Abstract 166: Novel Mechanism of Docosahexaenoic Acid Reducing Tissue Injury by Targeting Immune Cells and HMGB1 Release

Abstract

Introduction: Dysregulated immune blood cell response has been implicated in contributing to brain injury following cardiac arrest (CA). Specifically, increased plasma HMGB1 has emerged as a critical mediator of brain damage. However, the underlying mechanisms of the dysregulated immune response and increased HMGB1 after CA remains unclear. Moreover, limited efforts have been made to develop therapeutic interventions targeting this dysregulated immune response. Objective: To elucidate the pathologic immune response during early phase of post-resuscitation and explore this as a targeted therapeutic potential using LPC(22:6), a previously shown neuroprotective compound. Methods and Results: We examined changes in lymphocytes, neutrophils, and monocytes in blood samples obtained from human CA patients. Subsequently, we conducted a time course study in rat CA model to examine changes in these cell populations and investigate the mechanisms underlying the increased HMGB1 levels in post-CA blood with/without plasma supplementation of LPC(22:6). We observed an increase in lymphocytes and neutrophils within one-hour post-resuscitation in human patients and rats. In rats, the increased levels of lymphocytes and neutrophils were followed by an increase in plasma HMGB1 level and monocytes. We further, identified that HMGB1 was significantly upregulated in CD4-positive cells, indicating that T cell-released HMGB1 is the primary source for its elevation. Intriguingly, supplementation of LPC(22:6) prevented the overexpression of HMGB1 in CD4-positive cells, the increase in plasma HMGB1 levels, and the number of monocytes. These findings support the sequential events of dysregulated blood immune response initiated by lymphocyte activation, leading to increased HMGB1 levels and subsequent monocyte activation during early phase of resuscitation after CA. Thus, our results demonstrate the efficacy of LPC(22:6) in inhibiting the expression of HMGB1 in CD4-positive T cells, thereby mitigating this inflammatory cascade. Conclusion: These findings provide novel insights into the mechanisms underlying the dysregulated immune response after CA and highlight the therapeutic potential of targeting this immune response to improve brain function.