抄録
Non-steroidal anti-inflammatory drugs (NSAIDs) are a useful family of therapeutics. The anti-inflammatory actions of NSAIDs are mediated through their inhibitory effects on cyclooxygenase (COX) activity and resulting decrease in prostaglandins (PGs). On the other hand, NSAID use is associated with gastrointestinal complications. Although PGs have a strong protective effect on gastrointestinal mucosa, the inhibition of COX by NSAIDs is not the sole explanation for the gastrointestinal side effects of NSAIDs. In this study, we examined the COX-independent mechanism involved in NSAID-induced gastric lesions. Using DNA microarray analysis, we found that CHOP, a transcription factor with apoptosis-inducing ability is induced by NSAIDs and treatment of cells with NSAIDs caused apoptosis in wild-type cells but not in CHOP-knock out cells. We also found that NSAIDs have membrane permeabilization activity. Furthermore, intracellular Ca2+ chelator, BAPTA-AM inhibited the NSAID-induced apoptosis and induction of CHOP. In vivo, we proposed that both COX inhibition at gastric mucosa and direct gastric mucosal cell damage (such as induction of apoptosis) by NSAIDs are required for the production of gastric lesions. Results showed that NSAID-induced apoptosis is mediated by permeabilization of cytoplasmic membranes, increase in the intracellular Ca2+ levels and induction of CHOP. Furthermore, results suggest that NSAIDs without membrane permeabilizing activity have reduced aastrointestinal side effects.
