Abstract Body (Do not enter title and authors here): Background
Cardiac arrest (CA) alters circulating immune cells, triggering cytokine dysregulation and inflammatory pathways that contribute to brain injury and mortality. We previously showed decreased plasma lysophosphatidylcholine (LPC), especially LPC(22:6), post-CA. LPC(22:6) supplementation proved neuroprotection. Given the role of cytokines and HMGB1 in post-CA inflammation, we hypothesized that LPC(22:6) administration would suppress these mediators and reduce brain injury.

Methods
Blood samples were collected from 45 adult CA patients within one hour of achieving return of spontaneous circulation (ROSC) and 25 controls. Leukocyte subsets were analyzed in fresh blood, while LPC(22:6) levels, high-mobility group box 1 (HMGB1), interleukin-6 (IL-6), and interleukin-8 (IL-8) were measured in plasma. Similarly, leukocyte subsets, cytokines, and HMGB1 were measured in blood samples from adult male Sprague-Dawley rats that underwent 10 minutes of asphyxia-induced CA followed by cardiopulmonary resuscitation. To assess LPC(22:6) effects, rats received an intravenous injection of LPC(22:6) at a dose of 6 mg/kg one minute after ROSC. Blood samples from the rat model were collected at baseline and over a two-hour period.

Results
The data from human CA patients demonstrate a systemic immune response post-ROSC, marked by elevated lymphocyte counts, increased plasma levels of HMGB1, and heightened inflammatory cytokines such as IL-8 and IL-6, which inversely correlated with LPC(22:6) levels during the early phase of resuscitation (Figure 1). Our data from the rat model confirm this early-phase response observed in human patients and clarify the sequence of events: an initial rise in lymphocyte counts at baseline, HMGB1 overexpression in CD4-positive lymphocytes at 30 minutes, a gradual increase in plasma HMGB1 levels at 60 minutes, followed by a rise in monocyte and neutrophil counts at 120 minutes post-ROSC (Figure 2). There were no TNFα level changes in human plasma samples and the rat model. This demonstrates that LPC(22:6) can modulate the immune response by reducing systemic HMGB1 levels and preventing the increase in monocyte counts (Figure 3).
Conclusion
LPC(22:6) demonstrates potential in modulating the immune response post-ROSC by reducing key inflammatory markers and preventing increases in monocyte counts. These findings highlight LPC(22:6) as a promising therapeutic option for improving recovery outcomes after CA, warranting further investigation.