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

Simon G. Royce, William Dang, Katherine Ververis, Nishika De Sampayo, Assam El-Osta, Mimi L. K. Tang, Tom C Karagiannis

Research output: Contribution to journalArticleResearchpeer-review

12 Citations (Scopus)

Abstract

Airway remodeling and airway hyperresponsiveness are major aspects of asthma pathology that are not targeted optimally by existing anti-inflammatory drugs. Histone deacetylase inhibitors have a wide range of effects that may potentially 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 also inhibits class II histone deacetylases. We used valproic acid as a molecular model of histone deacetylase inhibition in vivo in chronic allergic airways disease mice with airway remodeling and airway hyperresponsiveness. Wild-type Balb/c mice with allergic airways disease were treated with valproic acid or vehicle control. Airway inflammation was assessed by bronchoalveolar lavage fluid cell counts and examination of lung tissue sections. Remodeling was assessed by morphometric analysis of histochemically stained slides and lung function was assessed by invasive plethysmography measurement of airway resistance. Valproic acid treatment did not affect inflammation parameters; however, valproic acid treatment resulted in reduced epithelial thickness as compared to vehicle treated mice (p <0.01), reduced subepithelial collagen deposition (p <0.05) and attenuated airway hyperresponsiveness (p <0.05 and p <0.01 for the two highest doses of methacholine, respectively). These findings show that treatment with valproic acid can reduce structural airway remodeling changes and hyperresponsiveness, providing further evidence for the potential use of histone deacetylase inhibitors for the treatment of asthma.
Original languageEnglish
Pages (from-to)1463 - 1470
Number of pages8
JournalEpigenetics
Volume6
Issue number12
DOIs
Publication statusPublished - Dec 2011

Keywords

  • valproic acid
  • asthma
  • airway remodeling
  • allergic airways disease
  • airway hyperresponsiveness

Cite this

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title = "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 targeted optimally by existing anti-inflammatory drugs. Histone deacetylase inhibitors have a wide range of effects that may potentially 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 also inhibits class II histone deacetylases. We used valproic acid as a molecular model of histone deacetylase inhibition in vivo in chronic allergic airways disease mice with airway remodeling and airway hyperresponsiveness. Wild-type Balb/c mice with allergic airways disease were treated with valproic acid or vehicle control. Airway inflammation was assessed by bronchoalveolar lavage fluid cell counts and examination of lung tissue sections. Remodeling was assessed by morphometric analysis of histochemically stained slides and lung function was assessed by invasive plethysmography measurement of airway resistance. Valproic acid treatment did not affect inflammation parameters; however, valproic acid treatment resulted in reduced epithelial thickness as compared to vehicle treated mice (p <0.01), reduced subepithelial collagen deposition (p <0.05) and attenuated airway hyperresponsiveness (p <0.05 and p <0.01 for the two highest doses of methacholine, respectively). These findings show that treatment with valproic acid can reduce structural airway remodeling changes and hyperresponsiveness, providing further evidence for the potential use of histone deacetylase inhibitors for the treatment of asthma.",
keywords = "valproic acid, asthma, airway remodeling, allergic airways disease, airway hyperresponsiveness",
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Protective effects of valproic acid against airway hyperresponsiveness and airway remodeling in a mouse model of allergic airways disease. / Royce, Simon G.; Dang, William; Ververis, Katherine; De Sampayo, Nishika; El-Osta, Assam; Tang, Mimi L. K.; Karagiannis, Tom C.

In: Epigenetics, Vol. 6, No. 12, 12.2011, p. 1463 - 1470.

Research output: Contribution to journalArticleResearchpeer-review

TY - JOUR

T1 - Protective effects of valproic acid against airway hyperresponsiveness and airway remodeling in a mouse model of allergic airways disease

AU - Royce, Simon G.

AU - Dang, William

AU - Ververis, Katherine

AU - De Sampayo, Nishika

AU - El-Osta, Assam

AU - Tang, Mimi L. K.

AU - Karagiannis, Tom C

PY - 2011/12

Y1 - 2011/12

N2 - Airway remodeling and airway hyperresponsiveness are major aspects of asthma pathology that are not targeted optimally by existing anti-inflammatory drugs. Histone deacetylase inhibitors have a wide range of effects that may potentially 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 also inhibits class II histone deacetylases. We used valproic acid as a molecular model of histone deacetylase inhibition in vivo in chronic allergic airways disease mice with airway remodeling and airway hyperresponsiveness. Wild-type Balb/c mice with allergic airways disease were treated with valproic acid or vehicle control. Airway inflammation was assessed by bronchoalveolar lavage fluid cell counts and examination of lung tissue sections. Remodeling was assessed by morphometric analysis of histochemically stained slides and lung function was assessed by invasive plethysmography measurement of airway resistance. Valproic acid treatment did not affect inflammation parameters; however, valproic acid treatment resulted in reduced epithelial thickness as compared to vehicle treated mice (p <0.01), reduced subepithelial collagen deposition (p <0.05) and attenuated airway hyperresponsiveness (p <0.05 and p <0.01 for the two highest doses of methacholine, respectively). These findings show that treatment with valproic acid can reduce structural airway remodeling changes and hyperresponsiveness, providing further evidence for the potential use of histone deacetylase inhibitors for the treatment of asthma.

AB - Airway remodeling and airway hyperresponsiveness are major aspects of asthma pathology that are not targeted optimally by existing anti-inflammatory drugs. Histone deacetylase inhibitors have a wide range of effects that may potentially 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 also inhibits class II histone deacetylases. We used valproic acid as a molecular model of histone deacetylase inhibition in vivo in chronic allergic airways disease mice with airway remodeling and airway hyperresponsiveness. Wild-type Balb/c mice with allergic airways disease were treated with valproic acid or vehicle control. Airway inflammation was assessed by bronchoalveolar lavage fluid cell counts and examination of lung tissue sections. Remodeling was assessed by morphometric analysis of histochemically stained slides and lung function was assessed by invasive plethysmography measurement of airway resistance. Valproic acid treatment did not affect inflammation parameters; however, valproic acid treatment resulted in reduced epithelial thickness as compared to vehicle treated mice (p <0.01), reduced subepithelial collagen deposition (p <0.05) and attenuated airway hyperresponsiveness (p <0.05 and p <0.01 for the two highest doses of methacholine, respectively). These findings show that treatment with valproic acid can reduce structural airway remodeling changes and hyperresponsiveness, providing further evidence for the potential use of histone deacetylase inhibitors for the treatment of asthma.

KW - valproic acid

KW - asthma

KW - airway remodeling

KW - allergic airways disease

KW - airway hyperresponsiveness

UR - http://www.ncbi.nlm.nih.gov/pubmed/22139576

U2 - 10.4161/epi.6.12.18396

DO - 10.4161/epi.6.12.18396

M3 - Article

VL - 6

SP - 1463

EP - 1470

JO - Epigenetics

JF - Epigenetics

SN - 1559-2294

IS - 12

ER -