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

幽门螺杆菌(Hp)感染或反复应用消炎痛可延缓实验性胃溃疡(包括醋酸性溃疡)的愈合。用吲哚美辛或幽门螺杆菌(cag A和vac A阳性)治疗沙土鼠溃疡2周有延迟溃疡愈合的趋势。另一方面，吲哚美辛对幽门螺杆菌感染的沙土鼠的溃疡愈合有显著的延迟作用。治疗4wk后，Hp单独及Hp+吲哚美辛治疗后胃溃疡愈合明显延迟。然而，幽门螺杆菌感染沙土鼠在使用消炎痛和不使用消炎痛之间并无显著差异。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，但在4周后。实验表明，幽门螺杆菌可能与炎症反应的发展有关，最终导致溃疡延迟愈合。众所周知，吲哚美辛显著延迟了…PGE_2合成减少可促进大鼠醋酸性溃疡愈合。此外，我们的结果提示，吲哚美辛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)不参与导致溃疡愈合延迟的血管生成抑制。事实上，随着醋酸溃疡的发展，bFGF的表达也逐渐减少，并且表达信号弱于消炎痛治疗组。溃疡愈合后，HSP47在溃疡基质中有明显表达，但随着溃疡愈合，HSP47表达减弱。结论：消炎痛延缓溃疡愈合的机制可能是：1)抑制PGE_2合成和α表达，抑制血管生成；2)HSP47过度表达导致溃疡基质中胶原含量增加。较少

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