New molecular mechanisms of duodenal ulceration.
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-1alpha). 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.
Szabo
Sandor
S
VA Medical Center, University of California-Irvine, School of Medicine, Long Beach, CA, USA. sandor.szabo@med.va.gov
Deng
Xiaoming
X
Khomenko
Tetyana
T
Chen
Longchuan
L
Tolstanova
Ganna
G
Osapay
Klara
K
Sandor
Zsuzsanna
Z
Xiong
Ximing
X
D020533:Angiogenesis Inhibitors / Q000502:physiology; D042501:Angiogenic Proteins / Q000502:physiology; D000818:Animals; D004381:Duodenal Ulcer / Q000139:chemically induced / Q000209:etiology* / Q000378:metabolism* / Q000473:pathology; D051766:Early Growth Response Protein 1 / Q000502:physiology; D019332:Endothelin-1 / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism; D006801:Humans
D020533:Angiogenesis Inhibitors; D042501:Angiogenic Proteins; D051766:Early Growth Response Protein 1; D019332:Endothelin-1