title: Endogenous Protease Inhibitors in Airway Epithelial Cells Contribute to Eosinophilic Chronic Rhinosinusitis.
abstract: Cystatin A and SPINK5 are endogenous protease inhibitors (EPIs) that may play key roles in epithelial barrier function.
  
  
  
  To investigate the roles of EPIs in the pathogenesis of chronic rhinosinusitis (CRS).
  
  
  
  We examined the expression of cystatin A and SPINK5 in the nasal epithelial cells of patients with CRS. Additionally, the in vitro effects of recombinant EPIs on the secretion of the epithelial-derived cytokines IL-25, IL-33, and thymic stromal lymphopoietin in airway epithelial cells, and the in vivo effects of recombinant EPIs in the nasal epithelium of mice exposed to multiple airborne allergens (MAA) were examined.
  
  
  
  Compared with control subjects and patients with noneosinophilic CRS, patients with eosinophilic CRS showed significantly lower protein and mRNA expression of cystatin A and SPINK5 in the nasal epithelium. Allergen-induced production of IL-25, IL-33, and thymic stromal lymphopoietin in normal human bronchial epithelial cells was inhibited by treatment with recombinant cystatin A or SPINK5. Conversely, the production of these cytokines was increased when cystatin A or SPINK5 were knocked down with small interfering RNA. Chronic MAA exposure induced goblet cell metaplasia and epithelial disruption in mouse nasal epithelium and decreased the tissue expression and nasal lavage levels of cystatin A and SPINK5. Intranasal instillations of recombinant EPIs attenuated this MAA-induced pathology.
  
  
  
  Cystatin A and SPINK5 play an important role in protecting the airway epithelium from exogenous proteases. The preservation of EPIs may have a therapeutic benefit in intractable airway inflammation, such as eosinophilic CRS.
authors: 1 Department of Otorhinolaryngology, Shiga University of Medical Science, Otsu, Shiga, Japan; and.
authors: Hideaki
authors: 0000-0001-5460-4967
authors: H
authors: Kouzaki
authors: 1 Department of Otorhinolaryngology, Shiga University of Medical Science, Otsu, Shiga, Japan; and.
authors: Koji
authors: 0000-0001-8839-3440
authors: K
authors: Matsumoto
authors: 1 Department of Otorhinolaryngology, Shiga University of Medical Science, Otsu, Shiga, Japan; and.
authors: Hirotaka
authors: H
authors: Kikuoka
authors: 1 Department of Otorhinolaryngology, Shiga University of Medical Science, Otsu, Shiga, Japan; and.
authors: Tomohisa
authors: T
authors: Kato
authors: 1 Department of Otorhinolaryngology, Shiga University of Medical Science, Otsu, Shiga, Japan; and.
authors: Ichiro
authors: I
authors: Tojima
authors: 1 Department of Otorhinolaryngology, Shiga University of Medical Science, Otsu, Shiga, Japan; and.
authors: Shino
authors: 0000-0002-0704-9048
authors: S
authors: Shimizu
authors: 2 Division of Allergic Diseases, Department of Internal Medicine, Mayo Clinic, Rochester, Minnesota.
authors: Hirohito
authors: H
authors: Kita
authors: 1 Department of Otorhinolaryngology, Shiga University of Medical Science, Otsu, Shiga, Japan; and.
authors: Takeshi
authors: 0000-0002-1344-7210
authors: T
authors: Shimizu
mesh_terms: D000328:Adult; D000368:Aged; D000818:Animals; D002908:Chronic Disease; D055312:Cystatin A / Q000378:metabolism; D004802:Eosinophilia / Q000150:complications / Q000378:metabolism*; D004847:Epithelial Cells / Q000378:metabolism*; D005260:Female; D006801:Humans; D020381:Interleukin-17 / Q000378:metabolism; D000067596:Interleukin-33 / Q000378:metabolism; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008875:Middle Aged; D009297:Nasal Mucosa / Q000378:metabolism; D011480:Protease Inhibitors / Q000378:metabolism*; D053491:Proteinase Inhibitory Proteins, Secretory / Q000378:metabolism; D012220:Rhinitis / Q000150:complications / Q000378:metabolism*; D000074163:Serine Peptidase Inhibitor Kazal-Type 5; D012852:Sinusitis / Q000150:complications / Q000378:metabolism*
chemical_list: D055312:Cystatin A; D020381:Interleukin-17; D000067596:Interleukin-33; D011480:Protease Inhibitors; D053491:Proteinase Inhibitory Proteins, Secretory; C120650:SPINK5 protein, human; D000074163:Serine Peptidase Inhibitor Kazal-Type 5
keywords: chronic rhinosinusitis; cytokine; endogenous protease inhibitor; epithelial cell; protease