Endogenous protease inhibitors in airway epithelial cells contribute to eosinophilic chronic rhinosinusitis

Hideaki Kouzaki, Koji Matsumoto, Hirotaka Kikuoka, Tomohisa Kato, Ichiro Tojima, Shino Shimizu, Hirohito Kita, Takeshi Shimizu

Research output: Contribution to journalReview articlepeer-review

32 Scopus citations


Rationale: Cystatin A and SPINK5 are endogenous protease inhibitors (EPIs) that may play key roles in epithelial barrier function. Objectives: To investigate the roles of EPIs in the pathogenesis of chronic rhinosinusitis (CRS). Methods: 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 epithelialderived 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. Measurements and Main Results: 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 lymphopoietininnormal humanbronchial 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 MAAexposure induced goblet cellmetaplasia and epithelial disruption inmousenasal 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. Conclusions: 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.

Original languageEnglish (US)
Pages (from-to)737-747
Number of pages11
JournalAmerican journal of respiratory and critical care medicine
Issue number6
StatePublished - Mar 15 2017


  • Chronic rhinosinusitis
  • Cytokine
  • Endogenous protease inhibitor
  • Epithelial cell
  • Protease

ASJC Scopus subject areas

  • Pulmonary and Respiratory Medicine
  • Critical Care and Intensive Care Medicine


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