Mepacrine inhibits subepithelial fibrosis by reducing the expression of arginase and TGF-β1in an extended subacute mouse model of allergic asthma

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Abstract
Asthma is a dynamic disorder of airway inflammation and airway remodeling with an imbalance in T helper type 1 (Th1)/Th2immune response. Increased Th2cytokines such as IL-4 and IL-13 induce arginase either directly or indirectly through transforming growth factor-β1(TGF-β1) 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 Th2cytokines 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 Th2cytokines, allergen-specific IgE, IgG1, increased cytosolic PLA2(cPLA2), and airway hyperresponsiveness. Presence of intraepithelial eosinophils and significant TGF-β1expression 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 Th2cytokines and subepithelial fibrosis and alleviated asthma features. These reductions by mepacrine were associated with a decrease in levels and expression of TGF-β1and 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-β1. These effects of mepacrine likely underlie its antiairway remodeling action in asthma.