Role of Endogenous Protease Inhibitor in Airway Epithelial Cells in the Pathogenesis of Eoshinophilic Chronic Rhinosinusitis

Chronic rhinosinusitis (CRS) is a heterogeneous disease with different etiologies and pathogenesis. Cystatin A and SPINK5 are endogenous protease inhibitors (EPIs), which may play important roles in epithelial barrier function. The purpose of this study is to investigate the role of EPIs in the pathogenesis of CRS. We examined the expression of Cystatin A and SPINK5 in nasal epithelial cells of CRS patients by ELISA, RT-PCR and immunofluorescence staining. We then examined the effects of recombinant EPIs in allergen-induced production of epithelial-derived cytokines, IL-25, IL-33 and TSLP from cultured normal human bronchial epithelial (NHBE) cells. The protein and mRNA expressions of cystatin A and SPINK5 were significantly low in nasal epithelium of patients with eosinophilic CRS (ECRS) as compared to those with non-eosinophilic CRS and control individuals. Immunofluorescence staining demonstrated that the expression levels of cystatin A and SPINK5 were decreased in nasal epithelium of ECRS patients. Allergen-induced production of IL-25, IL-33 and TSLP were inhibited in NHBE cells by treating with recombinant cystatin A or SPINK5. In contrast, allergens-induced secretion of IL-25, IL-33 and TSLP were significantly increased by infecting NHBE cells with small interfering RNA for SPINK5 or Cystatin A. These results indicate that cystatin A and SPINK5 play an important role in protecting airway epithelium from exogenous proteases, and that the decreased expression of EPIs may be involved in the pathogenesis of intractable eosinophilic CRS.