Gastroenterology

Gastroenterology

Volume 128, Issue 4, April 2005, Pages 975-986
Gastroenterology

Basic-alimentary tract
Therapeutic effects of rectal administration of basic fibroblast growth factor on experimental murine colitis

https://doi.org/10.1053/j.gastro.2005.01.006Get rights and content

Background & Aims: Basic fibroblast growth factor (bFGF) is a promising therapeutic agent for various diseases. It remains unclear, however, whether bFGF is effective for the treatment of inflammatory bowel disease. The aim of this study was to examine the efficacy of bFGF on 2 experimental murine colitis models and to investigate its molecular mechanisms. Methods: We evaluated the effects of human recombinant bFGF (hrbFGF) on mice with dextran sulfate sodium (DSS)-induced colitis and mice with trinitrobenzene sulfonic acid (TNBS)-induced colitis as well as normal mice. Body weight, survival rate, and histologic findings of the colonic tissues were examined. Gene expression of tumor necrosis factor (TNF)-α, cyclooxygenase (COX)-2, transforming growth factor (TGF)-β, mucin 2 (MUC2), intestinal trefoil factor (ITF), and vascular endothelial growth factor (VEGF) in the colonic tissues was determined. The proliferation activity of hrbFGF on the colonic epithelium was evaluated by immunohistochemistry. Results: Rectal administration of hrbFGF ameliorated DSS-induced colitis in a dose-dependent manner. Gene expression of TNF-α was significantly reduced in the colonic tissues of mice with DSS-induced colitis treated with hrbFGF, whereas MUC2 and ITF messenger RNA expression was up-regulated. Rectal administration of hrbFGF significantly improved the survival rate of mice with TNBS-induced colitis and partially ameliorated colitis. hrbFGF significantly increased the number of Ki-67-positive cells in the colonic epithelium of normal mice, and up-regulated the gene expression of COX-2, TGF-β, MUC2, ITF, and VEGF in the colonic tissues. Conclusions: Rectal administration of bFGF might be a promising option for the treatment of inflammatory bowel disease.

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Animals

Female C57BL/6 mice (8–10 weeks old; Japan SLC, Inc, Shizuoka, Japan) and female SJL/J mice (10–11 weeks old; Charles River Japan, Inc, Kanagawa, Japan) were used for the experiments. They were fed with standard laboratory chow and tap water ad libitum. All mice were housed in specific pathogen-free conditions in the animal facility of Kyoto University. The studies were approved by the animal protection committee of our institution.

Induction of colitis

To induce colitis, C57BL/6 mice were given 3% DSS (mol wt,

Body weight change

In the nontreated mice with DSS-induced colitis, body weight gradually decreased and did not recover at the end of the experiment. On the other hand, the body weight in mice with DSS-induced colitis treated with 1.0 or 5.0 mg/kg of hrbFGF significantly recovered in a dose-dependent manner compared with the nontreated mice with DSS-induced colitis (Figure 2).

Colonic length

The colonic length in the nontreated mice with DSS-induced colitis was significantly shorter than in normal mice. The colonic length in

Discussion

For the past 10 years, several growth factors, such as EGF, FGF, insulin-like growth factor, and hepatocyte growth factor, have been tested as potent therapeutic agents in a variety of experimental models of human IBD.30, 31, 32, 33, 34, 35, 36 Among them, a great deal of attention has been paid to the FGF family, especially KGF-1 and KGF-2, because several clinical and experimental studies showed that they are also effective for the treatment of epithelial damage in other tissues, such as skin

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    Supported in part by the Establishment of International COE for Integration of Transplantation Therapy and Regenerative Medicine (COE program of the Ministry of Education, Culture, Sports, Science, and Technology, Japan); Grant-in-Aid for Scientific Research (C) from the Ministry of Culture and Science in Japan (16560645); and Health and Labour Science Research Grants from the Japanese Ministry of Health, Labour and Welfare, and Research on Measures for Intractable Disease (Inflammatory Bowel Disease).

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