Hepatocyte growth factor as a key to modulate anti-ulcer action of prostaglandins in stomach.
Although the clinical efficacy of prostaglandins (PGs), especially on gastric mucosal injuries induced by nonsteroidal antiinflammatory drugs, is widely appreciated, their mechanism of action, apart from acid suppression, is quite unclear. In this study, we have established a primary culture system of human gastric fibroblasts and clearly demonstrated that PGs strongly induce the expression of hepatocyte growth factor (HGF) in the fibroblasts, which is mediated by PGE specific receptor, EP2 or EP4. Since HGF facilitates repair and protection of gastric epithelial cells in a paracrine manner, it is assumed that some of the beneficial effects of PGs may be mediated by HGF. To confirm this assumption, we established a simplified in vitro culture gastric mucosal model which consists of gastric epithelial cells and gastric fibroblasts. Using the model, we performed a round wound restitution assay. PGE1 remarkably accelerated restitution which was completely inhibited by anti-HGF antibody, indicating that the action was mediated by HGF. To confirm these in vitro data, we further demonstrated that HGF mRNA expression is downregulated at the edges of nonsteroidal antiinflammatory drug-induced gastric ulcers where PGs should be depleted. In summary, we proposed that gastric fibroblasts are newly recognized targets of PGs, and HGF produced by human gastric fibroblasts may be a key factor for anti-ulcer action of PGs in the stomach.
Takahashi
M
M
Second Department of Internal Medicine, Faculty of Medicine, University of Tokyo, Japan. TAKAHASHI-2IM@H.U-TOKYO.AC.JP
Ota
S
S
Hata
Y
Y
Mikami
Y
Y
Azuma
N
N
Nakamura
T
T
Terano
A
A
Omata
M
M
D000328:Adult; D000818:Animals; D000897:Anti-Ulcer Agents; D001483:Base Sequence; D002478:Cells, Cultured; D018920:Coculture Techniques; D000242:Cyclic AMP / Q000494:pharmacology; D005347:Fibroblasts / Q000166:cytology / Q000187:drug effects / Q000502:physiology; D005753:Gastric Mucosa / Q000166:cytology / Q000187:drug effects / Q000502:physiology*; D015870:Gene Expression / Q000187:drug effects; D017228:Hepatocyte Growth Factor / Q000096:biosynthesis*; D006801:Humans; D008969:Molecular Sequence Data; D016133:Polymerase Chain Reaction; D011453:Prostaglandins / Q000494:pharmacology* / Q000502:physiology*; D011817:Rabbits; D018078:Receptors, Prostaglandin E / Q000096:biosynthesis* / Q000502:physiology; D013270:Stomach / Q000166:cytology; D014158:Transcription, Genetic; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology
D000897:Anti-Ulcer Agents; D011453:Prostaglandins; D018078:Receptors, Prostaglandin E; D014409:Tumor Necrosis Factor-alpha; D017228:Hepatocyte Growth Factor; D000242:Cyclic AMP