Dataset Information

Proteomic study of potential emphysema biomarkers in blood plasma (EmphyseMARK-1)

ABSTRACT: We conducted a small cross-sectional proteomic study aiming to identify potential biomarkers of emphysema, as well as to identify COPD- and smoking-related biomarkers. This study was approved by the University Hospital Dubrava's Institutional Ethics Committee (approval no. 2022/2908‐05), as well as by the School of Medicine, University of Zagreb's Institutional Ethics Committee (approval no. 251-59-10106-24-111/119). This study included a total of 40 participants, divided into four equal age and gender-matched groups (N=10 participants per group): 1.) patients with COPD and radiologically verified emphysema on chest CT (CE group), confirmed by a radiologist, 2.) patients with COPD without radiological signs of emphysema on chest CT (CN group), confirmed by a radiologist, 3) healthy smokers (active smokers (>20 pack-years) without respiratory symptoms and normal spirometry) (HS group), 4) healthy never-smokers (without respiratory symptoms and with normal spirometry) (HN group). A graphic study outline is shown in Figure 1. Participants were included in the study in a non-probabilistic manner (in order to be age, gender, comorbidity and body mass index matched – so group homogeneity in these regards could be achieved). Patients with COPD (CE and CN groups) were GOLD 2B patients as defined by GOLD 2023, active smokers (>20 pack-years), on dual inhalation therapy (combination of long-acting β2 agonist (LABA) and long-acting muscarinic antagonist (LAMA)). Exclusion criteria were: reversible airflow limitation, positive bronchodilator test (either by the GINA criteria or by the ERS/ATS technical standard 2022; acute exacerbation of COPD in the last 6 months, concomitant malignancy, autoimmune disease or concomitant asthma, as well as alpha-1-antitrypsin deficiency. Patients that consumed tobacco products other than classical cigarettes (including e-cigarettes, heat not-burn tobacco products, vape, cigars and cigarillos) were also excluded from the study. None of the participants were taking glucocorticoids or other immunosuppressive medications. All subjects in the study signed an informed consent form. Comorbidities were assessed using the Charlson's comorbidity index and also a modified Charlson's comorbidity index in which “chronic pulmonary disease“ was excluded. The participants underwent spirometry testing and all COPD patients had a chest CT no older than 3 months prior to inclusion. Spirometry with a subsequent bronchodilator test (with 400mcg of salbutamol) was performed according to the international standards, using the Global Lung Initiative (GLI) reference values. Expiratory airflow limitation was determined using the proposed GOLD criteria with a fixed FEV1/FVC ratio of 0.7.

INSTRUMENT(S):

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Blood Plasma

DISEASE(S): Chronic Obstructive Pulmonary Disease

SUBMITTER: Václav Pustka

LAB HEAD: Zbynek Zdrahal

PROVIDER: PXD074107 | Pride | 2026-04-06

REPOSITORIES: Pride

ACCESS DATA

Dataset's files

Source:

			Action	DRS
	6810_HT4_DIA_RSLC_2col-110min_01_1_BA1_1_13772.d.zip	Other
	6810_HT4_DIA_RSLC_2col-110min_03_1_BA2_1_13817.d.zip	Other
	6810_HT4_DIA_RSLC_2col-110min_06_1_BA3_1_13766.d.zip	Other
	6810_HT4_DIA_RSLC_2col-110min_07_1_BA4_1_13811.d.zip	Other
	6810_HT4_DIA_RSLC_2col-110min_08_1_BA5_1_13823.d.zip	Other

Items per page:

