CoChat
Sign Up
Cited by 128Chronic Obstructive Pulmonary Disease (COPD) ResearchInterstitial Lung Diseases and Idiopathic Pulmonary FibrosisAsthma and respiratory diseases

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

Open access
Campbell, Joshua D, McDonough, John E, Zeskind, Julie E, Hackett, Tillie L, Pechkovsky, Dmitri V, Brandsma, Corry-Anke, Suzuki, Masaru, Gosselink, John V +12 more·2012·Genome Medicine
DOI 10.1186/gm367PMC PMC4064320
Open this paper in CoChat — free accountOpen PDF

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 × 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 (TGFβ) 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 TGFβ pathway activation. Treatment of human fibroblasts with GHK recapitulated TGFβ-induced gene-expression patterns, led to the organization of the actin cytoskeleton, and elevated the expression of integrin β1. Furthermore, addition of GHK or TGFβ 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 TGFβ and GHK each reverse the gene-expression signature of emphysematous destruction and the effects of this reversal on disease progression.

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

Integrity signals

Registry

Crossref · 10.1186/gm367

Cites

55 of 55 references verified0 citation errors · 0 not checkable

Statistics

Claims the paper makes

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

  • With addition of GHK, expression of pro-inflammatory genes in COPD lung tissue was reduced and expression of repair genes was restored.

    “Using the cMap, it was demonstrated that with addition of GHK the expression of pro-inflammatory genes in COPD lung tissue was reduced and the expression of repair genes was restored.”

    From GHK-Cu may Prevent Oxidative Stress in Skin by Regulating Copper and Modifying Expression of Numerous Antioxidant Genes (2015) · cites this paper as [19]

    The Results (Prediction of novel therapeutics for emphysema; page unavailable) show that GHK induced genes whose expression falls with increasing emphysema severity, supporting the repair-related portion of the claim. But the Connectivity Map analysis identified a potential reversal of the disease signature; the reported GHK treatment experiments used human lung fibroblasts, not COPD lung tissue, and do not demonstrate reduced pro-inflammatory gene expression in that tissue. (LLM, conf=0.88)

    Experimental — accuracy not yet measured

  • The COPD study (Campbell et al.) is the most representative because its gene signatures were derived from areas with histologically confirmed pathology, GHK's effects on affected lung tissue were tested in vitro, and their correlation to gene effects was well-established.

    “In our opinion, the COPD study (Campbell et al.) is the most representative in this aspect, because not only were the gene signatures derived from areas with histologically confirmed pathology, but also GHK’s effects on affected lung tissue were tested in vitro and their correlation to gene effects was well-established [37].”

    From Regenerative and Protective Actions of the GHK-Cu Peptide in the Light of the New Gene Data (2018) · cites this paper as [37]

    The Background and Materials and methods describe gene-expression profiling in cores adjacent to lung regions whose emphysema severity was measured by micro-CT, not pathology confirmed by histology. The Results report that GHK was tested in cultured lung fibroblasts derived from people with COPD—not intact affected lung tissue—and that GHK-induced gene-expression changes were compared with the emphysema signature. The authors’ view that this study is ‘most representative’ is their own judgment, not a finding attributed to Campbell et al. (LLM, conf=0.86)

    Experimental — accuracy not yet measured

  • GHK reverses the gene expression signature of emphysematous lung destruction.

    “A recent impressive collaborative study conducted by scientists from Boston University, University of Groningen (The Netherlands), University of British Columbia, and University of Pennsylvania established that the GHK peptide reverses the gene expression signature of emphysematous lung destruction.”

    From GHK-Cu may Prevent Oxidative Stress in Skin by Regulating Copper and Modifying Expression of Numerous Antioxidant Genes (2015) · cites this paper as [19]

  • Lung fibroblasts from COPD patients treated with GHK or TGF-β both restored function, and they had elevated expression of integrin beta 1.

    “Lung fibroblasts from COPD patients, which had impaired ability to contract and restructure collagen, were treated with GHK or TGF-β. Both molecules restored function of fibroblasts. They also had an elevated expression of integrin beta 1 [37,38].”

    From Regenerative and Protective Actions of the GHK-Cu Peptide in the Light of the New Gene Data (2018) · cites this paper as [37]

  • A study demonstrated that GHK can reverse expression of key genes in a COPD gene signature: 127 genes were altered in COPD patients, more severe emphysema correlated with degree of change, inflammatory genes were upregulated and tissue remodeling/repair genes downregulated, and GHK reversed changes associated with emphysematous destruction, including decreased TGF-β pathway activity, to activation

    “This is evident from a study which demonstrated GHK’s ability to reverse expression of key genes, included in a gene signature of COPD—Chronic Obstructive Pulmonary Disease. The expression of 127 genes was altered in COPD patients. More severe emphysema symptoms were correlated with the degree of change in gene expression. Genes whose expression was associated with inflammation were upregulated,”

    From Regenerative and Protective Actions of the GHK-Cu Peptide in the Light of the New Gene Data (2018) · cites this paper as [37]

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

The self-check needs the paper’s full text.

Cites

Flagged first, then by citations

Cited by

Sorted by citations

Related

Authors
Campbell, J. D., McDonough, J. E., Zeskind, J. E., Hackett, T. L., Pechkovsky, D. V., Brandsma, C.-A., Suzuki, M., Gosselink, J. V., Liu, G., Alekseyev, Y. O., Xiao, J., Zhang, X., Hayashi, S., Cooper, J. D., Timens, W., Postma, D. S., Knight, D. A., Lenburg, M. E., Hogg, J. C., & Spira, A.
Affiliations
  • Boston University (US)
  • University of British Columbia (CA)
  • University Medical Center Groningen (NL)
  • Hospital of the University of Pennsylvania (US)
Corresponding author
  • Lenburg, Marc E
  • Spira, Avrum
ORCID
Venue
Genome Medicine
Publisher
Springer Science and Business Media LLC
Published
2012-08-31
Volume
4
Issue
8
Pages
67-67
ISSN
1756-994X (ISSN-L)
DOI
10.1186/gm367
PMC
PMC4064320
OpenAlex
W2031896302
Cited by
128
References
55
Citations by year
2026: 1 · 2025: 8 · 2024: 4 · 2023: 8 · 2022: 4 · 2021: 10 · 2020: 8 · 2019: 10 · 2018: 14 · 2017: 19 · 2016: 12 · 2015: 13 · 2014: 10 · 2013: 5 · 2012: 2
FWCI
7.73
Type
journal article
Language
en
Open access
Licence
Locations
  • Genome Medicine (publishedVersion, cc-by)
  • Europe PMC (PubMed Central) (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • cIRcle (University of British Columbia) (submittedVersion, cc-by)
  • University of Groningen research database (University of Groningen / Centre for Information Technology) (submittedVersion, cc-by)
  • Open Collections
Funders
  • National Science Foundation
  • European Respiratory Society
  • British Columbia Lung Association
  • Division of Graduate Education
Topics
  • Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Chronic Obstructive Pulmonary Disease (COPD) Research
  • Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Interstitial Lung Diseases and Idiopathic Pulmonary Fibrosis
  • Health Sciences › Medicine › Physiology › Asthma and respiratory diseases
Keywords
emphysema, chronic obstructive pulmonary disease, gene expression signatures, TGF-beta signaling, emphysema severity, lung fibroblasts, collagen remodeling, beta1 integrin, actin cytoskeleton, B cell receptor signaling, tissue repair, smokers, drug target identification

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

Are you an author, or do you see a problem with this page? Request a review