title: 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: 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.
  
  
  
  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.
  
  
  
  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.
  
  
  
  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 cationic protein levels and radiographic scores in patients with 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.
  
  
  
  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.
authors.affiliation: Department of Otolaryngology, Northwestern University Feinberg School of Medicine, Chicago, Ill.
authors.forename: Jin-Young
authors.initials: JY
authors.lastname: Min
authors.affiliation: Division of Allergy-Immunology, Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, Ill.
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Ocampo
authors.affiliation: Division of Allergy-Immunology, Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, Ill.
authors.forename: Whitney W
authors.initials: WW
authors.lastname: Stevens
authors.affiliation: Department of Otolaryngology, Northwestern University Feinberg School of Medicine, Chicago, Ill.
authors.forename: Caroline P E
authors.initials: CPE
authors.lastname: Price
authors.affiliation: Department of Otolaryngology, Northwestern University Feinberg School of Medicine, Chicago, Ill.
authors.forename: Christopher F
authors.initials: CF
authors.lastname: Thompson
authors.affiliation: Division of Allergy-Immunology, Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, Ill; Division of Respiratory Medicine and Allergology, Department of Internal Medicine, Showa University School of Medicine, Tokyo, Japan.
authors.forename: Tetsuya
authors.initials: T
authors.lastname: Homma
authors.affiliation: Department of Otolaryngology, Northwestern University Feinberg School of Medicine, Chicago, Ill.
authors.forename: Julia H
authors.initials: JH
authors.lastname: Huang
authors.affiliation: Division of Allergy-Immunology, Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, Ill.
authors.forename: James E
authors.initials: JE
authors.lastname: Norton
authors.affiliation: Division of Allergy-Immunology, Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, Ill.
authors.forename: Lydia A
authors.initials: LA
authors.lastname: Suh
authors.affiliation: Division of Allergy-Immunology, Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, Ill.
authors.forename: Kathryn L
authors.initials: KL
authors.lastname: Pothoven
authors.affiliation: Department of Otolaryngology, Northwestern University Feinberg School of Medicine, Chicago, Ill.
authors.forename: David B
authors.initials: DB
authors.lastname: Conley
authors.affiliation: Department of Otolaryngology, Northwestern University Feinberg School of Medicine, Chicago, Ill.
authors.forename: Kevin C
authors.initials: KC
authors.lastname: Welch
authors.affiliation: Department of Otolaryngology, Northwestern University Feinberg School of Medicine, Chicago, Ill.
authors.forename: Stephanie
authors.initials: S
authors.lastname: Shintani-Smith
authors.affiliation: Division of Allergy-Immunology, Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, Ill.
authors.forename: Anju T
authors.initials: AT
authors.lastname: Peters
authors.affiliation: Division of Allergy-Immunology, Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, Ill.
authors.forename: Leslie C
authors.initials: LC
authors.lastname: Grammer
authors.affiliation: Division of Allergy-Immunology, Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, Ill.
authors.forename: Kathleen E
authors.initials: KE
authors.lastname: Harris
authors.affiliation: Division of Allergy-Immunology, Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, Ill.
authors.forename: Kathryn E
authors.initials: KE
authors.lastname: Hulse
authors.affiliation: Department of Otolaryngology, Northwestern University Feinberg School of Medicine, Chicago, Ill; Division of Allergy-Immunology, Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, Ill.
authors.forename: Atsushi
authors.initials: A
authors.lastname: Kato
authors.affiliation: Department of Physiology and Pharmacology, University of Toledo College of Medicine, Toledo, Ohio.
authors.forename: Nikolai N
authors.initials: NN
authors.lastname: Modyanov
authors.affiliation: Department of Otolaryngology, Northwestern University Feinberg School of Medicine, Chicago, Ill; Division of Allergy-Immunology, Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, Ill.
authors.forename: Robert C
authors.initials: RC
authors.lastname: Kern
authors.affiliation: Department of Otolaryngology, Northwestern University Feinberg School of Medicine, Chicago, Ill; Division of Allergy-Immunology, Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, Ill.
authors.forename: Robert P
authors.initials: RP
authors.lastname: Schleimer
authors.affiliation: Department of Otolaryngology, Northwestern University Feinberg School of Medicine, Chicago, Ill. Electronic address: b-tan@northwestern.edu.
authors.forename: Bruce K
authors.initials: BK
authors.lastname: Tan
mesh_terms: D000328:Adult; D000368:Aged; D001562:Benzimidazoles / Q000494:pharmacology; D002460:Cell Line; D002478:Cells, Cultured; D002908:Chronic Disease; D016207:Cytokines / Q000235:genetics / Q000276:immunology*; D004847:Epithelial Cells / Q000187:drug effects / Q000276:immunology; D005260:Female; D055785:Gene Knockdown Techniques; D017506:H(+)-K(+)-Exchanging ATPase / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology; D008297:Male; D008875:Middle Aged; D017817:Nasal Lavage Fluid / Q000276:immunology; D009297:Nasal Mucosa / Q000166:cytology / Q000187:drug effects / Q000276:immunology; D009298:Nasal Polyps / Q000000981:diagnostic imaging / Q000276:immunology*; D054328:Proton Pump Inhibitors / Q000494:pharmacology*; D011657:Pulmonary Eosinophilia / Q000000981:diagnostic imaging / Q000276:immunology; D012220:Rhinitis / Q000000981:diagnostic imaging / Q000276:immunology*; D012852:Sinusitis / Q000000981:diagnostic imaging / Q000276:immunology*; D014057:Tomography, X-Ray Computed; D055815:Young Adult
chemical_list: D001562:Benzimidazoles; D016207:Cytokines; D007093:Imidazoles; D054328:Proton Pump Inhibitors; C035235:Sch 28080; C088641:ATP12A protein, human; D017506:H(+)-K(+)-Exchanging ATPase
keywords: Chronic rhinosinusitis; H(+)-K(+)-exchanging ATPase; IL-13; eosinophils; eotaxin-1/CCL11; eotaxin-2/CCL24; eotaxin-3/CCL26; epithelial cells; omeprazole; proton pump inhibitors