Role of p38 mitogen-activated protein kinase in the healing of gastric ulcers in rats.
Role of p38 mitogen-activated protein kinase in the healing of gastric ulcers in rats.
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p38 丝裂原激活蛋白激酶在大鼠胃溃疡愈合中的作用。
DOI：
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发表时间：
2001
期刊：
影响因子：
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通讯作者：
S. Okabe
中科院分区：
文献类型：
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作者：
N. Kobayashi;T. Kataoka;A. Ono;Y. Tsukimi;S. Okabe
p38属于促分裂原活化蛋白激酶家族，在细胞对细胞因子和各种应激的反应中起关键作用。我们研究了p38在实验性胃溃疡愈合中的作用。通过向雄性大鼠粘膜下注射乙酸溶液诱导胃溃疡。蛋白质印迹法和激酶活性测定法检测溃疡组织中p38活性和磷酸化状态。口服FR 167653（p38激酶抑制剂）3 ~ 14 d后，采用酶联免疫吸附试验和蛋白质印迹法检测细胞因子的产生水平以及环氧合酶和诱导型一氧化氮合酶的蛋白质水平表达。仅在溃疡组织中的成纤维细胞和巨噬细胞/单核细胞中，发现p38被磷酸化，激酶活性水平升高。FR 167653抑制p38的活性，但对其磷酸化状态没有影响。该药物显著损害溃疡愈合（不影响酸分泌）和溃疡基底的血管生成。FR 167653治疗后，白细胞介素-1 β和肿瘤坏死因子-α的产生显著减少。此外，FR 167653抑制了溃疡胃中环氧合酶-2和诱导型一氧化氮合酶蛋白的表达增加的PGE 2产生和NOx分泌。从这些发现中，我们得出结论，p38，由胃溃疡激活，可能在大鼠胃溃疡的愈合中发挥一定的作用。
p38 belongs to the mitogen-activated protein kinase family and plays a crucial role in cellular responses to both cytokines and various stresses. We investigated the role of p38 in the healing of experimental gastric ulcers. Gastric ulcers were induced by submucosal injection of acetic acid solution into male rats. Western blotting and a kinase assay examined the p38 activity and phosphorylation state in ulcerated tisue. After orally administering FR167653 (p38 kinase inhibitor) for 3 to 14 days, the production level of cytokines and the protein-level expression of cyclooxygenase and inducible nitric oxide synthase were examined by enzyme-linked immunosorbent assay and Western blotting. Only in fibroblasts and macrophages/monocytes in ulcerated tissue, p38 was found to be phosphorylated with an elevated kinase activity level. FR 167653 inhibited the activity of p38, yet had no effect on its phosphorylation state. The drug significantly impaired ulcer healing (without affecting acid secretion) and angiogenesis in the ulcer base. The production of interleukin-1beta and tumor necrosis factor-alpha were significantly reduced after FR167653 treatment. In addition the expression of cyclooxygenase-2 and inducible nitric oxide synthase proteins increased PGE2 generation and NOx secretion in the ulcerated stomach were suppressed by FR167653. From these findings, we conclude that p38, activated by gastric ulceration, might play some role in the healing of gastic ulcers in rats.