Endocrine regulation of lung disease and inflammation

Abstract

Sex-based disparities have been identified in respiratory physiology, and in many chronic lung diseases including asthma, chronic obstructive pulmonary disease, and cystic fibrosis. The observed sex differences in lung disease prevalence and incidence have been linked to changes in circulating levels of sex hormones that start after puberty and that have been shown to affect physiological and immunological functions. While the exact roles of male and female sex hormones in these processes have not been fully elucidated, it is now evident that these can target many lung cell types and affect several functions of the respiratory system. In this mini-review, we have summarized seminal studies aimed to understand the effects of the most relevant male and female sex hormones (estrogens, progesterone, and androgens) and their receptors on lung function. Moreover, we have reviewed the known influences of sex hormones and of the hypothalamic–pituitary–gonadal axis in lung disease and immunity. Understanding the roles of sex hormones in the regulation of lung function and inflammation is the first step for the potential development of more effective therapeutic options to prevent and treat lung disease in men and women. Impact statement Sex-differences in the incidence and severity of inflammatory lung diseases have been recognized for years. Women of reproductive age are more likely to suffer from chronic lung disease, with higher mortality rates than men. Physiological changes in hormone levels such as those occurring during the menstrual cycle, pregnancy, and menopause have been associated with lung function changes and asthma symptoms. Despite this, the roles of sex hormones in the mechanisms associated with lung diseases have not been fully elucidated. This review summarizes basic and clinical studies of sex hormones as potential modulators of lung function and inflammation. The information obtained from sex-specific research on lung physiology and pathology will potentially help in the development of sex-specific therapeutics for inflammatory lung disease that may account for the hormonal status of the patient.

The role of sex in particle‐induced inflammation and injury

“…Inhaled nano‐carbons and cSiO 2 are reported to cause greater lung inflammation in female animals, but present greater carcinogenic and fibrotic potential in males (Brass et al, ; Kasai et al, ; Latoche et al, ). These results are similar to human reports of worse inflammatory lung disease in women and fibrosis and cancer in men (Fuentes & Silveyra, ; Pinkerton et al, ). Many of the studies in this review focus on the lungs as the primary target organ in inhalation exposures, however, it has been reported that NPs are able to translocate from the lungs to organs such as the brain, lymph nodes, liver, and kidneys (Mercer et al, ), and also have the ability to alter systemic immune function following inhalation exposure (Mitchell et al, ; Mitchell, Lauer, Burchiel, & McDonald, ; Smith, Brown, Zamboni, & Walker, ).…”

“…Often, lung pathology resulting from inhaled particles is not due to the pathogenic effects of the particles themselves, but rather the immune‐mediated inflammatory response (Jacobs & Kligerman, ). Clinical, epidemiological, and experimental data have demonstrated the importance of sex‐steroid hormone signaling on immune‐regulation in respiratory disease settings (Carey, Card, Voltz, Germolec, ; Fuentes & Silveyra, ; González‐Arenas & Agramonte‐Hevia, ; Sathish, Martin, & Prakash, ; Tam et al, ). Sex‐steroid hormone receptors are expressed by a variety of immune cell types including macrophages, dendritic cells, granulocytes (mast cells in particular), and lymphocytes (Buskiewicz, Huber, & Fairweather, ; Zierau, Zenclussen, & Jensen, ).…”

“…Epidemiological and clinical evidence has demonstrated that of the 1 billion people world‐wide suffering from acute or chronic lung disease, a disproportionate number of these individuals are women (Forum of International Respiratory Societies & European Respiratory Society, ; Fuentes & Silveyra, ). Lung diseases that present with increased incidence and/or severity in women include: non and cigarette‐mediated chronic obstructive pulmonary disease (COPD, particularly the chronic bronchitis form), autoimmune lung disease, pulmonary hypertension (Pinkerton et al, ), bronchiectasis (non and cystic fibrosis‐related; Vidaillac, Yong, Jaggi, Soh, & Chotirmall, ), chronic respiratory symptoms due to air pollution from ozone and particulate matter (Fuentes, Roy, Mishra, Cabello, & Silveyra, ; Yoshizaki et al, ), and adult asthma (Carey, Card, Voltz, Arbes Jr, ).…”

Modulation of the lung inflammatory response to ozone by the estrous cycle

“…). In addition, lung cells also express sex hormone receptors, including estrogen and progesterone nuclear and membrane receptors, known to mediate several functions of the organ, and specifically immune responses (Fuentes and Silveyra ). Some studies, including ours, have hypothesized that female sex hormones can act as functional regulators of lung function and immunity through regulation of inflammatory gene expression (Card and Zeldin ; Tam et al.…”

Female reproductive history in relation to chronic obstructive pulmonary disease and lung function in UK biobank: a prospective population-based cohort study

“…Female sex hormones are putative mediators of respiratory health, and regulate bronchodilation, cell proliferation, inflammation and metabolism of toxic cigarette smoke-related metabolites 1 4–7. Notably, oestrogen and progesterone appear to have varying effects on lung function across the lifespan 1.…”