The anti-asthma herbal medicine ASHMI acutely inhibits airway smooth muscle contraction via prostaglandin E₂activation of EP₂/EP₄receptors

Abstract

Our previous studies have shown that the anti-asthma traditional Chinese medicine herbal formula ASHMI (anti-asthma simplified herbal medicine intervention) inhibits acetylcholine-induced contractions of tracheal rings from ovalbumin-sensitized and naive mice in a ␤-adrenoceptor-independent manner. We sought to determine whether acute in vivo ASHMI administration inhibits airway hyperreactivity (AHR) in a murine model of allergic asthma and acetylcholine-induced tracheal ring constriction ex vivo and to elucidate the cellular mechanisms underlying these effects. Ovalbumin-sensitized mice received a single oral ASHMI dose 2 h before intravenous acetylcholine challenge. AHR was determined by invasive airway measurements. Myography was used to determine the effects of ASHMI on acetylcholine-induced constriction of tracheal rings from asthmatic mice with or without epithelial denudation. The effect of cyclooxygenase inhibition and EP2/EP4 receptor blockade on ASHMI attenuation of acetylcholine contractions was evaluated. Tracheal cAMP and PGE 2 levels were measured by ELISA. A single acute oral dose of ASHMI dramatically reduced AHR in response to acetylcholine provocation in ovalbuminsensitized mice (P Ͻ 0.001). In ex vivo experiments, ASHMI significantly and dose-dependently reduced tracheal ring constriction to acetylcholine (P Ͻ 0.05-0.001), which was epithelium independent and associated with elevated cAMP levels. This effect was abrogated by cyclooxygenase inhibition or EP 2/EP4 receptor blockade. ASHMI also inhibited contraction to high K ϩ (P Ͻ 0.001). ASHMI increased tracheal ring PGE 2 release in response to acetylcholine or high K ϩ (P Ͻ 0.05 for both). ASHMI produced direct and acute inhibition of AHR in vivo and blocked acetylcholine-induced tracheal ring constriction via the EP 2/EP4 receptor pathway, identifying the mechanism by which ASHMI is an orally active bronchoprotective agent.

PGE2 deficiency predisposes to anaphylaxis by causing mast cell hyperresponsiveness

“…In the current report, the suppressive effect of the EP4 agonist could be further enhanced by the EP2 agonist in accordance with other systems. 62,63 Although the EP3 agonist had a stimulatory effect on BMcMCs, inhibition by EP2 and especially by EP4 seemed to prevail and dictate the overall effect of PGE 2 . 64 Contrary to some literature, which detected enhanced secretory competence of MCs by PGE 2 (mostly via EP3) in vitro, the majority of previous reports and our current findings demonstrate a suppressive action of PGE 2 .…”

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“…For example, anti-asthma herbal medicine made from extracts from Ganoderma lucidum , Glycyrrhiza uralensis and Sophora flavescens alleviates bronchoconstriction in an animal model whilst restoring cytokines balance, contributing to longer lasting anti-asthma benefit after treatment [ 66 ]. The therapeutic effect only emanates from the synergistic effect of chemical components of the three herbal ingredients [ 67 , 68 ]. The adoption of Good Manufacturing Practises has allowed the increased use of plant-based medicines and many are now undergoing clinical trial for FDA approval [ 69 ].…”

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“…Lipid peroxidation, assessed as isoprostane levels, is found to be markedly increased in acute asthma, and falls with resolution of the exacerbation [48]. Srivastava et al found the anti-asthma herbal medicine ASHMI inhibited airway smooth muscle contraction via prostaglandin E2 activation of EP2/EP4 receptors [49]. PGD 2 can accelerate T H 2 type (IL-4 and IL-5) inflammation by induction of macrophage-derived chemokines [50].…”