Androgen Receptor-Mediated Regulation of Intracellular Calcium in Human Airway Smooth Muscle Cells

Kalidhindi, Rama Satyanarayana Raju; Katragadda, Rathnavali; Beauchamp, Kerri L; Pabelick, Christina M.; Prakash, Y. S.; Sathish, Venkatachalem

doi:10.33594/000000131

Cited by 26 publications

(27 citation statements)

References 61 publications

(112 reference statements)

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“…Acquisition of human lung samples and the isolation and culturing of human ASM cells have been previously described ( 5 , 6 , 22 , 28 , 30 , 32 ). Briefly, third- to sixth-generation human bronchi were obtained from lung specimens incidental to patient thoracic surgeries at Mayo Clinic (focal, noninfectious indications; typically lobectomies, rarely pneumonectomies).…”

Section: Methodsmentioning

confidence: 99%

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Sex steroids skew ACE2 expression in human airway: a contributing factor to sex differences in COVID-19?

Kalidhindi

Borkar

Ambhore

et al. 2020

American Journal of Physiology-Lung Cellular and Molecular Phys

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The incidence, severity and mortality of ongoing coronavirus infectious disease-19 (COVID-19) is greater in men compared to women, but the underlying factors contributing to this sex difference are still being explored. In the current study, using primary isolated human airway smooth muscle (ASM) cells from normal males vs. females as a model, we explored the effect of estrogen vs. testosterone in modulating the expression of angiotensin converting enzyme 2 (ACE2), a cell entry point for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Using confocal imaging, we found that ACE2 is expressed in human ASM. Furthermore, Western analysis of ASM cell lysates showed significantly lower ACE2 expression in females compared to males at baseline. In addition, ASM cells exposed to estrogen and testosterone for 24 h showed that testosterone significantly upregulates ACE2 expression in both males and females, whereas estrogen downregulates ACE2, albeit not significant compared to vehicle. These intrinsic and sex steroids induced differences may help explain sex differences in COVID-19.

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Section: Methodsmentioning

confidence: 99%

“…Serum-deprived human ASM cells were exposed to vehicle, E 2 [1 nM ( 5 , 7 )], and Tes (10 nM ( 22 ),) in DMEM/F12 (FBS free) for 24 h followed by protein collection for Western analyses ( 4 , 5 , 22 ).…”

Section: Methodsmentioning

confidence: 99%

Sex steroids skew ACE2 expression in human airway: a contributing factor to sex differences in COVID-19?

Kalidhindi

Borkar

Ambhore

et al. 2020

American Journal of Physiology-Lung Cellular and Molecular Phys

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“…Estimation of total and differential leukocyte count (DLC) in BALF was performed following previously published methods (Thompson et al, 1996;Raju et al, 2014;Ge et al, 2015;Ambhore et al, 2019a;Kalidhindi et al, 2019a). BALF was centrifuged at 2000 rpm for 5 min at 4°C and the supernatant was discarded.…”

Section: Total and Differential Leukocyte Count In Balfmentioning

confidence: 99%

“…In addition to genetic and environmental factors, sex/gender difference plays a pivotal role in the pathophysiology of asthma (Clough, 1993;Weiss and Gold, 1995;de Marco et al, 2000;Caracta, 2003;Carey et al, 2007b;Card and Zeldin, 2009;Woods et al, 2010;Townsend et al, 2012a;Cabello et al, 2015;Mishra et al, 2016;Fuentes and Silveyra, 2019b;Kalidhindi et al, 2019b). Incidence of asthma is more common in pre-pubescent boys and adult women and the severity of asthma is increased during pregnancy (de Marco et al, 2000;Caracta, 2003;Carey et al, 2007b;Bonds and Midoro-Horiuti, 2013).…”

Section: Introductionmentioning

confidence: 99%

Role of Estrogen Receptors α and β in a Murine Model of Asthma: Exacerbated Airway Hyperresponsiveness and Remodeling in ERβ Knockout Mice

