Sex Differences in Pulmonary Anatomy and Physiology

Sathish, Venkatachalem; Prakash, Y. S.

doi:10.1016/b978-0-12-802388-4.00006-9

Cited by 15 publications

(13 citation statements)

References 230 publications

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“…Asthma is a multifaceted and intricate disease involving diverse pathologies, which makes it challenging to identify and address the core mechanisms involved (Hershenson et al, 2008;Raju et al, 2014;Sathish et al, 2015b;Prakash, 2016). Akin to clinical data, sex differences and sex steroids play a crucial role in the incidence and severity of asthma (Clough, 1993;Redline and Gold, 1994;Weiss and Gold, 1995;Caracta, 2003;Carey et al, 2007c;Card and Zeldin, 2009;Antunes et al, 2010;Woods et al, 2010;Townsend et al, 2012a;Bonds and Midoro-Horiuti, 2013;Sathish et al, 2015b;Sathish and Prakash, 2016). Considering the fact that women are more prone to the occurrence of asthma than men (de Marco et al, 2000;Melgert et al, 2005;Carey et al, 2007b;Matsubara et al, 2008;Vink et al, 2010;Dursun et al, 2014;Fuseini and Newcomb, 2017;Pignataro et al, 2017;Han et al, 2018), identifying the role of sex steroids, especially estrogen in airways might shed some light on the pathology of asthma.…”

Section: Discussionmentioning

confidence: 99%

“…Estrogen has a systemic role beyond the reproductive system and the evidence suggests a wide array of roles for estrogen in both males and females in regulating cell growth and differentiation, intracellular calcium regulation and inflammation (Townsend et al, 2010;Townsend et al, 2012a;Townsend et al, 2012b;Sathish et al, 2015a;Sathish and Prakash, 2016). Given the facts about estrogen and the lack of consensus whether it is proinflammatory vs. anti-inflammatory and to define the consequences in structural cells of the airways, it is important to understand the mechanisms involved in estrogen signaling.…”

Section: Discussionmentioning

confidence: 99%

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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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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

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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“…Beyond its well-recognized roles in the reproductive system, recent studies have identified other roles for estrogen in different organs and tissues of both males and females, including cell growth and differentiation (Sathish et al, 2015, Townsend et al, 2012, Townsend et al, 2012). In this regard, various epidemiological and pre-clinical data have shown sex differences in asthma, and the potential effects of estrogens on airway function (Townsend et al, 2012, Sathish and Prakash, 2016), resulting in increased interest in exploring sex steroid receptor expression and function in airways. Our previous studies demonstrated that physiological concentrations of estrogen can induce bronchodilation by enhancing cAMP and protein kinase A and thus decreasing [Ca 2+ ] i levels in ASM (Townsend et al, 2010, Townsend et al, 2012).…”

Section: Discussionmentioning

confidence: 99%

Estrogen receptor beta signaling inhibits PDGF induced human airway smooth muscle proliferation

Ambhore

Katragadda

Kalidhindi

et al. 2018

Molecular and Cellular Endocrinology

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Airway smooth muscle (ASM) cell hyperplasia driven by persistent inflammation is a hallmark feature of remodeling in asthma. Sex steroid signaling in the lungs is of considerable interest, given epidemiological data showing more asthma in pre-menopausal women and aging men. Our previous studies demonstrated that estrogen receptor (ER) expression increases in asthmatic human ASM; however, very limited data are available regarding differential roles of ERα vs. ERβ isoforms in human ASM cell proliferation. In this study, we evaluated the effect of selective ERα and ERβ modulators on platelet-derived growth factor (PDGF)-stimulated ASM proliferation and the mechanisms involved. Asthmatic and non-asthmatic primary human ASM cells were treated with PDGF, 17β-estradiol, ERα-agonist and/or ERβ-agonist and/or G-protein-coupled estrogen receptor 30 (GPR30/GPER) agonist and proliferation was measured using MTT and CyQuant assays followed by cell cycle analysis. Transfection of small interfering RNA (siRNA) ERα and ERβ significantly altered the human ASM proliferation. The specificity of siRNA transfection was confirmed by Western blot analysis. Gene and protein expression of cell cycle-related antigens (PCNA and Ki67) and C/EBP were measured by RT-PCR and Western analysis, along with cell signaling proteins. PDGF significantly increased ASM proliferation in non-asthmatic and asthmatic cells. Treatment with PPT showed no significant effect on PDGF-induced proliferation, whereas WAY interestingly suppressed proliferation via inhibition of ERK1/2, Akt, and p38 signaling. PDGF-induced gene expression of PCNA, Ki67 and C/EBP in human ASM was significantly lower in cells pre-treated with WAY. Furthermore, WAY also inhibited PDGF-activated PCNA, C/EBP, cyclin-D1, and cyclin-E. Overall, we demonstrate ER isoform-specific signaling in the context of ASM proliferation. Activation of ERβ can diminish remodeling in human ASM by inhibiting pro-proliferative signaling pathways, and may point to a novel perception for blunting airway remodeling.

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“…Besides, asthma affects every 1 in 13 adults and 1 in 12 children making it one of the most common chronic diseases (1). Asthma is often a result of severe inflammation, hyperreactivity, and remodeling of the airways resulting in episodic bronchoconstriction (4)(5)(6)(7)(8)(9)(10)(11). Although age, gender, and race disparities constitute significant risk factors associated with the outcome of asthma disease severity, little is known about the role of these disparities in manifesting the differential disease phenotypes at molecular and immunological levels (9)(10)(11)(12)(13)(14).…”

Section: Introductionmentioning

confidence: 99%

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

Kalidhindi

Ambhore

Balraj

et al. 2021

American Journal of Physiology-Lung Cellular and Molecular Phys

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Epidemiological studies demonstrate an apparent sex-based difference in the prevalence of asthma, with a higher risk in boys than girls, which is reversed post-puberty, where women become more prone to asthma than men, suggesting a plausible beneficial role for male hormones, especially androgens as a regulator of pathophysiology in asthmatic lungs. Using a murine model of asthma developed with mixed allergen (MA) challenge, we report a significant change in airway hyperresponsiveness (AHR), as demonstrated by increased thickness of epithelial and airway smooth muscle layers and collagen deposition, as well as Th2/Th17 biased inflammation in the airways of non-gonadectomized (non-GDX) and gonadectomized (GDX) male mice. Here, compared to non-GDX mice, MA induced AHR and inflammatory changes were more prominent in GDX mice. Activation of androgen receptor (AR) using 5α-Dihydrotestosterone (5a-DHT, AR agonist) resulted in decreased Th2/Th17 inflammation and remodeling associated changes, resulting in improved lung function compared to MA alone challenged mice, especially in GDX mice. These changes were not observed with Flutamide (Flut, AR antagonist). Overall, we show that AR exerts a significant and beneficial role in asthma by regulating AHR and inflammation.

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Sex Differences in Pulmonary Anatomy and Physiology

Cited by 15 publications

References 230 publications

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

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

Estrogen receptor beta signaling inhibits PDGF induced human airway smooth muscle proliferation

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

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