Sex differences in the incidence of respiratory diseases have been reported. Women are more susceptible to inflammatory lung disease induced by air pollution and show worse adverse pulmonary health outcomes than men. However, the mechanisms underlying these differences remain unknown. In the present study, we hypothesized that sex differences in the expression of lung inflammatory mediators affect sex-specific immune responses to environmental toxicants. We focused on the effects of ground-level ozone, a major air pollutant, in the expression and regulation of lung immunity genes. We exposed adult male and female mice to 2 ppm of ozone or filtered air (control) for 3 h. We compared mRNA levels of 84 inflammatory genes in lungs harvested 4 h postexposure using a PCR array. We also evaluated changes in lung histology and bronchoalveolar lavage fluid cell counts and protein content at 24 and 72 h postexposure. Our results revealed sex differences in lung inflammation triggered by ozone exposure and in the expression of genes involved in acute phase and inflammatory responses. Major sex differences were found in the expression of neutrophil-attracting chemokines (Ccl20, Cxcl5, and Cxcl2), the proinflammatory cytokine interleukin-6, and oxidative stress-related enzymes (Ptgs2, Nos2). In addition, the phosphorylation of STAT3, known to mediate IL-6-related immune responses, was significantly higher in ozone-exposed mice. Together, our observations suggest that a differential regulation of the lung immune response could be implicated in the observed increased susceptibility to adverse health effects from ozone observed in women vs. men.

Pulmonary surfactant, a lipoprotein complex, maintains alveolar integrity and plays an important role in lung host defense, and control of inflammation. Altered inflammatory processes and surfactant dysfunction are well described events that occur in patients with acute or chronic lung disease that can develop secondary to a variety of insults. Genetic variants of surfactant proteins, including single nucleotide polymorphisms, haplotypes, and other genetic variations have been associated with acute and chronic lung disease throughout life in several populations and study groups. The hydrophilic surfactant proteins SP-A and SP-D, also known as collectins, in addition to their surfactant-related functions, are important innate immunity molecules as these, among others, exhibit the ability to bind and enhance clearance of a wide range of pathogens and allergens. This review focuses on published association studies of human surfactant proteins A and D genetic polymorphisms with respiratory, and non-respiratory diseases in adults, children, and newborns. The potential role of genetic variations in pulmonary disease or pathogenesis is discussed following an evaluation, and comparison of the available literature.

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.