Effects of the histone deacetylase inhibitor, trichostatin A, in a chronic allergic airways disease model in mice

Simon G. Royce, William Dang, Gao Yuan Yuan, Jenny Tran, Assam El-Osta, Tom Karagiannis, Mimi L. K. Tang

Research output: Contribution to journalArticleResearchpeer-review

15 Citations (Scopus)

Abstract

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.
Original languageEnglish
Pages (from-to)295-306
Number of pages12
JournalArchivum Immunologiae et Therapiae Experimentalis
Volume60
Issue number4
DOIs
Publication statusPublished - Aug 2012
Externally publishedYes

Keywords

  • Airway hyperresponsiveness
  • Airway remodeling
  • Asthma
  • Trichostatin A
  • Therapy

Cite this

@article{0bb85bf9ad964c98be88c32a953e35be,
title = "Effects of the histone deacetylase inhibitor, trichostatin A, in a chronic allergic airways disease model in mice",
abstract = "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.",
keywords = "Airway hyperresponsiveness, Airway remodeling, Asthma, Trichostatin A, Therapy",
author = "Royce, {Simon G.} and William Dang and Yuan, {Gao Yuan} and Jenny Tran and Assam El-Osta and Tom Karagiannis and Tang, {Mimi L. K.}",
year = "2012",
month = "8",
doi = "10.1007/s00005-012-0180-3",
language = "English",
volume = "60",
pages = "295--306",
journal = "Archivum Immunologiae et Therapiae Experimentalis",
issn = "0004-069X",
publisher = "Springer-Verlag London Ltd.",
number = "4",

}

Effects of the histone deacetylase inhibitor, trichostatin A, in a chronic allergic airways disease model in mice. / Royce, Simon G.; Dang, William; Yuan, Gao Yuan; Tran, Jenny; El-Osta, Assam; Karagiannis, Tom; Tang, Mimi L. K.

In: Archivum Immunologiae et Therapiae Experimentalis, Vol. 60, No. 4, 08.2012, p. 295-306.

Research output: Contribution to journalArticleResearchpeer-review

TY - JOUR

T1 - Effects of the histone deacetylase inhibitor, trichostatin A, in a chronic allergic airways disease model in mice

AU - Royce, Simon G.

AU - Dang, William

AU - Yuan, Gao Yuan

AU - Tran, Jenny

AU - El-Osta, Assam

AU - Karagiannis, Tom

AU - Tang, Mimi L. K.

PY - 2012/8

Y1 - 2012/8

N2 - 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.

AB - 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.

KW - Airway hyperresponsiveness

KW - Airway remodeling

KW - Asthma

KW - Trichostatin A

KW - Therapy

UR - http://link.springer.com/article/10.1007%2Fs00005-012-0180-3

U2 - 10.1007/s00005-012-0180-3

DO - 10.1007/s00005-012-0180-3

M3 - Article

VL - 60

SP - 295

EP - 306

JO - Archivum Immunologiae et Therapiae Experimentalis

JF - Archivum Immunologiae et Therapiae Experimentalis

SN - 0004-069X

IS - 4

ER -