I12 Repositioning andrographolide for airway inflammation: Mapping its mechanistic networks

Abstract

Inhaled corticosteroid is the first-line controller for asthma and COPD. However, about 10% of the asthmatics (severe/refractory asthma) and most of the COPD patients are resistant to the beneficial effects of corticosteroids. There is a pressing unmet medical need to develop novel therapeutic agents to restore corticosteroid efficacy in affected patients. Andrographolide, a bioactive molecule isolated from the plant Andrographis paniculata, has demonstrated anti-inflammatory and antioxidant properties in both asthma and COPD experimental models. In a severe asthma mouse model using combined IFN- γ /LPS exposure, production of IL-27 and methacholine-induced airway hyperresponsiveness (AHR) were found to be corticosteroid-resistant. Andrographolide significantly restored the suppressive effect of dexamethasone on LPS/IFN- γ -induced IL-27 levels in bronchoalveolar lavage (BAL) fluid and AHR in mice. LPS/IFN- γ markedly reduced the nuclear level of histone deacetylase-2 (HDAC2), an essential epigenetic enzyme that mediates corticosteroid anti-inflammatory actions. Andrographolide significantly restored nuclear HDAC2 levels and diminished total HAT/HDAC activity ratio in mouse lungs exposed to LPS/IFN- γ , possibly via suppression of PI3K/Akt/HDAC2 phosphorylation and up-regulation of the antioxidant transcription factor Nrf2 level. In a cigarette smoke (CS)-induced COPD model, andrographolide markedly restored dexamethasone actions in inhibiting CS-induced lung neutrophilia. In addition, andrographolide facilitated dexamethasone actions to suppress BAL fluid IL-6, IL-1b, KC and IL-17 levels. In lung lysates, andrographolide markedly restored total nuclear HDAC activity. The complete steroid re-sensitization mechanism of andrographolide remains to be unravelled. Nevertheless, our existing data strongly implicate a potentially novel steroid re-sensitizing activity of andrographolide in both severe asthma and COPD models. Acknowledgements This work was supported by a NUHS Bridging Grant R-184-000-267-733 and a CREATE Grant R-184-000-269-592 by the National Research Foundation (NRF) of Singapore to W.S.F.W.