Multi-modal rescue of pulmonary NRF2-insufficiency after burn and burn + inhalation injury to regulate innate immune dysfunction

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SUMMARY The American Burn Association estimates that there are ~3,500 deaths each year from burn injuries. There are multiple influences on morbidity and mortality in burn patients, with inhalation injury among the most significant as it leads to increased susceptibility to opportunistic bacterial infections and the associated morbidity and mortality. A trifecta of clinical need is associated with this clinical problem: 1) we lack the ability to predict risk of infection, 2) we do not understand the mechanism of infectious risk, and 3) we are unable to restore a patient’s immune system to homeostasis after injury to enable adequate control of infectious agents. The overall objective of this application is to delineate mechanisms responsible for the cycle of uncontrolled inflammation following burn-injury to refine prediction models patient outcomes and to refine therapeutic approaches to restore immune homeostasis, thus decreasing susceptibility to infection and preventing the associated morbidity and mortality. We and others have demonstrated in human samples and mouse models that burn and burn + inhalation (B+I) injury generates the local and systemic release of numerous Damage-Associated Molecular Patterns (DAMPs). DAMPs promote interactions, via key immune regulators, such as mammalian Target of Rapamycin (mTOR) to induce reactive oxygen species (ROS), inflammatory cytokines, and chemokines which results in tissue damage and immune cell recruitment. Immune homeostasis is normally restored at least in part by the transcription factor Nuclear Factor-Erythroid-2-Related Factor (NRF2). Our preliminary data demonstrate that Nrf2-/- knockout mice have profound mortality after B+I injury. However, our preliminary data also demonstrate that while pulmonary immune cell NRF2 protein translation is rapidly increased after B+I in wildtype mice, it is not translocated to the nucleus. Thus, we hypothesize that the NRF2-mediated homeostasis following burn and B+I injury is insufficient, but that pharmacological activation of the NRF2 pathway has the potential to reduce acute immune dysfunction. Using our pre-clinical models of burn and B+I injury, we will define NRF2-specific mechanisms of acute immune dysfunction following burn or B+I injury and validate these findings in human cohorts within in our high-volume burn center. In addition, we will utilize microparticle technology to develop and characterize NRF2-driven therapy to improve post-injury immune dysfunction. As we appreciate that the response to burn and B+I is multifactorial, we will leverage this technology to combine NRF2 activation with a second approach and inhibit mTOR to provide a novel multimodal therapeutic approach. The efficacy of these approaches will be evaluated using our pre- clinical models of burn and B+I. We are uniquely poised to successful complete this proposal which will allow us to fill the existing knowledge gaps and improve long-term outcomes of burn and B+I patients.