Metabolomics,Unknown,Transcriptomics,Genomics,Proteomics

Dataset Information

COPD-Specific Gene Expression Signatures of Alveolar Macrophages as well as Peripheral Blood Monocytes Overlap and Correlate with Lung Function

ABSTRACT: Rationale: Chronic Obstructive Pulmonary Disease (COPD) is considered a chronic inflammatory disease characterized by progressive airflow limitation and also has significant extrapulmonary (systemic) effects that lead to comorbid conditions. Very little is known about the pathomechanism of the disease. Objectives: Among inflammatory cell types, alveolar macrophages appear to have a key role in initiating and/or sustaining disease progression. These cells are derived from peripheral monocytes. Identification of disease and cell type specific gene expression profiles can be revealing and also practically useful in order to diagnose and characterize disease progression and the effect of drug treatment. Methods: We used Affymetrix microarrays to obtain gene expression data of alveolar macrophages and circulating monocytes of COPD and healthy control patients. The microarray results were confirmed by quantitative real-time polymerase chain reaction in multiple patient collections. Measurements and Main Results: We have identified gene sets specifically associated with COPD in alveolar macrophages and also in monocytes. Immune function, responses to stimuli, and cell death related genes appear to be impacted in both cell types. Remarkably, there is an overlapping gene set between the two cell types. Conclusions: Taken together, our data show that COPD-specific gene signatures can be identified and validated, and that the disease also affects peripheral monocytes. Moreover, monocytes and alveolar macrophages carry overlapping gene expression signatures. Our findings further support the notion that altered responsiveness to stimuli is the key characteristic of alveolar macrophages and also of their precursors, peripheral monocytes. Brochoalveolar lavage fluid samples were collected from of COPD and healthy control patients. Alveolar macrophages were isolated using Percoll gradient centrifugation, isolated using CD14+ magnetic beads, and total RNA was extracted using Qiagen RNeasy Kit. The monocyte samples represent a pool of RNA from 5 patients. Total RNA was labeled with biotin and individual samples were hybridized to Affymetrix HG U133A GeneChips. Affymetrix data files were analyzed using GeneSpring 7.3 software. Using a non-parametric statistical test, we compared the gene expression patterns of the COPD and the healthy control patients and identified a set a genes that showed differential expression between the two groups.

ORGANISM(S): Homo sapiens

SUBMITTER: Szilard Poliska

PROVIDER: E-GEOD-16972 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Chronic obstructive pulmonary disease-specific gene expression signatures of alveolar macrophages as well as peripheral blood monocytes overlap and correlate with lung function.

Poliska Szilard S Csanky Eszter E Szanto Attila A Szatmari Istvan I Mesko Bertalan B Szeles Lajos L Dezso Balazs B Scholtz Beata B Podani Janos J Kilty Iain I Takacs Laszlo L Nagy Laszlo L

Respiration; international review of thoracic diseases 20110323 6

<h4>Background</h4>Chronic obstructive pulmonary disease (COPD) is a chronic inflammatory disease characterized by progressive airflow limitation and significant extrapulmonary (systemic) effects that lead to co-morbid conditions, though the pathomechanism of COPD is largely undetermined. Alveolar macrophages (AM) derived from peripheral monocytes (MO) appear to play a key role in initiating and/or sustaining disease progression.<h4>Objectives</h4>To identify disease- and cell type-specific gene ...[more]

