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Gene expression profiling of cutaneous wound healing.

Deonarine K, Panelli MC, Stashower ME, Jin P, Smith K, Slade HB, Norwood C, Wang E, Marincola FM, Stroncek DF - J Transl Med (2007)

Bottom Line: Early in wound healing the expression of markers of both M1 and M2 macrophages were increased, but later M2 markers predominated.Subsequently and in the absence of infection, inflammation subsides and it is replaced by angiogenesis and remodeling.Understanding this transition which may be driven by a change from a mixed macrophage population to predominantly M2 macrophages, may help the interpretation of the cellular and molecular events occurring in the microenvironment of serially biopsied tissues.

View Article: PubMed Central - HTML - PubMed

Affiliation: Immunogenetics Section, Department of Transfusion Medicine, Clinical Center National Institutes of Health, Bethesda, MD 20892, USA. kavitasoleil@yahoo.com

ABSTRACT

Background: Although the sequence of events leading to wound repair has been described at the cellular and, to a limited extent, at the protein level this process has yet to be fully elucidated. Genome wide transcriptional analysis tools promise to further define the global picture of this complex progression of events.

Study design: This study was part of a placebo-controlled double-blind clinical trial in which basal cell carcinomas were treated topically with an immunomodifier--toll-like receptor 7 agonist: imiquimod. The fourteen patients with basal cell carcinoma in the placebo arm of the trial received placebo treatment consisting solely of vehicle cream. A skin punch biopsy was obtained immediately before treatment and at the end of the placebo treatment (after 2, 4 or 8 days). 17.5K cDNA microarrays were utilized to profile the biopsy material.

Results: Four gene signatures whose expression changed relative to baseline (before wound induction by the pre-treatment biopsy) were identified. The largest group was comprised predominantly of inflammatory genes whose expression was increased throughout the study. Two additional signatures were observed which included preferentially pro-inflammatory genes in the early post-treatment biopsies (2 days after pre-treatment biopsies) and repair and angiogenesis genes in the later (4 to 8 days) biopsies. The fourth and smallest set of genes was down-regulated throughout the study. Early in wound healing the expression of markers of both M1 and M2 macrophages were increased, but later M2 markers predominated.

Conclusion: The initial response to a cutaneous wound induces powerful transcriptional activation of pro-inflammatory stimuli which may alert the host defense. Subsequently and in the absence of infection, inflammation subsides and it is replaced by angiogenesis and remodeling. Understanding this transition which may be driven by a change from a mixed macrophage population to predominantly M2 macrophages, may help the interpretation of the cellular and molecular events occurring in the microenvironment of serially biopsied tissues.

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Signature clusters of genes whose expression was changed early in wound healing. Genes in signature clusters 3 and 4 whose expression was greatest on day 2 are shown. Pre and post wound biopsies are color coded by the horizontal bars as per figure 1.
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Figure 2: Signature clusters of genes whose expression was changed early in wound healing. Genes in signature clusters 3 and 4 whose expression was greatest on day 2 are shown. Pre and post wound biopsies are color coded by the horizontal bars as per figure 1.

Mentions: Two clusters included predominantly transcripts who expression was increased early on day 2 after wounding (Figure 2, clusters 3 and 4) and represented a wide variety of pro-inflammatory genes. Several markers were present indicating TNF activation (TNF receptor associated factor 1,2) and interferon (IFN) activation, (AIF1 and IFIT2). The expression of several macrophage markers was increased (CD163, FcγRI, macrophage scavenger receptor 1, and MHC class II α chain) as were markers of T cells (RAB7L1, and RAB18), B cells (immunoglobulin heavy chain) and neutrophils (cytochrome b-245). In addition, the expression of β2 integrin, CD18, which is found on many different leukocytes, was increased. Evidence of tissue repair was also present including the presence of the cysteine protease, cathepsin S, which is produced by smooth muscle cells and induces angiogenesis [18] and coagulation factor XIII, a platelet and monocyte protein that is involved with fibrin crosslinking and clot maturation and that increases endothelial cell migration and proliferation [19].


Gene expression profiling of cutaneous wound healing.

