Proton Pump Inhibitors (PPIs) May Modulate More Than Just Reflux in Chronic Rhinosinusitis with Nasal Polyps

Abstract

Chronic rhinosinusitis with nasal polyps (CRSwNP) is frequently characterized by tissue eosinophilia but the relationship of eosinophilia to other type 2 biomarkers has not been explored. Furthermore, recent data suggesting PPIs modulate eotaxin-3 production in eosinophilic esophagitis may have therapeutic implications for CRSwNP. We sought to characterize levels of type 2 mediators and their relationship to tissue eosinophilia and radiographic severity in CRS. We further aimed to evaluate whether PPIs have therapeutic potential in CRS and identify possible mechanisms of action in airway epithelium. Type 2 mediators in nasal tissue and lavage fluid from control and CRS patients were measured by Luminex assay. Human sinonasal epithelial cells and BEAS-2B cells were stimulated with IL-13 in the presence and absence of PPIs. The effects of PPIs on IL-13-induced effects were measured by ELISA, qRT-PCR, and pH imaging. IL-13, eotaxin-2 and eotaxin-3 were highly elevated in CRSwNP compared to control and were correlated with tissue ECP and radiographic severity. CRS patients taking PPIs had significantly lower tissue eotaxin-2 and eotaxin-3 levels than those not taking PPIs. In vitro, 5 different PPIs and the competitive H+/K+-ATPase inhibitor SCH-28080 all significantly inhibited IL-13-induced eotaxin-3 release by airway epithelial cells. In addition, IL-13-induced eotaxin-3 expression was dependent on the presence of extracellular K+ and associated with a PPI sensitive efflux of H+ions. IL-13, eotaxin-2, and eotaxin-3 in tissue are potential biomarkers of eosinophilia and severity in CRSwNP. Inhibition of IL-13-induced eotaxin-3 by PPIs may provide therapeutic benefit in CRSwNP via a novel H+/K+-dependent mechanism.