A gene expression signature of emphysematous lung destruction and its reversal by the tripeptide GHK
Open accessAbstract
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.
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GHK shifts gene expression in COPD lungs from destruction to healthy remodeling.
“and shift gene expression in COPD lungs from destruction to healthy remodeling.”
From Modulation of Gene Expression in Human Breast Cancer MCF7 and Prostate Cancer PC3 Cells by the Human Copper-Binding Peptide GHK-Cu (2021) · cites this paper as [3]
Campbell et al. demonstrated that GHK produced favorable changes in gene expression in COPD lung tissues.
“In 2012, Campbell et al. identified a gene expression signature characteristic for COPD (Chronic Obstructive Lung Disease) and demonstrated that GHK produced favorable changes in gene expression in COPD lung tissues.”
From Modulation of Gene Expression in Human Breast Cancer MCF7 and Prostate Cancer PC3 Cells by the Human Copper-Binding Peptide GHK-Cu (2021) · cites this paper as [3]
GHK, added to fibroblasts derived from COPD lung tissue, helped restore organization of the actin cytoskeleton, elevated the expression of integrin β1, collagen I contraction and remodeling by fibroblasts.
“They also conducted laboratory experiments, confirming that GHK, added to fibroblasts derived from COPD lung tissue, helped restore organization of the actin cytoskeleton, elevated the expression of integrin β1, collagen I contraction and remodeling by fibroblasts [3].”
From Modulation of Gene Expression in Human Breast Cancer MCF7 and Prostate Cancer PC3 Cells by the Human Copper-Binding Peptide GHK-Cu (2021) · cites this paper as [3]
Cites
Subramanian, A., Tamayo, P., Mootha, V. K., Mukherjee, S., Ebert, B. L., Gillette, M. A., Paulovich, A., Pomeroy, S. L., Golub, T. R., Lander, E. S., et al. (2005) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0506580102 · Cited by 53,625 · see citing works
DAVID: Database for Annotation, Visualization, and Integrated Discovery
Dennis, G., Sherman, B. T., Hosack, D. A., Yang, J., Gao, W., Lane, H. C., & Lempicki, R. A. (2003) · Genome biology · doi:10.1186/gb-2003-4-9-r60 · Cited by 2,383 · see citing works
Faith, J. J., Hayete, B., Thaden, J. T., Mogno, I., Wierzbowski, J., Cottarel, G., Kasif, S., Collins, J. J., & Gardner, T. S. (2007) · PLoS Biology · doi:10.1371/journal.pbio.0050008 · Cited by 1,563 · see citing works
Small-Airway Obstruction and Emphysema in Chronic Obstructive Pulmonary Disease
McDonough, J. E., Yuan, R., Suzuki, M., Seyednejad, N., Elliott, W. M., Sánchez, P. G., Wright, A. C., Gefter, W. B., Litzky, L. A., Coxson, H. O., et al. (2011) · New England Journal of Medicine · doi:10.1056/nejmoa1106955 · Cited by 1,208 · see citing works
Self-citationSirota, M., Dudley, J. T., Kim, J., Chiang, A. P.-F., Morgan, A. A., Sweet-Cordero, A., Sage, J., & Butte, A. J. (2011) · Science Translational Medicine · doi:10.1126/scitranslmed.3001318 · Cited by 801 · see citing works
Deaths: preliminary data for 2002.
Kochanek, K. D., & Smith, B. L. (2004) · PubMed · Cited by 700 · see citing works
Developing COPD: a 25 year follow up study of the general population
Løkke, A., Lange, P., Scharling, H., Fabricius, P. G., & Vestbo, J. (2006) · Thorax · doi:10.1136/thx.2006.062802 · Cited by 613 · see citing works
Computational Repositioning of the Anticonvulsant Topiramate for Inflammatory Bowel Disease
Dudley, J. T., Sirota, M., Shenoy, M. M., Pai, R. K., Roedder, S., Chiang, A. P.-F., Morgan, A. A., Sarwal, M., Pasricha, P. J., & Butte, A. J. (2011) · Science Translational Medicine · doi:10.1126/scitranslmed.3002648 · Cited by 604 · see citing works
Ning, W., Li, C., Kaminski, N., Feghali‐Bostwick, C. A., Alber, S. M., Di, Y. P., Otterbein, S. L., Song, R., Hayashi, S., Zhou, Z., et al. (2004) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0401168101 · Cited by 330 · see citing works
Self-citationRemodeling in Asthma and Chronic Obstructive Pulmonary Disease
Postma, D. S., & Timens, W. (2006) · Proceedings of the American Thoracic Society · doi:10.1513/pats.200601-006aw · Cited by 267 · see citing works
Self-citationThe Nature of Small-Airway Obstruction in Chronic Obstructive Pulmonary Disease
(2004) · New England Journal of Medicine · doi:10.1056/nejm200409233511329 · Cited by 225 · see citing works
The human tri-peptide GHK and tissue remodeling
Pickart, L. (2008) · Journal of Biomaterials Science, Polymer Edition · doi:10.1163/156856208784909435 · Cited by 218 · see citing works
Togo, S., Holz, O., Liu, X., Sugiura, H., Kamio, K., Wang, X., Kawasaki, S., Ahn, Y., Fredriksson, K., Sköld, C. M., et al. (2008) · American Journal of Respiratory and Critical Care Medicine · doi:10.1164/rccm.200706-929oc · Cited by 202 · see citing works
Gene Expression Profiling of Human Lung Tissue from Smokers with Severe Emphysema
Spira, A. E., Beane, J., Pinto-Plata, V., Kadar, A. Y., Liu, G., Shah, V., Celli, B. R., & Brody, J. S. (2004) · American Journal of Respiratory Cell and Molecular Biology · doi:10.1165/rcmb.2004-0273oc · Cited by 174 · see citing works
Self-citationGene Expression Profiling in Patients with Chronic Obstructive Pulmonary Disease and Lung Cancer
Wang, I., Stepaniants, S. B., Boie, Y., Mortimer, J. R., Kennedy, B. A., Elliott, M., Hayashi, S., Loy, L., Coulter, S., Cervino, S., et al. (2007) · American Journal of Respiratory and Critical Care Medicine · doi:10.1164/rccm.200703-390oc · Cited by 160 · see citing works
Self-citationLymphoid follicles in (very) severe COPD: beneficial or harmful?