PMID: 21430361

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Project description:Cigarette smoking is the leading cause of the respiratory diseases collectively known as chronic obstructive pulmonary disease (COPD). While the pathogenesis of COPD is complex, there is abundant evidence that alveolar macrophages (AM) play an important role. Based on the concept that COPD is a slow-progressing disorder likely involving multiple mediators released by AM activated by cigarette smoke, the present study focuses on the identification of previously unrecognized genes that may be linked to early events in the molecular pathogenesis of COPD, as opposed to factors associated with the presence of disease. To accomplish this, microarray analysis using Affymetrix microarrays was used to carry out an unbiased survey of the differences in gene expression profiles in the AM of phenotypically normal, ~20 pack-yr smokers compared to healthy non-smokers. Although smoking did not alter the global gene expression pattern of AM, 75 genes were modulated by smoking, with 40 genes up-regulated and 35 down-regulated in the AM of smokers compared to non-smokers. Most of these genes belong to the functional categories of immune/inflammatory response, cell adhesion and extracellular matrix, proteolysis and antiproteolysis, lysosomal function, antioxidant-related, signal transduction and regulation of transcription. Of these 75 genes, 69 have not been previously recognized to be up- or down-regulated in alveolar macrophages in association with smoking or COPD, including genes coding for proteins belonging to all of the above categories, and others belonging to various functional categories or of unknown function. These observations suggest that gene expression responses of alveolar macrophages associated with the stress of cigarette smoking are more complex than previously thought, and offer a variety of new insights into the complex pathogenesis of smoking-induced lung diseases. Experiment Overall Design: 5 non smokers and 5 smokers Experiment Overall Design: Alveolar macrophages were obtained from bronchoalveolar lavage

Project description:Background: When exposed to specific stimuli, macrophages exhibit distinct activation programs, M1 and M2 polarization, that define macrophage function as inflammatory/immune effectors or anti-inflammatory/tissue remodeling cells, respectively. Due to their position on the lung epithelial surface, alveolar macrophages (AM) directly interact with environmental stimuli such as cigarette smoke, the major risk factor for the development of chronic obstructive pulmonary disease (COPD). Based on the current paradigm that, in response to smoking, AM contribute to both inflammatory and tissue remodeling processes in the lung relevant to the pathogenesis of COPD, we hypothesized that chronic exposure to cigarette smoking activates both the M1 and M2 polarization programs in AM. Methods and Findings: To assess this hypothesis, global transcriptional profiling with TaqMan confirmation and flow cytometry analysis was carried out on AM obtained by bronchoalveolar lavage of 24 healthy nonsmokers, 34 healthy smokers and 12 smokers with COPD to assess the expression of 41 M1 genes and 32 M2 genes in each group. Contrary to our expectations, while there was up-regulation of some genes typical for M2-related phenotypes, AM of healthy smokers exhibited substantial suppression of M1-related inflammatory/immune genes. These M1- and M2-related changes progressed with the development of smoking-induced lung disease, with AM of smokers with COPD exhibiting further down-regulation of M1-related genes accompanied with further up-regulation of some M2-related genes. Conclusion: The data demonstrates that the modifications of the AM transcriptome associated with smoking result in a unique phenotype characterized by reprogramming of AM towards M1-deactivated partially M2-polarized macrophages and suggests that, while AM likely contribute to smoking-induced tissue remodeling, the role of AM in the early pathogenesis of smoking-induced COPD in humans is not inflammatory. This concept is a departure from the conventional concept that AM-mediated inflammation participates in the early derangements of the lung induced by smoking, and suggests a novel paradigm for conceptualizing COPD and developing new approaches to prevent the development of smoking-induced lung disease. Comparison of gene expression in alveolar macrophages of normal non-smokers and normal smokers and smokers with COPD

