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Comprehensive gene expression profiles reveal pathways related to the pathogenesis of chronic obstructive pulmonary disease.

ABSTRACT: To better understand the molecular basis of chronic obstructive pulmonary disease (COPD), we used serial analysis of gene expression (SAGE) and microarray analysis to compare the gene expression patterns of lung tissues from COPD and control smokers. A total of 59,343 tags corresponding to 26,502 transcripts were sequenced in SAGE analyses. A total of 327 genes were differentially expressed (1.5-fold up- or down-regulated). Microarray analysis using the same RNA source detected 261 transcripts that were differentially expressed to a significant degree between GOLD-2 and GOLD-0 smokers. We confirmed the altered expression of a select number of genes by using real-time quantitative RT-PCR. These genes encode for transcription factors (EGR1 and FOS), growth factors or related proteins (CTGF, CYR61, CX3CL1, TGFB1, and PDGFRA), and extracellular matrix protein (COL1A1). Immunofluorescence studies on the same lung specimens localized the expression of Egr-1, CTGF, and Cyr61 to alveolar epithelial cells, airway epithelial cells, and stromal and inflammatory cells of GOLD-2 smokers. Cigarette smoke extract induced Egr-1 protein expression and increased Egr-1 DNA-binding activity in human lung fibroblast cells. Cytomix (tumor necrosis factor alpha, IL-1beta, and IFN-gamma) treatment showed that the activity of matrix metalloproteinase-2 (MMP-2) was increased in lung fibroblasts from EGR1 control (+/+) mice but not detected in that of EGR1 null (-/-) mice, whereas MMP-9 was regulated by EGR1 in a reverse manner. Our study represents the first comprehensive analysis of gene expression on GOLD-2 versus GOLD-0 smokers and reveals previously unreported candidate genes that may serve as potential molecular targets in COPD.

SUBMITTER: Ning W

PROVIDER: S-EPMC522001 | biostudies-literature | 2004 Oct

REPOSITORIES: biostudies-literature

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Comprehensive gene expression profiles reveal pathways related to the pathogenesis of chronic obstructive pulmonary disease.

Ning Wen W Li Chao-Jun CJ Kaminski Naftali N Feghali-Bostwick Carol A CA Alber Sean M SM Di Yuanpu P YP Otterbein Sherrie L SL Song Ruiping R Hayashi Shizu S Zhou Zhihong Z Pinsky David J DJ Watkins Simon C SC Pilewski Joseph M JM Sciurba Frank C FC Peters David G DG Hogg James C JC Choi Augustine M K AM

Proceedings of the National Academy of Sciences of the United States of America 20041005 41

To better understand the molecular basis of chronic obstructive pulmonary disease (COPD), we used serial analysis of gene expression (SAGE) and microarray analysis to compare the gene expression patterns of lung tissues from COPD and control smokers. A total of 59,343 tags corresponding to 26,502 transcripts were sequenced in SAGE analyses. A total of 327 genes were differentially expressed (1.5-fold up- or down-regulated). Microarray analysis using the same RNA source detected 261 transcripts t ...[more]

PMID: 15469929

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Project description:RationaleThe airflow limitation that defines severity of chronic obstructive pulmonary disease (COPD) is caused by a combination of small airway obstruction and emphysematous lung destruction.ObjectivesTo examine the hypothesis that small airway obstructive and emphysematous destructive lesions are produced by differential expression of genes associated with tissue repair.MethodsThe expression of 54 genes associated with repair of repetitively damaged tissue was measured in 136 paired samples of small bronchioles and surrounding lung tissue separated by laser capture microdissection. These samples were collected from 63 patients at different levels of disease severity who required surgery for either lung cancer or lung transplantation for very severe COPD. Gene expression was measured by quantitative polymerase chain reaction in these paired samples and compared with the FEV(1) by linear regression analysis.Measurements and main resultsAfter corrections for false discovery rates, only 2 of 10 genes (serpin peptidase inhibitor/plasminogen activator inhibitor member 2 and matrix metalloproteinase [MMP] 10) increased, whereas 8 (MMP2, integrin-alpha1, vascular endothelial growth factor, a disintegrin and metallopeptidase domain 33, scatter factor/hepatocyte growth factor, tissue inhibitor of matrix metalloproteinase-2, fibronectin, and collagen 3alpha1) decreased in small airways in association with FEV(1). In contrast, 8/12 genes (early growth response factor 1, MMP1, MMP9, MMP10, plasminogen activator urokinase, plasminogen activator urokinase receptor, tumor necrosis factor, and IL13) increased and 4/12 (MMP2, tissue inhibitor of matrix metalloproteinase-1, collagen 1alpha1, and transforming growth factor-beta3) decreased in the surrounding lung tissue in association with progression of COPD.ConclusionsThe progression of COPD is associated with the differential expression of a cluster of genes that favor the degradation of the tissue surrounding the small conducting airways.

