EP4 agonist alleviates indomethacin-induced gastric lesions and promotes chronic gastric ulcer healing.
OBJECTIVE
To investigate EP4-selective agonist effect on indomethacin-induced gastric lesions and on the spontaneous healing of chronic gastric ulcers.


METHODS
In a mouse model of gastric bleeding with high dose of indomethacin (20 mg/kg), an EP4-selective agonist was administered orally. Stomach lesions and gastric mucous regeneration were monitored. In a mouse model of chronic gastric ulcer induced by acetic acid, EP4 agonist effect on the healing of chronic gastric ulcer was evaluated in the presence or absence of low dose indomethacin (3 mg/kg). In cultured human gastric mucous cells, EP4 agonist effect on indomethacin-induced apoptosis was assessed by flow cytometry.


RESULTS
The EP4-selective agonist reduced high dose indomethacin-induced acute hemorrhagic damage and promoted mucous epithelial regeneration. Low-dose indomethacin aggravated ulcer bleeding and inflammation, and delayed the healing of the established chronic gastric ulcer. The EP4 agonist, when applied locally, not only offset indomethacin-induced gastric bleeding and inflammation, but also accelerated ulcer healing. In the absence of indomethacin, the EP4 agonist even accelerated chronic gastric ulcer healing and suppressed inflammatory cell infiltration in the granulation tissue. In vitro, the EP4 agonist protected human gastric mucous cells from indomethacin-induced apoptosis.


CONCLUSIONS
EP4-selective agonist may prevent indomethacin-induced gastric lesions and promote healing of existing and indomethacin-aggravated gastric ulcers, via promoting proliferation and survival of mucous epithelial cells.
Jiang
Guang-Liang
GL
Department of Biological Sciences, Herbert Research Center, Allergan, Inc., Irvine, California, CA 92612, USA. jiang_guang-liang@allergan.com
Im
Wha-Bin
WB
Donde
Yariv
Y
Wheeler
Larry-A
LA
D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D005753:Gastric Mucosa / Q000187:drug effects / Q000473:pathology / Q000502:physiology; D006471:Gastrointestinal Hemorrhage / Q000139:chemically induced / Q000517:prevention & control*; D006801:Humans; D007213:Indomethacin / Q000009:adverse effects* / Q000494:pharmacology; D051379:Mice; D008810:Mice, Inbred C57BL; D018078:Receptors, Prostaglandin E / Q000819:agonists* / Q000627:therapeutic use*; D058309:Receptors, Prostaglandin E, EP4 Subtype; D012038:Regeneration / Q000187:drug effects / Q000502:physiology; D013272:Stomach Diseases / Q000139:chemically induced / Q000517:prevention & control*; D013276:Stomach Ulcer / Q000188:drug therapy* / Q000473:pathology; D014945:Wound Healing / Q000187:drug effects / Q000502:physiology*
C545650:PTGER4 protein, human; C545651:Ptger4 protein, mouse; D018078:Receptors, Prostaglandin E; D058309:Receptors, Prostaglandin E, EP4 Subtype; D007213:Indomethacin