EPHEDRA: Enhanced PHthisic by Environmental Disruptors of Resolution Agonists

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Abstract It now widely appreciated that uncontrolled inflammation is a unifying component in many widespread diseases 1, including chronic lung diseases 2,3. Inhalational exposure to respirable particulate matter can be an important precipitant or exacerbate of lung inflammation. From our earlier results, the resolution of inflammation is known today as an active process 4. There are several new families of specialized pro- resolving mediators (SPM) identified and characterized in acute inflammation 5. These protective mediators are enzymatically produced and are agonists at specific receptors transducing cell type specific functional responses critical in tissue resolution. Resolution programs of the inflammatory response are essentially uncharted in environmental health and medicine. Fundamental information is critically needed on the impact of new environmental agents within the resolution response and whether they perturb resolution to trigger chronic inflammatory responses and infections. Here, the B.D. Levy, C.N. Serhan and P. Demokritou labs unite to collaborate for NOT-ES-20018 and propose an innovative study entitled EPHEDRA: Enhanced PHthisic by Environmental Disruptors of Resolution Agonists, focusing on elucidating the impact of potentially hazardous environmental agents presented to the airway as nanoparticles on newly uncovered resolution programs that govern phagocyte functions and the return to homeostasis. Failed resolution or its disruption can lead to sustained lung inflammation and inefficient clearance of microbial pathogens, including viruses and bacteria. This proposal will test an innovative hypothesis, namely that specific environmental agents prime for sustained lung inflammation by disrupting cellular and molecular pro-resolving mechanisms that also increase susceptibility to lung infections; and replacement of resolvins and/or other specialized pro- resolving mediators that are potent agonists for resolution responses in lungs are required to protect lungs from hazardous environmental agents and restore effective microbial clearance. To test this hypothesis, we propose 3 specific aims to: 1) Determine the impact of environmental and engineered nanoparticles (NP) on the resolution of lung inflammation, 2) Establish the impact of NP disruptors of resolution on viral host responses and post-influenza secondary bacterial pneumonia, and 3) Determine the impact of NP exposure on macrophage efferocytosis, SPM production, pro-resolving receptors and SPM rescue. Results from these studies will elucidate fundamental mechanism(s) in the resolution of inflammation that are susceptible to disruptive environmental agents and toxic to resolution.