Gastrin enhances gastric mucosal integrity through cyclooxygenase-2 upregulation in rats.
Gastrin, PGs, and growth factors have important roles in maintaining gastrointestinal mucosal integrity. Cyclooxygenases (COX-1 and COX-2) are the key enzymes involved in PG synthesis. This study aimed to clarify the mechanisms of gastric mucosal protection by gastrin. Fasted rats were administered subcutaneous gastrin 17 with or without gastrin receptor antagonist YM022 pretreatment. Heparin-binding epidermal growth factor-like growth factor (HB-EGF) and COX-2 expression were examined using Western blot analysis. Another series of experiments investigated 1) PGE(2) levels in gastric mucosa, 2) the protective action of gastrin against gastric damage by acidified ethanol, 3) the effects of a specific HB-EGF-neutralizing antibody on gastrin-induced COX-2 expression, and 4) the effects of a specific COX-2 inhibitor NS-398 on PGE(2) synthesis and the mucosal protection afforded by gastrin. Gastrin dose-dependently increased HB-EGF, COX-2 expression, and PGE(2) levels and reduced gastric damage. However, pretreatment with YM022 dose-dependently abolished such effects of gastrin. A specific HB-EGF- neutralizing antibody and an EGF receptor inhibitor decreased gastrin-induced COX-2 expression. NS-398 blocked gastrin-induced PGE(2) synthesis and mucosal protection. In conclusion, this study demonstrates that gastrin enhances gastric mucosal integrity through COX-2, which is partially mediated by HB-EGF, and PGE(2) upregulation in rats.
Komori
Masato
M
Department of Internal Medicine and Therapeutics, Osaka University Graduate School of Medicine, 2-2 Yamadaoka, Suita, Japan.
Tsuji
Shingo
S
Sun
Wei-Hao
WH
Tsujii
Masahiko
M
Kawai
Naoki
N
Yasumaru
Masakazu
M
Kakiuchi
Yoshimi
Y
Kimura
Arata
A
Sasaki
Yutaka
Y
Higashiyama
Shigeki
S
Kawano
Sunao
S
Hori
Masatsugu
M
D000818:Animals; D000906:Antibodies / Q000494:pharmacology; D015153:Blotting, Western; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2; D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology; D015232:Dinoprostone / Q000032:analysis; D004815:Epidermal Growth Factor / Q000032:analysis / Q000276:immunology; D000431:Ethanol / Q000494:pharmacology; D005753:Gastric Mucosa / Q000737:chemistry / Q000187:drug effects / Q000473:pathology / Q000502:physiology*; D005755:Gastrins / Q000097:blood / Q000494:pharmacology*; D066257:Heparin-binding EGF-like Growth Factor; D017228:Hepatocyte Growth Factor / Q000032:analysis; D006863:Hydrogen-Ion Concentration; D007124:Immunoenzyme Techniques; D007150:Immunohistochemistry; D036341:Intercellular Signaling Peptides and Proteins; D007527:Isoenzymes / Q000032:analysis* / Q000378:metabolism; D008297:Male; D008565:Membrane Proteins; D009578:Nitrobenzenes / Q000494:pharmacology; D011451:Prostaglandin-Endoperoxide Synthases / Q000032:analysis* / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D013276:Stomach Ulcer / Q000473:pathology; D013449:Sulfonamides / Q000494:pharmacology
D000906:Antibodies; D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors; D005755:Gastrins; C587885:Hbegf protein, rat; D066257:Heparin-binding EGF-like Growth Factor; D036341:Intercellular Signaling Peptides and Proteins; D007527:Isoenzymes; D008565:Membrane Proteins; D009578:Nitrobenzenes; D013449:Sulfonamides; C080955:N-(2-cyclohexyloxy-4-nitrophenyl)methanesulfonamide; D000431:Ethanol; D004815:Epidermal Growth Factor; D017228:Hepatocyte Growth Factor; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2; D011451:Prostaglandin-Endoperoxide Synthases; C496513:Ptgs1 protein, rat; D015232:Dinoprostone