SEX SPECIFIC AIRWAY RESPONSE TO INHALED WOOD SMOKE EXPOSURE: A PROTEOMIC AND MACROPHAGE ANALYSIS IN HUMAN VOLUNTEERS

Wood smoke particles (WSP) are a significant contributor to global air pollution that affects millions of people. Previous research has shown that WSP induces airway inflammation and oxidative stress, but the underlying mechanisms of WSP remain unclear. Further, human cell models have shown that WSP exposure can alter gene expression in males and females differently, but further evaluation is required to define sex-specific responses to WSP exposure. This dissertation investigates the mechanisms underlying the effects of WSP on the human respiratory proteome and the transcriptomic macrophage responses in a sex-specific manner. Our data demonstrate that WSP exposure generates considerable responses in the respiratory proteome, with females producing a robust anti-inflammatory response to WSP characterized by strong inhibition of immune function pathways, whereas males show activation of many inflammatory pathways in response to WSP. We also observed that WSP condensate (WSPC) exposure diminished phagocytic response in monocyte derived macrophages (MDMs) regardless of polarization state and that pretreatment of male derived MDMs with estradiol can alter WSPC chemokine response. Furthermore, transcriptomic analysis reveals that, in response to WSP condensate, MDMs from females exhibit a greater number of affected genes than males, with female proinflammatory M1 macrophages displaying strong inhibition of inflammatory response pathways. Taken together, these findings demonstrate response to WSP is sex-specific, where females activate anti-inflammatory cell pathways and males activate inflammatory response. Further, these results suggest that WSP exposure suppresses female host response. Overall, these findings emphasize the need for ongoing research examining mechanisms driving the sex-specific responses to WSP and how these changes affect normal immune responses.