Borrelli Richard, Brussino Luisa, Lo Sardo Luca, Quinternetto Anna, Vitali Ilaria, Bagnasco Diego, Boem Marzia, Corradi Federica, Badiu Iuliana, Negrini Simone, Nicola Stefania
Department of Medical Sciences, University of Turin, 10128 Turin, Italy.
Immunology and Allergy Unit, AO Ordine Mauriziano di Torino, 10128 Turin, Italy.
Int J Mol Sci. 2025 May 30;26(11):5288. doi: 10.3390/ijms26115288.
Asthma is a chronic inflammatory disease characterized by airway hyperresponsiveness, variable airflow obstruction, and persistent inflammation. While its pathophysiology is well established, growing evidence highlights significant sex-based differences in its prevalence, severity, and treatment response. Epidemiological studies indicate that asthma is more common in prepubertal boys but shifts toward a female predominance after puberty, with adult women experiencing higher morbidity and greater healthcare utilization. These disparities suggest a crucial role for sex hormones, genetic predisposition, and epigenetic regulation in asthma pathogenesis. Sex hormones modulate immune responses, contributing to disease progression. Estrogen enhances type 2 inflammation, increases eosinophilic infiltration, and upregulates IL-4 and IL-13 expression, leading to greater airway hyperreactivity in women. Additionally, progesterone fluctuations correlate with perimenstrual asthma exacerbations, while testosterone appears to exert a protective effect by dampening Th2-driven inflammation and airway remodeling. These hormonal influences contribute to sex-specific asthma phenotypes and treatment responses. Genetic and epigenetic factors further shape sex-related differences in asthma. The X chromosome harbors immune-regulatory genes, including TLR7 and TLR8, which amplify inflammatory responses in females. The sex-dependent expression of IL13 and ORMDL3 influences eosinophilic inflammation and airway remodeling. Epigenetic modifications, such as DNA methylation and microRNA regulation, further impact immune activation and corticosteroid responsiveness. For instance, Let-7 miRNAs modulate IL-13 expression, contributing to sex-specific inflammatory profiles. Environmental factors, including air pollution, obesity, and diet, interact with hormonal and genetic influences, exacerbating sex disparities in asthma severity. Obesity-related metabolic dysfunction promotes systemic inflammation, airway remodeling, and steroid resistance, disproportionately affecting women. Given these complex interactions, sex-specific approaches to asthma management are essential. Personalized treatment strategies targeting hormonal pathways, immune regulation, and metabolic health may improve outcomes for both men and women with asthma. Future research should focus on sex-based therapeutic interventions to optimize disease control and mitigate healthcare disparities.
哮喘是一种慢性炎症性疾病，其特征为气道高反应性、可变气流受限和持续性炎症。虽然其病理生理学已得到充分确立，但越来越多的证据凸显了在其患病率、严重程度和治疗反应方面存在显著的性别差异。流行病学研究表明，哮喘在青春期前男孩中更为常见，但在青春期后则转变为以女性为主，成年女性的发病率更高，医疗保健利用率也更高。这些差异表明性激素、遗传易感性和表观遗传调控在哮喘发病机制中起着关键作用。性激素调节免疫反应，促进疾病进展。雌激素增强2型炎症，增加嗜酸性粒细胞浸润，并上调IL-4和IL-13表达，导致女性气道高反应性增强。此外，孕激素波动与经前期哮喘发作相关，而睾酮似乎通过抑制Th2驱动的炎症和气道重塑发挥保护作用。这些激素影响导致了性别特异性哮喘表型和治疗反应。遗传和表观遗传因素进一步塑造了哮喘中的性别相关差异。X染色体含有免疫调节基因，包括TLR7和TLR8，它们会放大女性的炎症反应。IL13和ORMDL3的性别依赖性表达影响嗜酸性粒细胞炎症和气道重塑。表观遗传修饰，如DNA甲基化和微小RNA调控，进一步影响免疫激活和皮质类固醇反应性。例如，Let-7微小RNA调节IL-13表达，导致性别特异性炎症特征。环境因素，包括空气污染、肥胖和饮食，与激素和遗传影响相互作用，加剧了哮喘严重程度方面的性别差异。与肥胖相关的代谢功能障碍促进全身炎症、气道重塑和类固醇抵抗，对女性的影响尤为严重。鉴于这些复杂的相互作用，针对哮喘管理的性别特异性方法至关重要。针对激素途径、免疫调节和代谢健康的个性化治疗策略可能改善哮喘男女患者的治疗效果。未来的研究应侧重于基于性别的治疗干预措施，以优化疾病控制并减少医疗保健差异。
