# Monitoring pro-resolving leukocyte responses in peripheral blood predicts clinical severity during sepsis

> **NIH NIH R21** · BRIGHAM AND WOMEN'S HOSPITAL · 2022 · $237,799

## Abstract

Abstract
Sepsis is characterized by immune cell dysfunction, which is linked to the pathophysiology of the disease with
consequent organ injury and increased associated mortality. In experimental sepsis in mice, regulating
leukocyte function decreases organ injury and lessens the severity of the infection. Assessment of peripheral
blood leukocyte activation and function may serve as prognostic clinical biomarkers and inform new
therapeutic strategies for the management of human sepsis and inflammatory diseases. Resolution of
inflammation is an active process with anti-inflammatory and pro-resolving mechanisms. There are several
families of resolution mediators, termed “specialized pro-resolving mediators (SPMs)”, that serve as agonists
at cognate receptors to transduce cell-type specific responses on leukocytes and in experimental model
systems these SPMs decrease the severity and duration of sepsis. Recently, in microliter quantities of
peripheral blood, we determined that functional characterization of leukocyte responses was more informative
than leukocyte counting for clinical assessment of the trajectory of critical illness. In response to the NIGMS
NOT-GM-19-054 “Exploring the Scientific Value of Existing or New Sepsis Human Biospecimen Collections”,
the proposed proof of concept and scale-up studies are designed to determine the scientific value of our
existing and ongoing Registry of Critical Illness biorepository of human sepsis biospecimens with associated
patient health record data. These biospecimens are collected at presentation, hospital day 3 and hospital 7 to
align with the clinical trajectory of the patient, linked to clinical datasets and represent transformative potential
for sepsis endotyping/stratification. Here, we propose the use of isodielectric separation as a contemporary
cutting-edge technology in the analysis of these biospecimens to uncover leukocyte activation during the
upslope and resolution of patient’s immune responses that will test the hypothesis: Sepsis hyper-
inflammatory responses result from defective endogenous resolution mechanisms and that these
defects are evident in peripheral blood leukocyte activation and functional responses to SPMs.
To address this hypothesis, we plan four specific aims. In the R21 phase, (1) demonstrate reproducible
isolation and functional analysis of neutrophils from capillary blood, and (2) demonstrate ability to obtain deep
proteomic and phosphoproteomic profiles from small numbers of neutrophils. In the R33 phase, (3) longitudinal
analysis of SPM pathway activation during sepsis resolution, and (4) inference and model generation and
testing with ex vivo assays. The goals of this application are to develop an improved understanding of the
resolution defects that unleash unrestrained inflammation of sepsis with a longer term goal for new therapeutic
targets and prognostic indicators of disease progression. Important products of this application include
provision of guidance on ...

## Key facts

- **NIH application ID:** 10354958
- **Project number:** 1R21GM144829-01
- **Recipient organization:** BRIGHAM AND WOMEN'S HOSPITAL
- **Principal Investigator:** Bruce D Levy
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $237,799
- **Award type:** 1
- **Project period:** 2022-01-01 → 2023-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10354958

## Citation

> US National Institutes of Health, RePORTER application 10354958, Monitoring pro-resolving leukocyte responses in peripheral blood predicts clinical severity during sepsis (1R21GM144829-01). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10354958. Licensed CC0.

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