Molecular mechanisms elucidating why old stomach is more vulnerable to indomethacin-induced damage than young stomach.

BACKGROUND/AIMS: Detailed underlying changes have never been explored to explain how old stomach is more susceptible to non-steroidal anti-inflammatory drugs (NSAIDs)-induced gastric damage than young stomach, although presumptively speculated as weakened mucosal defense system as well as attenuated regenerating capacity in old stomach. METHODS: In order to investigate molecular mechanisms relevant to NSAID-induced gastric damage, we administered indomethacin to 6-week-old and 60-week-old rats. RESULTS: In spite of the same oral administration of indomethacin (0.1 mg indomethacin dissolved in 1 ml carboxyl methylcellulose) irrespective of body weights of rat, gastric mucosal damages were significantly increased in the older rats compared to the younger rats (p < 0.05). Before indomethacin administration, inflammatory mediators including cytokines, chemokines, proteases, and adhesion molecules were significantly increased in old stomach and these differences were further increased after indomethacin administration (p < 0.05). Furthermore, the levels of total oxidants and apoptotic executors were significantly increased in old stomach, whereas lipoxin A4 and anti-apoptotic proteins such as survivin and Bcl-2 were significantly decreased. Increased NF-κB-DNA binding activity as well as the activation of JNK and p38 was responsible for the increased expressions of inflammatory mediators as well as oxidants. CONCLUSIONS: A preventive strategy to reduce either redox activation or pro-inflammatory mediators should be considered in older patients taking long-standing NSAID administration.