Proton pump inhibitors promote ulcer repair in nonsteroidal anti-inflammatory drug (NSAID)-treated patients with ongoing NSAID-induced gastric toxicity, although the underlying mechanisms remain unclear. We examined the healing mechanisms of esomeprazole on NSAID-induced gastric ulcerations in the presence of a continued NSAID treatment. Ulcerations were induced in rats by oral indomethacin (6 mu mol/kg/day) for 14 days. Indomethacin administration was continued, alone or combined with equivalent acid inhibitory doses of esomeprazole (5 mu mol/kg/day), lansoprazole (15 mu mol/kg/day) or famotidine (20 mu mol/kg/day), for additional 7 days. Stomachs were then processed for: histomorphometric analysis of mucosal injury; mucosal levels of prostaglandin E-2 (PGE(2)) and malondialdehyde (MDA); expression of vascular endothelial growth factor (VEGF), proliferating cell nuclear antigen (PCNA), caspase-3, and cyclooxygenase-2 (COX-2) (Western blot); expression of Ki-67 (immunohistochemistry). Indomethacin for 14 days elicited mucosal damage, reduced PGE(2) levels and increased MDA. After additional 7 days, indomethacin induced the following effects: further enhancement of mucosal damage and MDA content; decrease in PGE(2) levels; increase in COX-2 and activated caspase-3 expression; decrease in VEGF. PCNA and Ki-67 expression. In the presence of indomethacin, esomeprazole and lansoprazole were more effective than famotidine in promoting resolution of mucosal damage. Concomitantly, esomeprazole and lansoprazole, but not famotidine, restored PCNA and Ki-67 expression, and normalized MDA levels. Moreover, esomeprazole, lansoprazole and famotidine partly counteracted caspase-3 activation, without affecting VEGF expression. The healing activity of esomeprazole on indomethacin-induced gastric ulcerations can be ascribed to two mechanisms: (1) acid-dependent reduction of pro-apoptotic signalling; (2) acid-independent restoration of proliferating/repairing pathways. (C) 2010 Elsevier Ltd. All rights reserved.
Effects of esomeprazole on healing of non-steroidal anti-inflammatory drug (NSAID)-induced gastric ulcers in the presence of a continued NSAID treatment: characterization of molecular mechanisms
FORNAI, MATTEOPrimo
;ANTONIOLI, LUCA;UGOLINI C;NATALE, GIANFRANCO;BASOLO, FULVIO;BLANDIZZI, CORRADOUltimo
2011-01-01
Abstract
Proton pump inhibitors promote ulcer repair in nonsteroidal anti-inflammatory drug (NSAID)-treated patients with ongoing NSAID-induced gastric toxicity, although the underlying mechanisms remain unclear. We examined the healing mechanisms of esomeprazole on NSAID-induced gastric ulcerations in the presence of a continued NSAID treatment. Ulcerations were induced in rats by oral indomethacin (6 mu mol/kg/day) for 14 days. Indomethacin administration was continued, alone or combined with equivalent acid inhibitory doses of esomeprazole (5 mu mol/kg/day), lansoprazole (15 mu mol/kg/day) or famotidine (20 mu mol/kg/day), for additional 7 days. Stomachs were then processed for: histomorphometric analysis of mucosal injury; mucosal levels of prostaglandin E-2 (PGE(2)) and malondialdehyde (MDA); expression of vascular endothelial growth factor (VEGF), proliferating cell nuclear antigen (PCNA), caspase-3, and cyclooxygenase-2 (COX-2) (Western blot); expression of Ki-67 (immunohistochemistry). Indomethacin for 14 days elicited mucosal damage, reduced PGE(2) levels and increased MDA. After additional 7 days, indomethacin induced the following effects: further enhancement of mucosal damage and MDA content; decrease in PGE(2) levels; increase in COX-2 and activated caspase-3 expression; decrease in VEGF. PCNA and Ki-67 expression. In the presence of indomethacin, esomeprazole and lansoprazole were more effective than famotidine in promoting resolution of mucosal damage. Concomitantly, esomeprazole and lansoprazole, but not famotidine, restored PCNA and Ki-67 expression, and normalized MDA levels. Moreover, esomeprazole, lansoprazole and famotidine partly counteracted caspase-3 activation, without affecting VEGF expression. The healing activity of esomeprazole on indomethacin-induced gastric ulcerations can be ascribed to two mechanisms: (1) acid-dependent reduction of pro-apoptotic signalling; (2) acid-independent restoration of proliferating/repairing pathways. (C) 2010 Elsevier Ltd. All rights reserved.I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.
