W1720 Effects of Proton Pump Inhibitors on Healing of NSAID-Induced Gastric Ulcerations in the Presence of a Continued NSAID Treatment: Characterization of Molecular Mechanisms

Effects of Proton Pump Inhibitors on Healing of NSAID-Induced Gastric Ulcerations in the Presence of a Continued NSAID Treatment: Characterization of Molecular Mechanisms Matteo Fornai, Rocchina Colucci, Luca Antonioli, Oriana Awwad, Gianfranco Natale, Narcisa Ghisu, Clara Ugolini, Marco Tuccori, Fulvio Basolo, Mario Del Tacca, Corrado Blandizzi Introduction. Proton pump inhibitors are effective in promoting ulcer healing in NSAIDtreated patients with ongoing or recent history of NSAID-induced gastric toxicity. However, the mechanisms underlying such clinical effectiveness are unknown. This study examined the molecular pathways contributing to healing actions of esomeprazole (ESO) and lansoprazole (LAN) on NSAID-induced gastric ulcers in the presence of a continued NSAID treatment. Methods. Ulcers were induced in male rats (n=8 per group) by daily oral indomethacin (IND, 6 μmol/kg) for 14 days. Animals were then treated with IND (6 μmol/kg), alone or in combination with equivalent acid inhibitory doses of ESO (5 μmol/kg), LAN (15 μmol/ kg) or famotidine (FAM, 20 μmol/kg) for 7 days. Stomachs were processed for: 1) histomorphometric analysis of mucosal injury; 2) mucosal levels of prostaglandin E2 (PGE2) and malondialdehyde (MDA); 3) expression of cyclooxygenase-1 and -2 (COX-1/-2), VEGF, PCNA and cleaved caspase-3 (Western blot); 4) expression of Ki-67 (immunohistochemistry). AGA Abstracts S-726 Results. IND for 14 days induced mucosal damage (5.6±0.6%), reduced PGE2 mucosal levels (54.5±21.4 pg/mg) and increased MDA (8.4±1.0 nmol/mg). IND for additional 7 days enhanced further the mucosal damage and MDA, while PGE2 levels remained low. IND enhanced also the expression of COX-2 and caspase-3, reduced VEGF, PCNA and Ki-67, and did not affect COX-1. In the presence of IND, treatment with ESO, LAN or FAM affected differentially most of tested parameters, as shown in table. In summary: 1) ESO and LAN were more effective than FAM in reducing mucosal damage and MDA levels; 2) ESO and LAN, but not FAM, restored PCNA and Ki-67 expression; 3) ESO, LAN and FAM partly counteracted IND-induced caspase-3 activation, without affecting the decrease in VEGF expression. Conclusions. The superiority of ESO and LAN over FAM in promoting ulcer healing in the presence of a continued IND treatment is likely to depend on both aciddependent reduction of pro-apoptotic signalling (caspase-3) and acid-independent restoration of repairing pathways (PCNA, Ki-67).