Effects of the histone deacetylase inhibitor, trichostatin A, in a chronic allergic airways disease model in mice.
There is a need for new asthma therapies that can concurrently address airway remodeling, airway hyperresponsiveness and progressive irreversible loss of lung function, in addition to inhibiting inflammation. Histone deacetylase inhibitors (HDACi) alter gene expression by interfering with the removal of acetyl groups from histones. The HDACi trichostatin A (TSA) has pleiotropic effects targeting key pathological processes in asthma including inflammation, proliferation, angiogenesis and fibrosis. The aim was to evaluate the effects of TSA treatment in a mouse model of chronic allergic airways disease (AAD). Wild-type BALB/c mice with AAD were treated intraperitoneally with 5 mg/kg TSA or vehicle control. Airway inflammation was assessed by bronchoalveolar lavage fluid (BALF) cell counts and histological examination of lung tissue sections. Remodeling was assessed by morphometric analysis and airway hyperresponsiveness was assessed by invasive plethysmography. TSA-treated mice had a reduced number of total inflammatory cells and eosinophils within the BALF as compared to vehicle-treated mice (both p < 0.05). Furthermore, airway remodeling changes were significantly reduced with TSA compared to vehicle-treated mice, with fewer goblet cells (p < 0.05), less subepithelial collagen deposition (p < 0.05) and attenuated airway hyperresponsiveness at the highest methacholine dose. These findings demonstrate that treatment with an HDACi can concurrently reduce structural airway remodeling changes and airway hyperresponsiveness, in addition to attenuating airway inflammation in a chronic AAD model. This has important implications for the development of novel treatments for severe asthma.
Allergy and Immune Disorders, Murdoch Children's Research Institute, Melbourne, VIC, Australia. simon.royce@mcri.edu.au
Simon G
SG
Royce
William
W
Dang
Gao
G
Yuan
Jenny
J
Tran
Assam
A
El-Osta
Tom C
TC
Karagiannis
Mimi L K
ML
Tang
D056151:Airway Remodeling / Q000187:drug effects; D000818:Animals; D001249:Asthma / Q000139:chemically induced / Q000188:drug therapy* / Q000503:physiopathology; D016535:Bronchial Hyperreactivity / Q000188:drug therapy*; D001992:Bronchoalveolar Lavage Fluid / Q000166:cytology; D002908:Chronic Disease; D004195:Disease Models, Animal; D004804:Eosinophils / Q000187:drug effects / Q000276:immunology; D005260:Female; D056572:Histone Deacetylase Inhibitors / Q000008:administration & dosage* / Q000009:adverse effects; D006801:Humans; D006877:Hydroxamic Acids / Q000008:administration & dosage* / Q000009:adverse effects; D008168:Lung / Q000187:drug effects* / Q000473:pathology; D051379:Mice; D008807:Mice, Inbred BALB C
D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; C012589:trichostatin A