NUCLEAR FACTOR-ERYTHROID-2–RELATED FACTOR REGULATES SYSTEMIC AND PULMONARY BARRIER FUNCTION AND IMMUNE PROGRAMMING AFTER BURN AND INHALATION INJURY

作者：Roland F. Seim, Michelle Mac, Lucas M. Sjeklocha, Alexander J. Kwiatkowski, Benjamin George Keselowsky, Shannon Margaret Wallet, Bruce A. Cairns, Robert Maile · 发表于：Shock · 年份：2022 · DOI：10.1097/shk.0000000000002022 · 被引用次数：8 · 研究领域：Genomics, phytochemicals, and oxidative stress、Burn Injury Management and Outcomes

ABSTRACT: Major burn injury is associated with systemic hyperinflammatory and oxidative stresses that encompass the wound, vascular, and pulmonary systems that contribute to complications and poor outcomes. These stresses are exacerbated if there is a combined burn and inhalation (B+I) injury, which leads to increases in morbidity and mortality. Nuclear factor-erythroid-2-related factor (NRF2) is a transcription factor that functions to maintain homeostasis during stress, in part by modulating inflammation and oxidative injury. We hypothesized that the NRF2-mediated homeostasis after burn alone and combined B-I injury is insufficient, but that pharmacological activation of the NRF2 pathway has the potential to reduce/reverse acute hyper inflammatory responses. We found that, after burn and B+I injury, Nrf2 -/- mice have higher mortality and exhibit greater pulmonary edema, vascular permeability, and exacerbated pulmonary and systemic proinflammatory responses compared with injured wild-type (WT) controls. Transcriptome analysis of lung tissue revealed specific Nrf2 -dependent dysregulated immune pathways after injury. In WT mice, we observed that B+I injury induces cytosolic, but not nuclear, accumulation of NRF2 protein in the lung microenvironment compared with sham-injured controls. Bardoxolone methyl (CDDO-Me)-containing microparticles (CDDO-MPs) were developed that allow for dilution in saline and stable release of CDDO-Me. When delivered intraperitoneally into mice 1 ho...