Pharmacological approach to restoring steroid sensitivity in respiratory diseases / 中国药理学与毒理学杂志

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 therapeu-tic agents to restore corticosteroid efficacy in affected patients. There have been reports showing the promise of theophylline and rapamycin in reversing steroid resistance in COPD. Our laboratory has demonstrated that andrographolide, a bioactive diterpenoid lactone isolated from the plant Androgra-phis paniculata, is an effective anti-inflammatory and anti-oxidative compound 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 was found to restore the anti-inflammatory effect of dexameth-asone in 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, probably via suppression of PI3K/Akt/HDAC2 phosphorylation and up-regulation of the antioxi-dant 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,androgra-pholide 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 unraveled. Nevertheless, our existing data strongly implicate a potentially novel steroid re-sensitizing activity of andrographolide in both severe asthma and COPD models.