Effect of inhibitors of Na⁺/H⁺‐exchange and gastric H⁺/K⁺ ATPase on cell volume, intracellular pH and migration of human polymorphonuclear leucocytes

Abstract

1 Stimulation of chemotaxis of human polymorphonuclear leucocytes (PMNs) with the chemoattractive peptide fMLP (N-formyl-Met-Leu-Phe) is paralleled by profound morphological and metabolic alterations like changes of intracellular pH (pH i ) and cell shape. The present study was performed to investigate the interrelation of cell volume (CV) regulatory ion transport, pH i and migration of fMLP stimulated PMNs. 2 Addition of fMLP to PMNs stimulated directed migration in Boyden chamber assays and was accompanied by rapid initial intracellular acidi®cation and cell swelling. 3 Inhibition of the Na + /H + exchanger suppressed fMLP stimulated cell migration, accelerated the intracellular acidi®cation and inhibited the fMLP-induced cell swelling. 4Step omission of extracellular Na + caused intracellular acidi®cation, which was accelerated by subsequent addition of gastric H + /K + ATPase inhibitor SCH 28080, or by omission of extracellular K + ions. In addition Na + removal caused cell swelling, which was further enhanced by fMLP. 5 H + /K + ATPase inhibitors omeprazole and SCH 28080 inhibited stimulated migration and blunted the fMLP-induced increase in CV. 6 Increasing extracellular osmolarity by addition of mannitol to the extracellular solution caused cell shrinkage followed by regulatory volume increase, partially due to activation of the Na + /H + exchanger. In fMLP-stimulated cells the CV increase was counteracted by simultaneous addition of mannitol. Under these conditions the fMLP stimulated migration was inhibited. 7 The antibacterial activity of PMNs was not modi®ed by Hoe 694 or omeprazole. 8 Western analysis with a monoclonal anti gastric H + /K + ATPase b-subunit antibody detected a glycosylated 35 kD core protein in lysates of mouse and human gastric mucosa as well as in human PMNs. 9 The results indicate that fMLP leads to cell swelling of PMNs due to activation of the Na + /H + exchanger and a K + -dependent H + -extruding mechanism, presumably an H + /K + ATPase. Inhibition of these ion transporters suppresses the increase in CV and precludes PMNs from stimulated migration.

Implications of a poroelastic cytoplasm for the dynamics of animal cell shape

“…These localization data suggest an involvement of NHE1 and aquaporins in cell migration. Consistent with this idea, active ion pumping, and activity of both NHE1 and aquaporins, are required for normal migration in some cell types [56][57][58][59][60]. While these localization and necessity data point to a role of osmotic regulators in cell migration, they are subject to multiple interpretations, because water, sodium and protons play many roles in cell physiology.…”

Involvement of regulatory volume decrease in the migration of nasopharyngeal carcinoma cells

“…It is proposed that salt and osmotically obliged water uptake mediated by the parallel operation of Na + /H + and Cl -/HCO 3 -exchange as well as Na + -HCO 3 -cotransport at the front of migrating cells contribute to the extension of the lamellipodium [4,16,17]. Increasing volume and membrane tension eventually trigger massive ion efflux, resulting in a local shrinkage of the rear part.…”

Development of urinary incontinence in a 7-year old boy after therapy with proton pump inhibitors and complete resolution of his clinicopathologic features of eosinophilic esophagitis after H2-receptor antagonist treatment: A case report

“…It has been proposed that anti-inflammatory effects of PPIs in addition to their inhibition of acid secretion may be involved in PPI-REE (14)(15)(16)(17)(18)(19). To the best of our knowledge, resolution of extreme esophageal eosinophilia including other typical hallmarks of EoE with H2-receptor antagonists has never been reported.…”