1 - 5 of 47

Similar Datasets

Project description:Chronic obstructive pulmonary disease (COPD) is the fourth leading cause of death in the United States and the only leading cause of death that is steadily increasing in frequency. This project will establish a racially diverse cohort that is sufficiently large and appropriately designed for genome-wide association analysis of COPD. A total of 10,000 subjects will be recruited, including control smokers, definite COPD cases (GOLD Stage 2 to 4), and subjects not included in either group (GOLD 1 or GOLD-Unclassified). This cohort will be used for cross-sectional analysis, although long-term longitudinal follow-up will be a future goal. The primary focus of the study will be genome-wide association analysis to identify the genetic risk factors that determine susceptibility for COPD and COPD-related phenotypes. Detailed phenotyping of both cases and controls, including chest CT scan assessment of emphysema and airway disease, will allow identification of genetic determinants for the heterogeneous components of the COPD syndrome. The hypotheses to be studied are: 1) Precise phenotypic characterization of COPD subjects using computed tomography, as well as clinical and physiological measures, will provide data that will enable the broad COPD syndrome to be decomposed into clinically significant subtypes. 2) Genome-wide association studies will identify genetic determinants for COPD susceptibility that will provide insight into clinically relevant COPD subtypes. 3) Distinct genetic determinants influence the development of emphysema and airway disease. The initial phase of genome-wide association analysis included 500 COPD cases and 500 control subjects (all non-Hispanic White) genotyped with the Illumina Omni-1 chip. The second phase genotyped the entire study cohort using the Illumina Omni-Express chip. Unique aspects of the study include: 1) Inclusion of large numbers of African American subjects (approximately 1/3 of the cohort); 2) Obtaining chest CT scans (including inspiratory and expiratory images); and 3) Inclusion of the full range of disease severity. The COPDGene_v6 Cohort is utilized in the following dbGaP sub-studies. To view genotypes, other molecular data, and derived variables collected in these sub-studies, please click on the following sub-studies below or in the "Sub-studies" box located on the right hand side of this top-level study page phs000179 COPDGene_v6 Cohort. <ul> <li><a href="./study.cgi?study_id=phs000296">phs000296</a> ESP LungGO COPDGene</li> <li><a href="./study.cgi?study_id=phs000765">phs000765</a> COPDGene_Geno</li> </ul>

Project description:BACKGROUND: Chronic obstructive pulmonary disease (COPD) is a heterogeneous disease consisting of emphysema, small airway obstruction, and/or chronic bronchitis that results in significant loss of lung function over time. METHODS: In order to gain insights into the molecular pathways underlying progression of emphysema and explore computational strategies for identifying COPD therapeutics, we profiled gene expression in lung tissue samples obtained from regions within the same lung with varying amounts of emphysematous destruction from smokers with COPD (8 regions x 8 lungs = 64 samples). Regional emphysema severity was quantified in each tissue sample using the mean linear intercept (Lm) between alveolar walls from micro-CT scans. RESULTS: We identified 127 genes whose expression levels were significantly associated with regional emphysema severity while controlling for gene expression differences between individuals. Genes increasing in expression with increasing emphysematous destruction included those involved in inflammation, such as the B-cell receptor signaling pathway, while genes decreasing in expression were enriched in tissue repair processes, including the transforming growth factor beta (TGF beta) pathway, actin organization, and integrin signaling. We found concordant differential expression of these emphysema severity-associated genes in four cross-sectional studies of COPD. Using the Connectivity Map, we identified GHK as a compound that can reverse the gene-expression signature associated with emphysematous destruction and induce expression patterns consistent with TGF beta pathway activation. Treatment of human fibroblasts with GHK recapitulated TGF beta-induced gene-expression patterns, led to the organization of the actin cytoskeleton, and elevated the expression of integrin beta1. Furthermore, addition of GHK or TGF beta restored collagen I contraction and remodeling by fibroblasts derived from COPD lungs compared to fibroblasts from former smokers without COPD. CONCLUSIONS: These results demonstrate that gene-expression changes associated with regional emphysema severity within an individual¿s lung can provide insights into emphysema pathogenesis and identify novel therapeutic opportunities for this deadly disease. They also suggest the need for additional studies to examine the mechanisms by which TGF beta and GHK each reverse the gene-expression signature of emphysematous destruction and the effects of this reversal on disease progression.

