Gene expression and gene therapy in experimental duodenal ulceration

Gastroduodenal ulceration is still poorly understood and changes in gene ex pression may provide new mechanistic insights. Previously, we demonstrated that angiogenic growth factors are potent ulcer healing agents, and the syn thesis of bFGF, PDGF and VEGF is enhanced early in duodenal ulcer healing. The initial molecular event in duodenal ulceration seems to be the organ-sp ecific early release of ET-1 in the pre-ulcerogenic stages after the admini stration of duodenal ulcerogen cysteamine in rats. We also briefly review h ere data from literature indicating a central role of ET-1 in gastroduodena l 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 duod enal ulceration in rats. Following a brief review of principles of gene exp ression and gene therapy, we review our preliminary gene expression studies , involving monitoring about 1200 genes which revealed about 160 signals an d prominent changes in about 30 genes in the early stages of experimental d uodenal 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 lo cal 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 A V of VEGF or PDGF significantly accelerated chronic duodenal ulcer healing, and increased levels of VEGF and PDGF were detected by Western blotting an d ELISA in duodenal mucosa after both VEGF and PDGF gene therapy. Thus, gen e 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. (C) 2001 Published by Elsevier Science Lt d.