Molecular Mechanisms Elucidating Why Old Stomach Is More Vulnerable to Indomethacin-Induced Damage than Young Stomach

Abstract

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. In order to investigate molecular mechanisms relevant to NSAID-induced gastric damage, we administered indomethacin to 6-week-old and 60-week-old rats. 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-kappa B-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. A preventive strategy to reduce either redox activation or pro-inflammatory mediators should be considered in older patients taking long-standing NSAID administration.