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Identification of novel target genes in human lung tissue involved in chronic obstructive pulmonary disease.

ABSTRACT: Introduction:As part of a study aimed at illuminating at least some of the complex molecular events taking place in COPD, we screened tissues by means of transcriptome analyses. Materials and methods:Tissues were subjected to transcriptome analysis. Candidate genes were identified and validated by immunohistochemistry. Primary human lung cells were subjected to stimulation with cigarette smoke extract for further validation by real time PCR. Results:Six candidate genes were selected for further investigations: Aquaporin 3 (AQP3), extracellular matrix protein 1 (ECM1), four and a half LIM domain 1 (FHL1), milk fat globule epidermal growth factor 8 (MFGE8, lactadherin), phosphodiesterase 4D-interacting protein (PDE4DIP), and creatine transporter SLC6A8. All six proteins were allocated to distinct cell types by immunohistochemistry. Upon stimulation with cigarette smoke extract, human type II pneumocytes showed a dose-dependent down-regulation of MFGE8, while ECM1 and FHL1 also tended to be down-regulated. Although present, none of the candidates was regulated by cigarette smoke extract in primary human macrophages. Discussion:MFGE8 turned out to be an interesting new candidate gene in COPD deserving further studies.

SUBMITTER: Heinbockel L

PROVIDER: S-EPMC6065552 | biostudies-other | 2018

REPOSITORIES: biostudies-other

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Identification of novel target genes in human lung tissue involved in chronic obstructive pulmonary disease.

Heinbockel Lena L Marwitz Sebastian S Schromm Andra B AB Watz Henrik H Kugler Christian C Ammerpohl Ole O Schnepf Karoline K Rabe Klaus F KF Droemann Daniel D Goldmann Torsten T

International journal of chronic obstructive pulmonary disease 20180726

<h4>Introduction</h4>As part of a study aimed at illuminating at least some of the complex molecular events taking place in COPD, we screened tissues by means of transcriptome analyses.<h4>Materials and methods</h4>Tissues were subjected to transcriptome analysis. Candidate genes were identified and validated by immunohistochemistry. Primary human lung cells were subjected to stimulation with cigarette smoke extract for further validation by real time PCR.<h4>Results</h4>Six candidate genes were ...[more]

PMID: 30100715

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Project description:BACKGROUND:Oral taxa are often found in the chronic obstructive pulmonary disease (COPD) lung microbiota, but it is not clear if this is due to a physiologic process such as aspiration or experimental contamination at the time of specimen collection. METHODS:Microbiota samples were obtained from nine subjects with mild or moderate COPD by swabbing lung tissue and upper airway sites during lung lobectomy. Lung specimens were not contaminated with upper airway taxa since they were obtained surgically. The microbiota were analyzed with 16S rRNA gene qPCR and 16S rRNA gene hypervariable region 3 (V3) sequencing. Data analyses were performed using QIIME, SourceTracker, and R. RESULTS:Streptococcus was the most common genus in the oral, bronchial, and lung tissue samples, and multiple other taxa were present in both the upper and lower airways. Each subject's own bronchial and lung tissue microbiota were more similar to each other than were the bronchial and lung tissue microbiota of two different subjects (permutation test, p?=?0.0139), indicating more within-subject similarity than between-subject similarity at these two lung sites. Principal coordinate analysis of all subject samples revealed clustering by anatomic sampling site (PERMANOVA, p?=?0.001), but not by subject. SourceTracker analysis found that the sources of the lung tissue microbiota were 21.1% (mean) oral microbiota, 8.7% nasal microbiota, and 70.1% unknown. An analysis using the neutral theory of community ecology revealed that the lung tissue microbiota closely reflects the bronchial, oral, and nasal microbiota (immigration parameter estimates 0.69, 0.62, and 0.74, respectively), with some evidence of ecologic drift occurring in the lung tissue. CONCLUSION:This is the first study to evaluate the mild-moderate COPD lung tissue microbiota without potential for upper airway contamination of the lung samples. In our small study of subjects with COPD, we found oral and nasal bacteria in the lung tissue microbiota, confirming that aspiration is a source of the COPD lung microbiota.

Project description:Multiple gene expression studies have been performed in lung or airway tissues from subjects with chronic obstructive pulmonary disease (COPD). However, in comparison to genome-wide association studies (GWAS), there has been poor replication across these studies. We sought to perform gene expression profiling on a large sample of severe COPD cases and control smokers and use network methods to identify interacting genes and pathways. We collected surgically-resected lung tissue samples from subjects with severe COPD and controls with normal lung function; all subjects were former smokers. Gene expression profiling on homogenized lung tissue was performed using Illumina HumanHT-12 BeadChips. Protein and RNA binding studies, RNA-interference, a murine smoking model, and expression quantitative trait locus analyses were used to identify genes and proteins that may interact with three known COPD GWAS genes: IREB2, HHIP and FAM13A. Weighted Gene Co-Expression Network Analysis (WGCNA) was used to define co-expressed gene modules. Comparing 111 COPD cases and 40 control smokers, 214 genes were differentially expressed; none of these genes were at significant GWAS loci. However, the top differentially expressed gene was HMGB1, which interacts with AGER, a gene implicated through COPD GWAS. The genes differentially expressed in lung tissue showed strong enrichment for putative interactors of IREB2 and HHIP, with less support for FAM13A, based on the gene sets from the in vitro, in vivo, and in silico studies. In the WGCNA, the module most highly associated for COPD was enriched for B-cell pathways, which shared seventeen genes with the results of the Hhip+/- mouse smoking model. As in other common diseases, genes at COPD GWAS loci were not differentially expressed with COPD status; however, using a combination of network methods, experimental studies of interaction and careful phenotype definition, we found differential expression of putative interactors of these genes, and we replicated previous human and mouse microarray results involving B cell pathways.

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.

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Identification of novel target genes in human lung tissue involved in chronic obstructive pulmonary disease.

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Identification of novel target genes in human lung tissue involved in chronic obstructive pulmonary disease.

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