Previously, we reported that
TGP-580, a mutein of human
basic fibroblast growth factor (bFGF), accelerated the healing of gastric and
duodenal ulcers in rats. In the present study, we examined the effect of
TGP-580 on the healing of colonic
ulcers. In male Sprague Dawley rats,
ulcers were induced in the colon 6 cm from the anus by
enema of 50 μl of 3%
N-ethylmaleimide, a sulfhydryl
alkylator. The lesions were examined under a dissecting microscope (x10). The concentration of bFGF in the ulcerated colon was measured by
enzyme immunoassay, and both the distribution of bFGF and the density of microvessels in the
ulcer bed were examined by immunohistochemical staining. The content of bFGF in the ulcerated colon was markedly increased associated with
ulcer healing, and
ulcer healing was significantly delayed by
intravenous administration of a
monoclonal antibody for bFGF (MAb 3H3) once daily for 10 days. In the
ulcer bed, many cells such as fibroblasts, vascular endothelial cells and macrophages were positively stained with bFGF antiserum.
TGP-580, human bFGF or
dexamethasone was given intracolonally twice daily for 10 days, starting the day after
ulcer induction.
TGP-580 (0.2 - 20 μg/ml, 200 μl/rat) dose-dependently accelerated
ulcer healing, and its effect was more than 10 times stronger than that of human bFGF. Density (μm/0.01 mm(2)) of microvessels in the
ulcer bed was significantly increased by treatment with
TGP-580, and there was a good correlation between the density of microvessels and the decrease of ulcerated area (R(2) = 0.633). On the other hand
dexamethasone (20 μg/ml) inhibited angiogenesis in the
ulcer bed and delayed
ulcer healing. These results suggest that angiogenesis in the
ulcer bed plays an important role in
ulcer healing, and that bFGF mutein
TGP-580 accelerated colonic
ulcer healing, at least in part, by stimulating angiogenesis, whereas
glucocorticoids may delay the healing by inhibiting angiogenesis.