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

JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY

卷:139

Article

Min, Jin-Young¹  Ocampo, Christopher J.²  Stevens, Whitney W.²  Price, Caroline P. E.¹  Thompson, Christopher F.¹  Homma, Tetsuya^2,3  Huang, Julia H.¹  Norton, James E.²  Suh, Lydia A.²  Pothoven, Kathryn L.²  Conley, David B.¹  Welch, Kevin C.¹  Shintani-Smith, Stephanie¹  Peters, Anju T.²  Grammer, Leslie C., III²  Harris, Kathleen E.²  Hulse, Kathryn E.²  Kato, Atsushi^1,2  Modyanov, Nikolai N.⁴  Kern, Robert C.^1,2  Schleimer, Robert P.^1,2  Tan, Bruce K.¹ 

[1] Northwestern Univ, Dept Otolaryngol, Feinberg Sch Med, 676 North St Clair,Suite 1325, Chicago, IL 60611 USA

[2] Northwestern Univ, Dept Med, Div Allergy Immunol, Feinberg Sch Med, Chicago, IL 60611 USA

[3] Showa Univ, Sch Med, Dept Internal Med, Div Resp Med & Allergol, Tokyo, Japan

[4] Univ Toledo, Dept Physiol & Pharmacol, Coll Med, 2801 W Bancroft St, Toledo, OH 43606 USA

关键词: Chronic rhinosinusitis;    eotaxin-1/CCL11;    eotaxin-2/CCL24;    eotaxin-3/CCL26;    omeprazole;    proton pump inhibitors;    IL-13;    epithelial cells;    H(+)-K(+)-exchanging ATPase;    eosinophils;   

DOI  :  10.1016/j.jaci.2016.07.020

来源: Elsevier

【 摘 要 】

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 the expression of eotaxin-3, an eosinophil chemoattractant, in patients with eosinophilic diseases suggest therapeutic potential for PPIs in those with CRSwNP. Objective: We assessed the effect of type 2 mediators, particularly IL-13 and eotaxin-3, on tissue eosinophilia and disease severity in patients with chronic rhinosinusitis (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 using a multiplex immunoassay. Eotaxin-3 and other chemokines expressed in IL-13-stimulated human sinonasal epithelial cells (HNECs) and BEAS-2B cells with or without PPIs were assessed by using ELISA, Western blotting, real-time PCR, and intracellular pH imaging. Results: Nasal tissues and secretions from patients with CRSwNP had increased IL-13, eotaxin-2, and eotaxin-3 levels, and these were positively correlated with tissue eosinophil CRS (P < .05). IL-13 stimulation of HNECs and BEAS-2B cells dominantly induced eotaxin-3 expression, which was significantly inhibited by PPIs (P < .05). Patients with CRS taking PPIs also showed lower in vivo eotaxin-3 levels compared with those without PPIs (P < .05). Using intracellular pH imaging and 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 nongastric H, 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 nongastric H, K-ATPase is necessary for IL-13-mediated epithelial responses, and its inhibitors, including PPIs, might be of therapeutic value in patients with CRSwNP by reducing epithelial production of eotaxin-3.

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