory cells (TReg), favoring expansion of T effectors over Foxp31 TReg (21) while supporting the differentiation ofFoxp32 IL-10-producing Tr1 cells ...(22). ...IL-21's actions are complex, and although it has been reported to be overproduced in several autoimmune diseases (18), its ultimate role in COPD pathogenesis requires further study. Because LLFs are not unique to COPD, as the authors point out, this study has broader importance. ...understanding LLFs could help explain how adaptive immunity is involved in a wide range of lung diseases. ...it is significant that Ladjemi and colleagues found so few IgG-secreting B cells in COPD.
Abstract Purpose Microbial communities in or on the body (i.e., the microbiome) are highly physiologically active and influence human health. Although environmental scientists are increasingly aware ...of the gut microbiome, the respiratory microbiome's role in the human response to inhaled pollutants is largely unknown. Methods We reviewed the literature and present mechanisms by which the microbiome might mediate or modify human responses to inhaled pollutants. Results The respiratory microbiome has been shown to influence chronic lung disease exacerbations, and increasing evidence indicates a role in disease development. Research also suggests that the respiratory microbiome could plausibly metabolize inhaled pollutants or modulate host inflammatory responses to exposure. Because these responses depend on the microbes present, defining the composition of the resident microbiome and how microbial communities shift with exposure may help to explain variations in susceptibility to inhaled pollutants. Although more research is needed, significant measurement challenges remain for large epidemiologic studies of the respiratory microbiome. Conclusions The respiratory microbiome is likely an underexplored intermediate and potential cause of individual susceptibility to inhaled irritants/toxicants. Characterizing the microbiome's role in the human response to inhaled exposures could improve our understanding of the casual agents of exposure and suggest novel public health interventions.
DNA from phylogenetically diverse microbes is routinely recovered from healthy human lungs and used to define the lung microbiome. The proportion of this DNA originating from microbes adapted to the ...lungs, as opposed to microbes dispersing to the lungs from other body sites and the atmosphere, is not known. We use a neutral model of community ecology to distinguish members of the lung microbiome whose presence is consistent with dispersal from other body sites and those that deviate from the model, suggesting a competitive advantage to these microbes in the lungs. We find that the composition of the healthy lung microbiome is consistent with predictions of the neutral model, reflecting the overriding role of dispersal of microbes from the oral cavity in shaping the microbial community in healthy lungs. In contrast, the microbiome of diseased lungs was readily distinguished as being under active selection. We also assessed the viability of microbes from lung samples by cultivation with a variety of media and incubation conditions. Bacteria recovered by cultivation from healthy lungs represented species that comprised 61% of the 16S rRNA-encoding gene sequences derived from bronchoalveolar lavage samples.
Neutral distribution of microbes is a distinguishing feature of the microbiome in healthy lungs, wherein constant dispersal of bacteria from the oral cavity overrides differential growth of bacteria. No bacterial species consistently deviated from the model predictions in healthy lungs, although representatives of many of the dispersed species were readily cultivated. In contrast, bacterial populations in diseased lungs were identified as being under active selection. Quantification of the relative importance of selection and neutral processes such as dispersal in shaping the healthy lung microbiome is a first step toward understanding its impacts on host health.
No studies have examined the relationships between bacterial communities along sites of the upper aerodigestive tract of an individual subject. Our objective was to perform an intrasubject and ...intersite analysis to determine the contributions of two upper mucosal sites (mouth and nose) as source communities for the bacterial microbiome of lower sites (lungs and stomach). Oral wash, bronchoalveolar lavage (BAL) fluid, nasal swab, and gastric aspirate samples were collected from 28 healthy subjects. Extensive analysis of controls and serial intrasubject BAL fluid samples demonstrated that sampling of the lungs by bronchoscopy was not confounded by oral microbiome contamination. By quantitative PCR, the oral cavity and stomach contained the highest bacterial signal levels and the nasal cavity and lungs contained much lower levels. Pyrosequencing of 16S rRNA gene amplicon libraries generated from these samples showed that the oral and gastric compartments had the greatest species richness, which was significantly greater in both than the richness measured in the lungs and nasal cavity. The bacterial communities of the lungs were significantly different from those of the mouth, nose, and stomach, while the greatest similarity was between the oral and gastric communities. However, the bacterial communities of healthy lungs shared significant membership with the mouth, but not the nose, and marked subject-subject variation was noted. In summary, microbial immigration from the oral cavity appears to be the significant source of the lung microbiome during health, but unlike the stomach, the lungs exhibit evidence of selective elimination of Prevotella bacteria derived from the upper airways.
We have demonstrated that the bacterial communities of the healthy lung overlapped those found in the mouth but were found at lower concentrations, with lower membership and a different community composition. The nasal microbiome, which was distinct from the oral microbiome, appeared to contribute little to the composition of the lung microbiome in healthy subjects. Our studies of the nasal, oral, lung, and stomach microbiomes within an individual illustrate the microbiological continuity of the aerodigestive tract in healthy adults and provide culture-independent microbiological support for the concept that microaspiration is common in healthy individuals.
Efferocytosis and Lung Disease McCubbrey, Alexandra L., BS; Curtis, Jeffrey L., MD
Chest,
06/2013, Letnik:
143, Številka:
6
Journal Article
Recenzirano
Odprti dostop
In healthy individuals, billions of cells die by apoptosis each day. Clearance of these apoptotic cells, termed “efferocytosis,” must be efficient to prevent secondary necrosis and the release of ...proinflammatory cell contents that disrupt tissue homeostasis and potentially foster autoimmunity. During inflammation, most apoptotic cells are cleared by macrophages; the efferocytic process actively induces a macrophage phenotype that favors tissue repair and suppression of inflammation. Several chronic lung diseases, particularly airways diseases such as chronic obstructive lung disease, asthma, and cystic fibrosis, are characterized by an increased lung burden of uningested apoptotic cells. Alveolar macrophages from individuals with these chronic airways diseases have decreased efferocytosis relative to alveolar macrophages from healthy subjects. These two findings have led to the hypothesis that impaired apoptotic cell clearance may contribute causally to sustained lung inflammation and that therapies to enhance efferocytosis might be beneficial. This review of the English-language scientific literature (2006 to mid-2012) explains how such existing therapies as corticosteroids, statins, and macrolides may act in part by augmenting apoptotic cell clearance. However, efferocytosis can also impede host defenses against lung infection. Thus, determining whether novel therapies to augment efferocytosis should be developed and in whom they should be used lies at the heart of efforts to differentiate specific phenotypes within complex chronic lung diseases to provide appropriately personalized therapies.
Chronic obstructive pulmonary disease diagnosis rests on chronic pulmonary symptoms and airflow obstruction. This study showed that people may have chronic COPD symptoms but no airflow obstruction. ...Such patients have more COPD exacerbations than those without chronic symptoms.
Among the criteria that are needed to make a diagnosis of chronic obstructive pulmonary disease (COPD) are deficits in the rate at which one can forcefully exhale. Most experts consider a low ratio (<0.70) of the forced expiratory volume in 1 second (FEV
1
) to the forced vital capacity (FVC) after bronchodilator use to be a key diagnostic criterion.
1
Once the diagnosis of COPD has been established, the Global Initiative for Chronic Obstructive Lung Disease (GOLD) nomenclature grades severity according to the degree to which the measured FEV
1
is lower than the patient’s predicted value. GOLD stage 1, . . .
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