Asano Teita, Tanaka Ken-Ichiro, Yamakawa Naoki, Adachi Hiroaki, Sobue Gen, Goto Hidemi, Takeuchi Koji, Mizushima Tohru
Graduate School of Medical and Pharmaceutical Sciences, Kumamoto University, Kumamoto 862-0973, Japan.
J Pharmacol Exp Ther. 2009 Aug;330(2):458-67. doi: 10.1124/jpet.109.152181. Epub 2009 May 20.
In line with improvements in diagnostic procedures to detect intestinal lesions, it has become clear that nonsteroidal anti-inflammatory drugs (NSAIDs) such as indomethacin induce lesions not only in the stomach but also in the small intestine. However, clinical protocols for the treatment of NSAID-induced lesions of the small intestine have not been established. It is known that heat shock proteins (HSPs), particularly HSP70, confer protection against various stressors, and more recently, the anti-inflammatory activity of HSP70 was revealed. In this study, we examined the effect of expression of HSP70 on indomethacin-induced lesions of the small intestine. The extent of indomethacin-induced lesions to the small intestine was reduced in transgenic mice expressing HSP70 compared with controls. Oral administration of indomethacin increased the expression of HSP70 in the small intestine. Administration of indomethacin also induced mucosal cell apoptosis and expression of proinflammatory cytokines in the small intestines of control mice, with both of these responses suppressed in the transgenic mice. Geranylgeranylacetone (GGA), a clinically used antiulcer drug, increased expression of HSP70 in the small intestine and suppressed indomethacin-induced lesions of the small intestines in wild-type mice. These results suggest that indomethacin-induced increase in HSP70 expression reduces the extent of lesions to the small intestine by suppressing mucosal cell apoptosis and inflammatory responses. The HSP-inducing activity of GGA seems to contribute to the protective effect of drug against the lesions. Based on these results, we propose that nontoxic HSP70-inducers, such as GGA, would be therapeutically beneficial for treating NSAID-induced lesions of the small intestine.
随着检测肠道病变的诊断程序的改进，已明确非甾体抗炎药（NSAIDs）如吲哚美辛不仅会在胃中引发病变，也会在小肠中引发病变。然而，针对NSAIDs诱导的小肠病变的临床治疗方案尚未确立。已知热休克蛋白（HSPs），尤其是HSP70，可对各种应激源提供保护，并且最近发现了HSP70的抗炎活性。在本研究中，我们检测了HSP70表达对吲哚美辛诱导的小肠病变的影响。与对照相比，表达HSP70的转基因小鼠中吲哚美辛诱导的小肠病变程度降低。口服吲哚美辛可增加小肠中HSP70的表达。给予吲哚美辛还会诱导对照小鼠小肠中的黏膜细胞凋亡和促炎细胞因子的表达，而在转基因小鼠中这两种反应均受到抑制。临床使用的抗溃疡药物香叶基香叶基丙酮（GGA）可增加小肠中HSP70的表达，并抑制野生型小鼠中吲哚美辛诱导的小肠病变。这些结果表明，吲哚美辛诱导的HSP70表达增加通过抑制黏膜细胞凋亡和炎症反应降低了小肠病变的程度。GGA的HSP诱导活性似乎有助于该药物对病变的保护作用。基于这些结果，我们提出无毒的HSP70诱导剂，如GGA，在治疗NSAIDs诱导的小肠病变方面可能具有治疗益处。
