Protective effects of valproic acid against airway hyperresponsiveness and airway remodeling in a mouse model of allergic airways disease

Abstract

Airway remodeling and airway hyperresponsiveness are major aspects of asthma pathology that are not targetedoptimally by existing anti-inflammatory drugs, Histone deacetylase inhibitors have a wide range of effects that maypotentially abrogate aspects of remodeling, One such histone deacetylase inhibitor is valproic acid (2-propylvaleric acid).Valproic acid is used clinically as an anti-epileptic drug and is a potent inhibitor of class I histone deacetylases but alsoinhibits class II histone deacetylases, We used valproic acid as a molecular model of histone deacetylase inhibition invivo in chronic allergic airways disease mice with airway remodeling and airway hyperresponsiveness, Wild-type Balb/cmice with allergic airways disease were treated with valproic acid or vehicle control, Airway inflammation was assessedby bronchoalveolar lavage fluid cell counts and examination of lung tissue sections, Remodeling was assessed bymorphometric analysis of histochemically stained slides and lung function was assessed by invasive plethysmographymeasurement of airway resistance, Valproic acid treatment did not affect inflammation parameters, however, valproicacid treatment resulted in reduced epithelial thickness as compared with vehicle treated mice (p < 0.01), reducedsubepithelial collagen deposition (p < 0.05) and attenuated airway hyperresponsiveness (p < 0.05 and p < 0.01 for thetwo highest doses of methacholine, respectively), These findings show that treatment with valproic acid can reducestructural airway remodeling changes and hyperresponsiveness, providing further evidence for the potential use ofhistone deacetylase inhibitors for the treatment of asthma. © 2011 Landes Bioscience.