Effects of Ginger and Its Constituents on Airway Smooth Muscle Relaxation and Calcium Regulation

Townsend, Elizabeth; Siviski, Matthew E.; Zhang, Yi; Xu, Carrie; Hoonjan, Bhupinder; Emala, Charles W.

doi:10.1165/rcmb.2012-0231oc

Cited by 105 publications

(79 citation statements)

References 43 publications

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“…Dixon and Santana (40) recently asked the question, "does inhibition of PKC in ASM increase airflow during asthma and COPD?" Our current data, together with our previous in vivo studies (9), argue that this is a potential signaling mechanism to explain the bronchorelaxant properties of 6-gingerol, 8-gingerol, and 6-shogaol, and may prove a yet-unrealized target for future asthma therapies. n Author disclosures are available with the text of this article at www.atsjournals.org.…”

Section: What This Means For B 2 -Ar Desensitization and Future Therasupporting

confidence: 60%

“…Increased PKA activity due to increases in cAMP reduces intracellular calcium by phosphorylating IP 3 receptors on the sarcoplasmic reticulum of ASM cells (35). We previously showed that pretreatment with 8-gingerol or 6-shogaol attenuated G q -induced increases in intracellular calcium (9). These effects may be attributed to increases in cAMP through PDE4-inhibitory actions of these compounds, leading to increased PKA activity.…”

Section: B-agonist-induced Relaxation In the Airwaymentioning

confidence: 95%

“…We were the first group to demonstrate that purified components of the ginger root (Zingiber officinale) can relax human ASM and to confirm that 6-gingerol, 8-gingerol, and 6-shogoal are the active components responsible for bronchorelaxation (9). By better understanding the mechanisms by which purified components of ginger exert their effects on the airway, we can explore the use of these naturally derived phytotherapeutics in alleviating asthma symptoms alone and in combination with existing therapies.…”

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confidence: 99%

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Active Components of Ginger Potentiate β-Agonist–Induced Relaxation of Airway Smooth Muscle by Modulating Cytoskeletal Regulatory Proteins

Townsend

Zhang

et al. 2014

Am J Respir Cell Mol Biol

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b-Agonists are the first-line therapy to alleviate asthma symptoms by acutely relaxing the airway. Purified components of ginger relax airway smooth muscle (ASM), but the mechanisms are unclear. By elucidating these mechanisms, we can explore the use of phytotherapeutics in combination with traditional asthma therapies. The objectives of this study were to: (1) determine if 6-gingerol, 8-gingerol, or 6-shogaol potentiate b-agonist-induced ASM relaxation; and (2) define the mechanism(s) of action responsible for this potentiation. Human ASM was contracted in organ baths. Tissues were relaxed dose dependently with b-agonist, isoproterenol, in the presence of vehicle, 6-gingerol, 8-gingerol, or 6-shogaol (100 mM). Primary human ASM cells were used for cellular experiments. Purified phosphodiesterase (PDE) 4D or phospholipase C b enzyme was used to assess inhibitory activity of ginger components using fluorescent assays. A G-LISA assay was used to determine the effects of ginger constituents on Ras homolog gene family member A activation. Significant potentiation of isoproterenol-induced relaxation was observed with each of the ginger constituents. 6-Shogaol showed the largest shift in isoproterenol half-maximal effective concentration. 6-Gingerol, 8-gingerol, or 6-shogaol significantly inhibited PDE4D, whereas 8-gingerol and 6-shogaol also inhibited phospholipase C b activity. 6-Shogaol alone inhibited Ras homolog gene family member A activation. In human ASM cells, these constituents decreased phosphorylation of 17-kD protein kinase C-potentiated inhibitory protein of type 1 protein phosphatase and 8-gingerol decreased myosin light chain phosphorylation. Isolated components of ginger potentiate b-agonist-induced relaxation in human ASM. This potentiation involves PDE4D inhibition and cytoskeletal regulatory proteins. Together with b-agonists, 6-gingerol, 8-gingerol, or 6-shogaol may augment existing asthma therapy, resulting in relief of symptoms through complementary intracellular pathways.Keywords: asthma; adrenergic receptor; myosin light chain; lung; bronchodilation Clinical RelevanceNatural herbal remedies, including ginger, have long been used to treat respiratory conditions. Many individuals with asthma use herbal therapies to self-treat their asthma symptoms; however, little is known regarding how these compounds work in the airway. In the current work, we show that 6-gingerol, 8-gingerol, and 6-shogaol potentiate b-agonist-induced relaxation of airway smooth muscle by inhibiting both phosphodiesterase 4D and phosphatidylinositol-specific phospholipase C, leading to downstream regulation of contractile proteins. These data suggest that natural compounds can work in combination with traditional asthma therapies to relieve asthma symptoms.

