Inflammatory changes and glymphatic dysfunction in carbon monoxide neuropathology

ABSTRACT This project is to elucidate the role of inflammation and perturbations of the brain glial-based lymphatic (glymphatic) pathway in carbon monoxide (CO)-induced brain injuries. Based on preliminary data we hypothesize that astrocyte-derived microparticles (MPs) expressing thrombospindin-1 play a causal role in CO-induced neuropathology that includes glymphatic dysfunction. Further, once these MPs are liberated to the bloodstream they activate circulating neutrophils that sequester along the neurovasculature to exacerbate inflammation, leading to functional neurological deficits. Specific aims are: (1) Assess glymphatic function in response to CO in mice by MRI and fluorescence microscopy; (2) Identify the role of glymphatic outflow to CO-neuropathology in mice; (3) Determine the relationship of neuroinflammation and glymphatic dysfunction to functional deficits; (4) Evaluate associations of morbidity in CO poisoned patients with MPs elevations and intra-particle pro-inflammatory agents.