Sex plays an essential role as a biological variable in lung health, leading to observed differences in lung disease susceptibility. Some respiratory conditions are more common in women than men, especially after puberty, indicating the influence of ovarian hormones on disease mechanisms. Other conditions display sex disparities that begin in utero and progress throughout the life span. Preclinical and clinical studies have indicated that both sex chromosomes and hormones can influence lung disease outcomes, immune responses, susceptibility to viral and bacterial infection, and responses to environmental challenges. This review summarizes the latest research on how sex affects lung physiology and health, drawing on a wide range of studies in respiratory physiology and anatomy, genetics, molecular and cellular biology, environmental health, and immunity. We emphasize how biological sex, gonadal hormones, and occupational and environmental exposures can impact disease mechanisms and outcomes. As clinical outcomes among women have not improved at the same rate as men over the past few decades, it is crucial to understand the role played by the sex variable in designing strategies to prevent and mitigate disease. The collective research indicates that sex-induced differences in the respiratory system are essential determinants of physiological responses and clinical outcomes.

Asthma, a chronic inflammatory airway disease, leads to airflow obstruction and exhibits sex differences in prevalence and severity. Immunomodulatory diets, such as the ketogenic diet (high fat, low carbohydrate, moderate protein), may offer complementary benefits in managing airway inflammation. While anti-inflammatory effects of ketogenic diets are documented in cardiovascular diseases, their impact on asthma, especially regarding sex-specific differences, remains unexplored. Few studies on diet and asthma have considered sex as a biological factor. To test the hypothesis that a ketogenic diet affects airway inflammation in a sex-specific manner, we used a mouse allergic airway inflammation model. Male and female C57BL/6J mice (3–4 weeks old, n = 5–6/group) were fed a ketogenic diet or normal chow for 12 weeks. From weeks 7 to 12, mice were challenged intranasally with house dust mite allergens (HDM) 5 days/week to induce airway inflammation. Lung tissue was analyzed 72 h post-exposure using flow cytometry to assess immune cell populations, and data were analyzed with two-way ANOVA. The ketogenic diet increased body weight in allergen-exposed mice, with a greater effect in males than females (p = 0.0512). Significant sex–diet interactions were noted for alveolar macrophages, CD103⁺, CD11B⁺, and plasmacytoid dendritic cells (p < 0.05). Eosinophil reductions were observed in males but not females on the ketogenic diet. The diet also increased NKT cells and decreased NK cells in males but not females (p < 0.001). These findings highlight sex-specific effects of ketogenic diets on lung immune responses, with stronger impacts in males.

The emerging concern about chemicals in electronic cigarettes, even those without nicotine, demands the development of advanced criteria for their exposure and risk assessment. This study aims to highlight the sensitivity of lung nuclear receptors (NRs) to electronic cigarette e-liquids, independent of nicotine presence, and the influence of the sex variable on these effects. Adult male and female C57BL/6J mice were exposed to electronic cigarettes with 0%, 3%, and 6% nicotine daily (70 mL, 3.3 s, 1 puff per min/30 min) for 14 days, using the inExpose full body chamber (SCIREQ). Following exposure, lung tissues were harvested, and RNA extracted. The expression of 84 NRs was determined using the RT² profiler mRNA array (Qiagen). Results exhibit a high sensitivity to e-liquid exposure irrespective of the presence of nicotine, with differential expression of NRs, including one (females) and twenty-four (males) in 0% nicotine groups compared to non-exposed control mice. However, nicotine-dependent results were also significant with seven NRs (females), fifty-three NRs (males) in 3% and twenty-three NRs (female) twenty-nine NRs (male) in 6% nicotine groups, compared to 0% nicotine mice. Sex-specific changes were significant, but sex-related differences were not observed. The study provides a strong rationale for further investigation.

This study provides new insights into how sex chromosomes and gonadal sex independently and interactively shape immune cell responses during allergic airway inflammation. Using the four core genotype (FCG) mouse model, we show that both genetic and hormonal factors significantly influence pulmonary immune cell populations after allergen exposure. These findings advance our understanding of the biological basis for sex differences in asthma and highlight the need for sex-informed approaches in respiratory disease research and therapy development.

Background/Objectives: Sex differences in lung cancer incidence and outcomes are well recognized, yet the relative contributions of sex chromosomes and gonadal sex remain incompletely defined. We aimed to disentangle chromosomal complement and hormonal sex in urethane-induced lung tumorigenesis using the Four Core Genotypes mouse model. Methods: Mice (6–8 weeks old) with independently varied chromosomal complement (XX vs. XY) and gonadal sex received urethane (1 g/kg body weight) weekly for 10 weeks and were evaluated after a 20-week latency period. Tumor multiplicity, tumor area, normalized tumor burden, and Ki-67 proliferation indices were quantified histologically. Hepatic Cyp2e1 expression was measured to assess carcinogen bioactivation. Tumor mutations were analyzed by Sanger sequencing. RAS Q61R immunoreactivity and ERK phosphorylation were evaluated to assess oncogenic signaling. Bronchoalveolar lavage fluid cellularity was analyzed. Survival was monitored. Statistical analyses tested the main effects of chromosomal complement, gonadal sex, and their interaction. Results: Tumor multiplicity (p = 0.0729), tumor area (p = 0.5302), normalized tumor burden (p = 0.5316), and Ki-67 indices (p = 0.6551) did not differ among genotypes. Hepatic Cyp2e1 expression was comparable across groups (genotype p = 0.076; treatment p = 0.445). Sanger sequencing confirmed canonical Kras Q61R mutations. Anti-RAS (Q61R) immunohistochemistry revealed a significant genotype effect on mutant RAS expression (F(3,23) = 3.48, p = 0.032), with the highest H-scores observed in XYF mice compared with male gonadal genotypes; ERK phosphorylation did not differ. Bronchoalveolar lavage fluid analysis revealed increased lymphocytes after urethane exposure without genotype-dependent effects. Survival differed significantly, with XX females demonstrating prolonged survival relative to XY males. Conclusions: Sex influenced survival independently of tumor burden, indicating that sex-associated differences in lung cancer outcomes are likely driven by systemic or microenvironmental factors rather than tumor-intrinsic growth mechanisms.