NRF2 is insufficient in preventing pulmonary damage after burn and inhalation injury
Immune and tissue homeostasis is restored by transcriptional activation of protective genes by the Antioxidant Responsive Element (ARE). The transcription factor Nuclear Factor-Erythroid-2-Related Factor (NRF2) regulates and binds to ARE. Cellular stress, including hypoxia and immune activation, induces dissociation of the repressive Keap1 (Kelch-like ECH-Associated Protein 1)-NRF2 complex, allowing NRF2 to translocate to the nucleus and promote transcription of antioxidant, superoxide de-toxifying, and anti-inflammatory immune genes. We hypothesize that the NRF2-mediated homeostasis following burn and B+I injury is insufficient, so that pharmacological activation of the NRF2 pathway can reduce/reverse acute oxidative damage and hyper-inflammation.

Selected References:
Alves MD, Clark RA, Hernandez DA, Bucci MP, Chen D, Efron PA, Wallet SM, Keselowsky BG, Maile R. Multimodal Nuclear Factor-Erythroid-2-Related Factor (NRF2) Therapy in the Context of Mammalian Target of Rapamycin (mTOR) Inhibition Reprograms the Acute Systemic and Pulmonary Immune Response after Combined Burn and Inhalation Injury. Shock. 2024 PMID: 39178221 Seim RF, Mac M, Sjeklocha LM, Kwiatkowski AJ, Keselowsky BG, Wallet SM, Cairns BA, and Maile R. Nuclear Factor-Erythroid-2-Related Factor regulates systemic and pulmonary barrier function and immune programming after burn and inhalation injury. Shock. 2022 Nov 3. PMID: 36730842