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A gene expression signature of emphysema-related lung destruction and its reversal by the tripeptide GHK.

ABSTRACT: 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.

ORGANISM(S): Homo sapiens

SUBMITTER: Joshua Campbell

PROVIDER: E-GEOD-27597 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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A gene expression signature of emphysema-related lung destruction and its reversal by the tripeptide GHK.

Campbell Joshua D JD McDonough John E JE Zeskind Julie E JE Hackett Tillie L TL Pechkovsky Dmitri V DV Brandsma Corry-Anke CA Suzuki Masaru M Gosselink John V JV Liu Gang G Alekseyev Yuriy O YO Xiao Ji J Zhang Xiaohui X Hayashi Shizu S Cooper Joel D JD Timens Wim W Postma Dirkje S DS Knight Darryl A DA Lenburg Marc E ME Hogg James C JC Spira Avrum A

Genome medicine 20120831 8

<h4>Background</h4>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.<h4>Methods</h4>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 ...[more]

PMID: 22937864

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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: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.

Dataset Information

A gene expression signature of emphysema-related lung destruction and its reversal by the tripeptide GHK.

Publications

A gene expression signature of emphysema-related lung destruction and its reversal by the tripeptide GHK.

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