1. Academic Validation
  2. Therapeutic effects of histone deacetylase inhibitors in a murine asthma model

Therapeutic effects of histone deacetylase inhibitors in a murine asthma model

  • Inflamm Res. 2016 Dec;65(12):995-1008. doi: 10.1007/s00011-016-0984-4.
Yuan Ren 1 Xinming Su 2 Lingfei Kong 1 Menglu Li 1 Xuan Zhao 1 Na Yu 1 Jian Kang 3
Affiliations

Affiliations

  • 1 Department of Respiratory Medicine, Institute of Respiratory Diseases, The First Affiliated Hospital of China Medical University, 155 North Nanjing Street, Shenyang, 110001, People's Republic of China.
  • 2 Department of Respiratory Medicine, Institute of Respiratory Diseases, The First Affiliated Hospital of China Medical University, 155 North Nanjing Street, Shenyang, 110001, People's Republic of China. xinming_med@126.com.
  • 3 Department of Respiratory Medicine, Institute of Respiratory Diseases, The First Affiliated Hospital of China Medical University, 155 North Nanjing Street, Shenyang, 110001, People's Republic of China. kangjian58@163.com.
Abstract

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 muscle was also decreased.

Conclusions: The results suggested that treatment with HDAC inhibitors can reduce airway inflammation, airway remodeling, and airway hyperresponsiveness in chronic allergic airway disease in mice.

Keywords

Airway hyperresponsiveness; Airway inflammation; Bronchial asthma; Histone deacetylase.

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