Attenuation of airway smooth muscle contractility via flavonol-mediated inhibition of phospholipase-Cβ

Abstract

hanced contractility of airway smooth muscle (ASM) is a major pathophysiological characteristic of asthma. Expanding the therapeutic armamentarium beyond ␤-agonists that target ASM hypercontractility would substantially improve treatment options. Recent studies have identified naturally occurring phytochemicals as candidates for acute ASM relaxation. Several flavonoids were evaluated for their ability to acutely relax human and murine ASM ex vivo and murine airways in vivo and were evaluated for their ability to inhibit procontractile signaling pathways in human ASM (hASM) cells. Two members of the flavonol subfamily, galangin and fisetin, significantly relaxed acetylcholine-precontracted murine tracheal rings ex vivo (n ϭ 4 and n ϭ 5, respectively, P Ͻ 0.001). Galangin and fisetin also relaxed acetylcholine-precontracted hASM strips ex vivo (n ϭ 6 -8, P Ͻ 0.001). Functional respiratory in vivo murine studies demonstrated that inhaled galangin attenuated the increase in lung resistance induced by inhaled methacholine (n ϭ 6, P Ͻ 0.01). Both flavonols, galangin and fisetin, significantly inhibited purified phosphodiesterase-4 (PDE4) (n ϭ 7, P Ͻ 0.05; n ϭ 7, P Ͻ 0.05, respectively), and PLC␤ enzymes (n ϭ 6, P Ͻ 0.001 and n ϭ 6, P Ͻ 0.001, respectively) attenuated procontractile Gq agonists' increase in intracellular calcium (n ϭ 11, P Ͻ 0.001), acetylcholine-induced increases in inositol phosphates, and CPI-17 phosphorylation (n ϭ 9, P Ͻ 0.01) in hASM cells. The prorelaxant effect retained in these structurally similar flavonols provides a novel pharmacological method for dual inhibition of PLC␤ and PDE4 and therefore may serve as a potential treatment option for acute ASM constriction. bronchodilation; flexiVent; myograph; phosphodiesterase; phytochemical THERE ARE LIMITED PHARMACOLOGICAL options available to asthmatic patients that provide acute relaxation of airway smooth muscle (ASM). ␤-Agonists or anticholinergic medications remain the primary therapeutic classes of medications available for acute bronchodilation; however, in a growing number of patients frequent exacerbations remain a challenge. More recent formulations have combined long-acting ␤-agonists with inhaled steroids in an attempt to improve asthma symptomology. For example, in poorly controlled persistent asthmatic patients, the current recommendation is the addition of longacting ␤-agonist (LABA) to be used in combination with an inhaled corticosteroid. Somewhat paradoxically, when asthma exacerbations occur in patients treated with LABAs, they are often also administered a shorter acting member of the same drug class (i.e., short-acting ␤-adrenoceptor agonists). Thus clinicians heavily rely on ␤-agonists (both short and longacting), in both acute and chronic settings. This reliance has led to several concerns including the pathophysiological consequences of tolerance and airway hyperresponsiveness as well as a growing controversy regarding an association with negative clinical outcomes such as increased exacerbations and an increased risk of de...

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“…Mizuta et al (2015) showed that long-chain free fatty acid binding to fatty acid receptors increased inositol phosphate synthesis in human airway smooth muscle cells (hASM). Brown et al (2016) showed that flavonols significantly inhibited purified phosphodiesterase-4 (PDE4) and PLCβ enzymes, attenuated acetylcholine-induced increases in inositol phosphates and CPI-17 phosphorylation in hASM cells and relaxed airway smooth muscle. These studies indicated the crucial role of inositol phosphate metabolism in asthma.…”

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“…Besides, glycolysis or gluconeogenesis pathway also showed a potential changing trend in asthmatic energy metabolic network. Inositol phosphate metabolism, which was associated with another differentiated hexose, myo-inositol, has been reported to participate in the regulation of the airway smooth muscle contractility [ 51 ].…”

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