Basic fibroblast growth factor (bFGF) is essential in angiogenesis since it stimulates endothelial cell migration and proliferation. The mechanism of this growth factor in endothelial cell migration has not been well characterized in contrast to that of endothelial cell proliferation. We here studied the signal transduction pathway of bFGF in human dermal microvascular endothelial cell (HDMEC) migration. The implication of signal transducers and activators of transcription (STAT) 3 in keratinocyte migration has been reported. Several studies indicated that STAT is another important pathway downstream of bFGF. This led us to hypothesize that STAT3 phosphorylation plays a critical role in HDMEC migration. Therefore, we studied a role of STAT3 in the migration of HDMEC. HDMEC expressed a marked increase of phosphorylated STAT3 in the nuclear fraction after addition of bFGF by immunohistochemical staining. SOCS1 and SOCS3 mRNA also increased in HDMEC after stimulation of bFGF. These data demonstrate that STAT3 and its phosphorylation are involved in the downstream pathway of bFGF/bFGFR interaction and regulate bFGF-induced HDMEC migration.

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Skin fibrotic disorders are understood to develop under the influence of some growth factors, such as transforming growth factor-beta (TGF-β), basic fibroblast growth factor (b-FGF), or connective tissue growth factor (CTGF). To establish an appropriate animal model of skin fibrosis by exogenous application of growth factors, we investigated the effects of growth factors in vivo by injecting TGF-β, CTGF and bFGF into subcutaneous tissue of newborn mice. A single application of TGF-β resulted in the formation of transient granulated tissue that disappeared despite 7days of consecutive injections. However, persistent fibrosis was observed when CTGF was injected from 4 to 7 days after TGF-β injections for the first 3days. Also, injecting TGF-β plus bFGF produced fibrotic tissue. Thus, we succeeded in established an animal model of skin fibrotic disorders by the exogenous application of growth factors, and this animal model will be useful for future studies in this area.

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We summarized previous reports pertaining to the effects of bFGF on the in vitro cell growth of keratinocytes and on in vivo re-epithelialization of wounds. We also described the effects of bFGF on the cell growth of human keratinocytes cultured on various extracellular matrices based on a study we did recently. When bFGF is used clinically as a wound-treatment drug, it is important to know the conditions under which it will have its maximal effects.

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Human skin, especially epidermis, shows various morphological characteristics depending on the body-site, such as scalp, face, lip, trunk, palmoplantar and so on. Although the differences have been explained by the number of skin appendages or the variance of epidermal keratinocytes, it was recently elucidated that dermal fibroblasts showed biochemical characteristics depending on body-site. In order to reveal site-specific characteristic of tinnk, palroplactor skin or oral incosa by gene aiorry, we compared the expressions of the extracellular matrix and adhesion molecinles among fibroblasts of those body sites. As the result, we elucidated that fibroblasts showed various site-specific gene expressions. Furthermore, in order to examine differences of site-specific fibroblasts in wound healing, we analyzed the response to basic fibroblast growth factor. Proliferative rate of oral mucosal fibroblasts was accelerated more than trunk or palmoplantar skin. The mechanism is unclear. However, it might be a factor that oral mucosa heals faster than other body-sites.

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Fibroblast-collagen matrix contraction has been used as a model system to study how cells organize connective tissue. Previous work showed that lysophosphatidic acid(LPA)-stimulated floating collagen matrix contraction is independent of Rho kinase while platelet-derived growth factor(PDGF)-stimulated contraction is Rho kinase-dependent. The current studies were carried out to determine the signaling mechanisms of basic fibroblast growth factor(bFGF)-stimulated fibroblast-collagen matrix contraction. LPA, PDGF and bFGF each equally well stimulated collagen matrix contraction. Both of two kinase inhibitors, LY294002 for phosphatidylinositol-3-Kinase(PI3K)and Y27632 for Rho kinase, suppressed the bFGF-stimulated fibroblast-collagen matrix contraction. With bFGF stimulation, fibroblasts in collagen matrix spread with prominent stress fiber network formation. The present study implicates PI3K→Rac→Rho→Rho kinase as being involved in bFGF-stimulated collagen matrix contraction. Since this pathway is similar to PDGF but not LPA, the combination therapy with bFGF and LPA is worthwhile to future strategy for the treatment of chronic cutaneous wound. The elucidation of bFGF-triggered signal transduction may be an important clue to understand the roles of bFGF and study the possibility of the combination therapy in wound healing.

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Basic fibroblast growth factor (bFGF) is widely expressed in skin tissue. There are several mechanism of the elevated serum bFGF levels in patients with various skin or internal organ diseased.

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The stimulatory effect of basic fibroblast growth factor (bFGF, Fiblast^® spray) on healing in wounds prepared in vitro in reconstructed human skin and in vivo in rabbit ear skin was histologically evaluated. In the in vitro in study, bFGF showed the strongest stimulatory effect on reepithelialization, at a dose of 0.1μg/cm², similar to that induced by PDGF-BB. Likewise, in the in vivo wound model using 6mm-size rounded full-thickness skin wounds, the bFGF treated group (1.0μg/cm²) showed significant stimulation of reepithelialization and granulation tissue formation (p<0.05). These results suggest that bFGF stimulates wound healing by enhancing reepithelialization as well as granulation tissue formation.

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During the wound healing process, inflammatory cell infiltration induces inflammatory process and promotes the wound healing by producing various growth factors and proinflammatory cytokines. This inflammatory cell infiltration is the process that is highly regulated by multiple cell adhesion molecule expression. Consistent with this notion, the would healing is delayed in mice lacking cell adhesion molecules. This delayed would healing by the absence of cell adhesion molecules is normalized by treatment with basic fibroblast growth factor. This indicates that basic fibroblast growth factor plays an important and critical role in the wound healing process.

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Bacic fibroblast growth factor (bFGF) which is one of the growth factors gives us good useful clinical effects for skin ulcers and pressure sores. It operates on good vascularization and good granulation. In addition, we experienced that the combination therapy using bFGF and an artificial dermis can make sufficient granulation tissues in intractable ulcers with the bared bone and, further, we confirmed experimentally that the combination therapy using bFGF and an artificial dermis was effective with full-thickness skin defect to the bare cartilage in rabbits through tissue samples with H-E staining and molded blood vessels with scanning electron microscopes. It concluded that the combination therapy using bFGF and an artificial dermis was effective for intractable ulcers with the bared bone or cartilage.

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