Abstract 145: High Mobility Group Box 1 (HMGB1) is a Major Mediator of the Post-cardiac Arrest Syndrome

Abstract

Introduction: Profound immune disorders are triggered by cell death and subsequent release of danger signals after cardiac arrest (CA). Hypothesis: High mobility group box-1 (HMGB1) is one of the main endogenous mediators released by ischemic cell death. Our goal was to determine whether its inhibition could provide neuroprotection and improve the outcome after experimental CA. Methods: After 10 min of ventricular fibrillation and resuscitation, rabbits either received an administration of saline (CT group, n=10) or glycyrrhizin (GL group, n=10), a direct inhibitor of HMGB1 (4 mg/kg, i.v.). Animals were followed during 3 days after CA to evaluate the neurological dysfunction. Additional animals were submitted to the same protocol with brain withdrawal 2 or 6 h after CA for immune cell count by cytometry. Results: After CA, HMGB1 blood levels was significantly reduced in CT vs GL group (30±7 vs 17±2 ng/ml at t=30 min after CA). The systemic inflammatory response was subsequently attenuated in GL vs CT, as shown by reduced interleukin-6 concentration (231±34 vs 993±331 pg/ml at 180 min, respectively). In the CT group, a rapid accumulation of neutrophils (CD11b+) and T cells (CD3+, CD4+ and CD8+) was also evidenced in the brain after cardiac arrest. GL specifically reduced the influx of T cells (e.g., 2.7±0.3 vs 7.3±2.6% of CD3+ cells in the brain at 6 h after CA in GL vs CT, respectively) without modifying neutrophils counts. This effect was neither related to differences in blood cells counts nor a modification of blood-brain-barrier permeability between groups, which then suggests a specific inhibition of cerebral chemo-attraction of T cells by glycyrrhizin. Those modifications were ultimately associated with a reduction in neuronal cell death (fluorojade C staining), as well as improved neurological recovery in GL vs CT groups (mean neurological dysfunction scores at day 3 = 58±13 vs 100±0 %, respectively). Conclusion: HMGB1 is a major mediator of the cerebral early infiltration by T cells following CA. Its inhibition by glycyrrhizin could be a relevant therapeutic target to prevent the propagation of neurological damages.