Calcaratarin D, a Labdane Diterpenoid, Attenuates Mouse Asthma Via Modulating Alveolar Macrophage Function

Background and PurposeAlveolar macrophages (AMs) contribute to airway inflammation and remodelling in allergic asthma. Calcaratarin D (CalD), a labdane diterpenoid from 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 ApproachThe effects of CalD on AMs in contributing to anti-inflammatory effects in asthma were investigated through in vivo, ex vivo, and in vitro experiments. Key ResultsCalD reduced total bronchoalveolar lavage fluid and differential cell count, serum IgE levels, mucus hypersecretion, and airway hyperresponsiveness in HDM-challenged mice. Additionally, CalD affected a wide array of pro-inflammatory cytokines and chemokines and oxidative damage markers in isolated lung tissues. CalD suppressed the HDM-induced increase in Arg1 (M2 macrophage marker) in AMs from lung tissue and reduced lung polyamine levels. CalD weakened antigen presentation capability of AMs by reducing CD80 expression, reduced AM-derived CCL17 and CCL22 levels, and lessened Th2 cytokines from CD4(+) T-cells from asthma lung digest. CalD blocked the HDM-induced FoxO1/IRF4 pathway and restored impaired the 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 the alpha,beta-unsaturated gamma-butyrolactone in CalD is capable of forming covalent bonds with cellular protein targets essential for its action. Conclusion and ImplicationsOur results demonstrate for the first time that CalD is a novel anti-inflammatory natural compound for allergic asthma that modulates AM function.