Wood smoke (WS) is an ever-increasing source of air pollution across the world as the prevalence of wildfire events rise with climate change, causing over 7 million premature deaths worldwide. Respiratory effects of WS are associated with reduced lung function and inflammation, yet effects and mechanisms have not been well-characterized. Healthy and asthmatic subjects aged 18-40 years were exposed to 500?g/m3 of WS derived from red oak for 2hrs in a controlled exposure chamber. Pre- and post-exposure lung function was evaluated and induced sputum was collected. Induced sputum was analyzed by cell differential, immune mediators, proteomics, metabolomics, and microbiome. Results suggest WS altered lung function, which was modified by sex and disease state, altered proteins at baseline in individuals responsive and non-responsive to WS, and altered proteins with exposure. 1854 proteins were altered with exposure including Transglutaminase 2 (TGM2), C-X-C motif chemokine ligand 6 (CXCL6), and glutathione S-transferase omega 1 (GSTO1). Enriched pathways include the UDP-N-acetylglucosamine metabolic process and amino and nucleotide sugar metabolism, while protein clusters included antioxidant activity and glutathione metabolism. Other susceptibility factors under investigation include GSTM1 status, sex, and asthma diagnosis. Multi-omics integrated analysis of proteome, microbiome, and metabolome is also ongoing. Overall, WS exposure differentially alters the respiratory secretome and evidence from this study supports differential susceptibility by a variety of factors including sex and pre-existing respiratory disease.