Lansoprazole Protects and Heals Gastric Mucosa from\ud Non-steroidal Anti-inflammatory Drug (NSAID)-induced\ud Gastropathy by Inhibiting Mitochondrial as Well as\ud Fas-mediated Death Pathways with Concurrent Induction of\ud Mucosal Cell Renewal

摘要

Wehave investigated the mechanism of antiapoptotic and cell\udrenewal effects of lansoprazole, a proton pump inhibitor, to protect\udand heal gastric mucosal injury in vivo induced by indomethacin,\uda non-steroidal anti-inflammatory drug (NSAID).\udLansoprazole prevents indomethacin-induced gastric damage\udby blocking activation of mitochondrial and Fas pathways of\udapoptosis. Lansoprazole prevents indomethacin-induced\udup-regulation of proapoptotic Bax and Bak and down-regulation\udof antiapoptotic Bcl-2 and BclxL to maintain the normal\udproapoptotic/antiapoptotic ratio and thereby arrests indomethacin-\udinduced mitochondrial translocation of Bax and collapse\udof mitochondrial membrane potential followed by cytochrome\udc release and caspase-9 activation. Lansoprazole also\udinhibits indomethacin-induced Fas-mediated mucosal cell\uddeath by down-regulating Fas or FasL expression and inhibiting\udcaspase-8 activation. Lansoprazole favors mucosal cell renewal\udsimultaneously by stimulating gene expression of prosurvival\udproliferating cell nuclear antigen, survivin, epidermal growth\udfactor, and basic fibroblast growth factor. The up-regulation of\udFlt-1 further indicates that lansoprazole activates vascular epidermal\udgrowth factor-mediated controlled angiogenesis to\udrepair gastric mucosa. Lansoprazole also stimulates the healing\udof already formed ulcers induced by indomethacin. Time\udcourse study of healing indicates that it switches off the mitochondrial\uddeath pathway completely but not the Fas pathway.\udHowever, lansoprazole heals mucosal lesions almost completely\udafter overcoming the persisting Fas pathway, probably\udby favoring the prosurvival genes expression. This study thus\udprovides the detailed mechanism of antiapoptotic and prosurvival\udeffects of lansoprazole for offering gastroprotection\udagainst indomethacin-induced gastropathy.