Mucosal immune alterations at the early onset of tissue destruction in Chronic Obstructive Pulmonary Disease
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE239897 | GEO | 2023/10/09
REPOSITORIES: GEO
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Project description:Background: Chronic obstructive pulmonary disease (COPD) is a major risk factor for the development of lung adenocarcinoma (AC). AC often develops on underlying COPD, thus the differentiation of both entities by biomarker is challenging. Although survival of AC patients strongly depends on early diagnosis, a biomarker panel for AC detection and differentiation from COPD is still missing. Methods: Plasma samples from 176 patients with AC with or without underlying COPD, COPD patients, and hospital controls were analyzed using mass spectrometry-based proteomics. We performed univariate statistics and additionally evaluated machine learning algorithms regarding the differentiation of AC vs. COPD and AC with COPD vs. COPD. Results: Univariate statistics revealed significantly regulated proteins that were significantly regulated between the patient groups. Furthermore, Random forest classification yielded the best performance for differentiation of AC vs. COPD (area under the curve (AUC) 0.935) and AC with COPD vs. COPD (AUC 0.916). The most influential proteins were identified by permutation feature importance and compared to those identified by univariate testing. Conclusion: We demonstrate the great potential of machine learning for differentiation of highly similar disease entities and present a panel of biomarker candidates that should be considered for the development of a future biomarker panel.
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Project description:To profile airway and parenchyma transcriptomes in our mouse model of asthma chronic obstructive pulmonary disease overlap, we employed RNA-Seq (TruSeq Stranded mRNA sample preparation, NovaSeq 6000, 20 million 100 bp single reads) as a discovery tool to identify mRNAs of interest in the development of experimental asthma chronic obstructive pulmonary disease overlap. Experimental asthma: Some mice were sensitized and challenged intranasally with house dust mite (HDM) extract 5 days per week for 3 weeks. In other mice, this was HDM treatment 3 times/week from weeks 4-11. Controls received phosphate buffered saline (PBS). Experimental chronic obstructive pulmonary disease (COPD): Mice were exposed to cigarette smoke (CS) twice per day, 5 days per week for 8 weeks. Control mice were exposed to normal air (AIR). Experimental asthma-COPD overlap (ACO): Mice were sensitized and challenged intranasally with HDM or PBS. From weeks 4-11, mice were also exposed to CS or AIR. Treatment with dexamethasone (DEX): Separate groups of mice were treated with DEX during week 11. Lungs were excised, airway and parenchyma tissue were isolated through blunt dissection, and total RNA isolated.
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Project description:Purpose:To identify whether accelerated aging can be observed in the airways of PLWH with COPD, manifest by a unique DNA methylation signature. Methods: Bronchial epithelial brushings from PLWH with and without COPD and HIV-uninfected adults with and without COPD (n=76) were profiled for DNA methylation and gene expression. We evaluated global Alu and LINE-1 methylation and calculated the epigenetic age using the Horvath clock and the methylation telomere length estimator. To identify genome-wide differential DNA methylation and gene expression associated with HIV and COPD, robust linear models were used followed by an expression quantitative trait methylation (eQTM) analysis. Results:Epigenetic age acceleration and shorter methylation estimates of telomere length were found in PLWH with COPD compared to PLWH without COPD and uninfected patients with and without COPD. We identified CpG sites, genes, and eQTM-gene pairs associated with the interaction between HIV and COPD. Conclusions: Methylation age acceleration is observed in the airway epithelium of PLWH with COPD, a process that may be responsible for the heightened risk of COPD in this population. Their distinct methylation profile, differing from that observed in patients with COPD alone, suggests a unique pathogenesis to HIV-associated COPD that warrants investigation into the candidate genes identified.
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Project description:Purpose:To identify whether accelerated aging can be observed in the airways of PLWH with COPD, manifest by a unique DNA methylation signature. Methods: Bronchial epithelial brushings from PLWH with and without COPD and HIV-uninfected adults with and without COPD (n=76) were profiled for DNA methylation and gene expression. We evaluated global Alu and LINE-1 methylation and calculated the epigenetic age using the Horvath clock and the methylation telomere length estimator. To identify genome-wide differential DNA methylation and gene expression associated with HIV and COPD, robust linear models were used followed by an expression quantitative trait methylation (eQTM) analysis. Results:Epigenetic age acceleration and shorter methylation estimates of telomere length were found in PLWH with COPD compared to PLWH without COPD and uninfected patients with and without COPD. We identified CpG sites, genes, and eQTM-gene pairs associated with the interaction between HIV and COPD. Conclusions: Methylation age acceleration is observed in the airway epithelium of PLWH with COPD, a process that may be responsible for the heightened risk of COPD in this population. Their distinct methylation profile, differing from that observed in patients with COPD alone, suggests a unique pathogenesis to HIV-associated COPD that warrants investigation into the candidate genes identified.
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Project description:Background: Chronic obstructive pulmonary disease (COPD) is a heterogeneous disease characterized by varying degrees of emphysematous lung destruction and small airway disease, each with distinct effects on clinical outcomes. There is little known about how microRNAs contribute specifically to the emphysema phenotype. We examined how microRNA expression is altered with regional emphysema severity within the lung and how these microRNAs regulate disease-associated gene-expression networks. Results: We profiled microRNAs in different regions in the lung with varying degrees of emphysema from 6 smokers with COPD and 2 controls (8 regions x 8 lungs = 64 samples). 63 microRNAs (p<0.05) were altered with regional emphysema severity as quantified by mean linear intercept (Lm). MicroRNA and gene expression data were then integrated in the same samples. A subset of microRNAs, including miR-638, miR-30c, and miR-181d, correlated with many of their predicted gene targets, suggesting a role in regulating the gene networks that underlie emphysematous lung destruction. Modulating miR-638 expression in primary human lung fibroblasts recapitulated the alterations in its targeted gene-expression network associated with emphysema progression. Pathway analysis revealed that genes involved in oxidative stress and accelerated aging were affected by miR-638 knock-down in fibroblasts. Many miR-638 gene targets in these pathways were amongst those negatively correlated with miR-638 expression in emphysematous lung tissue. Conclusions: Our findings demonstrate that microRNAs are altered with regional emphysema severity and modulate disease-associated gene expression networks. Furthermore, miR-638 may regulate gene expression associated with the oxidative stress response and aging in emphysematous lung tissue and fibroblasts. Paired samples were obtained from 8 regions at regular intervals between the apex and base of each explanted lung from six patients with severe COPD and two donors. The degree of emphysematous destruction was quantified in one sample from each region by mean linear intercept (Lm), while microRNA expression was profiled in the adjacent sample from the same region using the NCode Version 3 microRNA microarrays (Invitrogen, Carlsbad, CA). After quality control 60 samples were used for the analysis.
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