Endothelin-1, an ulcer inducer, promotes gastric ulcer healing via mobilizing gastric myofibroblasts and stimulates production of stroma-derived factors.
Endothelin-1, an ulcer inducer, promotes gastric ulcer healing via mobilizing gastric myofibroblasts and stimulates production of stroma-derived factors.
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DOI：
10.1152/ajpgi.00462.2005
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发表时间：
2006-05
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影响因子：
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通讯作者：
T. Nishida;S. Tsuji;A. Kimura;M. Tsujii;S. Ishii;Toshiyuki Yoshio;S. Shinzaki;S. Egawa;T. Irie;M. Yasumaru;H. Iijima;H. Murata;S. Kawano;N. Hayashi
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作者：
T. Nishida;S. Tsuji;A. Kimura;M. Tsujii;S. Ishii;Toshiyuki Yoshio;S. Shinzaki;S. Egawa;T. Irie;M. Yasumaru;H. Iijima;H. Murata;S. Kawano;N. Hayashi
内皮素（ET）-1是消化性溃疡的强诱导剂。然而，ET-1在溃疡愈合中的作用仍不清楚，这些在小鼠中进行了研究。小鼠胃溃疡是由醋酸引起的。三天后，小鼠被给予中和ET-1抗体或未免疫血清。分析溃疡大小、纤维化和肌成纤维细胞数量以及ET-1和ET（A/B）受体的定位。为了阐明ET-1的作用机制，我们研究了有或没有ET-1的胃肌成纤维细胞的增殖，迁移，生长和血管生成因子的释放。RT-PCR检测胃肌成纤维细胞中ET-1前体蛋白prepro-ET-1和ET-转换酶-1的表达。ET-1的免疫中和延迟胃溃疡愈合。抗ET-1抗体组纤维化面积和肌成纤维细胞面积均小于对照组。ET-1在胃上皮、肌成纤维细胞和其他细胞类型中表达。肌成纤维细胞中存在ET（A）受体，但不存在ET（B）受体。ET-1促进胃肌成纤维细胞增殖和迁移。ET-1刺激胃肌成纤维细胞释放肝细胞生长因子、VEGF、PGE（2）和IL-6。ET-1前原和ET-转换酶-1mRNA也有表达。ET-1促进胃溃疡处胃肌成纤维细胞和胶原纤维的积聚。ET-1还刺激胃肌成纤维细胞的迁移和增殖，并增强生长因子、血管生成因子和PGE的释放（2）。因此，ET-1不仅在溃疡形成中起重要作用，而且通过动员肌成纤维细胞和诱导基质衍生因子的产生而在溃疡愈合中起重要作用。
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.