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TRANSLATIONAL PHYSIOLOGY

Mepacrine inhibits subepithelial fibrosis by reducing the expression of arginase and TGF-β₁ in an extended subacute mouse model of allergic asthma

Molecular Immunogenetics Laboratory, Institute of Genomics and Integrative Biology, Delhi, India

Submitted 24 April 2009 ; accepted in final form 15 June 2009

Asthma is a dynamic disorder of airway inflammation and airway remodeling with an imbalance in T helper type 1 (Th₁)/Th₂ immune response. Increased Th₂ cytokines 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 Th₂ 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 Th₂ cytokines, allergen-specific IgE, IgG₁, increased cytosolic PLA₂ (cPLA₂), and airway hyperresponsiveness. Presence of intraepithelial eosinophils and significant TGF-β₁ 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 Th₂ cytokines and subepithelial fibrosis and alleviated asthma features. These reductions by mepacrine were associated with a decrease in levels and expression of TGF-β₁ 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-β₁. These effects of mepacrine likely underlie its antiairway remodeling action in asthma.

transforming growth factor-β₁; lung

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