Project description:Disparate Oxidant-related Gene Expression of Human Small Airway Epithelium Compared to Autologous Alveolar Macrophages in Response to the In Vivo Oxidant Stress of Cigarette Smoking The oxidant burden of cigarette smoking induces lung cell dysfunction, and play a significant role in the pathogenesis of lung disease. Two cell populations directly exposed to the oxidants in cigarette smoke are the small airway epithelium and alveolar macrophages. Of these, the epithelium appears to be more vulnerable to smoking, becoming disordered in differentiation, repair and function, while alveolar macrophages become activated, without becoming diseased. In this context, we asked: for the same individuals, what is the baseline trancriptome of oxidant-related genes in small airway epithelium compared to alveolar macrophages and do the responses of the transcriptome of these 2 cell populations differ substantially to inhaled cigarette smoke? To address these questions we used microarray gene expression and TaqMan analysis to assess the gene expression profile of known oxidant-related genes in paired samples recovered by bronchoscopy from small airway epithelium and alveolar macrophages from the same healthy nonsmokers and normal smokers. Of the 155 oxidant-related genes surveyed, 122 (77%) were expressed in both cell populations in nonsmokers. However, of the genes expressed by both cell populations, oxidant related gene expression levels were higher in alveolar macrophages (67 genes, 43%) than small airway epithelium (37 genes, 24%). There were more oxidant-related genes uniquely expressed in the small airway epithelium (17%), than in alveolar macrophages (5%). In healthy smokers, the majority of oxidant-related genes were expressed in both cell populations, but there were marked differences in the numbers of oxidant-related genes that smoking up- or down-regulated. While smoking up-regulated 15 genes (10%) and down-regulated 7 genes (5%) in the small airway epithelium, smoking had far less effect on alveolar macrophages [only 4 (3%) genes up-regulated, and only 1 (0.6%) down-regulated]. Only a small number of smoking responsive oxidant-related genes overlapped between the two cell types (2 up-regulated, and no down-regulated genes). Consistent with this observation, pathway analysis of smoking-responsive genes in the small airway epithelium showed oxidant-related pathways dominated, but in alveolar macrophages immune-response pathways dominated. Thus, the responses of the oxidant-related transcriptome of cells with an identical genome and exposed to the same oxidant stress of cigarette smoking are very different, with responses of oxidant-related genes of alveolar macrophages far more subdued than that of small airway epithelium, consistent with the clinical observation that, while the small airway epithelium is vulnerable, alveolar macrophages are not "diseased" in response to the oxidant stress of cigarette smoking. Gene expression profiles of known oxidant-related genes in paired samples recovered by bronchoscopy from small airway epithelium and alveolar macrophages from the same healthy nonsmokers and normal smokers.

Project description:Macrophage activation is associated with profound transcriptional reprogramming. Although much progress has been made in the understanding of macrophage activation, polarization and function, the transcriptional programs regulating these processes remain poorly characterized. We stimulated human macrophages with diverse activation signals, acquiring a dataset of 299 macrophage transcriptomes. Analysis of this dataset revealed a spectrum of macrophage activation states extending the current M1 versus M2-polarization model. Network analyses identified central transcriptional regulators associated with all macrophage activation complemented by regulators related to stimulus-specific programs. Applying these transcriptional programs to human alveolar macrophages from smokers and patients with chronic obstructive pulmonary disease (COPD) revealed an unexpected loss of inflammatory signatures in COPD patients. Finally, by integrating murine data from the ImmGen project we propose a refined, activation-independent core signature for human and murine macrophages. This resource serves as a framework for future research into regulation of macrophage activation in health and disease. Illumina: To better understand the transcriptional program of human macrophages a set of different stimuli were used to activate and differentiate human macrophages in vitro. These macrophages were then assessed by transcriptomics and analyzed by different approaches using gene co-regulation analysis, SOM-clustering, hierarchical clustering, reverse network engineering and statistical models such as ANOVA. Affymetrix: To understand the relationship of in vivo macrophages with in vitro stimulations, two alveaolar macrophage datasets GSE13896 (COPD patients, smokers and non-smokers) and GSE2125 (asthmatic patients, smokers and non-smokers) were downloaded and processed together. In total, the combined dataset consists of 12 COPD samples, 15 asthmatic, 49 smoker samples and 39 non-smokers as control. Clustering of the samples (such as correlation network, principal component analysis and hierarchical clustering) and Gene Set Enrichment Analysis was performed on differentially expressed genes from 28 in vitro conditions.

Dataset Information

COPD-Specific Gene Expression Signatures of Alveolar Macrophages as well as Peripheral Blood Monocytes Overlap and Correlate with Lung Function

Publications

Chronic obstructive pulmonary disease-specific gene expression signatures of alveolar macrophages as well as peripheral blood monocytes overlap and correlate with lung function.

Similar Datasets

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