Search

The alteration of normal dermal fibroblast function that leads to the development of hypertrophic scar after thermal injury is unknown. To determine functional differences that might explain this process, fibroblasts were cultured from biopsies of post-thermal injury mature hypertrophic scars and patient-matched normal skin. The mitogenic responses of scar cells to fetal bovine serum, epidermal growth factor (EGF), platelet-derived growth factor (PDGF), and tumor necrosis factor α (TNFα) were determined and compared to normal skin cells. Collagen synthetic rate was also compared in the presence and absence of transforming growth factor β1 (TGFβ1). Whereas both scar and normal cells responded with increased thymidine uptake to serum and cytokines, the stimulation to EGF and serum was significantly lower in scar cells. In contrast, synthesis of collagen, but not of non-collagenous proteins, was increased in scar relative to normal cells, both basally and when stimulated with low doses of TGFβ1. Additionally, the fraction of protein synthesized as collagen was significantly higher in scar fibroblasts. These results suggest that fibroblasts from hypertrophic scars demonstrate stable phenotypic differences in cytokine responsiveness in comparison to cells from unaffected skin. The increased rate of collagen synthesis and decreased responsiveness to mitogens are consistent with the increased extracellular matrix content and decreased cellularity of hypertrophic scars. [ABSTRACT FROM AUTHOR]

Abnormal wound healing encompasses a wide spectrum, from chronic wounds to hypertrophic scars. Both conditions are associated with an abnormal cytokine profile in the wound bed. In this study, we sought to understand the dynamic relationships between myofibroblast differentiation and mechanical performance of the collagen matrix under tissue growth factor–β (TGF-β) and tumor necrosis factor–α (TNF-α) stimulation. We found TGF-β increased α-smooth muscle actin (α-SMA) and TNF-α alone decreased the basal α-SMA expression. When TGF-β1 and TNF-α were both added, the α-SMA expression was suppressed below the baseline. Real-time PCR showed that TNF-α suppresses TGF-β1-induced myofibroblast (fibroproliferative) phenotypic genes, for example, α-SMA, collagen type 1A, and fibronectin at the mRNA level. TNF-α suppresses TGF-β1-induced gene expression by affecting its mRNA stability. Our results further showed that TNF-α inhibits TGF-β1-induced Smad-3 phosphorylation via Jun N-terminal kinase signaling. Mechanical testing showed that TNF-α decreases the stiffness and contraction of the lattices after 5 days in culture. We proposed that changes in α-SMA, collagen, and fibronectin expression result in decreased contraction and stiffness of collagen matrices. Therefore, the balance of cytokines in a wound defines the mechanical properties of the extracellular matrix and optimal wound healing.Journal of Investigative Dermatology (2007) 127, 2645–2655; doi:10.1038/sj.jid.5700890; published online 31 May 2007 [ABSTRACT FROM AUTHOR]