Neutrophils induce smooth muscle hyperplasia via neutrophil elastase‐induced FGF‐2 in a mouse model of asthma with mixed inflammation

• Published in: Clinical and experimental allergy Vol. 48; no. 12; pp. 1715 - 1725
• Main Authors: Ogawa, Hirohisa, Azuma, Masahiko, Tsunematsu, Takaaki, Morimoto, Yuuki, Kondo, Mayo, Tezuka, Toshifumi, Nishioka, Yasuhiko, Tsuneyama, Koichi
• Format: Journal Article
• Language: English
• Published: England Wiley Subscription Services, Inc 01.12.2018
• Subjects: airway remodelling; Animal models; Antigens; Asthma; Catenin; Cytokines; E-cadherin; Elastase; Eosinophilia; Eosinophils; Epithelial cells; fibroblast growth factor‐2; House dust; Hyperplasia; Hypersensitivity; Hypertrophy; IL‐17; Inflammation; Leukocytes (eosinophilic); Leukocytes (neutrophilic); Lungs; Lymphocytes T; Muscles; Neutralization; neutrophil; Neutrophils; Respiratory tract; Smooth muscle; Therapeutic applications; fibroblast growth factor-2; asthma; neutrophil; IL-17; airway remodelling
• ISSN: 0954-7894; 1365-2222
• DOI: 10.1111/cea.13263

Summary Background Bronchial asthma is traditionally characterized by chronic allergic inflammation, including eosinophilia and elevated Th2 cytokines. Recently, IL‐17‐derived neutrophil infiltration was shown to correlate with asthma severity and airway remodelling. Objective To investigate the role of IL‐17‐derived neutrophils in airway remodelling in chronic bronchial asthma. Methods We utilized house dust mite antigen‐induced mouse models of asthma. Intranasal sensitization and chronic antigen challenge caused a mixed allergic inflammation that included eosinophils and neutrophils (Mix‐in group). We neutralized IL‐17 and fibroblast growth factor (FGF‐2) and investigated the mechanism of airway remodelling in the Mix‐in group. Results The Mix‐in group displayed neutrophilic infiltration and high levels of IL‐17 in lung tissue. The Mix‐in group also exhibited more bronchial smooth muscle hyperplasia. IL‐17 neutralization decreased the magnitude of all of these effects in the Mix‐in group. Antibody arrays revealed an increase in FGF‐2 in the Mix‐in Group relative to the Eo‐ip group, and FGF‐2 elevation was associated with smooth muscle hypertrophy/hyperplasia. High concentrations of neutrophil elastase enhanced E‐cadherin/β‐catenin signalling in bronchial epithelial cells. Neutrophil elastase inhibitor treatment decreased FGF‐2 production and E‐cadherin/β‐catenin signalling, which inhibited smooth muscle hyperplasia. Conclusion The IL‐17/neutrophil axis may play an important role in airway remodelling by contributing to smooth muscle hypertrophy/hyperplasia in mixed allergic inflammation and accordingly represents an attractive therapeutic target for severe asthma.