Zsuzsa Sandor

Basic fibroblast growth factor and PDGF in GI diseases

This chapter is focused on the relatively recent investigations demonstrating a pharmacological and pathophysiological role for bFGF and PDGF in ulcerative and inflammatory lesions in the upper and lower GI tract. Our initial animal model experiment revealed a potent healing of chronic cysteamine-induced duodenal ulcer in rats treated by intragastric administration of bFGF-w, the acid-resistant bFGF-CS23 or PDGF-BB without decreasing gastric acid secretion or concentration. Subsequently we and others have demonstrated that these peptides accelerate the healing of chronic gastric ulcers, chronic erosive gastritis and ulcerative colitis. Contrary to the potent ulcer healing properties of bFGF and PDGF, these growth factors exert no or modest acute gastroprotection. Nevertheless, new biochemical, molecular biological and immunohistochemical studies indicate that both bFGF and PDGF play a pathophysiological role in the natural history of ulcer healing.

Gene expression and gene therapy in experimental duodenal ulceration

Gastroduodenal ulceration is still poorly understood and changes in gene expression may provide new mechanistic insights. Previously, we demonstrated that angiogenic growth factors are potent ulcer healing agents, and the synthesis of bFGF, PDGF and VEGF is enhanced early in duodenal ulcer healing. The initial molecular event in duodenal ulceration seems to be the organ-specific early release of ET-1 in the pre-ulcerogenic stages after the administration of duodenal ulcerogen cysteamine in rats. We also briefly review here data from literature indicating a central role of ET-1 in gastroduodenal ulceration. After studying the involvement of immediate early genes (e.g. egr-1, Sp1) in ulcer development, we now investigated expression of other genes in the duodenal mucosa in the early stages of chemically induced duodenal ulceration in rats. Following a brief review of principles of gene expression and gene therapy, we review our preliminary gene expression studies, involving monitoring about 1200 genes which revealed about 160 signals and prominent changes in about 30 genes in the early stages of experimental duodenal ulceration. Cysteamine enhanced ET-B receptor gene expression in 30 min, while transcription factors (MAX, STAT 3) showed increased expression in 12 h. We recently also initiated gene therapy studies to enhance the local synthesis of PDGF and VEGF to accelerate duodenal ulcer healing, using a single dose of naked DNA (ND) or adenoviral (AV) vectors of VEGF and PDGF in rats with cysteamine-induced duodenal ulcers. Gene therapy with ND or AV of VEGF or PDGF significantly accelerated chronic duodenal ulcer healing, and increased levels of VEGF and PDGF were detected by Western blotting and ELISA in duodenal mucosa after both VEGF and PDGF gene therapy. Thus, gene expression studies provide new insights into the molecular mechanisms of duodenal ulceration and VEGF or PDGF gene therapy seems to be a new option to achieve a rapid ulcer healing.

Radiation-induced enterocolitis: Basic and applied science

We adapted and introduced in our laboratory a simplified animal model of radiation-induced enterocolitis. After a shielding of the parenchymatous organs, our dose-response studies revealed that 20 Gy x-ray radiation resulted in about 20% mortality and reproducible lesions in the terminal ileum and proximal colon. These changes are optimal for pharmacologic studies since they may be decreased or aggravated by drugs. Sucralfate dose-dependently decreased the clinical signs of enterocolitis (e.g., lethargy, diarrhea) as well as the number and area of ileal and colonic erosions and ulcers. The wet weight of the ileum and colon were also decreased by sucralfate. bFGF at the small doses used exerted a beneficial effect only on a few of the parameters of enterocolitis. Thus sucralfate, and maybe bFGF, might decrease the severity and accelerate the healing of radiation-induced enterocolitis.

Growth factors in gastrointestinal diseases.

This review focuses on the recent investigations demonstrating a pharmacological and pathophysiological role for basic fibroblast growth factor (bFGF), platelet-derived growth factor (PDGF) and vascular endothelial growth factor (VEGF) in ulcerative and inflammatory lesions in the upper and lower gastrointestinal (GI) tract.Our initial experiments revealed that intragastric administration of bFGF-w, acid-resistant bFGF-CS23 and PDGF-BB healed chronic cysteamine (mercap-tamine)-induced duodenal ulcer in rats, without decreasing gastric acid secretion or concentration. Subsequently we and others have demonstrated that these peptides accelerate the healing of chronic gastric ulcers, chronic erosive gastritis and ulcerative colitis although they have no or modest acute gastric protective activity. Our recent results revealed a decreased bioactivity of bFGF and PDGF in the presence of certain strains of Helicobacter pylori, and this might explain, at least in part, the poor rates of ulcer healing in H. pylori-positive patients. VEGF, in addition to stimulating angiogenesis and granulation tissue production in duodenal ulcer healing, also has an acute gastroprotective effect.New biochemical, molecular biological and immunohistochemical studies indicate that bFGF, PDGF and VEGF play a pathophysiological role in the natural history of ulcer healing. Thus, growth factor research, especially regarding their possible use as a therapeutic tool in duodenal ulcer and colitis, is challenging. On the other hand, in some GI malignancies the diagnostic use of bFGF might be of clinical benefit. However, much research work is needed to transform these ‘endogenous drugs’ to ‘diagnostic tools’ and ‘exogenous drugs’.