Burn Injury-Induced HMGB1 Release Leads to Lung Damage Through Pulmonary Intercellular Barrier Disruption.

Background: Extensive burns induce systemic inflammation and increase vascular permeability, resulting in dehydration and edema. During burn injury, the release of high-mobility group box 1 (HMGB1) from damaged cells may promote an inflammatory response. In this study, we examined the relationship between changes in blood HMGB1 levels, vascular permeability, and lung tissue damage following burn injury. Methods: We examined changes in blood levels of HMGB1 using a mouse model of skin burns. Additionally, we examined intercellular adhesion structures that regulate the barrier function both the skin and lung. To assess changes in vascular permeability, lung tissues of mice with burn injuries were stained with Evans blue. To elucidate the role of HMGB1 in mediating the observed changes, cultured human vascular endothelial cells (HUVECs) and alveolar epithelial cells (H441) were treated with mouse burn serum or HMGB1 protein. Results: Herein, we observed HMGB1 leakage from burned mouse skin and elevated blood levels of HMGB1. Vascular permeability experiments using Evans blue staining confirmed increased permeability in the lung tissues of mice with burn injuries. Measurement of transendothelial electrical resistance revealed enhanced vascular permeability and reduced expression of the intercellular junction proteins in HUVECs. Conversely, treatment of H441 cells with HMGB1 disrupted the location and expression of the tight junction protein, zonula occludens-1. Treatment with the anti-HMGB1 antibody suppressed the disruption of cell-cell junctions in HMGB1-treated cells. These altered adhesion structures were also detected in pulmonary cells of mice with burn injuries. In H441 cells, HMGB1 treatment increased the activation of atypical protein kinase C (aPKC), which is essential for the formation of epithelial-specific cell-cell junctional structures. Inhibition of aPKC suppressed HMGB1-induced disruption of intercellular junction structures. Conclusion: Collectively, these findings suggest that HMGB1-mediated dysregulation of aPKC activity may underlie burn injury-induced vascular hyperpermeability by disrupting cell-cell adhesion.