et al. 2020

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Epidemiological data suggests increased prevalence of asthma in females than males, suggesting a plausible role for sex-steroids, especially estrogen in the lungs. Estrogen primarily acts through estrogen-receptors (ERa and ERb), which play a differential role in asthma. Our previous studies demonstrated increased expression of ERb in asthmatic human airway smooth muscle (ASM) cells and its activation diminished ASM proliferation in vitro and airway hyperresponsiveness (AHR) in vivo in a mouse (wild-type, WT) model of asthma. In this study, we evaluated the receptor specific effect of circulating endogenous estrogen in regulating AHR and remodeling using ERa and ERb knockout (KO) mice. C57BL/6J WT, ERa KO, and ERb KO mice were challenged intranasally with a mixedallergen (MA) or PBS. Lung function was measured using flexiVent followed by collection of broncho-alveolar lavage fluid for differential leukocyte count (DLC), histology using hematoxylin and eosin (H&E) and Sirius red-fast green (SRFG) and detecting asmooth muscle actin (a-SMA), fibronectin and vimentin expression using immunofluorescence (IF). Resistance (Rrs), elastance (Ers), tissue-damping (G) and tissue-elasticity (H) were significantly increased, whereas compliance (Crs) was significantly decreased in WT, ERa KO, and ERb KO mice (males and females) challenged with MA compared to PBS. Interestingly, ERb KO mice showed declined lung function compared to ERa KO and WT mice at baseline. MA induced AHR, remodeling and immune-cell infiltration was more prominent in females compared to males across all populations, while ERb KO females showed maximum AHR and DLC, except for neutrophil count. Histology using H&E suggests increased smooth muscle mass in airways with recruitment of inflammatory cells, while SRFG staining showed increased collagen deposition in MA challenged ERb KO mice compared to ERa KO and WT mice (males and females), with pronounced effects in ERb KO females. Furthermore, IF studies showed increased expression of a-SMA, fibronectin and vimentin in MA challenged populations compared to PBS, with prominent changes in ERb KO females. This novel study indicates ERb plays a pivotal role

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“…24 Androgens have also been shown to weaken tumour necrosis factor (TNF)-α or IL-13-induced enhancement of (Ca 2+ )i in human airway smooth muscle cells, which lessens airway responsiveness. 25 Collectively, bronchodilating and anti-inflammatory effects of testosterone may explain our results for asthma, current wheeze and asthma hospitalisations.…”

Section: Discussionmentioning

confidence: 79%

Serum free testosterone and asthma, asthma hospitalisations and lung function in British adults

Han

Yan

Yang

et al. 2020

Thorax

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ObjectiveWe examined the relation between serum-free testosterone and asthma, wheeze, asthma hospitalisations and lung function in older adults.DesignCross-sectional study.SettingUK.Participants256 419 adults aged 40 to 69 years, recruited from 2006 to 2010.Main outcome measuresMultivariable logistic or linear regression was used for the analysis of free testosterone and physician-diagnosed asthma, current wheeze, asthma hospitalisations and lung function measures, which was adjusted for serum estradiol, smoking status and other covariates.ResultsFree testosterone levels above the lowest quartile (Q1) were significantly associated with lower odds of asthma in both women (adjusted OR (aOR) for Q4 (the highest quartile) versus Q1=0.67, 95% CI=0.64 to 0.71) and men (aOR for Q4 versus Q1=0.87, 95% CI=0.82 to 0.91). Among subjects with asthma, free testosterone levels above Q1 were significantly associated with lower odds of current wheeze in women (aOR range=0.78 to 0.87), and free testosterone levels in Q4 were associated with lower odds of current wheeze in men (aOR for Q4 versus Q1=0.86, 95% CI=0.77 to 0.95). Among women with asthma, free testosterone levels in Q4 were also associated with lower odds of ≥1 asthma hospitalisation. Among men, free testosterone was positively associated with FEV1 and FVC. Among women, free testosterone was negatively and weakly associated with FVC.ConclusionIn a large study of British adults, elevated free testosterone levels are associated with lower odds of asthma and current wheeze in women and men, lower odds of asthma hospitalisations in women, and higher FEV1 and FVC in men.Dissemination to participants, and related patient and public communitiesThe results of the study will be linked to the UK Biobank website.

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Androgen Receptor-Mediated Regulation of Intracellular Calcium in Human Airway Smooth Muscle Cells

Cited by 26 publications

References 61 publications

Sex steroids skew ACE2 expression in human airway: a contributing factor to sex differences in COVID-19?

Sex steroids skew ACE2 expression in human airway: a contributing factor to sex differences in COVID-19?

Role of Estrogen Receptors α and β in a Murine Model of Asthma: Exacerbated Airway Hyperresponsiveness and Remodeling in ERβ Knockout Mice

Serum free testosterone and asthma, asthma hospitalisations and lung function in British adults

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