抗炎症薬による胃損傷誘発・潰瘍治癒遅延作用とそれらの機序の分子レベルでの解明

从分子水平阐明抗炎药引起的胃损伤和溃疡愈合延迟效应及其机制

• 批准号: 11470490
• 负责人: OKABE Susumu
• 金额: $ 10.56万
• 依托单位: Kyoto Pharmaceutical University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (B).
• 财政年份: 1999
• 资助国家: 日本
• 起止时间: 1999 至 2000
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-11470490/
• 关键词: NSAID; Mongolian gerbil; Cytokines; Aceti acid ulcer; Helicobacter pylori; Angiogenesis; Prostaglandin; Delayed ulcer healing; ヘリコバクターピロリ; COX-2選択的阻害薬; 抗炎症薬

It is known that Helicobacter pylori (H.pylori) infection or repeated administration of indomethacin delays the healing of experimental gastric ulcers (including acetic acid ulcers). Treatment with indomethacin or H.pylori (cag A and vac A positive) for 2 weeks to gerbils with ulcers tended to delay the ulcer healing. On the other hand, treatment with indomethacin to H.pylori-infected gerbils significantly delayed the ulcer healing. After 4-wk treatment, the healing of gastric ulcers was significantly delayed by H.pylori alone and H.pylori+indomethacin. However, there was no significant difference between H.pylori-infected gerbils with or without indomethacin treatment. This finding strongly suggests that prostaglandin (PG) plays an important role for the initial healing, but with 4 week. experiments, H.pylori might be related to the development of an inflammatory response, ultimately leading to delayed healing of the ulcers. It is also well known that indomethacin significantly delays … More healing of acetic acid ulcers-induced in rats due to the reduced PGE_2 synthesis. In addition, our results suggest that the inhibited angiogenesis and abnormal formation of granulation tissue with indomethacin treatment involve in the mechanism underlying the delayed healing. We found that vascular endothelial growth factor (VEGF) was not involved in the inhibited angiogenesis responsible to delayed ulcer healing. Indeed, bFGF expression was decreased according to the development of acetic acid ulcers, and the expression signal was weaker than indomethacin-treated group. While HSP47 were markedly expressed in the ulcer base after ulceration, but decreased with ulcer healing. Indomethacin treatment markedly enhanced HSP47 expression in the ulcer base and the expression of Collagen I (α) mRNA, resulting in the increased content of collagen.In conclusion, the mechanism by which indomethacin delays ulcer healing appears to be due to 1) the inhibition of angiogenesis following the reduction of PGE_2 synthesis and bFGF expression, 2) over expression of HSP47 leading to the accumulation of collagen content in the ulcer base. Less

已知幽门螺杆菌（H.pylori）感染或重复施用吲哚美辛延迟实验性胃溃疡（包括乙酸溃疡）的愈合。用吲哚美辛或幽门螺杆菌（cag A和vac A阳性）治疗溃疡沙土鼠2周，有延迟溃疡愈合的趋势。另一方面，吲哚美辛治疗幽门螺杆菌感染的沙鼠显著延迟溃疡愈合。治疗4周后，幽门螺杆菌单独和幽门螺杆菌+吲哚美辛明显延迟胃溃疡的愈合。然而，幽门螺杆菌感染的沙土鼠与吲哚美辛治疗或不治疗之间没有显着差异。这一发现有力地表明，前列腺素（PG）在最初的愈合中起着重要作用，但需要4周。在实验中，幽门螺杆菌可能与炎症反应的发展有关，最终导致溃疡的延迟愈合。众所周知，吲哚美辛显著延迟 ...更多信息 PGE_2合成减少导致大鼠醋酸性溃疡愈合。此外，我们的研究结果表明，消炎痛抑制血管生成和肉芽组织的异常形成参与了延迟愈合的机制。我们发现，血管内皮生长因子（VEGF）并不参与抑制血管生成负责延迟溃疡愈合。事实上，随着醋酸溃疡的发展，碱性成纤维细胞生长因子的表达减少，并且表达信号弱于消炎痛治疗组。而HSP 47在溃疡形成后在溃疡基底部有明显表达，但随溃疡愈合而减少。消炎痛治疗明显增强溃疡基底部HSP 47的表达和I型胶原（α）mRNA的表达，导致胶原含量增加。总之，消炎痛延迟溃疡愈合的机制似乎是由于1）PGE_2合成减少和bFGF表达减少后抑制血管生成，（2）HSP 47的过度表达导致溃疡基底部胶原含量的积累。少

项目成果

Amagase K.et al.: "A new ulcer model,"unhealed gastric ulcers",induced by chronic treatment with indomethacin in rats with acetic acid ulcers."Joural of Pharmacology and Physiology. 50. 169-181 (1999)

Amagase K.等人：“一种新的溃疡模型，“未愈合的胃溃疡”，是通过对患有醋酸溃疡的大鼠长期使用吲哚美辛治疗而诱导的。”《药理学和生理学杂志》。

Yoshihiro Keto,Misako Ebata and Susumu Okabe: "Gastric mucosal changes induced by lomg term infection with Helicobacter pylori in Mongolian gerbils. Effects of bacteria eradication"J.Physiology(Paris). (in press).

Yoshihiro Keto、Misako Ebata 和 Susumu Okabe：“蒙古沙鼠长期感染幽门螺杆菌引起的胃粘膜变化。细菌根除的效果”J.Physiology（巴黎）。

毛戸祥博,岡部進: "砂ネズミにおける酢酸潰瘍の治癒と再発に対するHelicobacter pylori感染の影響"Ulcer Research. 27,2. 144-146 (2000)

Yoshihiro Keto、Susumu Okabe：“幽门螺杆菌感染对沙鼠醋酸性溃疡愈合和复发的影响”溃疡研究 27,2 (2000)。

Yoshihiro Keto, Misako Ebata and Susumu Okabe: "Influence of Helicobacter pylori infection on the healing and relapse of acetic acid ulcers in Mongolian gerbils."Dig.Dis.Sci.. (in press). (2001)

Yoshihiro Keto、Misako Ebata 和 Susumu Okabe：“幽门螺杆菌感染对蒙古沙鼠醋酸溃疡愈合和复发的影响。”Dig.Dis.Sci..（出版中）。

Takahashi S.et al.: "Role of thromboxane A2 in healing of gastric ulcers in rats."Japanese Journal of Pharmacology. 79. 101-107 (1999)

Takahashi S.et al.：“血栓素 A2 在大鼠胃溃疡愈合中的作用。”日本药理学杂志。