title: 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 × 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.
authors.affiliation: Division of Computational Biomedicine, Department of Medicine, Boston University School of Medicine, 72 East Concord Street, Boston, MA 02118, USA ; Bioinformatics Program, Boston University, 44 Cummington Street, Boston, MA 02215, USA.
authors.forename: Joshua D
authors.initials: JD
authors.lastname: Campbell
authors.affiliation: UBC James Hogg Research Centre, Providence Heart + Lung Institute, St. Paul's Hospital and Department of Pathology and Laboratory Medicine, University of British Columbia, 1081 Burrard St, Vancouver, BC V6Z 1Y6, Canada.
authors.forename: John E
authors.initials: JE
authors.lastname: McDonough
authors.affiliation: Division of Computational Biomedicine, Department of Medicine, Boston University School of Medicine, 72 East Concord Street, Boston, MA 02118, USA ; Bioinformatics Program, Boston University, 44 Cummington Street, Boston, MA 02215, USA.
authors.forename: Julie E
authors.initials: JE
authors.lastname: Zeskind
authors.affiliation: UBC James Hogg Research Centre, Providence Heart + Lung Institute, St. Paul's Hospital and Department of Pathology and Laboratory Medicine, University of British Columbia, 1081 Burrard St, Vancouver, BC V6Z 1Y6, Canada.
authors.forename: Tillie L
authors.initials: TL
authors.lastname: Hackett
authors.affiliation: UBC James Hogg Research Centre, Providence Heart + Lung Institute, St. Paul's Hospital and Department of Pathology and Laboratory Medicine, University of British Columbia, 1081 Burrard St, Vancouver, BC V6Z 1Y6, Canada.
authors.forename: Dmitri V
authors.initials: DV
authors.lastname: Pechkovsky
authors.affiliation: Department of Pathology and Medical Biology, University Medical Center Groningen, University of Groningen, Hanzeplein 1, 9713 Groningen, Netherlands.
authors.forename: Corry-Anke
authors.initials: CA
authors.lastname: Brandsma
authors.affiliation: UBC James Hogg Research Centre, Providence Heart + Lung Institute, St. Paul's Hospital and Department of Pathology and Laboratory Medicine, University of British Columbia, 1081 Burrard St, Vancouver, BC V6Z 1Y6, Canada.
authors.forename: Masaru
authors.initials: M
authors.lastname: Suzuki
authors.affiliation: UBC James Hogg Research Centre, Providence Heart + Lung Institute, St. Paul's Hospital and Department of Pathology and Laboratory Medicine, University of British Columbia, 1081 Burrard St, Vancouver, BC V6Z 1Y6, Canada.
authors.forename: John V
authors.initials: JV
authors.lastname: Gosselink
authors.affiliation: Division of Computational Biomedicine, Department of Medicine, Boston University School of Medicine, 72 East Concord Street, Boston, MA 02118, USA.
authors.forename: Gang
authors.initials: G
authors.lastname: Liu
authors.affiliation: Department of Pathology and Laboratory Medicine, Boston University School of Medicine, 72 East Concord Street, Boston, MA 02118, USA.
authors.forename: Yuriy O
authors.initials: YO
authors.lastname: Alekseyev
authors.affiliation: Division of Computational Biomedicine, Department of Medicine, Boston University School of Medicine, 72 East Concord Street, Boston, MA 02118, USA.
authors.forename: Ji
authors.initials: J
authors.lastname: Xiao
authors.affiliation: Division of Computational Biomedicine, Department of Medicine, Boston University School of Medicine, 72 East Concord Street, Boston, MA 02118, USA.
authors.forename: Xiaohui
authors.initials: X
authors.lastname: Zhang
authors.affiliation: UBC James Hogg Research Centre, Providence Heart + Lung Institute, St. Paul's Hospital and Department of Pathology and Laboratory Medicine, University of British Columbia, 1081 Burrard St, Vancouver, BC V6Z 1Y6, Canada.
authors.forename: Shizu
authors.initials: S
authors.lastname: Hayashi
authors.affiliation: Hospital of the University of Pennsylvania, Division of Thoracic Surgery, 3400 Spruce Street 6 White Building, Philadelphia, PA 19104, USA.
authors.forename: Joel D
authors.initials: JD
authors.lastname: Cooper
authors.affiliation: Department of Pathology and Medical Biology, University Medical Center Groningen, University of Groningen, Hanzeplein 1, 9713 Groningen, Netherlands.
authors.forename: Wim
authors.initials: W
authors.lastname: Timens
authors.affiliation: Department of Pulmonary Diseases, University Medical Center Groningen, University of Groningen, Hanzeplein 1, 9713 Groningen, Netherlands.
authors.forename: Dirkje S
authors.initials: DS
authors.lastname: Postma
authors.affiliation: UBC James Hogg Research Centre, Providence Heart + Lung Institute, St. Paul's Hospital and Department of Pathology and Laboratory Medicine, University of British Columbia, 1081 Burrard St, Vancouver, BC V6Z 1Y6, Canada.
authors.forename: Darryl A
authors.initials: DA
authors.lastname: Knight
authors.affiliation: Division of Computational Biomedicine, Department of Medicine, Boston University School of Medicine, 72 East Concord Street, Boston, MA 02118, USA ; Bioinformatics Program, Boston University, 44 Cummington Street, Boston, MA 02215, USA.
authors.forename: Marc E
authors.initials: ME
authors.lastname: Lenburg
authors.affiliation: UBC James Hogg Research Centre, Providence Heart + Lung Institute, St. Paul's Hospital and Department of Pathology and Laboratory Medicine, University of British Columbia, 1081 Burrard St, Vancouver, BC V6Z 1Y6, Canada.
authors.forename: James C
authors.initials: JC
authors.lastname: Hogg
authors.affiliation: Division of Computational Biomedicine, Department of Medicine, Boston University School of Medicine, 72 East Concord Street, Boston, MA 02118, USA ; Bioinformatics Program, Boston University, 44 Cummington Street, Boston, MA 02215, USA.
authors.forename: Avrum
authors.initials: A
authors.lastname: Spira