Ellagic acid facilitates indomethacin-induced gastric ulcer healing via COX-2 up-regulation

VEGF is a highly specific stimulator of endothelial cells and may play an important role in angiogenesis in the process of tissue regeneration. We previously showed that cyclooxygenase-2 (COX-2) expressed in mesenchymal cells of the ulcer bed is involved in the ulcer repair process. To clarify the role of COX-2 in angiogenesis during gastric ulcer healing, we investigated the relation between COX-2 expression and VEGF production in human gastric fibroblasts in vivo and in vitro. Gastric fibroblasts were cultured in RPMI 1640 with and without IL-1α or IL-1β in the presence or absence of NS-398, a selective COX-2 inhibitor. Supernatant VEGF and PGE2 concentrations were measured by enzyme-linked immunosorbent assay. COX-2 expression in fibroblasts was determined by Western blot analysis. VEGF and COX-2 expression in surgical resections of human gastric ulcer tissue was examined immunohistochemically. IL-1 dose dependently enhanced VEGF release in cultured gastric fibroblasts after a 24-h stimulation. IL-1 also stimulated PGE2 production in gastric fibroblasts via COX-2 induction. NS-398 significantly suppressed VEGF and PGE2 release from IL-1-stimulated gastric fibroblasts; concurrent addition of PGE2 restored NS-398-inhibited VEGF release. COX-2 and VEGF immunoreactivity were colocalized in fibroblast-like cells in the ulcer bed of gastric tissues. These results suggest that COX-2 plays a key role in VEGF production in gastric fibroblasts stimulated by IL-1 in vitro and that angiogenesis induced by the COX-2-VEGF pathway might be involved in gastric ulcer healing.

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Sa1622 - Role of Cox-2 Gene Promoter Methylation and Helicobacter Pylori Infection in Gastric Ulcer Healing

Gastroenterology ◽

10.1016/s0016-5085(18)31446-x ◽

2018 ◽

Vol 154 (6) ◽

pp. S-332

Author(s):

Hiroshi Yasuda ◽

Yoshiyuki Watanabe ◽

Fumio Itoh

Keyword(s):

Helicobacter Pylori ◽

Gastric Ulcer ◽

Promoter Methylation ◽

Ulcer Healing ◽

Gene Promoter ◽

Helicobacter Pylori Infection ◽

Gastric Ulcer Healing ◽

Cox 2

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A vascular endothelial growth factor mimetic accelerates gastric ulcer healing in an iNOS-dependent manner

AJP Gastrointestinal and Liver Physiology ◽

10.1152/ajpgi.90325.2008 ◽

2008 ◽

Vol 295 (2) ◽

pp. G374-G381 ◽

Cited By ~ 21

Author(s):

Genevieve K. Dudar ◽

Luca D. D'Andrea ◽

Rossella Di Stasi ◽

Carlo Pedone ◽

John L. Wallace

Keyword(s):

Vascular Endothelial Growth Factor ◽

Gastric Ulcer ◽

Growth Factor ◽

Ulcer Healing ◽

No Production ◽

Dependent Manner ◽

Vascular Endothelial ◽

Gastric Ulcer Healing ◽

Cox 2 ◽

Endothelial Growth Factor

Angiogenesis is crucial to all types of wound healing, including gastric ulcer healing. The most potent promoter of angiogenesis is vascular endothelial growth factor (VEGF). We hypothesized that a 15-amino acid peptide designed to mimic the angiogenic action of VEGF would accelerate gastric ulcer healing. Gastric ulcers were induced in mice by serosal application of acetic acid. Treatment with the VEGF mimetic accelerated gastric ulcer healing when administered orally or intraperitoneally, at a dose of 50 ng/kg or greater. Such healing was not observed when the reverse sequence pentadecapeptide or the full-length VEGF protein was administered. Contrary to our hypothesis, the VEGF mimetic did not significantly increase angiogenesis in the ulcerated stomach. The enhancement of ulcer healing by the VEGF mimetic occurred independently of cyclooxygenase-2 (COX-2) activity but was blocked by inhibitors of inducible nitric oxide synthase (iNOS). These results demonstrate that a VEGF mimetic is a potent stimulus for gastric ulcer healing, even when given orally. The effects of the mimetic were independent of stimulatory effects on angiogenesis and COX-2 activity but were dependent on iNOS-derived NO production.

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