TY - JOUR
T1 - Endogenous protease inhibitors in airway epithelial cells contribute to eosinophilic chronic rhinosinusitis
AU - Kouzaki, Hideaki
AU - Matsumoto, Koji
AU - Kikuoka, Hirotaka
AU - Kato, Tomohisa
AU - Tojima, Ichiro
AU - Shimizu, Shino
AU - Kita, Hirohito
AU - Shimizu, Takeshi
N1 - Publisher Copyright:
© 2017 by the American Thoracic Society.
PY - 2017/3/15
Y1 - 2017/3/15
N2 - 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.
AB - 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.
KW - Chronic rhinosinusitis
KW - Cytokine
KW - Endogenous protease inhibitor
KW - Epithelial cell
KW - Protease
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U2 - 10.1164/rccm.201603-0529OC
DO - 10.1164/rccm.201603-0529OC
M3 - Review article
C2 - 27779422
AN - SCOPUS:85015907259
SN - 1073-449X
VL - 195
SP - 737
EP - 747
JO - American journal of respiratory and critical care medicine
JF - American journal of respiratory and critical care medicine
IS - 6
ER -