Interactions between mesenchyme and epithelium are critical for the growth and morphogenesis of many organs, and play an important role in physiological processes such as wound healing and hair growth. KGF is among the key soluble mediators involved in these interactions. KGF is a member of the heparin- binding Fibroblast growth factor (FGF) family and was shown to function as a mesenchymally-derived mitogen for a variety of epithelial cell types. We have demonstrated that the immunomodulator AS101 (ammonium thrichlro [dioxoethylene-o-o'] tellurate), which was shown to protect humans and rodents against cytosine arabinoside (ARA-C)- induced alopecia, strongly induces the expression of KGF. In vivo studies determined that administration of AS101 2 hr prior to the onset of ARA-C protecd neonatal rats against chemotherapy- induced alopecia, and analysis of skin byopsies derived from AS101-treated animals revealed a time- dependent elevation in KGF and correlated with protection against alopecia. Similarly to KGF, we observed that in a variety of human dermal fibroblasts, AS101 also stimulates the production of mRNA for hepatocyte growth factor/scatter factor (HGF/SF), another heparin-binding epithelial mitogen recently implicated in hair growth. The effect of AS101 on HGF/SF expression was time- and dose-dependent, was reflected at the protein and bioactivity levels and could be observed in vitro andin vivo. In order to determine whether KGF could mediate other epithelial cytoprotective effects of AS101, we utilized a rat model in which gastric lesions were induced by intragastric instillation of HCl. Results indicated that intraperitoneal (ip) administration of AS101 3 hr prior to HCl challenge was sufficient to elevate KGF expression by gastric mesenchymal cells and to significantly reduced the extension of HCl-induced gastric lesions, when compared to control untreated animals. Thus, the AS101-mediated increase in KGF expression by dermal and gastric mesenchymal cells suggests a possible role for KGF as a general mediator of the protective effects of AS101 against chemotherapy-induced alopecia and HCl-induced gastric lesions.
