The inhibitory effects of H+K+ATPase inhibitors on human neutrophils in vitro: Restoration by a K+ ionophore

Oliveira, Rafael Martins de; Antunes, Edson; Pedrazzoli, José; Gambero, Alessandra

doi:10.1007/s00011-006-6127-6

Cited by 37 publications

(12 citation statements)

References 32 publications

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“…PPIs can also affect other cytoskeletal-mediated processes, such as neutrophil chemotaxis [21], gallbladder relaxation [22], smooth muscle activity [20], and vas deferens contractility [23] by altering intracellular calcium homeostasis [22]. Similarly, omeprazole and lansoprazole have been found to affect arterial contractions by modulating intracellular calcium [19].…”

Section: Discussionmentioning

confidence: 98%

Transmucosal Gastric Leak Induced by Proton Pump Inhibitors

et al. 2008

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Despite their remarkable safety profile and lack of clinical side effects, proton pump inhibitors (PPIs) induce a transmucosal gastric leak to non-electrolyte probes of various sizes. The ex vivo addition of PPIs to isolated rat gastric corpus increases transmucosal permeability in a dose-dependent manner, which corresponds with PPIs' dose-dependent inhibition of acid secretion. Upon the addition of omeprazole, lansoprazole, or esomeprazole, a small decrease in transepithelial resistance and the concomitant stimulation of short circuit current was observed. Additionally, transepithelial flux of (14)C-[D]-mannitol (MW 182.17) across the gastric mucosa increased by a mean of 68% immediately following the addition of 200 microM omeprazole. This flux increase was bidirectional. Omeprazole also increased the paracellular permeability to larger radiolabeled probes, including (14)C-sucrose (MW 342.3) and (14)C-polyethylene glycol (MW 4,000) by 118% and 350%, respectively. However, the flux of still larger probes, 10,000 and 70,000 MW dextrans, was not increased. Because PPIs are so widely used and are assumed to be innocuous, this transmucosal gastric leak must be further investigated, as it may carry considerable biomedical implications.

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Section: Discussionmentioning

confidence: 98%

Transmucosal Gastric Leak Induced by Proton Pump Inhibitors

et al. 2008

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“…PPIs interact with the catalytic α-subunit of H + /K + -ATPase and thereby inhibit its ability to exchange K + for H + , hydrolyze ATP, and maintain an electrochemical gradient across the plasma membrane. In addition to reduction of gastric acid secretion through H + /K + -ATPase inhibition, various biological effects of omeprazole have been investigated, including antileishmanial (antimicrobial) activity [25], relaxation of human arteries [26], and inhibition of neutrophil chemotaxis [27]. Although the major target of PPIs is heretofore believed to be gastric H + /K + -ATPase (known to be mainly in parietal cells of stomach), other molecules, for example putative H + /K + -ATPase that are sensitive to PPIs and are unrelated to gastric H + /K + -ATPase or completely new targets other than proton pump, might be influenced by PPIs, considering the effects of PPIs on neutrophils or arteries.…”

Section: Discussionmentioning

confidence: 99%

Proton Pump Inhibitors Exert Anti-Allergic Effects by Reducing TCTP Secretion

et al. 2009

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BackgroundExtracellular translationally controlled tumor protein (TCTP) is known to play a role in human allergic responses. TCTP has been identified outside of macrophages, in activated mononuclear cells, and in biological fluids from allergic patients. Even TCTP devoid of signal sequences, is secreted to extracellular environment by an yet undefined mechanism. This study is aimed at understanding the mechanism of TCTP release and its regulation. A secondary goal is to see if inhibitors of TCTP release can serve as potential anti-allergic asthmatic drugs.Methodology/Principal FindingsUsing Western blotting assay in HEK293 and U937 cells, we found that TCTP secretion is reduced by omeprazole and pantoprazole, both of which are proton pump inhibitors. We then transfected HEK293 cells with proton pump expression vectors to search for the effects of exogeneously overexpressed H+/K+-ATPase on the TCTP secretion. Based on these in vitro data we checked the in vivo effects of pantoprazole in a murine model of ovalbumin-induced allergy. Omeprazole and pantoprazole reduced TCTP secretion from HEK293 and U937 cells in a concentration-dependent fashion and the secretion of TCTP from HEK293 cells increased when they over-expressed H+/K+-ATPase. In a murine model of ovalbumin-induced allergy, pretreatment with pantoprazole reduced infiltration of inflammatory cells, increased goblet cells, and increased TCTP secretion induced by OVA challenge.ConclusionSince Omeprazole and pantoprazole decrease the secretion of TCTP which is associated with the development of allergic reaction, they may have the potential to serve as anti-allergic (asthmatic) drugs.

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“…In particular, omeprazole can decrease the migration, bactericidal activity, and oxygen-derived free radical production by neutrophils [36–38]. PPIs can also affect NK cells [39] and monocytes [40].…”

Section: Discussionmentioning

confidence: 99%

The effect of omeprazole on the development of experimental autoimmune encephalomyelitis in C57BL/6J and SJL/J mice

et al. 2014

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BackgroundGastric disturbances such as dyspepsia are routinely encountered by multiple sclerosis (MS) patients, and these conditions are often treated with gastric acid suppressors such as proton pump inhibitors, histamine H2 receptor antagonists, or antacids. The proton pump inhibitor omeprazole can alter the gut flora and immune responses, both of which can influence the course of experimental autoimmune encephalomyelitis (EAE), an animal model of MS. The objective of the current study was to examine the effect of omeprazole treatment on the development of EAE. Bacterial microbiome analysis of mouse fecal pellets was determined in C57BL/6J EAE mice chronically treated with omeprazole, and spleen immune cell content, clinical scores, weight, rotarod latency, and histopathology were used as outcome measures in C57BL/6J and SJL/J mice with EAE.ResultsOmeprazole treatment resulted in decreases in Akkermansia muciniphila and Coprococcus sp. and an increase in unidentified bacteria in the family S24-7 (order Bacteroidales) in C57BL/6J mice with EAE. Omeprazole did not alter spleen immune cell content compared to vehicle in EAE mice, but differences independent of treatment were observed in subsets of T cells between early and advanced disease in C57BL/6J mice as well as between the two strains of mice at an advanced disease stage. Omeprazole caused no difference in clinical scores in either strain, but significantly lowered weight gain compared to vehicle in the C57BL/6J mice with EAE. Omeprazole also did not alter rotarod behavior or hindbrain inflammatory cell infiltration compared to vehicle in both strains of mice with EAE. Rotarod latency did reveal a negative correlation with clinical scores during active disease in both mouse strains, but not during clinical remission in SJL/J mice, suggesting that rotarod can detect disability not reflected in the clinical scores.ConclusionsDespite alterations in the gut microbiota and weight gain in the C57BL/6J EAE model, omeprazole had no effect on multiple measures of disease activity in C57BL/6J and SJL/J mice with EAE, supporting the notion that omeprazole does not substantially influence disease activity in MS patients.Electronic supplementary materialThe online version of this article (doi:10.1186/1756-0500-7-605) contains supplementary material, which is available to authorized users.

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The inhibitory effects of H+K+ATPase inhibitors on human neutrophils in vitro: Restoration by a K+ ionophore

Abstract: 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.

Cited by 37 publications

References 32 publications

Transmucosal Gastric Leak Induced by Proton Pump Inhibitors

Transmucosal Gastric Leak Induced by Proton Pump Inhibitors

Proton Pump Inhibitors Exert Anti-Allergic Effects by Reducing TCTP Secretion

The effect of omeprazole on the development of experimental autoimmune encephalomyelitis in C57BL/6J and SJL/J mice

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