Proton pump inhibitors decrease eotaxin-3/CCL26 expression in patients with chronic rhinosinusitis with nasal polyps: Possible role of the nongastric H,K-ATPase

Abstract

Background Chronic rhinosinusitis with nasal polyps (CRSwNP) is often characterized by tissue eosinophilia that is associated with poor prognosis. Recent findings that proton pump inhibitors (PPIs) directly modulate expression of eotaxin-3, an eosinophil chemoattractant, in eosinophilic diseases suggest therapeutic potential for PPIs in CRSwNP. Objective We assessed the effect of type-2 mediators, particularly IL-13 and eotaxin-3, on tissue eosinophilia and disease severity in CRS. Further investigation focused on PPI suppression of eotaxin-3 expression in vivo and in vitro with exploration of underlying mechanisms. Methods Type-2 mediator levels in nasal tissues and secretions were measured by multiplex immunoassay. Eotaxin-3 and other chemokines expressed in IL-13-stimulated human sinonasal epithelial cells (HNECs) and BEAS-2Bs with or without PPIs was assessed by using ELISA, Western blot, real-time PCR, and intracellular pH (pHi) imaging. Results Nasal tissues and secretions from CRSwNP patients had increased IL-13, eotaxin-2 and eotaxin-3 levels, and these were positively correlated with tissue ECP and radiographic scores in CRS (P<.05). IL-13-stimulation of HNECs and BEAS-2Bs dominantly induced eotaxin-3 expression, which was significantly inhibited by PPIs (P<.05). CRS patients taking PPIs also showed lower in vivo eotaxin-3 levels compared with those without PPIs (P<.05). Using pHi imaging and by altering extracellular [K+], we found that IL-13 enhanced H+,K+-exchange, which was blocked by PPIs and the mechanistically unrelated H,K-ATPase inhibitor, SCH-28080. Furthermore, knockdown of ATP12A (gene for the non-gastric H,K-ATPase [ngH,K-ATPase]) significantly attenuated IL-13-induced eotaxin-3 expression in HNECs. PPIs also had effects on accelerating IL-13-induced eotaxin-3 mRNA decay. Conclusion Our results demonstrated that PPIs reduce IL-13-induced eotaxin-3 expression by airway epithelial cells. Furthermore, mechanistic studies suggest that the ngH,K-ATPase is necessary for IL-13-mediated epithelial responses, and its inhibitors, including PPIs, may be of therapeutic value in CRSwNP by reducing epithelial production of eotaxin-3.

A prospective analysis evaluating tissue biopsy location and its clinical relevance in chronic rhinosinusitis with nasal polyps

“…Therefore, the conclusions made from these studies have relatively limited specificity regarding relevant subtypes or sinonasal regions. Our findings that UT ECP is more strongly correlated with CT scores than NP ECP are in line with the results reported by Min et al 9 ( r = 0.58 and r = 0.37). Together, these results suggest that eosinophilic inflammation in UT may have stronger associations with radiographic severity in patients with CRSwNP.…”

“…ECP is an eosinophil granule protein that correlates well with cytokines (eg, interleukin 5 [IL-5] and IL-13) and chemokines (eg, eotaxin-2/CCL24 and eotaxin-3/CCL26) as well as blood and tissue eosinophilia. 9, 24, 25 In prior studies, we found that NP has higher levels of ECP than uncinate tissue (UT) even among patients with CRSwNP. More recently, we found that although ECP levels measured in NP were higher than in UT, UT ECP levels were moderately to strongly correlated with radiographic severity and other type-2 mediators.…”

“…More recently, we found that although ECP levels measured in NP were higher than in UT, UT ECP levels were moderately to strongly correlated with radiographic severity and other type-2 mediators. 9 In contrast, when examining the relationship of NP with those factors, only weak correlations were found. Thus, the objective of this study was to compare the value of ECP measured in UT vs NP to serve as a biomarker of severity and recurrence in CRSwNP patients.…”

“…9–13 It is additionally recognized that the presence of NP and eosinophilia at the time of sinus surgery are also associated with increased rates of postsurgical medication use, recurrence, and revision sinus surgery. 14–20 Thus, accurately identifying patients at risk for recurrence is important for tailoring individualized treatment plans.…”

Contemporary Pharmacotherapy for Allergic Rhinitis and Chronic Rhinosinusitis

“…9,11,17–19 Classically, the initiation of type 2 inflammation was postulated to begin with allergen/antigen uptake by dendritic cells that processed the antigens and influenced the T-cell response through the production of cytokines including IL-4 that differentiated Th0 cells into Th2 lymphocytes. 20–23 More recently, epithelial cells have been shown to have innate responses that can directly activate a class of lymphocytes called innate lymphoid cells (ILCs) that produce many of the same cytokines traditionally ascribed to T-cells.…”