title: The anti-asthma herbal medicine ASHMI acutely inhibits airway smooth muscle contraction via prostaglandin E2 activation of EP2/EP4 receptors.
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 β-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 PGE2 levels were measured by ELISA. A single acute oral dose of ASHMI dramatically reduced AHR in response to acetylcholine provocation in ovalbumin-sensitized mice (P < 0.001). In ex vivo experiments, ASHMI significantly and dose-dependently reduced tracheal ring constriction to acetylcholine (P < 0.05-0.001), which was epithelium independent and associated with elevated cAMP levels. This effect was abrogated by cyclooxygenase inhibition or EP2/EP4 receptor blockade. ASHMI also inhibited contraction to high K(+) (P < 0.001). ASHMI increased tracheal ring PGE2 release in response to acetylcholine or high K(+) (P < 0.05 for both). ASHMI produced direct and acute inhibition of AHR in vivo and blocked acetylcholine-induced tracheal ring constriction via the EP2/EP4 receptor pathway, identifying the mechanism by which ASHMI is an orally active bronchoprotective agent.
authors.affiliation: Pediatric Allergy and Immunology, The Mount Sinai School of Medicine, One Gustave L. Levy Place, New York, NY 10029-6574. xiu-min.li@mssm.edu.
authors.forename: Kamal
authors.initials: K
authors.lastname: Srivastava
authors.forename: Hugh A
authors.initials: HA
authors.lastname: Sampson
authors.forename: Charles W
authors.initials: CW
authors.lastname: Emala
authors.forename: Xiu-Min
authors.initials: XM
authors.lastname: Li
mesh_terms: D000818:Animals; D018927:Anti-Asthmatic Agents / Q000627:therapeutic use*; D001249:Asthma / Q000188:drug therapy; D015232:Dinoprostone / Q000378:metabolism*; D004365:Drugs, Chinese Herbal / Q000008:administration & dosage / Q000627:therapeutic use*; D029001:Herbal Medicine / Q000379:methods; D051379:Mice; D009119:Muscle Contraction / Q000187:drug effects*; D009130:Muscle, Smooth / Q000187:drug effects / Q000378:metabolism*; D010047:Ovalbumin / Q000494:pharmacology; D018078:Receptors, Prostaglandin E / Q000378:metabolism*; D014132:Trachea / Q000187:drug effects
chemical_list: C555782:ASHMI herbal formula; D018927:Anti-Asthmatic Agents; D004365:Drugs, Chinese Herbal; D018078:Receptors, Prostaglandin E; D010047:Ovalbumin; D015232:Dinoprostone
keywords: PGE2; contraction; mice; myography; ovalbumin sensitization; tracheal rings