Background
Chronic inflammatory lung diseases, such as those associated with allergic asthma represent a risk factor for lung cancer (LC). Allergic asthma arises acutely or chronically from IgE-mediated sensitization to environmental allergens, driving eosinophilic airway inflammation, excessive mucus production, and increased airway hyperresponsiveness. These changes prompt lung epithelial cells to release alarmins, some tied to carcinogenesis and tumor immunity, alongside activation of oxidative stress–response and tissue-repair genes. Furthermore, sex differences may influence susceptibility and severity of asthma and associated inflammation, making sex a possible biological variable for LC progression.
Objectives
To gain knowledge on the mechanisms by which chronic pulmonary inflammation promotes carcinogenesis in the lungs, we aim to investigate the immunological, inflammatory, oxidative and metabolic events in a mouse model of allergic asthma and induced carcinogenesis in relation to sex.
Methods
Using a mouse model of eosinophilic allergic asthma induced by house dust mite (HDM), we evaluated how the carcinogen urethane (URE) exposure influences LC development in male and female mice. At three different time points, analyses of the lung tissue and bronchoalveolar lavage fluid (BALF) to search for markers of metabolic changes by nuclear magnetic resonance (NMR), expression/release of inflammatory mediators, immune cell landscape and histopathology were carried out. Redox balance by electron paramagnetic resonance (EPR) and serum IgE were analyzed in the peripheral blood.
Results
After two week-immunization with HDM, females exhibit higher serum IgE levels and pulmonary eosinophils than males, indicating greater allergic sensitization to HDM. After 10 weeks of exposure to the carcinogen URE (tumor initiation stage), mostly females treated with HDM+URE displayed elevated pro-inflammatory cytokines, alarmins and pro-angiogenic factors in both lung tissue and BALF compared to males under the same regimen. After a 15-week URE-resting period (tumor promotion stage) many tumoral markers were further increased in HDM+URE treated females compared to males. Lung tissue from females revealed also a higher inflammatory burden than in males (HDM+URE condition). NMR spectroscopy detected gender-specific metabolic changes across all timepoints, particularly in lung lipid profiles, which was more disrupted in females, especially in response to the allergen. However, EPR analysis indicated higher reactive oxidizing species production in males with respect to females.
Conclusions
Our results indicate that HDM sensitization triggers stronger allergic inflammation in females than males and that urethane exposure further amplifies this response and elevates tumor markers selectively in females. Pulmonary lipid metabolism shows gender-specific alterations, while only males produce more reactive oxygen species when HDM is combined with urethane. These findings may help elucidate key immunological and biochemical events in neoplastic transformation. From a translational perspective, these studies may lead to the identification of risk or tumor-promoting factors associated with allergic asthma that may allow the adoption of specific diagnostic and preventive measures.