Anti-inflammatory Strategies for Post Cardiac Arrest Syndrome (PCAS)
Cerebral ischemia-reperfusion injury during
post-cardiac arrest syndrome is modeled
by 3-vessel occlusion and intraperitoneal
LPS injection (3VO/LPS).
Apart from induced hypothermia, there are no neuroprotective therapies currently in use for cardiac arrest. This remains a significant issue given the common nature of this disorder and the fact that few patients survive their neurological injuries. After return of spontaneous circulation, many patients develop coagulopathy, adrenal insufficiency, systemic inflammation, and multi-organ injury related in part to leukocyte extravasation and local tissue damage; these symptoms collectively make up Post-Cardiac Arrest Syndrome (PCAS).
Neutrophils (PMNs) are the first cells to respond to an inflammatory stimulus and can cause direct neurotoxicity by producing reactive oxygen species, degradative enzymes, and chemokines that recruit more cells to the site of injury. PMN priming is a two-stage activation process that results in maximal degranulation and NADPH oxidase activity at the terminal site of migration. Our lab explores PMN priming and trafficking in a mouse model of cerebral ischemia-reperfusion and systemic inflammation. Using the 3VO global ischemia model, we find that cerebral ischemia-reperfusion injury is significantly exacerbated by conditions of systemic inflammation, consistent with observations from the clinical literature.
In the current project, we test the hypothesis that activated PMNs, primed in the periphery by systemic inflammation, play a causative role in the exacerbation of brain injury. Recent work in the fields of pulmonary and critical care suggests that priming is reversible and mediated at the PMN-pulmonary endothelium interface. In particular these studies highlight the potential role of lung-brain coupling in ischemia-reperfusion injury and focus on the PMN priming circuit as a potential target for therapeutic intervention.
The paradox of the neutrophil's role in tissue injury.
Visualization of neutrophil margination
across into the cortex in mice
subjected to transient global ischemia.
Hoechst stained sections from lysM-EGFP transgenic
mouse spleen demonstrating GFP fluorescent
granulocytes located in the marginal zone
surrounding the splenic white pulp.
Visualization of predominantly neutrophils (green)
and IBA-1 positive monycytes
and macrophages (red). Hoechst
nuclear counterstain highlights regions
of red and white pulp.
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