Heat shock protein 90 inhibitors reduce airway inflammation in a mouse model of allergic asthma.

Abstract

Narrowing of the airways, the cardinal feature of asthma, is frequently a result of airway inflammation that produces mucous hyper‐secretion and airway smooth muscle proliferation and migration, leading to airway remodeling. Heat shock protein 90 (hsp90) inhibitors are a new class of chemotherapeutics that have also been reported to possess strong anti‐inflammatory activity. Thus, the present study was designed to test the hypothesis that hsp90 inhibitors may ameliorate the airway inflammation associated with allergic asthma. Female BALB/c mice were subjected to a standard 25‐day regimen of saline (control mice) or ovalbumin (OVA) sensitization (asthmatic mice). During the last week of OVA treatment, mice also received a daily dose of either vehicle or of the hsp90 inhibitor, 17‐AAG (5mg/kg/day, intranasally). On day 26, mice were anesthetized and bronchoalveolar lavage (BAL) was performed. Asthmatic mice exhibited pronounced leukocytosis in the BAL fluid (BALF) compared to controls. This increase in BALF leukocytes was prevented in asthmatic mice treated with 17‐AAG. BALF cell differential analysis showed that, compared to vehicle‐treated asthmatics, a significant decrease in the number of neutrophils occurred in 17‐AAG‐treated asthmatic mice. Similarly, histological examination of lungs fixed by tracheal instillation, demonstrated less inflammation, less cell infiltration and reduced mucus production in the airways of asthmatic animals treated with 17‐AAG, as compared to vehicle‐treated asthmatic mice. These data suggest that hsp90 inhibitors may be useful in the management of allergic asthma.