Brusselle, G., Demoor, T., Bracke, K. R., Brandsma, C., & Timens, W. (2009) · European Respiratory Journal · doi:10.1183/09031936.00150208 · Cited by 151 · see citing works
Self-citationGosselink, J. V., Hayashi, S., Elliott, W. M., Xing, L., Chan, B., Yang, L., Wright, C., Sin, D. D., Paré, P. D., Pierce, J. A., et al. (2010) · American Journal of Respiratory and Critical Care Medicine · doi:10.1164/rccm.200812-1902oc · Cited by 148 · see citing works
Self-citationEmphysema Lung Tissue Gene Expression Profiling
Golpon, H. A., Coldren, C. D., Zamora, M. R., Cosgrove, G. P., Moore, M. D., Tuder, R. M., Geraci, M. W., & Voelkel, N. F. (2004) · American Journal of Respiratory Cell and Molecular Biology · doi:10.1165/rcmb.2004-0008oc · Cited by 130 · see citing works
THIERS, B. H. (2007) · Yearbook of Dermatology and Dermatologic Surgery · doi:10.1016/s0093-3619(08)70659-2 · Cited by 129 · see citing works
Siméon, A., Wegrowski, Y., Bontemps, Y., & Maquart, F.-X. (2000) · Journal of Investigative Dermatology · doi:10.1046/j.1523-1747.2000.00166.x · Cited by 119 · see citing works
Maquart, F. X., Bellon, G., Chaqour, B., Wegrowski, J., Patt, L. M., Trachy, R. E., Monboisse, J. C., Chastang, F., Birembaut, P., & Gillery, P. (1993) · Journal of Clinical Investigation · doi:10.1172/jci116842 · Cited by 110 · see citing works
Molecular Biomarkers for Quantitative and Discrete COPD Phenotypes
Bhattacharya, S., Srisuma, S., DeMeo, D. L., Shapiro, S. D., Bueno, R., Silverman, E. K., Reilly, J. J., & Mariani, T. J. (2008) · American Journal of Respiratory Cell and Molecular Biology · doi:10.1165/rcmb.2008-0114oc · Cited by 108 · see citing works
Functional Significance of Apoptosis in Chronic Obstructive Pulmonary Disease
Park, J.-W., Ryter, S. W., & Choi, A. M. K. (2007) · COPD Journal of Chronic Obstructive Pulmonary Disease · doi:10.1080/15412550701603775 · Cited by 90 · see citing works
Altered expression of the Smad signalling pathway: implications for COPD pathogenesis
Zandvoort, A., Postma, D. S., Jonker, M. R., Noordhoek, J. A., Vos, J. T. W. M., van der Geld, Y. M., & Timens, W. (2006) · European Respiratory Journal · doi:10.1183/09031936.06.00078405 · Cited by 84 · see citing works
Self-citationSpringer, J., Scholz, F. R., Peiser, C., Groneberg, D. A., & Fischer, A. (2004) · Biological Chemistry · doi:10.1515/bc.2004.080 · Cited by 77 · see citing works
Smad gene expression in pulmonary fibroblasts: indications for defective ECM repair in COPD
Zandvoort, A., Postma, D. S., Jonker, M. R., Noordhoek, J. A., Vos, J. T. W. M., & Timens, W. (2008) · Respiratory Research · doi:10.1186/1465-9921-9-83 · Cited by 67 · see citing works
Self-citationAn integrative ChIP-chip and gene expression profiling to model SMAD regulatory modules
Qin, H., Chan, M. W., Liyanarachchi, S., Balch, C., Potter, D., Souriraj, I. J., Cheng, A. S. L., Agosto-Perez, F., Nikonova, E. V., Yan, P. S., et al. (2009) · BMC Systems Biology · doi:10.1186/1752-0509-3-73 · Cited by 67 · see citing works
Noordhoek, J. A., Postma, D. S., Chong, L. L., Menkema, L., Kauffman, H. F., Timens, W., Straaten, J. F. M. V., & van der Geld, Y. M. (2005) · COPD Journal of Chronic Obstructive Pulmonary Disease · doi:10.1081/copd-200050678 · Cited by 64 · see citing works
Self-citationBignon, J., Khoury, F., Even, P., André, J., & Brouet, G. (1969) · PubMed · doi:10.1164/arrd.1969.99.5.669 · Cited by 63 · see citing works
Copper–GHK increases integrin expression and p63 positivity by keratinocytes
