R Martins de Oliveira1, E Antunes, J Pedrazzoli, A Gambero. 1. Clinical Pharmacology and Gastroenterology Unit, São Francisco University Medical School, Av. São Francisco de Assis 218, 12916-900, Bragança Paulista, SP, Brazil.
Abstract
OBJECTIVE: This study investigated the ability of proton pump inhibitors (PPI), such as omeprazole and pantoprazole, to inhibit neutrophil migration, calcium mobilization and the mechanisms involved in this inhibition. METHODS: Neutrophils were incubated with different concentrations of omeprazole and pantoprazole for 30 min and stimulated to migrate with fMLP and IL-8. Treatment toxicity was assessed by MTT assay. The intracellular calcium levels were analyzed in neutrophils pre-treated with omeprazole and pre-loaded with FURA-2AM, when stimulated with fMLP. The activity of p38 MAP Kinase was evaluated by Western blot after treatment with omeprazole. RESULTS: Omeprazole is able to inhibit neutrophil chemotaxis to fMLP and IL-8. Pantoprazole demonstrated the same ability. This inhibitory effect was not due to a toxic effect of the proton pump inhibitors. Inhibition of v-ATPase by bafilomycin did not modify the ability of fMLP or IL-8 to induce neutrophil migration. Omeprazole was also able to decrease intracellular calcium availability. The addition of a potassium ionophore, nigericin, restored the migratory ability, as well as the intracellular calcium levels. The activity of p38 MAP Kinase was decreased in neutrophils pretreated with omeprazole. CONCLUSION: Proton pump inhibitors promote inhibition of H+ K+ ATPase in neutrophils, resulting in cationic flow disturbances through the cellular membrane that, consequently, inhibit migratory and intracellular events such as calcium influx and p38 MAP Kinase activation.
OBJECTIVE: This study investigated the ability of proton pump inhibitors (PPI), such as omeprazole and pantoprazole, to inhibit neutrophil migration, calcium mobilization and the mechanisms involved in this inhibition. METHODS: Neutrophils were incubated with different concentrations of omeprazole and pantoprazole for 30 min and stimulated to migrate with fMLP and IL-8. Treatment toxicity was assessed by MTT assay. The intracellular calcium levels were analyzed in neutrophils pre-treated with omeprazole and pre-loaded with FURA-2AM, when stimulated with fMLP. The activity of p38 MAP Kinase was evaluated by Western blot after treatment with omeprazole. RESULTS:Omeprazole is able to inhibit neutrophil chemotaxis to fMLP and IL-8. Pantoprazole demonstrated the same ability. This inhibitory effect was not due to a toxic effect of the proton pump inhibitors. Inhibition of v-ATPase by bafilomycin did not modify the ability of fMLP or IL-8 to induce neutrophil migration. Omeprazole was also able to decrease intracellular calcium availability. The addition of a potassium ionophore, nigericin, restored the migratory ability, as well as the intracellular calcium levels. The activity of p38 MAP Kinase was decreased in neutrophils pretreated with omeprazole. CONCLUSION: Proton pump inhibitors promote inhibition of H+ K+ ATPase in neutrophils, resulting in cationic flow disturbances through the cellular membrane that, consequently, inhibit migratory and intracellular events such as calcium influx and p38 MAP Kinase activation.
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