Calcaratarin D, a labdane diterpenoid, attenuates mouse asthma via modulating alveolar macrophage function.

BACKGROUND AND PURPOSE: Alveolar macrophages (AMs) contribute to airway inflammation and remodeling in allergic asthma. Calcaratarin D (CalD), a labdane diterpenoid isolated from the rhizomes of the medicinal plant Alpinia calcarata, has recently been shown to possess anti-inflammatory properties. The present study evaluated protective effects of CalD in a house dust mite (HDM)-induced asthma mouse model.

EXPERIMENTAL APPROACH: The effects of CalD on AMs in contributing to anti-inflammatory effects in asthma were investigated through a series of in vivo, ex vivo and in vitro experiments.

KEY RESULTS: CalD reduced bronchoalveolar lavage fluid total and differential cell counts, serum IgE levels, mucus hypersecretion and airway hyperresponsiveness in HDM-challenged mice. Besides, CalD abrogated a wide array of pro-inflammatory cytokines and chemokines, and oxidative damage markers in isolated lung tissues. CalD suppressed HDM-induced increase in Arg1 (M2 marker) in AMs from lung tissues, and reduced lung polyamine levels. CalD weakened antigen presentation capability of AMs by abating CD80 expression, reduced AM-derived CCL17 and CCL22 levels, and lessened Th2 cytokines from CD4+ T cells from asthma lung digest. CalD blocked HDM-induced FoxO1/IRF4 pathway and restored impaired Nrf2/HO-1 antioxidant pathway in lung tissues. CalD inhibited IL-4/IL-13-stimulated JAK1/STAT6 pathway, FoxO1 protein expression, and chemokine production in primary AMs. Structure-activity relationship study revealed that α,β-unsaturated γ-butyrolactone in CalD capable of forming covalent bonds with cellular protein targets is essential for its action.

CONCLUSION AND IMPLICATIONS: Our results demonstrated for the first time that CalD is a novel anti-inflammatory natural compound for allergic asthma by modulating AM functions.