Exploratory analysis of the impact of sex on sputum proteomic response to inhaled wood smoke in humans

Wildfires have surged in frequency and severity, and in 2022, they contributed to nearly 30% of the fine inhalable particulate matter (PM2.5) in the United States. Health effects from wildfire-induced wood smoke (WS) exposure include worsened pre-existing lung diseases and lung function, increased emergency room visits, and increased risk of premature death. Evidence suggests that males and females have unique responses to air pollutants, but sex-specific responses to WS remain understudied. To evaluate whether males and females differentially respond to WS, we analyzed induced sputum samples in humans following a controlled chamber exposure to WS. A total of 79 participants were exposed to 500 µg/m3 of WS for 2 h with intermittent exercise, and a subset of participants' samples were analyzed for cellularity and cytokine concentrations, and protein expression in the sputum supernatants. Cell differentials were compared between pre-, 6 h, and 24 h post-exposure, and proteomic and cytokine signatures were compared between pre- and 24 h post-exposure. A total of 368 proteins were significantly different in females, and 27 were significantly different in males post-exposure. Pathway analysis revealed inhibition of leukocyte extravasation signaling, phagosome formation, and macrophage nitric oxide and reactive oxygen species pathways in females versus males. Females had a lower percentage of iNOS+ and a higher percentage of CD301+ sputum macrophages versus males. Overall, this exploratory analysis suggests that in response to acute WS exposure, different pathways are affected in females compared with males. Future studies are needed to determine whether this confers an immune advantage and to understand the mechanisms of sex-specific WS-induced respiratory effects.