Deonarine K, Panelli MC, Stashower ME, Jin P, Smith K, Slade HB, Norwood C, Wang E, Marincola FM, Stroncek DF - J Transl Med (2007)

Signature clusters of genes whose expression was changed early in wound healing. Genes in signature clusters 3 and 4 whose expression was greatest on day 2 are shown. Pre and post wound biopsies are color coded by the horizontal bars as per figure 1.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC1804259&req=5

Figure 2: Signature clusters of genes whose expression was changed early in wound healing. Genes in signature clusters 3 and 4 whose expression was greatest on day 2 are shown. Pre and post wound biopsies are color coded by the horizontal bars as per figure 1.
Mentions: Two clusters included predominantly transcripts who expression was increased early on day 2 after wounding (Figure 2, clusters 3 and 4) and represented a wide variety of pro-inflammatory genes. Several markers were present indicating TNF activation (TNF receptor associated factor 1,2) and interferon (IFN) activation, (AIF1 and IFIT2). The expression of several macrophage markers was increased (CD163, FcγRI, macrophage scavenger receptor 1, and MHC class II α chain) as were markers of T cells (RAB7L1, and RAB18), B cells (immunoglobulin heavy chain) and neutrophils (cytochrome b-245). In addition, the expression of β2 integrin, CD18, which is found on many different leukocytes, was increased. Evidence of tissue repair was also present including the presence of the cysteine protease, cathepsin S, which is produced by smooth muscle cells and induces angiogenesis [18] and coagulation factor XIII, a platelet and monocyte protein that is involved with fibrin crosslinking and clot maturation and that increases endothelial cell migration and proliferation [19].

Bottom Line: Early in wound healing the expression of markers of both M1 and M2 macrophages were increased, but later M2 markers predominated.Subsequently and in the absence of infection, inflammation subsides and it is replaced by angiogenesis and remodeling.Understanding this transition which may be driven by a change from a mixed macrophage population to predominantly M2 macrophages, may help the interpretation of the cellular and molecular events occurring in the microenvironment of serially biopsied tissues.

View Article: PubMed Central - HTML - PubMed

Affiliation: Immunogenetics Section, Department of Transfusion Medicine, Clinical Center National Institutes of Health, Bethesda, MD 20892, USA. kavitasoleil@yahoo.com

ABSTRACT

Background: Although the sequence of events leading to wound repair has been described at the cellular and, to a limited extent, at the protein level this process has yet to be fully elucidated. Genome wide transcriptional analysis tools promise to further define the global picture of this complex progression of events.

Study design: This study was part of a placebo-controlled double-blind clinical trial in which basal cell carcinomas were treated topically with an immunomodifier--toll-like receptor 7 agonist: imiquimod. The fourteen patients with basal cell carcinoma in the placebo arm of the trial received placebo treatment consisting solely of vehicle cream. A skin punch biopsy was obtained immediately before treatment and at the end of the placebo treatment (after 2, 4 or 8 days). 17.5K cDNA microarrays were utilized to profile the biopsy material.

Results: Four gene signatures whose expression changed relative to baseline (before wound induction by the pre-treatment biopsy) were identified. The largest group was comprised predominantly of inflammatory genes whose expression was increased throughout the study. Two additional signatures were observed which included preferentially pro-inflammatory genes in the early post-treatment biopsies (2 days after pre-treatment biopsies) and repair and angiogenesis genes in the later (4 to 8 days) biopsies. The fourth and smallest set of genes was down-regulated throughout the study. Early in wound healing the expression of markers of both M1 and M2 macrophages were increased, but later M2 markers predominated.

Conclusion: The initial response to a cutaneous wound induces powerful transcriptional activation of pro-inflammatory stimuli which may alert the host defense. Subsequently and in the absence of infection, inflammation subsides and it is replaced by angiogenesis and remodeling. Understanding this transition which may be driven by a change from a mixed macrophage population to predominantly M2 macrophages, may help the interpretation of the cellular and molecular events occurring in the microenvironment of serially biopsied tissues.

Show MeSH
Related in: MedlinePlus