Endothelin-1, an ulcer inducer, promotes gastric ulcer healing via mobilizing gastric myofibroblasts and stimulates production of stroma-derived factors.
Endothelin (ET)-1 is a potent inducer of peptic ulcers. The roles of ET-1 in ulcer healing, however, have remained unclear, and these were investigated in mice. Gastric ulcers were induced in mice by serosal application of acetic acid. Three days later, mice were given a neutralizing ET-1 antibody or nonimmunized serum. The ulcer size, amount of fibrosis and myofibroblasts, and localization of ET-1 and ET(A/B) receptors were analyzed. To elucidate the mechanisms underlying the effects of ET-1, we examined the proliferation, migration, and release of growth and angiogenic factors in gastric myofibroblasts with or without ET-1. The expression of prepro-ET-1 (an ET-1 precursor) and ET-converting enzyme-1 was examined in gastric myofibroblasts using RT-PCR. Immunoneutralization of ET-1 delayed gastric ulcer healing. The areas of fibrosis and myofibroblasts were smaller in the anti-ET-1 antibody group than in the control. ET-1 was expressed in the gastric epithelium, myofibroblasts, and other cell types. ET(A) receptors, but not ET(B) receptors, were present in myofibroblasts. ET-1 increased proliferation and migration of gastric myofibroblasts. ET-1 stimulated the release of hepatocyte growth factor, VEGF, PGE(2), and IL-6 from gastric myofibroblasts. mRNA for prepro-ET-1 and ET-converting enzyme-1 was also expressed. ET-1 promotes the accumulation of gastric myofibroblasts and collagen fibrils at gastric ulcers. ET-1 also stimulates migration and proliferation of gastric myofibroblasts and enhances the release of growth factors, angiogenic factors, and PGE(2). Thus ET-1 has important roles not only in ulcer formation but also in ulcer healing via mobilizing myofibroblasts and inducing production of stroma-derived factors.
Nishida
Tsutomu
T
Department of Gastroenterology and Hepatology, Clinical Research Bldg. (K1), Osaka University Graduate School of Medicine, 2-2 Yamadaoka, Suita, Osaka 565-0871, Japan. tnishida@medone.med.osaka-u.ac.jp
Tsuji
Shingo
S
Kimura
Arata
A
Tsujii
Masahiko
M
Ishii
Syuji
S
Yoshio
Toshiyuki
T
Shinzaki
Shinichiro
S
Egawa
Satoshi
S
Irie
Takanobu
T
Yasumaru
Masakazu
M
Iijima
Hideki
H
Murata
Hiroaki
H
Kawano
Sunao
S
Hayashi
Norio
N
D043925:Angiogenesis Inducing Agents / Q000378:metabolism; D000818:Animals; D000906:Antibodies / Q000276:immunology; D002465:Cell Movement; D049109:Cell Proliferation; D016207:Cytokines / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D019332:Endothelin-1 / Q000276:immunology / Q000378:metabolism*; D005347:Fibroblasts / Q000378:metabolism* / Q000502:physiology; D005753:Gastric Mucosa / Q000378:metabolism*; D006133:Growth Substances / Q000378:metabolism; D007150:Immunohistochemistry; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D010456:Peptides, Cyclic / Q000494:pharmacology; D010919:Placebos; D044022:Receptor, Endothelin A / Q000378:metabolism; D044023:Receptor, Endothelin B / Q000378:metabolism; D013270:Stomach / Q000473:pathology; D013276:Stomach Ulcer / Q000628:therapy*; D013997:Time Factors; D014456:Ulcer / Q000378:metabolism*
D043925:Angiogenesis Inducing Agents; D000906:Antibodies; D016207:Cytokines; D019332:Endothelin-1; D006133:Growth Substances; D010456:Peptides, Cyclic; D010919:Placebos; D044022:Receptor, Endothelin A; D044023:Receptor, Endothelin B; C072247:cyclo(Trp-Asp-Pro-Val-Leu)