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.

MiRNAs play important roles in regulating gene and environmental interactions. However, their role in mediating sex differences in allergic responses and lung diseases has not been elucidated. Our study used a targeted omics approach to characterize the contributions of gonadal hormones and chromosomal components to lung responses to an allergen challenge. Our results point to the influence of sex hormones in miRNA expression and proinflammatory markers in allergic airway inflammation.

Gene expression profiling helps to provide deep insight into the global view of disease-related mechanisms and responses to therapy. Using the Four-Core Genotype mouse model, our findings revealed the influence of sex hormones and sex chromosomes in the gene expression of lungs exposed to an aeroallergen (House Dust Mite) and identified sex-specific pathways to better understand sex disparities associated with allergic airway inflammation.

Recently, the gut microbiome and its role in chronic respiratory disease have been the subject of extensive research and the establishment of its involvement in immune functions. Using the FCG mouse model, our findings revealed the influence of gonads and sex chromosomes on the microbial community structure before and after exposure to HDM. Our data provide a potential new avenue to better understand mediators of sex disparities associated with allergic airway inflammation.

Lung diseases are major global causes of morbidity and mortality, yet the molecular basis of their observed sex differences remains unclear. Beyond their roles in reproductive biology, estrogens are central regulators of pulmonary homeostasis through three principal receptors: 1) estrogen receptor α (ERα), 2) estrogen receptor β (ERβ), and 3) the G-protein-coupled estrogen receptor 1 (GPER1). These receptors are widely expressed across the airway epithelium, smooth muscle, fibroblasts, lung endothelium, and immune cells, where they integrate slow, genomic transcriptional programs and rapid, membrane-initiated signaling cascades to regulate inflammation, oxidative balance, and tissue remodeling. ERβ, often the dominant pulmonary isoform, tends to preserve extracellular matrix integrity and attenuate maladaptive inflammation, whereas ERα frequently amplifies proinflammatory transcriptional programs. GPER1 mediates rapid nongenomic responses that modulate vascular tone, airway smooth-muscle reactivity, and innate immune function, and is both an important regulator of allergic inflammation and a modulator of oncogenic signaling. Together, estrogen receptor subtype balance, subcellular localization, and ligand context determine whether estrogenic signaling is protective or pathogenic. Clinically, this framework helps explain life course and sex differences, such as postpubertal female predominance of asthma, menstrual and pregnancy-related exacerbations, and enhanced chronic obstructive pulmonary disease (COPD) susceptibility in women at lower tobacco exposure. In this review, we synthesize mechanistic and clinical evidence across lung diseases; delineate areas where data remain incomplete or contradictory; and outline opportunities for experimental and translational innovation. These include development of receptor-selective or biased ligands, inhaled or localized delivery, and implementation of sex-aware clinical trial designs to leverage estrogen-receptor biology for precision respiratory therapeutics.

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.