Reversal of emphysema by restoration of pulmonary endothelial cells
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA589628 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR10446900.fastq.gz | Fastqsanger.gz | |||
| SRR10446901.fastq.gz | Fastqsanger.gz | |||
| SRR10446890.fastq.gz | Fastqsanger.gz | |||
| SRR10446891.fastq.gz | Fastqsanger.gz | |||
| SRR10446892.fastq.gz | Fastqsanger.gz |
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Project description:Chronic obstructive pulmonary disease (COPD) is a heterogenous disorder marked by small airway inflammation and distal airspace enlargement (emphysema) leading to progressive airflow obstruction and eventual respiratory failure. Current therapies are limited in their ability to halt the pathogenesis of COPD merely relieving symptoms of dyspnea and airflow limitation. Microvasculature dysfunction, an understudied area of investigation, is associated with the severity of COPD. However, it is not known if abnormal lung endothelium drives COPD pathology and/or if correcting endothelial dysfunction has therapeutic potential. Here, we show the centrality of specialized pulmonary endothelial cells to lung pathogenesis in an elastase-induced murine model of COPD. Airspace disease was marked by aberrant endothelial cell loss and dysfunction, which was rescued by intravenous delivery of healthy lung endothelial cells. Airspace injury triggered regulation of a distinct module of maladaptive endothelial transcripts comprising lost endothelial cell function. Endothelial leucine-rich alpha-2-glycoprotein-1 (LRG1) was identified as a key driver of the emphysematous pathology and selective deletion of Lrg1 from endothelial cells rescued elastase-induced defects of pulmonary parenchymal destruction. Hence, targeting lung endothelial cell biology through regenerative methods and/or inhibition of the LRG1 pathway may represent novel therapeutic strategies of immense potential for the treatment of emphysema.
2021-06-22 | GSE140413 | GEO
Project description:Chronic obstructive pulmonary disease (COPD) is marked by airway inflammation and airspace enlargement (emphysema) leading to airflow obstruction and eventual respiratory failure. Microvasculature dysfunction is associated with COPD/emphysema. However, it is not known if abnormal endothelium drives COPD/emphysema pathology and/or if correcting endothelial dysfunction has therapeutic potential. Here, we show the centrality of endothelial cells to the pathogenesis of COPD/emphysema in human tissue and using an elastase-induced murine model of emphysema. Airspace disease showed significant endothelial cell loss, and transcriptional profiling suggested an apoptotic, angiogenic, and inflammatory state. This alveolar destruction was rescued by intravenous delivery of healthy lung endothelial cells. Leucine-rich α-2-glycoprotein-1 (LRG1) was a driver of emphysema, and deletion of Lrg1 from endothelial cells rescued vascular rarefaction and alveolar regression. Hence, targeting endothelial cell biology through regenerative methods and/or inhibition of the LRG1 pathway may represent strategies of immense potential for the treatment of COPD/emphysema.
| S-EPMC8298104 | biostudies-literature
Project description:Lung diseases develop when telomeres are shortened beyond a critical point. We have constructed a mouse model in which the catalytic subunit of telomerase (mTert), or its catalytically inactive form (mTertCI), is expressed from the p21Cdkn1a promoter. We found that this particular expression of mTert reduces senescence of endothelial cells (EC) in lungs of aged mice, as well as emphysema and pulmonary perivascular fibrosis. We also show that mTert counteracts the decline in capillary density in aged mice and promotes the maintenance of high numbers of Cd34+ cells, identified as a subclass of endothelial cells with proliferative capacity. In line with these results, young p21+/Tert mice treated with a VEGF receptor inhibitor combined with hypoxia are also protected against senescence and emphysema induced by this treatment. The catalytic activity of mTert is required for all the effects observed. However, and unexpectedly, we found that both mTert and mTertCI expression significantly reduced p21 levels in the lungs of aged mice. mTert thus protects against age-related and induced loss of capillary vessels and subsequent lung emphysema.
2023-06-29 | GSE165218 | GEO
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.
2012-09-11 | GSE27597 | GEO
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. 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.
2012-09-11 | E-GEOD-27597 | biostudies-arrayexpress
Project description:The purpose of this study is to comprehensively elucidate the role of nitric oxide and nitric oxide synthase isoforms in pulmonary emphysema using cap analysis of gene expression (CAGE) sequencing.
2021-01-18 | GSE164521 | GEO
Project description:Combined pulmonary fibrosis and emphysema (CPFE) is characterized by upper-lobe emphysema combined with lower-lobe fibrosis and a high prevalence of pulmonary hypertension. The aim of this study was to measure and analyze gene expression profiles in the lungs of CPFE patients. The results showed that the expression profiles of the fibrotic and emphysematous lesions were remarkably different in terms of function. Genes related to immune system, structural constituents of cytoskeleton, and cellular adhesion were overexpressed in fibrotic lesions, while genes associated with cellular fraction, cell membrane structures, vascular growth and biology, second-messenger-mediated signaling, and lung development (all processes that contribute to the destruction and repair of cells, vessels, and lung) were overexpressed in emphysematous lesions. The differences in gene expression were detected in fibrotic and emphysematous lesions in CPFE patients. We propose that the development of coexisted fibrotic and emphysematous lesions in CPFE is implemented by these different patterns of gene expressions. Lung tissue specimens from fibrous lesions and emphysematous lesions of 3 patients with combined pulmonary fibrosis and emphysema (CPFE) were obtained for RNA extraction and hybridization on Affymetrix microarrays. We hypothesized that coexisted fibrosis and emphysema in CPFE are programmed by differential gene expressions in the corresponding lesions in the lungs of smokers susceptible to CPFE. Given the importance of genetic susceptibility in understanding the etiology and pathogenesis of CPFE, we examined tissues from patients with CPFE to systemically identify genes significantly expressed in lung tissues with fibrotic lesions as well as genes significantly expressed in tissues with emphysematous lesions.
2012-06-26 | E-GEOD-38934 | biostudies-arrayexpress
Project description:Patients with chronic obstructive pulmonary disease (COPD) having higher blood eosinophil levels exhibit worse lung function and more severe emphysema, implying the potential role of eosinophils in emphysema development. However, the specific mechanism underlying eosinophil-mediated emphysema development is not fully elucidated. In this study, single-cell RNA sequencing was used to identify eosinophil subgroups in mouse models of asthma and emphysema and analyze their functions. Analysis of the accumulated eosinophils revealed differential transcriptomes between the mouse lungs of elastase-induced emphysema and ovalbumin-induced asthma., Eosinophil depletion alleviated elastase-induced emphysema. Notably, eosinophil-derived cathepsin L (CTSL) degraded the extracellular matrix (ECM), causing emphysema in the pulmonary tissue. Eosinophils were positively correlated with serum CTSL levels, which were increased in patients with emphysema than in those without emphysema. Collectively, these results suggest that CTSL expression in eosinophils plays an important role in ECM degradation and remodeling and is related to emphysema in patients with COPD. Therefore, eosinophil-derived CTSL may serve as a potential therapeutic target for patients with emphysema.
2023-10-17 | GSE237749 | GEO
Project description:Dysregulated myogenesis and autophagy in genetically induced pulmonary emphysema
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Project description:Comparison of severely emphysematous tissue removed at lung volume reduction surgery to that of normal or mildly emphysematous lung tissue resected from smokers with nodules suspicious for lung cancer. Data obtained from the 18 patients with severe emphysema and 12 patients with mild/no emphysema. Research may provide insights into the pathogenetic mechanisms involved in chronic obstructive pulmonary disease (COPD).
2007-08-13 | E-GEOD-1650 | biostudies-arrayexpress