Rapid effects of estrogen on intracellular Ca<sup>2+</sup> regulation in human airway smooth muscle

Townsend, Elizabeth; Thompson, Michael A.; Pabelick, Christina M.; Prakash, Y. S.

doi:10.1152/ajplung.00287.2009

Cited by 86 publications

(93 citation statements)

References 55 publications

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“…Nevertheless, exposed PS could served as a beacon for specific molecules, such as GAS6 or MFG-E8 (32), leading to the downstream effects. In contrast to the present results, a former study has demonstrated that acute estrogen exposure leads to the ERα-dependent blunting of agonist-induced [Ca 2+ ] responses (34). This discrepancy may be due to the fact that E2/ERα signaling is largely dependent on the recruitment of coactivators or corepressors in different cellular and tissue contexts (35).…”

Section: Figurecontrasting

confidence: 99%

Estrogen promotes Leydig cell engulfment by macrophages in male infertility

Yu¹,

Zheng²,

Lin³

et al. 2014

J. Clin. Invest.

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Male infertility accounts for almost half of infertility cases worldwide. A subset of infertile men exhibit reduced testosterone and enhanced levels of estradiol (E2), though it is unclear how increased E2 promotes deterioration of male fertility. Here, we utilized a transgenic mouse strain that overexpresses human CYP19, which encodes aromatase (AROM+ mice), and mice with knockout of Esr1, encoding estrogen receptor α (ERαKO mice), to analyze interactions between viable Leydig cells (LCs) and testicular macrophages that may lead to male infertility. In AROM+ males, enhanced E2 promoted LC hyperplasia and macrophage activation via ERα signaling. E2 stimulated LCs to produce growth arrest-specific 6 (GAS6), which mediates phagocytosis of apoptotic cells by bridging cells with surface exposed phosphatidylserine (PS) to macrophage receptors, including the tyrosine kinases TYRO3, AXL, and MER. Overproduction of E2 increased apoptosis-independent extrusion of PS on LCs, which in turn promoted engulfment by E2/ERα-activated macrophages that was mediated by AXL-GAS6-PS interaction. We further confirmed E2-dependant engulfment of LCs by real-time 3D imaging. Furthermore, evaluation of molecular markers in the testes of patients with nonobstructive azoospermia (NOA) revealed enhanced expression of CYP19, GAS6, and AXL, which suggests that the AROM+ mouse model reflects human infertility. Together, these results suggest that GAS6 has a potential as a clinical biomarker and therapeutic target for male infertility.

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Section: Figurecontrasting

confidence: 99%

Estrogen promotes Leydig cell engulfment by macrophages in male infertility

Yu¹,

Zheng²,

Lin³

et al. 2014

J. Clin. Invest.

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“…Immortalized and primary human ASM cell lines were prepared as described previously (17,18) and grown in phenol red-free Dulbecco's Modified Eagle's Medium/F12 media (GIBCO, Grand Island, NY), with 10% FBS and antibiotics.…”

Section: Cultured Human Airway Smooth Muscle Cellsmentioning

confidence: 99%

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

Townsend

Siviski

Zhang

et al. 2013

Am J Respir Cell Mol Biol

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109

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The prevalence of asthma has increased in recent years, and is characterized by airway hyperresponsiveness and inflammation. Many patients report using alternative therapies to self-treat asthma symptoms as adjuncts to short-acting and long-acting b-agonists and inhaled corticosteroids (ICS). As many as 40% of patients with asthma use herbal therapies to manage asthma symptoms, often without proven efficacy or known mechanisms of action. Therefore, investigations of both the therapeutic and possible detrimental effects of isolated components of herbal treatments on the airway are important. We hypothesized that ginger and its active components induce bronchodilation by modulating intracellular calcium ([Ca 21 ] i ) in airway smooth muscle (ASM). In isolated human ASM, ginger caused significant and rapid relaxation. Four purified constituents of ginger were subsequently tested for ASM relaxant properties in both guinea pig and human tracheas: ] i regulation. These purified compounds may provide a therapeutic option alone or in combination with accepted therapeutics, including b 2 -agonists, in airway diseases such as asthma.

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“…We have previously demonstrated that progesterone and its immediate 5b-reduced metabolite, pregnanolone, induce a nongenomic relaxation of guinea pig trachea (Perusquía et al 1997). Likewise, estrogens have also been reported to be nongenomic relaxants (Townsend et al 2010(Townsend et al , 2012. Little attention has also been paid to the effect of androgens on ASM, only three basic research studies have examined this issue.…”

Section: Introductionmentioning

confidence: 99%

Androgens are bronchoactive drugs that act by relaxing airway smooth muscle and preventing bronchospasm

Montaño¹,

Espinoza²,

Flores‐Soto³

et al. 2014

Journal of Endocrinology

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Changes in the androgen levels in asthmatic men may be associated with the severity of asthma. Androgens induce a nongenomic relaxation in airway smooth muscle, but the underlying mechanisms remain unclear. The aim of this study was to investigate the potential bronchorelaxing action of testosterone (TES) and its metabolites (5a-and 5b-dihydrotestosterone (DHT). A preventive effect on ovalbumin (OVA)-induced bronchospasm was observed in sensitized guinea pigs for each androgen. Androgens were studied in response to bronchoconstrictors: carbachol (CCh) and KCl in isolated trachea rings with and without epithelium from non-sensitized and sensitized animals as well as on OVA-induced contraction. Androgens concentration-dependently abolished the contraction in response to CCh, KCl, and OVA. There were significant differences in the sensitivity to the relaxation induced by each androgen. 5b-DHT was more potent for relaxing KCl-induced contraction, while TES and 5a-DHT were more potent for CCh-and OVA-induced contraction. No differences were found in preparations with and without epithelium or in the presence of a nitric oxide (NO) synthase inhibitor or an inhibitor of K C channels. These data indicate the absence of involvement of the epithelium-, NO-and K C channels-dependent pathway in androgen-induced relaxation. However, in dissociated tracheal myocytes loaded with the calcium-binding fluorescent dye Fura -2, physiological concentrations of androgens decreased the KCl-induced [Ca 2C ] i increment. 5b-DHT was the most potent at decreasing KCl-induced [Ca 2C ] i increment and preventing bronchospasm. We suggest that androgen-induced brochorelaxation was mediated via decreased Ca 2C influx through L-type Ca 2C channels but additional Ca 2C entry blockade may be involved. Molecular changes in androgen structure may determine its preferential site of action. Key Words" asthma " testosterone " 5a-dihydrotestosterone" 5b-dihydrotestosterone " bronchoactive steroids " airway smooth muscle

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Rapid effects of estrogen on intracellular Ca²⁺ regulation in human airway smooth muscle

Cited by 86 publications

References 55 publications

Estrogen promotes Leydig cell engulfment by macrophages in male infertility

Estrogen promotes Leydig cell engulfment by macrophages in male infertility

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

Androgens are bronchoactive drugs that act by relaxing airway smooth muscle and preventing bronchospasm

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Rapid effects of estrogen on intracellular Ca2+ regulation in human airway smooth muscle

Cited by 86 publications

References 55 publications

Estrogen promotes Leydig cell engulfment by macrophages in male infertility

Estrogen promotes Leydig cell engulfment by macrophages in male infertility

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

Androgens are bronchoactive drugs that act by relaxing airway smooth muscle and preventing bronchospasm

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Rapid effects of estrogen on intracellular Ca²⁺ regulation in human airway smooth muscle