Ximing Xiong

New molecular mechanisms of duodenal ulceration.

Abstract:  Stress is a major etiologic factor in the pathogenesis of gastric and duodenal ulceration, as first described in rats by Hans Selye. In patients with “peptic ulcers” duodenal ulcers are more frequent than gastric ulcers (except in Japan). Thus, our research during the last three decades focused on the molecular mechanisms of duodenal ulcer in rodent models of chemically induced duodenal ulceration, and here we review our three recent findings: Endothelins (ET‐1), the immediate early gene egr‐1 and imbalance of angiogenic/antiangiogenic molecules. Namely, we found an enhanced expression and release of ET‐1 within 15–30 min after the administration of duodenal ulcerogen cysteamine, resulting in local ischemia that triggers the expression of hypoxia‐inducible factors (HIF‐1α). Our gene expression studies also revealed an early (0.5–2 h) increase in the expression of egr‐1 that is followed (12–24 h) by upregulation of angiogenic growth factors (e.g., VEGF, bFGF, PDGF). Surprisingly, this event is also associated with an enhanced production of angiostatin and endostatin that probably counteract the beneficial effect of angiogenic molecules. Thus, the initial injury to endothelial and epithelial cells in duodenal ulceration seems to be aggravated (and not initiated) by HCl and proteolytic enzymes. The resulting mucosal necrosis does not rapidly heal because of the imbalance of VEGF and angiostatin/endostatin, hence duodenal ulcers develop. The experimental ulcers Selye described morphologically are now characterized at the molecular and genome level, involving unexpected mediators like ET‐1, egr‐1 and angiogenesis‐related molecules.

Inappropriate Angiogenic Response as a Novel Mechanism of Duodenal Ulceration and Impaired Healing

BackgroundDespite recent advances and better understanding of the etiology and the pathogenesis of gastrointestinal ulcer diseases, e.g., duodenal ulcer, the molecular events leading to ulcer development, delayed healing, and recurrence remain poorly elucidated.AimsAfter we found that duodenal ulcers did not heal despite increased levels of vascular endothelial growth factor (VEGF), we tested the hypothesis that an imbalance in angiogenic VEGF and anti-angiogenic endostatin and angiostatin might be important in the development and delayed healing of experimental duodenal ulcers.MethodsLevels of VEGF, endostatin, and angiostatin, and the expression and activity of related matrix metalloproteinases (MMP) 2 and 9 were measured in scrapings of rat proximal duodenal mucosa in the early and late stages of chemically induced duodenal ulceration. Furthermore, animals were treated with recombinant endostatin and MMP 2 inhibitor to test the relationship between MMP2 and endostatin and their involvement in healing of experimental duodenal ulcers.ResultsA concurrent increase of duodenal VEGF, endostatin, and angiostatin was noted during duodenal ulceration. Endostatin treatment aggravated duodenal ulcer. Levels of MMP2, but not MMP9, were increased. Inhibition of MMP2 reduced levels of endostatin and angiostatin, and attenuated duodenal ulcers.ConclusionsIncreased levels of endostatin and angiostatin induced by MMP2 delayed healing of duodenal ulcers despite concurrently increased VEGF. Thus, an inappropriate angiogenic response or “angiogenic imbalance” may be an important new mechanism in ulcer development and impaired healing.

Su1944 Formation of a “Histodilutional Barrier” in Gastric Mucosa: Protective Effect of VEGF on Ethanol-Induced Hemorrhagic Gastric Erosions in Rats

acid-induced hyperemia, further declined by IND pretreatment (10 mg/kg, sc). These results suggest that although GPR43 activation enhances duodenal mucosal defenses by increased DBS via 5HT4 activation, GPR43 activation combined with COX inhibition may increase vulnerability of duodenal mucosa to gastric acid via 5HT3 activation and reduction of blood flow. Excess 5-HT release via GPR43 activation with accompanying acid exposure may be implicated in functional dyspepsia symptoms.