Project description:Chronic obstructive pulmonary disease (COPD) is one of the most prevalent lung diseases, and involves persistent airflow limitation and incorporates both emphysema and chronic bronchitis. Cigarette smoking has been identified as the main risk factor for disease development and progression. In a basic model of COPD, the disease is initiated when the physiologic response mechanisms to cigarette smoke exposure are overwhelmed; for example, because of long-term exposure effects or other aging-related changes. In this parallel-group case-controlled clinical study we asked to what extent the different transitions in a chronic-exposure-to-disease model are reflected in the proteome and cellular transcriptome of induced sputum samples from the lung. For this, we selected 60 age- and gender-matched individuals for each of four study groups: current healthy smokers, current-smoker COPD patients, former smokers, and never smokers (a total of 240 individuals). Induced sputum was collected, the cell-free supernatant was analyzed by quantitative proteomics (isobaric-tag based), and the cellular mRNA fraction was analyzed by microarray-based expression profiling. The sputum proteome of current smokers (healthy or COPD patients) clearly reflected the common physiological responses to smoke exposure, including alterations in mucin/trefoil proteins (e.g., MUC5AC and TFF1/3up-regulation), peptidase regulators (e.g., TIMP1 up-regulation), and a prominent xenobiotic/oxidative stress response (e.g., NQO1 and ALDH3A1 up-regulation). The latter response also was observed in the sputum transcriptome, which additionally demonstrated an immune-related polarization change (toward a M2 signature). The (long-term) former smoker group showed nearly complete reversal of the observable biological effects. Thirteen differentially abundant proteins between the COPD and healthy smoker groups were identified. These abundant proteins included previously reported COPD-associated proteins (e.g., TIMP1 (up-regulation) and APOA1 (down-regulation)) and novel proteins such as C6orf58 and BPIFB1 (LPLUNC1) (both up-regulated in the COPD group compared with the healthy smokers). In summary, our study demonstrates that sputum proteomics/transcriptomics can capture the complex and reversible physiological response to cigarette smoke exposure, which appears to be only slightly modulated in early-stage COPD patients. The study has been registered on ClinicalTrials.gov with identifier NCT01780298.

Project description:BACKGROUND: Chronic obstructive pulmonary disease (COPD) is a heterogeneous disease consisting of emphysema, small airway obstruction, and/or chronic bronchitis that results in significant loss of lung function over time. METHODS: In order to gain insights into the molecular pathways underlying progression of emphysema and explore computational strategies for identifying COPD therapeutics, we profiled gene expression in lung tissue samples obtained from regions within the same lung with varying amounts of emphysematous destruction from smokers with COPD (8 regions x 8 lungs = 64 samples). Regional emphysema severity was quantified in each tissue sample using the mean linear intercept (Lm) between alveolar walls from micro-CT scans. RESULTS: We identified 127 genes whose expression levels were significantly associated with regional emphysema severity while controlling for gene expression differences between individuals. Genes increasing in expression with increasing emphysematous destruction included those involved in inflammation, such as the B-cell receptor signaling pathway, while genes decreasing in expression were enriched in tissue repair processes, including the transforming growth factor beta (TGF beta) pathway, actin organization, and integrin signaling. We found concordant differential expression of these emphysema severity-associated genes in four cross-sectional studies of COPD. Using the Connectivity Map, we identified GHK as a compound that can reverse the gene-expression signature associated with emphysematous destruction and induce expression patterns consistent with TGF beta pathway activation. Treatment of human fibroblasts with GHK recapitulated TGF beta-induced gene-expression patterns, led to the organization of the actin cytoskeleton, and elevated the expression of integrin beta1. Furthermore, addition of GHK or TGF beta restored collagen I contraction and remodeling by fibroblasts derived from COPD lungs compared to fibroblasts from former smokers without COPD. CONCLUSIONS: These results demonstrate that gene-expression changes associated with regional emphysema severity within an individualÂ¿s lung can provide insights into emphysema pathogenesis and identify novel therapeutic opportunities for this deadly disease. They also suggest the need for additional studies to examine the mechanisms by which TGF beta and GHK each reverse the gene-expression signature of emphysematous destruction and the effects of this reversal on disease progression. 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 gene expression was profiled in the adjacent sample from the same region using the Affymetrix Human Exon 1.0 ST GeneChip. Human fibroblast cell lines (HLF-1) were treated with GHK or TGF-Beta1 for 48 hours and profiled using the Affymetrix Human Gene 1.0 ST GeneChip.

Dataset Information

Proteomic study of potential emphysema biomarkers in blood plasma (EmphyseMARK-1)

Dataset's files

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets