TLR4 antagonist suppresses airway remodeling in asthma by inhibiting the T-helper 2 response.

Airway remodeling is a hallmark of bronchial asthma. Our group has previously reported that the thymic stromal lymphopoietin (TSLP), an airway epithelial-derived cytokine, has a central role in the pathogenesis of airway remodeling, and that toll-like receptor (TLR) 4 signaling in epithelial cells may trigger T-helper 2 (Th2) immune responses by overexpression of TSLP. However, it is currently unclear whether TLR4 is a target in the treatment of airway remodeling in asthma. The present study established a house dust mite (HDM)-induced chronic asthmatic model in female BALB/c mice and treated the HDM-exposed mice with 3 mg/kg TAK242, as a TLR4 antagonist, 30 min prior to HDM challenge for up to 2 weeks. General structural changes in the airways were subsequently evaluated and the levels of TSLP in the bronchoalveolar lavage fluid (BALF) and interleukin (IL)-4, IL-13 and interferon (IFN)-γ in the blood serum were determined. Results indicated that TAK242 treatment markedly reduced pathological changes in the airways of HDM-induced asthmatic mice, as demonstrated by reductions in airway wall thickening, peribronchial collagen deposition and subepithelial fibrosis. Furthermore, airway hyperresponsiveness to inhaled methacholine and the levels of TSLP in the BALF and IL-4, IL-13 and IFN-γ in the peripheral blood were significantly reduced by TAK242 treatment (P<0.05). Furthermore, the shift in the IFN-γ/IL-4 ratio induced by HDM treatment was significantly reversed following TAK242 pretreatment, which indicated that TAK242 modulated Th1/Th2 immune homeostasis in the chronic asthma mouse model. The present findings in a chronic asthma mouse model suggest that TAK242 may be an efficient treatment for airway remodeling, possibly through the inhibition of TSLP overexpression and Th2 airway inflammation. [ABSTRACT FROM AUTHOR]