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INFLAMMATION, IMMUNOPHARMACOLOGY, AND ASTHMA

Gastric Antisecretory Drugs Induce Leukocyte-Endothelial Cell Interactions through Gastrin Release and Activation of CCK-2 Receptors

Centro de Investigación Biomédica en Red-Enfermedades Hépaticas y Digestivas (Á.Á., S.C.) and Departamento de Farmacología (Á.Á., M.S.I., M.M.A., A.B.-G., S.C.), Facultad de Medicina, Universidad de Valencia, Valencia, Spain

Antisecretory drugs are effective antiulcer agents, but its chronic use generates hypergastrinemia and accelerates the development of atrophic gastritis in Helicobacter pylori-positive patients. We have recently shown that gastrin exerts a proinflammatory effect in rats through CCK-2 receptor activation that contributes to the inflammation induced by H. pylori. The present study was designed to examine whether gastrin hypersecretion in response to treatment with antisecretory drugs induces an inflammatory response that could promote mucosal atrophy. The effects of omeprazole or famotidine on leukocyte/endothelial cell interactions in vivo were analyzed in rat mesenteric venules using intravital microscopy. Administration of a single dose of omeprazole or famotidine acutely increased gastrinemia and leukocyte rolling and adhesion, but not emigration into the interstitium. Daily treatment with omeprazole for a short period (3 days) induced a similar response, but when this treatment was extended to 14 days and a steady hyper-gastrinemic state was established, increased leukocyte rolling, adhesion, and emigration was observed. Pretreatment with the CCK-2 receptor antagonist proglumide prevented these inflammatory events in all cases. Leukocytes from rats treated with omeprazole showed increased expression of CD11b/CD18 initially in granulocytes (3-day protocol) and later in monocytes and lymphocytes (14-day protocol). These changes were not observed in animals pretreated with proglumide, and they were not reproduced by incubation of leukocytes from untreated animals in vitro with gastrin. Thus, hypergastrinemia induced by chronic treatment with antisecretory drugs may promote inflammation, which could partly explain their worsening effect in corpus gastritis observed in H. pylori-infected patients.

Address correspondence to: Dr. Sara Calatayud, Departamento de Farmacología, Facultad de Medicina, Universidad de Valencia, Avd. Blasco Ibáñez 15, 46010 Valencia, Spain. E-mail: sara.calatayud{at}uv.es