Chemokines, cytokines, and growth factors in keratinocytes and dermal endothelial cells in the margin of chronic diabetic foot ulcers

Abstract

Keratinocytes and dermal endothelial cells, excluding leukocytes that infiltrate wounds, are the main source of soluble factors regulating healing of skin ulcers. We used immunohistochemistry to analyze the expression of various chemotactic and growth factors and their receptors in the margin of diabetic foot ulcers and in normal nondiabetic foot skin. Our study found significantly elevated expression of transforming growth factor-beta1 (TGF-beta1) and type I TGF-beta receptors (TGFbetaR1), granulocyte macrophage colony-stimulating factor (GM-CSF), and epidermal growth factor (EGF) in keratinocytes in the ulcer margin (p < 0.05). Significantly increased expression of monocyte chemotactic protein-1, GM-CSF, CXCR1, and TGFbetaRI and decreased expression of interleukin (IL)-10, IL-15, and TGF-beta1 were observed in ulcer dermal endothelial cells (p < 0.05). There was a lack of up-regulation of IL-8, CCR2A, IL-10 receptor, GM-CSF receptor, platelet-derived growth factors and their receptors, vascular endothelial growth factor and its type II receptor, EGF receptor, insulin-like growth factor-1, and nitric oxide synthase-2 in both KCs and endothelial cells in the ulcer. Finally, there was a lack of up-regulation of IL-10 and IL-15 in keratinocytes and of EGF, basic fibroblast growth factor, and nitric oxide synthase-3 in endothelial cells in the ulcer margins. The enhanced expression of some factors responsible for KC behavior could suggest an unimpaired capacity of keratinocytes to reepithelialize the margin of diabetic foot ulcers. However, lack of up-regulation of some angiogenic and leukocyte chemotactic factors, associated with the reduced influx of immune cells, may account for a poor formation of granulation tissue and chronicity of ulcer epithelialization.

Therapeutic Potential of HDL in Cardioprotection and Tissue Repair

“…Pressure ulcers or decubitus wounds typically occur on sacrum, shoulder blades, and heels. Several factors contribute to deficient wound healing in patients with diabetes: deficient growth factor production (Galkowska et al 2006), impaired neovascularisation (Galiano et al 2004b), attenuated keratinocyte and fibroblast proliferation and migration (Gibran et al 2002), and altered balance between extracellular matrix accumulation and remodelling of the extracellular matrix by matrix metalloproteinases (Lobmann et al 2002). Foot ulcers occur in a diabetic population with a prevalence of 5 % and lifetime incidence of 15 % (Abbott et al 2002;Muller et al 2002).…”

Efficacy of Clerodendrum infortunatum on Wound Healing in Streptozotocin-Induced Diabetic Rats

“…Many known physiologic factors are responsible for the difficulties in wound healing with diabetes individual. These factors are decreased or impaired growth factor production (Galkowska et al, 2006;Goren et al, 2006;Falanga, 2005), decrease angiogenic response (Galiano et al, 2004), macrophage function (Maruyama et al, 2007), collagen accumulation, epidermal barrier function, quantity of granulation tissue (Falanga, 2005), keratinocyte and fibroblast migration and proliferation, number of epidermal nerves (Gibran et al, 2002 ), bone healing, and balance between the accumulation of ECM components and their remodeling by MMPs (Lobamann et al, 2002). The phytochemical analysis of the ethanolic extracts of C. infortunatum plants indicated the presence of major phytochemical compounds, including alkaloids, glycosides, reducing sugars, sterol, terpene were found in higher extent which may have been responsible for the observed wound healing activities, anti-inflammatory activity, antioxidant activities and antimicrobial activities (Abbaszadeh et al,2014;Kapoor et al,2001).…”

“…Diabetes and its subsequent complications present a significant challenge to our healthcare system. The common complications associated with the delayed wound healing in the diabetes are decrease in production of growth factors, diminished angiogenic response, alteration in macrophage function, less quantity of granulation tissue, less collagen accumulation, decrease in migration and proliferation of keratinocyte and fibroblasts (Gibran et al, 2002;Galiano et al, 2004;Falanga, 2005;Galkowska et al, 2006;Goren et al, 2006;Maruyama et al, 2007) There were no available reports regarding the wound healing effect of hydro-alcoholic leave extracts of C. infortunatum.…”

A Pilot Study to Evaluate the Efficacy of IZN 6D4 for the Treatment of Diabetic Foot Ulcers

“…At the cellular level, fibroblasts in the diabetic ulcer show signs of senescence and have a decreased proliferative response to growth factors as compared to fibroblasts in non-diabetic wounds [11,12]. At the molecular level, biopsies taken from diabetic ulcers have lower levels of TGF-β and type 2 TGF-β receptors as compared to wounds from non-diabetic individuals [13,14]. This is a critical factor as TGF mediated signal transduction is important in wound healing [15].…”