Reversal of allergen-induced airway remodeling by CysLT1 receptor blockade

Am J Respir Crit Care Med. 2006 Apr 1;173(7):718-28. doi: 10.1164/rccm.200501-088OC. Epub 2005 Dec 30.

Abstract

Rationale: Airway inflammation in asthma is accompanied by structural changes, including goblet cell metaplasia, smooth muscle cell layer thickening, and subepithelial fibrosis. This allergen-induced airway remodeling can be replicated in a mouse asthma model.

Objectives: The study goal was to determine whether established airway remodeling in a mouse asthma model is reversible by administration of the cysteinyl leukotriene (CysLT)1 receptor antagonist montelukast, the corticosteroid dexamethasone, or the combination montelukast + dexamethasone.

Methods: BALB/c mice, sensitized by intraperitoneal ovalbumin (OVA) as allergen, received intranasal OVA periodically Days 14-73 and montelukast or dexamethasone or placebo from Days 73-163.

Measurements and main results: Allergen-induced trafficking of eosinophils into the bronchoalveolar lavage fluid and lung interstitium and airway goblet cell metaplasia, smooth muscle cell layer thickening, and subepithelial fibrosis present on Day 73 persisted at Day 163, 3 mo after the last allergen challenge. Airway hyperreactivity to methacholine observed on Day 73 in OVA-treated mice was absent on Day 163. In OVA-treated mice, airway eosinophil infiltration and goblet cell metaplasia were reduced by either montelukast or dexamethasone alone. Montelukast, but not dexamethasone, reversed the established increase in airway smooth muscle mass and subepithelial collagen deposition. By immunocytochemistry, CysLT1 receptor expression was significantly increased in airway smooth muscle cells in allergen-treated mice compared with saline-treated controls and was reduced by montelukast, but not dexamethasone, administration.

Conclusions: These data indicate that established airway smooth muscle cell layer thickening and subepithelial fibrosis, key allergen-induced airway structural changes not modulated by corticosteroids, are reversible by CysLT1 receptor blockade therapy.

Publication types

  • Comparative Study
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acetates / therapeutic use*
  • Animals
  • Asthma / drug therapy
  • Asthma / metabolism
  • Asthma / pathology*
  • Disease Models, Animal
  • Female
  • Follow-Up Studies
  • Glucocorticoids / therapeutic use
  • Leukotriene Antagonists / therapeutic use*
  • Lung / metabolism
  • Lung / pathology*
  • Membrane Proteins / antagonists & inhibitors*
  • Membrane Proteins / metabolism
  • Mice
  • Mice, Inbred BALB C
  • Muscle, Smooth / metabolism
  • Muscle, Smooth / pathology
  • Quinolines / therapeutic use*
  • Receptors, Leukotriene / metabolism
  • Respiratory Mucosa / metabolism
  • Respiratory Mucosa / pathology
  • Treatment Outcome

Substances

  • Acetates
  • Glucocorticoids
  • Leukotriene Antagonists
  • Membrane Proteins
  • Quinolines
  • Receptors, Leukotriene
  • leukotriene D4 receptor
  • montelukast