HSP70 Confers Protection against Indomethacin-Induced Lesions of the Small Intestine

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.