Review article: transcription factors and growth factors in ulcer healing

This review is focused on recent investigations demonstrating a pharmacological and pathophysiologic role in gastroduodenal ulceration for growth factors such as basic fibroblast growth factor (bFGF), platelet-derived growth factor (PDGF) and vascular endothelial growth factor (VEGF), as well as for transcription factors. Our experiments revealed accelerated healing, without decreased gastric acid secretion, of chronic cysteamine-induced duodenal ulcers in rats treated daily for 3 weeks with intragastric administration of bFGF, PDGF or VEGF. Our recent studies also indicate a pathophysiological role of endogenous growth factors in the natural history of experimental duodenal ulcer development and healing. More recently, we investigated the genetic regulation of these growth factors in experimental duodenal ulceration. Since gene expression is most effectively controlled by transcription factors, proteins that bind to cis-acting elements of DNA and guide the binding of polymerase II to start the transcription of specific mRNA, we tested the hypothesis that the expression of IEGs and their transcription factor products, such as Egr-1 and Sp1, might precede the increased synthesis of bFGF, PDGF and VEGF in duodenal ulcer healing. Indeed, the duodenal ulcerogen cysteamine, but not its nonulcerogen and toxic analogue ethanolamine, rapidly increased duodenal (but not gastric) mucosal levels of ET-1, which was followed by enhanced expression of Egr-1 and a decrease in Sp1 in the preulcerogenic stage of duodenal ulceration. These changes in levels of ET-1 and expression of transcription factors were also accompanied by increased expression of the CDK inhibitor p21. Thus, not only growth factors such as bFGF, PDGF and VEGF, but also transcription factors such as Egr-1 and Sp1 and the cell cycle regulator p21, may play a role in the natural history of experimental duodenal ulceration.