Esculentoside A Attenuates Allergic Airway Inflammation via Activation of the Nrf-2 Pathway

Abstract

Background: The role of airway inflammation and inflammation-induced oxidative stress in the pathogenesis and progression of chronic inflammatory airway diseases has received increasing attention in recent years. We investigated the potential anti-inflammatory and antioxidative effects of esculentoside A (EsA), a saponin isolated from the Chinese herb Phytolacca esculenta, in comparison to dexamethasone, a potent corticosteroid, in a murine model of allergic asthma. Methods: EsA was added to cultures of A549 cells at different concentrations or for different lengths of time, and nuclear factor erythroid 2-related factor 2 (Nrf-2) translocation and heme oxygenase 1 expression were monitored. Mice treated with or without EsA and Nrf-2 siRNA were sensitized and challenged with ovalbumin (OVA) and developed airway inflammation and oxidative lung damage. The Th2-type cytokine levels and inflammatory cells in bronchoalveolar lavage fluid (BALF) and the serum immunoglobulin production and adhesion molecule expression in the lung tissues were measured. The activities of related antioxidases and glutathione were measured using assay kits. Results: EsA enhanced nuclear Nrf-2 translocation in both A549 cells and the lungs of OVA-challenged mice. Airway inflammation induced by OVA was reduced. Additionally, EsA increased mRNA expression of antioxidant enzymes regulated by Nrf-2, leading to a reduction in Th2 cytokines and the expression of adhesion molecule mRNA in the BALF and lung tissues. Inhibition of Nrf-2 by siRNA abrogated the regulatory effects of EsA on inflammation and oxidant stress. Conclusions: This is the first study to illustrate that EsA acts as a novel Nrf-2 activator, which modulates the oxidative stress pathway to improve lung injury and ameliorate the development of airway inflammation.