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

Abstract

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

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

“…Multiple groups, including our own, have shown a role for sex steroids, especially estrogen ( 3 – 5 , 12 , 15 – 17 , 21 , 22 , 31 , 33 , 37 – 39 ) and testosterone ( 11 , 18 , 22 , 24 , 27 ) in regulating the pathophysiology of lung diseases such as asthma or COPD as well as the known sex differences in these conditions ( 9 ). In this regard, sex steroids can differentially influence the expression and functionality of multiple signaling pathways in lung cells including ASM, contributing to altered airway reactivity and remodeling.…”

Androgen receptor activation alleviates airway hyperresponsiveness, inflammation, and remodeling in a murine model of asthma

“…Multiple studies, including our own, have reported a crucial role of sex-steroids on airway physiology, especially estrogen and its receptors (estrogen receptor, ERa, and ERb) in regulating the airway structure and function (18)(19)(20)(21)(22). From these studies, it is evident that estrogen differentially regulates airway physiology via diversified signaling of ERa versus ERb (detrimental vs. beneficial) in cellular aspects such as [Ca 2 þ ] i (21), proliferation (19), ECM (18) in vitro, and airway structure and function in vivo (22,23). However, the role of androgens in airway physiology remains unclear and is still being investigated.…”

“…Apart from their characteristic function in influencing reproductive organs, sex-steroids also influence a multitude of other organs and tissues eliciting their effects via sex-steroid receptors and regulate crucial cellular functions such as proliferation, migration, extracellular matrix (ECM) dynamics, intracellular calcium ([Ca 2 þ ] i ), and the local inflammatory milieu (9,11). Multiple studies, including our own, have reported a crucial role of sex-steroids on airway physiology, especially estrogen and its receptors (estrogen receptor, ERa, and ERb) in regulating the airway structure and function (18)(19)(20)(21)(22). From these studies, it is evident that estrogen differentially regulates airway physiology via diversified signaling of ERa versus ERb (detrimental vs. beneficial) in cellular aspects such as [Ca 2 þ ] i (21), proliferation (19), ECM (18) in vitro, and airway structure and function in vivo (22,23).…”

“…Apart from this, limited in vivo studies suggest androgens play a protective role in regulating airway physiology but have mostly focused on the inflammation-associated changes with local inflammatory cell recruitment (39)(40)(41)(42)(43). Our recent in vivo studies focused on ER activation and its effect on airways suggest that intact male mice show reduced airway hyperresponsiveness (AHR), inflammation, and remodeling compared with intact females in a mouse model of asthma (22,23). Although earlier studies suggest a beneficial role of androgens in asthma, comprehensive mechanistic data on the role of androgens modulating airway inflammation, AHR, and remodeling are still lacking.…”

COVID-19 infection can cause chemotherapy resistance development in patients with breast cancer and tamoxifen may cause susceptibility to COVID-19 infection

“…This effect of tamoxifen is on breast tissue; however, its effect may not be limited to breast tissue alone. There is plenty of ER in the lung tissue [8]. It has been reported that tamoxifen may have an apoptotic effect on ER receptors in the lung tissue [9].…”