Asthma is a dynamic disorder of airway
inflammation and
airway remodeling with an imbalance in T helper type 1 (Th(1))/Th(2) immune response. Increased Th(2)
cytokines such as
IL-4 and
IL-13 induce
arginase either directly or indirectly through transforming growth factor-beta(1) (TGF-beta(1)) and lead to subepithelial
fibrosis, which is a crucial component of
airway remodeling. Synthetic
antimalarials have been reported to have immunomodulatory properties.
Mepacrine is known for its reduction of airway
inflammation in short-term
allergen challenge model by reducing Th(2)
cytokines and cysteinyl
leukotrienes, which has an important role in the development of
airway remodeling features. Therefore, we hypothesized that
mepacrine may reduce
airway remodeling. For this, extended subacute
ovalbumin mice model of
asthma was developed; these mice showed an increased expression of profibrotic mediators, subepithelial
fibrosis, and goblet cell
metaplasia along with airway
inflammation, increased Th(2)
cytokines,
allergen-specific
IgE,
IgG(1), increased cytosolic PLA(2) (cPLA(2)), and
airway hyperresponsiveness. Presence of intraepithelial eosinophils and significant TGF-beta(1) expression in subepithelial mesenchymal regions by repeated
allergen exposures indicate that asthmatic mice of this study have developed human mimicking as well as late stages of
asthma. However,
mepacrine treatment decreased Th(2)
cytokines and subepithelial
fibrosis and alleviated
asthma features. These reductions by
mepacrine were associated with a decrease in levels and expression of TGF-beta(1) and the reduction in activity, expression of
arginase in lung cytosol, and immunolocalization in inflammatory cells present in perivascular and peribronchial regions. These results suggest that
mepacrine might reduce the development of subepithelial
fibrosis by reducing the
arginase and TGF-beta(1). These effects of
mepacrine likely underlie its antiairway remodeling action in
asthma.