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Bleomycin-induced scleroderma in mice is an established model for human scleroderma. Making use of this, we have established a new model for wound retardation. After inducing dermal sclerosis by local bleomycin treatment in nude mice, a full-thickness wound was made by punch excision on the bleomycin application site. Mice pretreated with bleomycin showed a significant delay in wound closure, as compared with mice pretreated with phosphate-buffered saline. Proliferation of keratinocytes was significantly inhibited and the number of Ki-67-positive keratinocytes was significantly lower in the bleomycin-pretreated skin. Also, the number of CD31-positive blood vessels was markedly reduced in the bleomycin-treated skin. The topical daily application of basic fibroblast growth factor (bFGF) significantly promoted wound closure, while increasing blood vessel formation and reducing transforming growth factor-β and alpha-smooth muscle actin mRNA levels. Furthermore, only two applications of PG-FGF1, a fusion protein of FGF1 with heparan sulfate proteoglycan, overcame the delay in wound closure. Wound delay in this model mainly occurred as a result of decreased vessel formation and keratinocyte migration following bleomycin treatment. It is expected that this model will provide novel insights into the pathogenesis of wound healing and the exploration of possible candidate drugs for refractory or chronic wounds in the clinical setting. [ABSTRACT FROM AUTHOR]

Keloid is a clinically intractable disease that causes disfigurement, itching, and pain due to abnormal proliferation of fibroblasts and production of collagen. Pirfenidone is a novel anti-fibrotic agent that inhibits the progression of fibrosis occurring in the keloid lesions of the lung and kidney. In order to examine whether pirfenidone has a therapeutic effect on keloid lesions, we prepared an in vitro wound contraction model with keloid fibroblasts. The gel contractility of a mixture of keloid fibroblasts and an acid-soluble collagen solution was examined with/without transforming growth factor (TGF)-β1 in the presence or absence of pirfenidone. Real time RT-PCR was performed to detect mRNA expression of TGFB1, CTGF, aSMA, and Col1A1 quantitatively in keloid fibroblasts incubated with/without TGF-β1 in the presence or absence of pirfenidone. The contractility of keloid fibroblast-embedded collagen gel was increased after the addition of TGF-β1. Pirfenidone suppressed gel contraction with TGF-β1 dose dependently. TGF-β1 stimulated mRNA expression of TGFB1, CTGF, aSMA, and Col1A1 in keloid fibroblasts, while pirfenidone significantly inhibited mRNA expression of CTGF and aSMA in the identical cells. These findings suggest that pirfenidone suppresses the contraction of keloid-derived fibroblasts by inhibiting the down-stream pathway of TGF-β1, thus demonstrating its therapeutic utility for the treatment of keloid lesions. [ABSTRACT FROM AUTHOR]

The topical application of a mixture of sugar and povidone-iodine (PI) has been reported to accelerate the healing of cutaneous wounds and ulcers by promoting reepithelialization and granulation tissue formation, as well as by having an anti-microbial effect. In order to clarify the efficacy of a 70% sugar and 3% PI paste (U-PASTA™)(SP) on infectious skin ulcers, we made a bacterial infection model using methicillin-resistant Staphylococcus aureus (MRSA) on the skin of diabetic db/db mice, and investigated the effect of the paste on the healing process of wounds. Full-thickness wounds were made on the backs of female diabetic mice, (C57BL/ksJ db/db) and inoculated with S. aureus. SP was applied to the closed wounds for 8 days. The degree of repair was evaluated using three histological parameters: The degree of reepithelialization was given a percentage value of 0–100%; the amount of granulation tissue was quantified by measuring the area of granulation (mm2); and the number of capillary lumens in the granulation tissue was counted in the complete wound cross-section at 100× magnification. In addition, the colony-forming units (CFU) of MRSA on the wounds were counted. Continuous MRSA infection in the wounds of db/db mice was demonstrated with macroscopic and histopathological images. Wounding and infection caused by MRSA on the back of the diabetic mice significantly induced delayed reepithelialization, granulation tissue formation with inflammatory cell infiltrate and increased CFU on wounds ( P < 0.01, respectively) compared to those of the MRSA-infected normal mice. Application of SP significantly accelerated reepithelialization ( P < 0.01) and decreased CFU ( P < 0.05) of the ulcers in the MRSA-infected wounds, compared to the non-treated group. Histopathological evaluation and CFU on this animal model revealed no significant difference between Methicilin-sensitive Staphylococcus aureus and MRSA infection. These results indicate that wounding on db/db mice provides a useful animal model of bacterial skin infections, and that SP is an effective topical agent for the treatment of diabetic skin ulcers. [ABSTRACT FROM AUTHOR]

Sphingosylphosphorylcholine (SPC) has been reported to stimulate wound healing by its potent mitogenic effect. Fibronectin (FN) is a cell-adhesion protein that plays an important role in cell migration and collagen deposition during wound healing. In order to elucidate further the mechanism involved in the accelerated wound healing stimulated by SPC, we studied the role of SPC in FN production in cultured human dermal fibroblasts. We demonstrated that SPC dose- and time-dependently enhanced the expression of FN in human dermal fibroblast at the protein and mRNA levels. IL-6 is known to stimulate the production of FN in fibroblasts. SPC also markedly induced IL-6 production in cultured human dermal fibroblasts in a dose- and time-dependent manner. We also demonstrated that FN mRNA expression in human dermal fibroblasts was upregulated 4 h after IL-6 treatment. Moreover, pretreatment with neutralizing anti-IL-6 antibodies partially blocked the upregulation of FN mRNA expression induced by SPC in human dermal fibroblasts. These results indicate that SPC may stimulate FN synthesis through IL-6 production in cultured human dermal fibroblasts. [ABSTRACT FROM AUTHOR]