Blockade of cysteinyl leukotriene-1 receptors suppresses airway remodelling in mice overexpressing GATA-3.
BACKGROUND
We demonstrated previously that GATA-3 overexpression markedly enhanced allergen-induced airway inflammation and airway remodelling, including subepithelial fibrosis, and smooth muscle cell hyperplasia, in transgenic mice.


OBJECTIVE
Because cysteinyl leukotrienes (cysLTs) have been shown to be involved in such structural changes, the effects of a specific cysLT1 receptor antagonist, montelukast, were evaluated in a mouse model of chronic asthma.


METHODS
GATA-3-overexpressing mice and wild-type Balb/c mice were sensitized and repeatedly challenged by ovalbumin (OVA) or saline. The effects of montelukast on the development of airway remodelling were compared between the two mouse genotypes.


RESULTS
CysLTs in the lung were increased after repeated allergen challenges, and significantly enhanced in GATA-3-overexpressing mice. The enhanced cysLT levels were accompanied by the development of eosinophilia, smooth muscle cell hyperplasia, and increased stromal cell-derived factor-1 gene expression with a small increase in pro-collagen gene expression in OVA-challenged GATA-3-overexpressing mice, but not in wild-type mice. Montelukast significantly decreased lung cysLT levels and inhibited the GATA-3-overexpression-related airway remodelling, potently preventing smooth muscle cell hyperplasia, but partially suppressed the increased pro-collagen gene expression and eosinophilic inflammation. Increases in the levels of IL-4, IL-5, IL-13, and eotaxin in bronchial lavage and TGF-β gene expression in the lungs were induced by OVA in both mouse genotypes. Montelukast treatment also significantly reduced these levels to the levels seen after saline challenges in GATA-3-overexpressing mice.


CONCLUSIONS
Montelukast efficaciously prevented airway inflammation and remodelling in a GATA-3-overexpression antigen challenge mouse model by decreasing the cysLT-driven Th2 cytokine cycle of amplification of airway pathologies.
Kiwamoto
T
T
Department of Respiratory Medicine, University of Tsukuba, Tsukuba, Ibaraki, Japan.
Ishii
Y
Y
Morishima
Y
Y
Yoh
K
K
Kikuchi
N
N
Haraguchi
N
N
Masuko
H
H
Kawaguchi
M
M
Nomura
A
A
Sakamoto
T
T
Takahashi
S
S
Hizawa
N
N
D000085:Acetates / Q000494:pharmacology; D056151:Airway Remodeling / Q000187:drug effects*; D000818:Animals; D003521:Cyclopropanes; D004195:Disease Models, Animal; D050990:GATA3 Transcription Factor / Q000235:genetics*; D051379:Mice; D008807:Mice, Inbred BALB C; D008822:Mice, Transgenic; D011804:Quinolines / Q000494:pharmacology; D018077:Receptors, Leukotriene / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013440:Sulfides; D018418:Th2 Cells / Q000187:drug effects / Q000276:immunology
D000085:Acetates; D003521:Cyclopropanes; D050990:GATA3 Transcription Factor; C494748:Gata3 protein, mouse; D011804:Quinolines; D018077:Receptors, Leukotriene; D013440:Sulfides; C083169:leukotriene D4 receptor; C093875:montelukast