The blocking effect of essential controller medications during aspirin challenge in patients with aspirin-exacerbated respiratory disease

Abstract

RATIONALE:We previously demonstrated that the Chinese herbal formula ASHMI reduced inflammation associated hyperreactivity in a murine model of allergic asthma. In this study we investigated possible direct modulation of airway reactivity by ASHMI using tracheal ring preparations. METHODS: Reactivity of tracheal rings isolated from allergic or naïve BALB/C mice to acetylcholine (Ach) or prostaglandin E2 (PGE2) challenge was measured by myography. Contractility to Ach was monitored in the presence or absence of ASHMI (100ug/ml) with or without beta-adrenergic antagonist ICI118, 551 (10uM) or the cyclooxygenase inhibitor indomethacin (5uM). PGE2 release and tissue cyclic AMP levels following Ach and PGE2 stimulation were evaluated by ELISA. RESULTS: ASHMI-pretreated rings showed significantly reduced Achinduced contractility (26.3±11.5 vs 236.9±19.6, % contraction, P<.001). Suppression of responses to Ach was unaffected by ICI118, 551(43.5±12.0 vs 45±11.5, % contraction), but markedly reversed in the presence of indomethacin (78.5±3.8 vs 20.68±7.2, % contraction, P<.001). Increased levels of PGE2 release were observed in ASHMI-pretreated Ach-stimulated ring preparations (6905±769 vs 3314±160, pg/ml P<.001). Furthermore, ASHMI-pretreated rings showed an increased relaxation response to PGE2 (25.03±6.9 vs 58.4±4.0, % contraction, P<0.01). Elevated levels of tissue cAMP were observed in ASHMI-pretreated rings exposed to Ach (287±88.8 vs 98±20.2 uM/mg tissue, P<.001) or PGE2 (988±18.3 vs 852±33.7 uM/mg tissue, P<0.05) implying possible phosphodiesterase inhibition. CONCLUSIONS: Pretreatment of tracheal rings with ASHMI reduced contractile responses to Ach in a beta-adrenergic independent manner and potentiated relaxation to PGE2, making it an attractive option for asthma therapy. Funding: NCCAM