Tripeptide Drug Reverses the Gene Expression Signature in Chronically Damaged Lung Tissue

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. COPD is particularly common in cigarette smokers where the chronic irritants present in tobacco smoke cause oxidative stress and chronic inflammation, which over time results in emphysema, the destruction of lung alveolar cells.

Investigators at the Boston University School of Medicine (MA, USA) profiled gene expression in lung tissue samples obtained from regions within the same lung with varying amounts of emphysematous destruction from smokers with COPD. Eight sections from eight different smokers were analyzed.

Results published in the August 31, 2012, online edition of the journal Genome Medicine revealed 127 genes with expression profiles that 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 (TGF) pathway, actin organization, and integrin signaling.

The investigators then used the Connectivity Map to identify the tripeptide GHK (Gly-His-Lys) as a compound that could reverse the gene-expression signature associated with emphysematous destruction and induce expression patterns consistent with TGF pathway activation. Treatment of human fibroblasts with GHK recapitulated TGF-induced gene-expression patterns, led to the organization of the actin cytoskeleton, and elevated the expression of integrin 1. Furthermore, addition of GHK or TGF restored collagen I contraction and remodeling by fibroblasts derived from COPD lungs compared to fibroblasts from former smokers without COPD.

The Broad Institute's Connectivity Map (cmap) (Cambridge, MA, USA) is a collection of genome-wide transcriptional expression data from cultured human cells treated with bioactive small molecules and simple pattern-matching algorithms that together enable the discovery of functional connections between drugs, genes, and diseases through the transitory feature of common gene-expression changes.

A web interface provides access to the current version of Connectivity Map, which contains more than 7,000 expression profiles representing 1,309 compounds. It is designed to allow biologists, pharmacologists, chemists, and clinical scientists to use cmap without the need for any specialist ability in the analysis of gene-expression data.

"When we searched the Connectivity Map database, which is essentially a compendium of experiments that measure the effect of therapeutic compounds on every gene in the genome, we found that how genes were affected by the compound GHK, a drug known since the 1970s, was the complete opposite of what we had seen in the cells damaged by emphysema," said senior author Dr. Avrum Spira, associate professor of medicine, pathology, and bioinformatics at the University of Boston School of Medicine."


Related Links:
Boston University School of Medicine
Broad Institute's Connectivity Map