Therapeutic effects of histone deacetylase inhibitors in a murine asthma model

作者：Yuan Ren, Xinming Su, Lingfei Kong, Menglu Li, Xuan Zhao, Na Yu, Jian Kang · 发表于：Inflammation Research · 年份：2016 · DOI：10.1007/s00011-016-0984-4 · 被引用次数：71 · 研究领域：Histone Deacetylase Inhibitors Research、Asthma and respiratory diseases、Peptidase Inhibition and Analysis

OBJECTIVE AND DESIGN: To investigate the therapeutic effects of various HDAC inhibitors on the development of chronic allergic airway disease in mice with airway inflammation, airway remodeling, and airway hyperresponsiveness. SUBJECTS: Wild-type BALB/C mice (N = 72). TREATMENT: Tubastatin A HCl [TSA, a selective histone deacetylase 6 (HDAC6) inhibitor], PCI-34051 (a selective HDAC8 inhibitor), and givinostat (a broad-spectrum HDAC inhibitor that inhibits class I and class II HDACs and several pro-inflammatory cytokines). METHODS: Mice were divided into six groups: control, asthma, dexamethasone (positive control), TSA, PCI-34051, and givinostat (n = 12 per group). Twenty-four hours after OVA nebulization, airway hyperresponsiveness, inflammation, and remodeling were assessed. RESULTS: The chronic asthma mouse model produced typical airway inflammation, airway remodeling, and airway hyperresponsiveness. Administration of PCI-34051 and dexamethasone reduced the eosinophilic inflammation and airway hyperresponsiveness in asthma to reduce the airway remodeling. Treatment with Tubastatin A HCl reduced airway inflammation and was associated with decreased IL-4, IL-5 and total inflammatory cell count, as well as goblet cell metaplasia and subepithelial fibrosis; however, this outcome was not as effective as that with dexamethasone. TGF-β1 expression in the cytoplasm of airway epithelium of mice in the Tubastatin A HCl group was reduced and expression of α-SMA in the airway smooth m...