Sex differences in the inflammatory immune response to multi-walled carbon nanotubes and crystalline silica

BACKGROUND: Respiratory disease is a leading cause of death and disability worldwide. These diseases frequently present with a sex-bias in occurrence and severity, yet the mechanisms responsible for these sex-biases is a critically understudied area of basic research. METHODS: Male and female C57BL/6 mice were exposed to multi-walled carbon nanotubes (MWCNTs) or crystalline silica (cSiO(2)) via oropharyngeal aspiration. Acute assessments were conducted 24-hours and 7-days after a single exposure. In chronic experiments mice were exposed to respective particles once per week for 4 weeks and sacrificed 8 weeks after the last exposure. Lung lavage fluid (LLF) was assessed for markers of injury and inflammation. Immune cell populations were analyzed by flow cytometry and histopathology assessment was performed on lung tissue from chronically exposed mice. RESULTS: Female mice exposed to a single dose of MWCNTs generated a greater eosinophilic response than males 24-hours and 7-days post-exposure. Eosinophilia was accompanied by elevated type 2 cytokine production in LLF. The exaggerated acute response in females was consistent with lung pathology observed in the chronic model: females had greater alveolitis and epithelial cell hyperplasia compared to males. There were no sex-differences 24-hours after cSiO(2) exposure, but by 7-days post-exposure female mice had greater airspace neutrophilia and inflammatory cytokine levels compared to males. However, following repeated exposure to cSiO(2), male mice had worse alveolitis and greater dendritic cell presence within the lungs. CONCLUSIONS: Female mice are more susceptible to acute and chronic MWCNT-induced inflammation, but male mice are more susceptible to chronic cSiO(2)-induced lung pathology.