Novel Therapeutics for Emphysema
We have followed with great interest recent data on gene expression signature of emphysema-related lung destruction and its reversal by the tripeptide GHK - Genome Medicine CLICK HERE
Excerpt: "As the CMap examined the effect of GHK in cancer cell lines, we next sought to verify the effect of GHK treatment in a cell type more relevant to emphysema pathogenesis. We utilized human lung fibroblasts because fibroblasts are the major interstitial cell within the alveolar unit that can synthesize and remodel the ECM and previous studies have demonstrated that GHK can induce ECM production in dermal fibroblasts [32–34]... Genes whose expression is decreased with increasing emphysema severity are enriched among genes induced by GHK at 10 nM (FDR < 0.05, GSEA; Figure 5a,b). Genes whose expression is altered by GHK treatment at either concentration are also enriched among genes that change with TGFβ1 treatment.
Reversal of COPD-related phenotypes in fibroblasts by GHK
Genes induced in human lung fibroblasts after treatment with GHK were enriched in actin cytoskeleton organization and focal adhesion pathways (FDR <0.05, DAVID). These included integrins involved in collagen attachment, such as ITGB1. ITGB1 gene expression was also down-regulated with increasing emphysema severity in lung tissue (P = 0.008). Resolution of damaged tissue requires mesenchymal cells to attach to collagen fibers through integrin-dependent mechanisms and generate mechanical tension via the actin cytoskeleton to promote tissue contraction and wound size reduction. Using distal lung fibroblasts isolated from former smokers with and without COPD, we found that GHK (10 nM), like TGFβ1 (10 ng/ml), induced alterations in integin-β1 localization (green staining in Figure 6a) and reorganized actin to form contractile filaments (red staining in Figure 6a). We further demonstrated using a three-dimensional collagen gel contraction bioassay that distal lung fibroblasts derived from former smokers with COPD (n = 5) were unable to fully contract collagen I gels compared to fibroblasts obtained from former smokers without COPD (n = 5, P < 0.05; Figure 6b,c; see Additional file 12 for subject demographics), similar to what has been previously described ...
This study has provided insights into molecular processes associated with emphysematous destruction of the lung and revealed mechanisms that contribute to the pathogenesis of COPD. Whole genome gene-expression analysis supports the role of the immune response in regional emphysema and elucidates additional pathways involved in the process of emphysematous destruction. The suggestion that progressive emphysematous destruction is associated with down-regulation of genes involved in or downstream of tissue remodeling and wound repair pathways supports a role for defects in ECM homeostasis and angiogenesis in the emphysematous destruction that occurs with chronic inflammation in COPD. We propose that these processes could be linked through decreased TGFβ pathway activation. These data are supported by our identification of GHK as a compound with the potential to mimic TGFβ pathway activity and induce collagen contraction, an important functional component of wound repair."