Graduate School of Medical and Pharmaceutical Sciences, Kumamoto University, Kumamoto 862-0973, Japan.
Curr Pharm Des. 2010;16(10):1190-6. doi: 10.2174/138161210790945986.
It is well known that heat shock proteins (HSPs) are induced by various stressors in order to confer protection against such stressors. Since stressor-induced tissue damage is involved in various diseases, especially gastrointestinal diseases, such as gastric ulcer, it has been thought that HSPs are protective against these diseases. Indirect lines of evidence, such as identification of geranylgeranylacetone (GGA, a leading anti-ulcer drug in Japanese market) as non-toxic HSP-inducer, suggest that HSPs provide a major protective mechanism against irritant-induced gastric lesions. However, no direct evidences that support this notion exits. Furthermore, because GGA has other gastroprotective effects, it was not clear whether HSP-induction by GGA is the main mechanism for its anti-ulcer effect. In this article, I review our recent work on protective roles of HSPs against gastrointestinal diseases, using transgenic mice. We obtained genetic evidence showing not only that HSPs are protective against irritant-induced gastric lesions but also that GGA achieves its anti-ulcer effect through induction of HSPs. We also obtained genetic evidence that HSPs are protective against inflammatory bowel disease (IBD)-related colitis and lesions of small intestine. Furthermore, we found that GGA is effective against these diseases. Based on these observations, we propose that non-toxic HSP-inducers, such as GGA are therapeutically beneficial for these diseases.
众所周知，热休克蛋白（HSPs）可被各种应激原诱导产生，以抵御应激原的侵害。由于应激原诱导的组织损伤与各种疾病有关，特别是胃肠道疾病，如胃溃疡，因此人们认为 HSPs 对这些疾病具有保护作用。间接证据，如发现香叶基丙酮（GGA，日本市场上的一种主要抗溃疡药物）是一种无毒的 HSP 诱导剂，表明 HSPs 提供了一种针对刺激性物质诱导的胃损伤的主要保护机制。然而，目前还没有直接证据支持这一观点。此外，由于 GGA 具有其他胃保护作用，因此不清楚 GGA 通过诱导 HSPs 来发挥其抗溃疡作用是否是其主要机制。在本文中，我使用转基因小鼠综述了我们最近关于 HSPs 对胃肠道疾病的保护作用的研究工作。我们获得了遗传证据，不仅表明 HSPs 可抵抗刺激性物质诱导的胃损伤，而且 GGA 通过诱导 HSPs 来实现其抗溃疡作用。我们还获得了遗传证据，表明 HSPs 可抵抗与炎症性肠病（IBD）相关的结肠炎和小肠损伤。此外，我们发现 GGA 对这些疾病有效。基于这些观察结果，我们提出无毒的 HSP 诱导剂，如 GGA，对这些疾病具有治疗益处。
