NUCLEAR FACTOR-ERYTHROID-2-RELATED FACTOR REGULATES SYSTEMIC AND PULMONARY BARRIER FUNCTION AND IMMUNE PROGRAMMING...

Area of Science:

• Biomedical Science
• Immunology
• Pharmacology

Background:

• Major burn injuries induce systemic hyperinflammation and oxidative stress, worsening outcomes.
• Combined burn and inhalation (B+I) injury exacerbates these stresses, increasing morbidity and mortality.
• Nuclear factor-erythroid-2-related factor (NRF2) is a key regulator of cellular stress response and homeostasis.

Purpose of the Study:

• To investigate the sufficiency of NRF2-mediated homeostasis in burn and B+I injuries.
• To determine if pharmacological activation of NRF2 can mitigate acute hyperinflammatory responses.
• To explore the therapeutic potential of NRF2 activation for burn and B+I patients.

Main Methods:

• Utilized Nrf2 knockout (Nrf2-/-) and wild-type (WT) mice subjected to burn and B+I injury models.
• Analyzed mortality, pulmonary edema, vascular permeability, and inflammatory responses.
• Conducted transcriptome analysis of lung tissue and assessed NRF2 protein localization.
• Administered Bardoxolone methyl-containing microparticles (CDDO-MPs) to injured mice.

Main Results:

• Nrf2-/- mice exhibited higher mortality, increased pulmonary edema, and exacerbated inflammatory responses post-injury compared to WT controls.
• B+I injury led to cytosolic NRF2 accumulation in WT mouse lungs, indicating a potential pathway deficiency.
• CDDO-MP treatment significantly reduced mortality and cytokine dysfunction in B+I injured mice.

Conclusions:

• NRF2 plays a critical role in regulating pulmonary and systemic immune responses following burn and B+I injury.
• There is a deficiency in controlling immune dysregulation after these injuries.
• Pharmacological activation of the NRF2 pathway holds promise for improving clinical outcomes in patients with burn and B+I injuries.