Sex Hormone–Dependent Regulation of Cilia Beat Frequency in Airway Epithelium

Abstract

Previous studies have demonstrated a female disadvantage in airway diseases, such as asthma and bronchiectasis. The basis for this sex disparity is unknown. We hypothesized that the female sex hormone, progesterone (P4), inhibits functions of the normal airway mucociliary apparatus. P4 receptor (PR) expression was evaluated in human lung and cultured primary human airway epithelial cells isolated from male and female lung transplant donors. PR expression was restricted to the proximal region of the cilia of airway epithelia, and was similar in men and women. Expression of isoform PR-B was more abundant than PR-A in cells from both sexes. Airway epithelial cell exposure to P4 decreased cilia beat frequency (CBF) by 42.3% (67.2). Inhibition of CBF was prevented by coadministration of P4 with the active form of estrogen, 17b-estradiol, or the PR antagonist, mifepristone. P4 inhibition was time and dose dependent, with a significant decrease by 8 hours and maximal effect at 24 hours, accompanied by translocation of PR from the cilia to the nucleus. Inhibition of cilia beat was also prevented by treatment of cells with actinomycin D, suggesting that CBF inhibition is a transcriptionally mediated event. Together, these findings indicate that sex hormones influence the function of a key component of the mucociliary apparatus. These mechanisms may contribute to the sex disparity present in airway diseases and provide therapeutic targets for the treatment of these debilitating airway diseases.Keywords: cilia; progesterone receptor; cilia beat frequency; sex disparity; lung diseaseMultiple epidemiologic studies have established that women have more severe airway disease than men (1, 2). Women with asthma and chronic obstructive lung disease have more frequent and severe exacerbations than men, and a lower disease-specific quality of life (1, 3). Bronchiectasis affects women more commonly, and is more aggressive than in men (2, 4). For example, in cystic fibrosis (CF), a disease in which the impact of bronchiectasis has been extensively studied, women have worse outcomes and a decreased life expectancy compared with men, despite a similar cause of disease. This has been attributed specifically to a greater severity of lung disease, and is present even after adjusting for potentially confounding morphometric, nutritional, compliance, and microbial factors (4, 5). In addition, in models of Pseudomonas aeruginosa infection, one of the most common pathogens found in bronchiectasis, female mice are more affected than males, again for unclear reasons (6). Defects in mucociliary clearance are a central component to the development of bronchiectasis. We, therefore, hypothesize that female sex hormones regulate the mucociliary apparatus.The major female sex hormones, estrogen and progesterone (P4), vary in levels during ovulatory cycles, pregnancy, menopause, and with exogenous delivery. Although their roles in the uterus, ovary, oviduct, and breast have been well studied, expression and function in other tissues are less well desc...

Autism genes are selectively targeted by environmental pollutants including pesticides, heavy metals, bisphenol A, phthalates and many others in food, cosmetics or household products

“…The fungicide benomyl and its metabolites, butyl isocyanate and carbendazim, decrease ciliary beat frequency in canine tracheal epithelial tissue [298] . Progesterone inhibits cilia beat frequency in human lung and cultured primary human airway epithelial cells, an effect inhibited by 17beta-estradiol [299]. No effects could be found in relation to endocrine disruptors, although they might be expected to exert effects in relation to those of these steroid hormones.…”

Failure of Respiratory Defenses in the Pathogenesis of Bacterial Pneumonia of Cattle

“…Using in vitro systems, acute exposure to inflammatory cytokines increased ciliary beat frequency, while this was reduced with chronic exposure to interleukin 8. 4,163,179 In vitro ciliary beat frequency was inhibited by progesterone treatment but restored with estrogen, 90 a preliminary finding of potential relevance to feedlot cattle treated with growth promotants. Thus, reasons for failure of mucociliary clearance in cattle include infection with viruses and cold exposure, with more poorly characterized contributions from dehydration, exposure to organic particulates or noxious gases in the barn environment, and chronic airway inflammation.…”

Cilia Dysfunction in Lung Disease

“…Multiple signaling molecules, including cAMP, Ca 2+ and nitric oxide, and progesterone regulate airway cilia beat frequency (33–36). In an important observation, Welsh and co-workers (37) identified sensory bitter taste receptors (T2R) on cilia of differentiated human airway epithelium, providing a mechanism by which airway cilia sense the environment.…”