Project description:BackgroundSarcopenia is characterized by the loss of skeletal muscle mass and strength and is associated with poor prognosis in patients with chronic obstructive pulmonary disease (COPD). Cigarette smoke (CS) exposure, a major cause for COPD, induces mitochondrial damage, which has been implicated in sarcopenia pathogenesis. The current study sought to examine the involvement of insufficient Parkin-mediated mitophagy, a mitochondrion-selective autophagy, in the mechanisms by which dysfunctional mitochondria accumulate with excessive reactive oxygen species (ROS) production in the development of COPD-related sarcopenia.MethodsThe involvement of Parkin-mediated mitophagy was examined using in vitro models of myotube formation, in vivo CS-exposure model using Parkin-/- mice, and human muscle samples from patients with COPD-related sarcopenia.ResultsCigarette smoke extract (CSE) induced myotube atrophy with concomitant 30% reduction in Parkin expression levels (P < 0.05). Parkin-mediated mitophagy regulated myotube atrophy by modulating mitochondrial damage and mitochondrial ROS production. Increased mitochondrial ROS was responsible for myotube atrophy by activating Muscle Ring Finger 1 (MuRF-1)-mediated myosin heavy chain (MHC) degradation. Parkin-/- mice with prolonged CS exposure showed enhanced limb muscle atrophy with a 31.7% reduction in limb muscle weights (P < 0.01) and 2.3 times greater MuRF-1 expression (P < 0.01) compared with wild-type mice with concomitant accumulation of damaged mitochondria and oxidative modifications in 4HNE expression. Patients with COPD-related sarcopenia exhibited significantly reduced Parkin but increased MuRF-1 protein levels (35% lower and 2.5 times greater protein levels compared with control patients, P < 0.01 and P < 0.05, respectively) and damaged mitochondria accumulation demonstrated in muscles. Electric pulse stimulation-induced muscle contraction prevented CSE-induced MHC reduction by maintaining Parkin levels in myotubes.ConclusionsTaken together, COPD-related sarcopenia can be attributed to insufficient Parkin-mediated mitophagy and increased mitochondrial ROS causing enhanced muscle atrophy through MuRF-1 activation, which may be at least partly preventable through optimal physical exercise.

Project description:BackgroundChronic obstructive pulmonary disease (COPD) pathogenesis is influenced by environmental factors, including Benzo(a)pyrene (BaP) exposure. This study aims to identify BaP-related toxicological targets and elucidate their roles in COPD development.MethodsA comprehensive bioinformatics approach was employed, including the retrieval of BaP-related targets from the Comparative Toxicogenomics Database (CTD) and Super-PRED database, identification of differentially expressed genes (DEGs) from the GSE76925 dataset, and protein-protein interaction (PPI) network analysis. Functional enrichment and immune infiltration analyses were conducted using GO, KEGG, and ssGSEA algorithms. Feature genes related to BaP exposure were identified using SVM-RFE, Lasso, and RF machine learning methods. A nomogram was constructed and validated for COPD risk prediction. Molecular docking was performed to evaluate the binding affinity of BaP with proteins encoded by the feature genes.ResultsWe identified 72 differentially expressed BaP-related toxicological targets in COPD. Functional enrichment analysis highlighted pathways related to oxidative stress and inflammation. Immune infiltration analysis revealed significant increases in B cells, DC, iDC, macrophages, T cells, T helper cells, Tcm, and TFH in COPD patients compared to controls. Correlation analysis showed strong links between oxidative stress, inflammation pathway scores, and the infiltration of immune cells, including aDC, macrophages, T cells, Th1 cells, and Th2 cells. Seven feature genes (ACE, APOE, CDK1, CTNNB1, GATA6, IRF1, SLC1A3) were identified across machine learning methods. A nomogram based on these genes showed high diagnostic accuracy and clinical utility. Molecular docking revealed the highest binding affinity of BaP with CDK1, suggestive of its pivotal role in BaP-induced COPD pathogenesis.ConclusionsThe study elucidates the molecular mechanisms of BaP-induced COPD, specifically highlighting the role of oxidative stress and inflammation pathways in promoting immune cell infiltration. The identified feature genes may serve as potential biomarkers and therapeutic targets. Additionally, the constructed nomogram demonstrates high accuracy in predicting COPD risk, providing a valuable tool for clinical application in BaP-exposed individuals.

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Comprehensive gene expression profiles reveal pathways related to the pathogenesis of chronic obstructive pulmonary disease.

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Comprehensive gene expression profiles reveal pathways related to the pathogenesis of chronic obstructive pulmonary disease.

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