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Section: What This Means For B 2 -Ar Desensitization and Future Therasupporting

confidence: 60%

Section: B-agonist-induced Relaxation In the Airwaymentioning

confidence: 95%

mentioning

confidence: 99%

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Active Components of Ginger Potentiate β-Agonist–Induced Relaxation of Airway Smooth Muscle by Modulating Cytoskeletal Regulatory Proteins

Townsend

Zhang

et al. 2014

Am J Respir Cell Mol Biol

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“…Using a flexiVent (SciReq, Montreal, PQ, Canada) as previously described (18,19), anesthetized, HDM-sensitized WT mice received nebulized XHe-III-74 (25 ml, 10 mM) or vehicle (25% ethanol in PBS) via tracheostomy 10 minutes before measuring in vivo R RS during a nebulized methacholine challenge.…”

Section: In Vivo Mouse Respiratory System Resistance Testingmentioning

confidence: 99%

Targeting the γ-Aminobutyric Acid A Receptor α4 Subunit in Airway Smooth Muscle to Alleviate Bronchoconstriction

Yocum

Gallos

Zhang

et al. 2016

Am J Respir Cell Mol Biol

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We previously demonstrated that airway smooth muscle (ASM) cells express g-aminobutyric acid A receptors (GABA A Rs), and that GABA A R agonists acutely relax ASM. Among the GABA A R a subunits, human ASM cells express only a4 and a5, providing the opportunity for selective pharmacologic targeting. Novel GABA A R-positive allosteric modulators designed for enhanced a4/a6 subunit selectivity were synthesized using iterative computational analyses (CMD-45 and XHe-III-74). Studies using oocyte heterologous expression systems confirmed that CMD-45 and XHe-III-74 led to significantly greater augmentation of currents induced by a 3% maximal effective concentration (EC 3 ) of GABA [EC 3 ]-induced currents in oocytes expressing a4 or a6 subunits (along with b3 and g2) compared with other a subunits. CMD-45 and XHe-III-74 also led to greater ex vivo relaxation of contracted wild-type mouse tracheal rings compared with tracheal rings from GABA A R a4 subunit (Gabra4) knockout mice. Furthermore, CMD-45 and XHe-III-74 significantly relaxed precontracted human ASM ex vivo, and, at a low concentration, both ligands led to a significant leftward shift in albuterolmediated ASM relaxation. In vivo, inhaled XHe-III-74 reduced respiratory system resistance in an asthmatic mouse model. Pretreatment of human ASM cells with CMD-45 and XHe-III-74 inhibited histamine-induced increases in intracellular calcium concentrations in vitro, an effect that was lost when calcium was omitted from the extracellular buffer, suggesting that inhibition of calcium influx due to alterations in plasma membrane potential may play a role in the mechanism of ASM relaxation. Selective targeting of the GABA A R a4 subunit with inhaled ligands may be a novel therapeutic pathway to treat bronchoconstriction, while avoiding sedative central nervous system effects, which are largely mediated by a1-3 subunit-containing GABA A Rs in the brain.

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“…NOVEL ROLES OF AIRWAY SMOOTH MUSCLE activity, both of which may contribute to reduced IP 3 levels (310,312). In terms of CD38, several previous studies have demonstrated that inflammation can substantially increase CD38 levels and thus enhance cADPR-mediated [Ca 2ϩ ] i and contractility (101, 125, 141-144, 147, 300, 301), and more recent data show that altered CD38/cADPR signaling contributes to the asthma phenotype (141).…”

Section: L918mentioning

confidence: 99%

Airway smooth muscle in airway reactivity and remodeling: what have we learned?

Prakash

2013

American Journal of Physiology-Lung Cellular and Molecular Phys

177

154

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Prakash YS. Airway smooth muscle in airway reactivity and remodeling: what have we learned? Am J Physiol Lung Cell Mol Physiol 305: L912-L933, 2013. First published October 18, 2013 doi:10.1152/ajplung.00259.2013.-It is now established that airway smooth muscle (ASM) has roles in determining airway structure and function, well beyond that as the major contractile element. Indeed, changes in ASM function are central to the manifestation of allergic, inflammatory, and fibrotic airway diseases in both children and adults, as well as to airway responses to local and environmental exposures. Emerging evidence points to novel signaling mechanisms within ASM cells of different species that serve to control diverse features, including 1) [Ca 2ϩ ]i contractility and relaxation, 2) cell proliferation and apoptosis, 3) production and modulation of extracellular components, and 4) release of pro-vs. anti-inflammatory mediators and factors that regulate immunity as well as the function of other airway cell types, such as epithelium, fibroblasts, and nerves. These diverse effects of ASM "activity" result in modulation of bronchoconstriction vs. bronchodilation relevant to airway hyperresponsiveness, airway thickening, and fibrosis that influence compliance. This perspective highlights recent discoveries that reveal the central role of ASM in this regard and helps set the stage for future research toward understanding the pathways regulating ASM and, in turn, the influence of ASM on airway structure and function. Such exploration is key to development of novel therapeutic strategies that influence the pathophysiology of diseases such as asthma, chronic obstructive pulmonary disease, and pulmonary fibrosis.

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Effects of Ginger and Its Constituents on Airway Smooth Muscle Relaxation and Calcium Regulation

Cited by 105 publications

References 43 publications

Active Components of Ginger Potentiate β-Agonist–Induced Relaxation of Airway Smooth Muscle by Modulating Cytoskeletal Regulatory Proteins

Active Components of Ginger Potentiate β-Agonist–Induced Relaxation of Airway Smooth Muscle by Modulating Cytoskeletal Regulatory Proteins

Targeting the γ-Aminobutyric Acid A Receptor α4 Subunit in Airway Smooth Muscle to Alleviate Bronchoconstriction

Airway smooth muscle in airway reactivity and remodeling: what have we learned?

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