# Adenosinergic Signaling in the Immunoinflammatory Response After Cardiac Arrest

> **NIH NIH P20** · MAINEHEALTH · 2022 · $348,544

## Abstract

Abstract
 Of the ~600,000 annual cardiac arrest events in the USA, <7% result in survival with a good neurological
outcome. Patient heterogeneity and variations in emergency care affect ischemia time, rates of resuscitation,
and post-resuscitation outcomes. The early hours after resuscitation are a critical window to promote cell
recovery. This project builds upon a robust post-resuscitation clinical program and our prior work identifying
unique neutrophil populations and their interactions with lymphocytes in “post-cardiac arrest syndrome” in
humans. In our patients, low numbers of CD73-expressing (CD73+) lymphocytes after resuscitation and a high
neutrophil to CD73+ lymphocyte ratio are each associated with worse outcomes. CD73 is a key enzyme in the
generation of adenosine, which is neuroprotective and regulates vasoreactivity. Because increased duration of
ischemia also increases risk of poor outcome, we predict that the longer ischemic times associated with
cardiac arrest in patients living in rural areas will be reflected in fewer CD73+ circulating lymphocytes post-
resuscitation. We expect regional differences in emergency care to contribute to heterogeneity of the
inflammatory response, emphasizing the importance of diversity and inclusion in cardiac arrest research. In
addition to our clinical observations, our studies show critical immunomodulatory effects of CD73+
lymphocytes on neutrophil activation, specifically on a novel subpopulation of highly inflammatory neutrophils
we have named cardiac arrest-associated neutrophils (CAANs). We will characterize molecular signaling
associated with CD73+ lymphocytes with respect to neutrophil and endothelial cell function. We hypothesize
that activation of CD73+ lymphocytes is an acute protective response to whole-body ischemia-reperfusion
injury that dampens the inflammatory consequences of global ischemia. Further, we predict that low numbers
of CD73+ lymphocytes correlate with pathological neutrophil activation and impaired endothelial function,
leading to decreased blood flow at end-vascular territories and tissue infarction in the brain and other
vulnerable organs. Our aims are to: 1) determine the inflammatory profiles and associated clinical phenotypes
in cardiac arrest patients with varying levels of CD73+ lymphocytes, and 2) characterize the effects of CD73+
lymphocytes against neutrophil-mediated injury to the endothelial cell barrier.
 This is the first major attempt to characterize the cellular immune response after resuscitation from cardiac
arrest, and represents a novel translational research direction for Dr. David Seder, an experienced clinical
trialist. Dr. Seder will expand his clinical research skills into laboratory-based skills in molecular phenotyping of
human-derived inflammatory cells, and receive mentorship from senior physician-scientists with successful
careers in patient care, academic medicine, and clinical and translational research (C. Rosen and D. Sawyer).
The co...

## Key facts

- **NIH application ID:** 10348682
- **Project number:** 5P20GM139745-02
- **Recipient organization:** MAINEHEALTH
- **Principal Investigator:** David B. Seder
- **Activity code:** P20 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $348,544
- **Award type:** 5
- **Project period:** 2021-02-10 → 2026-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10348682

## Citation

> US National Institutes of Health, RePORTER application 10348682, Adenosinergic Signaling in the Immunoinflammatory Response After Cardiac Arrest (5P20GM139745-02). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10348682. Licensed CC0.

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