Kang, Y.-A., Choi, H.-R., Na, J.-I., Huh, C.-H., Kim, M.-J., Youn, S.-W., Kim, K.-H., & Park, K.-C. (2009) · Archives of Dermatological Research · doi:10.1007/s00403-009-0942-x · Cited by 51 · see citing works
Novel strategy to identify genetic risk factors for COPD severity: a genetic isolate
van Diemen, C. C., Postma, D. S., Aulchenko, Y. S., Snijders, P. J. L. M., Oostra, B. A., van Duijn, C. M., & Boezen, H. M. (2009) · European Respiratory Journal · doi:10.1183/09031936.00054408 · Cited by 50 · see citing works
Self-citationExpression profiling identifies genes involved in emphysema severity
Francis, S. M. S., Larsen, J. E., Pavey, S. J., Bowman, R., Hayward, N. K., Fong, K. M., & Yang, I. A. (2009) · Respiratory Research · doi:10.1186/1465-9921-10-81 · Cited by 43 · see citing works
Abraham, T., Carthy, J. M., & McManus, B. M. (2009) · Journal of Structural Biology · doi:10.1016/j.jsb.2009.07.023 · Cited by 41 · see citing works
Cigarette smoke-induced emphysema: A role for the B Cell?
van der Strate, B. W., Postma, D. S., Brandsma, C., Melgert, B. N., Luinge, M. A., Geerlings, M., Hylkema, M. N., van den Berg, A., Timens, W., & Kerstjens, H. A. M. (2006) · Respiratory Medicine COPD Update · doi:10.1016/j.rmedu.2006.03.026 · Cited by 35 · see citing works
Self-citationCOMPARISON OF SMOKING-INDUCED GENE EXPRESSION ON AFFYMETRIX EXON AND 3'-BASED EXPRESSION ARRAYS
Zhang, X., Liu, G., Lenburg, M. E., & Spira, A. E. (2007) · International Conference on Genome Informatics (GIW) · doi:10.1142/9781860949920_0024 · Cited by 16 · see citing works
Self-citationChoong, C. K. C., Haddad, F. J., Martinez, C., Hu, D., Pierce, J. A., Meyers, B. F., Patterson, G. A., & Cooper, J. D. (2005) · Journal of Thoracic and Cardiovascular Surgery · doi:10.1016/j.jtcvs.2005.03.046 · Cited by 11 · see citing works
Self-citationChronic Obstructive Pulmonary Disease Exacerbations: Accurate and Easy Measurement Promises Much
Rennard, S. I., & Bailey, K. L. (2012) · American Journal of Respiratory and Critical Care Medicine · doi:10.1164/rccm.201202-0227ed · Cited by 6 · see citing works
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Pickart, L., & Margolina, A. (2018) · International Journal of Molecular Sciences · doi:10.3390/ijms19071987 · Cited by 158 · see citing works
Meiners, S., & Eickelberg, O. (2012) · Genome Medicine · doi:10.1186/gm371 · Cited by 10 · see citing works
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Pickart, L., Vasquez-Soltero, J. M., & Margolina, A. (2015) · Springer eBooks · doi:10.1007/978-3-642-27814-3_162-1 · Cited by 3 · see citing works
The Role of Bioactive Small Molecules in COPD Pathogenesis
Liao, S., & Chen, Y. (2024) · COPD Journal of Chronic Obstructive Pulmonary Disease · doi:10.1080/15412555.2024.2307618 · Cited by 3 · see citing works
Resetting Skin Genome Back to Health Naturally with GHK
Pickart, L., Vasquez-Soltero, J. M., & Margolina, A. (2016) · Springer eBooks · doi:10.1007/978-3-662-47398-6_162 · Cited by 2 · see citing works
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Pickart, L., & Margolina, A. (2018) · OBM Geriatrics · doi:10.21926/obm.geriatr.1803009 · Cited by 2 · see citing works
- 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)
- ORCID
- Venue
- Genome Medicine
- Published
- 2012
- Volume
- 4
- Issue
- 8
- Pages
- 67
- ISSN
- 1756-994X (ISSN-L)
- OpenAlex
- W4255443313
- Cited by
- 5
- References
- 38
- Citations by year
- 2024: 1 · 2018: 1 · 2016: 1 · 2015: 1 · 2012: 1
- FWCI
- 0.52
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- Genome Medicine (publishedVersion)
- 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
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