Sex steroid signaling in the lung (particularly estrogens) is of considerable interest, given epidemiological data showing more asthma in pre-menopausal women and aging men, making this of importance in both sexes. However, a fundamental issue is that while studies in immune cells and some animal studies suggest estrogens enhance inflammation per se other studies find that estrogens blunt asthma symptoms, and furthermore blunt airway reactivity. These conflicting data reflect the complexity of estrogen signaling that cannot be explained by effects on the immune system alone, and could involve perhaps opposite effects on structural cells of the airway. In this regard, what is also not clear is whether specific estrogen receptors (ERs) play differential roles that might explain these contrasts. The overall goal is to understand ER expression and signaling in structural airway cells in the context of inflammation and asthma, using airway smooth muscle (ASM) as a model. In asthma, inflammation enhances ASM contractility, proliferation and extracellular matrix (ECM) production. We find that human ASM from both sexes expresses ER? and ER but not G-protein coupled GPR30. While estrogens can non-genomically reduce ASM [Ca2+]i, what is not known are: A) Effects of inflammation or asthma on ER expression and functionality; B) Roles of ER? vs. ER in inflamed/asthmatic ASM, particularly genomic actions likely more relevant in vivo. Preliminary studies in human ASM show: 1) Asthmatic or cytokine-exposed ASM from both sexes express more ER than ER?; 2) With inflammation, ER functionality is enhanced compared to ER?, helping reduce [Ca2+]i, ASM proliferation and ECM at physiological estradiol levels; 3) ER? and ER signaling diverge in inflamed ASM, with differential effects on cAMP vs. NF?B and p38. In vivo, in a mixed allergen mouse model with a Th2 immune profile, ASM ER is increased (less so in epithelium), while ER KO results in greater airway thickening, reactivity, and ASM expression of Ca2+ regulatory and ECM proteins. Conversely, ER-specific agonists blunt inflammation, airway reactivity and remodeling, and ASM expression of ECM proteins due to mixed allergens. Thus, our overall hypothesis is that inflammation leads to a differential and greater role for ER in ASM, and that ER can blunt contractility and remodeling. These concepts will be explored via the following Specific Aims.
Aim 1 : To determine mechanisms by which inflammation alters ER expression profile in human ASM;
Aim 2 : To determine the enhanced and differential role of ER in human ASM contractility with inflammation/asthma;
Aim 3 : To determine mechanisms by which ER? vs. ER blunt human airway remodeling;
Aim 4 : In a mouse model of allergic asthma, to determine the effect of ER? vs. ER on structural and functional airway changes.
In Aims 1 -3, we will use human ASM tissues from 30-50y old non-asthmatic and asthmatic males and females to examine mechanisms by which inflammation/asthma alters ER? vs. ER expression (Aim 1; focusing on NF?B, MAPK and STAT6), and mechanisms by which ER? vs. ER reduce [Ca2+]i/contractility (Aim 2) and remodeling (proliferation, ECM;
Aim 3), focusing on the differential roles of cAMP/PKA/CREB vs. NF?B and p38.
In Aim 4, a mixed allergen model will be applied to ER? vs. ER KO mice with/without ovariectomy and with/without THC or DPN (specific agonists) treatment. Structural, functional and signaling changes in ASM relevant to ER? vs. ER will be evaluated. The clinical significance lies in understanding how sex steroids influence structural airway cells in inflammation and asthma, overall helping to appreciate the mechanistic bases of the conflicting data regarding estrogens and asthma.

Public Health Relevance

The incidence and severity of asthma is higher in both pre-menopausal women and in aging men, suggesting a role for female sex steroids such as estrogens in modulating this disease. However it is not clear whether and how estrogens impact the airway. We propose that in the inflamed or asthmatic airway, estrogens might actually be beneficial in terms of their effects on airway smooth muscle: the important cell type involved in airway contractility and also in structural changes (remodeling) that occurs in asthma. Our studies using human airway smooth muscles from both male and female asthmatics vs. non-asthmatics, along with animal studies where we control estrogen levels or their signaling, will substantially enhance our understanding of how and why estrogens influence the asthmatic airway. This is a necessary and clinically important step if we are to develop novel therapeutic strategies for asthma in males or females using modulators of sex steroids and their effects.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Project (R01)
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Lung Cellular, Molecular, and Immunobiology Study Section (LCMI)
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Lu, Jining
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North Dakota State University
Schools of Pharmacy
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Aravamudan, Bharathi; Goorhouse, Katelyn J; Unnikrishnan, Ghanashyam et al. (2017) Differential Expression of Estrogen Receptor Variants in Response to Inflammation Signals in Human Airway Smooth Muscle. J Cell Physiol 232:1754-1760
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Wang, Sheng-Yu; Freeman, Michelle R; Sathish, Venkatachalem et al. (2016) Sex Steroids Influence Brain-Derived Neurotropic Factor Secretion From Human Airway Smooth Muscle Cells. J Cell Physiol 231:1586-92