# Aberrant RBC SNO transport and endothelial adhesion in sepsis

> **NIH VA I01** · DURHAM VA MEDICAL CENTER · 2022 · —

## Abstract

In critically ill patients, anemia is a well-established risk factor for poor outcomes but, paradoxically, liberal RBC
transfusion in these patients does not improve outcomes as compared with a restrictive strategy in which patients
remain moderately anemic. Changes taking place very early in the storage process may contribute by impairing
RBC function. We have identified functional and biochemical changes in the first day of RBC storage that
contribute to a proadhesive effect of blood banking. Most recently, we identified a novel mechanism whereby
healthy human RBCs export the nitric oxide (NO) derivative, S-nitrosothiol (SNO), to oppose endothelial
adhesion of RBCs in vitro and in vivo in mice. This RBC SNO export is depressed after RBC storage. To study
the physiological significance of this pathway, we engineered a mouse in which the responsible SNO transporter
is inducibly deleted from endothelial cells. ECs from this mouse import SNO poorly as predicted, and RBC
adhesion is increased in the lungs of these mice after transfusion. In mice with sepsis (injurious response to
serious infection), we find that RBC export of SNO is decreased even though RBC SNO content is elevated. We
hypothesize that in sepsis, intercellular SNO transport is deficient, promoting the adhesivity of RBCs (native or
transfused) and neutrophils. We will test this hypothesis by accomplishing these Specific Aims:
1. Determine the influence of sepsis on antiadhesive SNO export from RBCs. We find that after cecal
ligation and puncture (CLP), the ability of murine RBCs to export antiadhesive SNO is deficient. We will test
whether the SNO deficiency and proadhesive effect in this sepsis model are related, such as by testing rescue
using extracellular CSNO (S-nitrosocysteine). We will test whether SNO export by one RBC population can
influence the adhesivity of other RBCs in paracrine fashion. The relevance to human sepsis in Veterans will be
tested by studying the LAT1-dependent ability of patient RBCs to export SNO basally and in hypoxia.
2. Determine the influence of LAT1-mediated SNO export on neutrophil adhesion. Neutrophil adhesion to
the endothelium is a key early event in immune responses to infection. Antiadhesive NO/SNO is abundant in
sepsis and may limit organ damage. We will determine the role of LAT1 and SNO export in modulating the
adhesivity of neutrophils. We will determine the role of RBC SNO export in modulating the adhesion of
neutrophils. We will identify the adhesion receptors and counterreceptors mediating LAT1/SNO-sensitive
neutrophil adhesion. Finally, we will determine the role of LAT1-mediated SNO export (and EC SNO import) in
the adhesivity of adoptively transferred neutrophils.
3. Determine the role of SNO export by RBCs and neutrophils in adhesion and extravasation in a mouse
model of CLP-induced sepsis. We will measure the adhesion of both RBCs and neutrophils, and indices of
organ injury, in sepsis secondary to CLP in our mice conditionally defi...

## Key facts

- **NIH application ID:** 10377331
- **Project number:** 5I01BX003478-06
- **Recipient organization:** DURHAM VA MEDICAL CENTER
- **Principal Investigator:** TIMOTHY J MCMAHON
- **Activity code:** I01 (R01, R21, SBIR, etc.)
- **Funding institute:** VA
- **Fiscal year:** 2022
- **Award amount:** —
- **Award type:** 5
- **Project period:** 2017-01-01 → 2025-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10377331

## Citation

> US National Institutes of Health, RePORTER application 10377331, Aberrant RBC SNO transport and endothelial adhesion in sepsis (5I01BX003478-06). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10377331. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*