title: Endothelin-1, an ulcer inducer, promotes gastric ulcer healing via mobilizing gastric myofibroblasts and stimulates production of stroma-derived factors.
abstract: 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.
authors.affiliation: 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
authors.forename: Tsutomu
authors.initials: T
authors.lastname: Nishida
authors.forename: Shingo
authors.initials: S
authors.lastname: Tsuji
authors.forename: Arata
authors.initials: A
authors.lastname: Kimura
authors.forename: Masahiko
authors.initials: M
authors.lastname: Tsujii
authors.forename: Syuji
authors.initials: S
authors.lastname: Ishii
authors.forename: Toshiyuki
authors.initials: T
authors.lastname: Yoshio
authors.forename: Shinichiro
authors.initials: S
authors.lastname: Shinzaki
authors.forename: Satoshi
authors.initials: S
authors.lastname: Egawa
authors.forename: Takanobu
authors.initials: T
authors.lastname: Irie
authors.forename: Masakazu
authors.initials: M
authors.lastname: Yasumaru
authors.forename: Hideki
authors.initials: H
authors.lastname: Iijima
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Murata
authors.forename: Sunao
authors.initials: S
authors.lastname: Kawano
authors.forename: Norio
authors.initials: N
authors.lastname: Hayashi
mesh_terms: 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*
chemical_list: 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)