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

众所周知，幽门螺杆菌（H.pylori）感染或反复使用吲哚美辛会延迟实验性胃溃疡（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）治疗溃疡的沙鼠2周往往会延迟溃疡愈合。另一方面，用吲哚美辛治疗幽门螺旋杆菌感染的沙鼠明显延迟溃疡愈合。治疗4周后，单独幽门螺杆菌组和幽门螺杆菌+吲哚美辛组均明显延迟胃溃疡愈合。然而，使用或不使用吲哚美辛治疗的幽门螺杆菌感染沙鼠之间无显著差异。这一发现强烈提示前列腺素（PG）在初始愈合中起重要作用，但需要4周。实验表明，幽门螺杆菌可能与炎症反应的发展有关，最终导致溃疡愈合延迟。吲哚美辛还能显著延缓大鼠醋酸性溃疡的愈合，因为它能减少PGE_2的合成。此外，我们的研究结果表明，吲哚美辛治疗对血管生成的抑制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）不参与抑制血管生成负责延迟溃疡愈合。确实，随着醋酸溃疡的发展，bFGF表达降低，且表达信号较消炎痛组弱。而HSP47在溃疡后在溃疡基底中显著表达，但随着溃疡愈合而降低。吲哚美辛处理可显著提高溃疡基底组织中HSP47的表达和I （α）胶原mRNA的表达，导致胶原含量升高。综上所述，吲哚美辛延缓溃疡愈合的机制可能是：1)抑制血管生成，降低PGE_2合成和bFGF表达；2)过度表达HSP47导致溃疡基底胶原含量积累。少

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