Aesculetin Inhibits Airway Thickening and Mucus Overproduction Induced by Urban Particulate Matter through Blocking Inflammation and Oxidative Stress Involving TLR4 and EGFR

Abstract

Particulate matter (PM) is a mixture of solid and liquid air pollutant particles suspended in the air, varying in composition, size, and physical features. PM is the most harmful form of air pollution due to its ability to penetrate deep into the lungs and blood streams, causing diverse respiratory diseases. Aesculetin, a coumarin derivative present in the Sancho tree and chicory, is known to have antioxidant and anti-inflammatory effects in the vascular and immune system. However, its effect on PM-induced airway thickening and mucus hypersecretion is poorly understood. The current study examined whether naturally-occurring aesculetin inhibited airway thickening and mucus hypersecretion caused by urban PM₁₀ (uPM₁₀, particles less than 10 μm). Mice were orally administrated with 10 mg/kg aesculetin and exposed to 6 μg/mL uPM₁₀ for 8 weeks. To further explore the mechanism(s) involved in inhibition of uPM₁₀-induced mucus hypersecretion by aesculetin, bronchial epithelial BEAS-2B cells were treated with 1-20 µM aesculetin in the presence of 2 μg/mL uPM₁₀. Oral administration of aesculetin attenuated collagen accumulation and mucus hypersecretion in the small airways inflamed by uPM₁₀. In addition, aesculetin inhibited uPM₁₀-evoked inflammation and oxidant production in lung tissues. Further, aesculetin accompanied the inhibition of induction of bronchial epithelial toll-like receptor 4 (TLR4) and epidermal growth factor receptor (EFGR) elevated by uPM₁₀. The inhibition of TLR4 and EGFR accompanied bronchial mucus hypersecretion in the presence of uPM₁₀. Oxidative stress was responsible for the epithelial induction of TLR4 and EGFR, which was disrupted by aesculetin. These results demonstrated that aesculetin ameliorated airway thickening and mucus hypersecretion by uPM₁₀ inhalation by inhibiting pulmonary inflammation via oxidative stress-stimulated TLR4 and EGFR. Therefore, aesculetin may be a promising agent for treating airway mucosa-associated disorders elicited by urban coarse particulates.

Keywords: aesculetin inflammation; airway thickening; mucus hypersecretion; oxidative stress; urban particulate matter.