# Targeting cell-free hemoglobin in sepsis to reduce lung microvascular permeability: mechanistic and translational studies

> **NIH NIH R01** · VANDERBILT UNIVERSITY MEDICAL CENTER · 2020 · $511,205

## Abstract

Project Summary
Sepsis-induced acute respiratory distress syndrome (ARDS) is a leading cause of acute respiratory failure in
critical illness. Morbidity and mortality are high and there are no proven pharmacologic therapies other than
antimicrobials. Increased permeability of the pulmonary microvascular endothelium is a defining pathogenic
feature that leads to acute pulmonary edema and lung dysfunction in sepsis-associated ARDS. Although the
mechanisms that regulate microvascular permeability are an area of intensive research effort, the proximal
triggers of increased pulmonary microvascular permeability in sepsis-associated ARDS are not well
understood. There is a vital need to identify these early triggers of increased microvascular permeability in
sepsis, both to enhance our understanding of pathophysiology, and critically, to identify new therapeutic targets
for prevention and early treatment of sepsis-induced ARDS. Our recent translational studies in patients, the
isolated perfused human lung, and mouse models of sepsis have identified cell-free hemoglobin (CFH) as a
key proximal mediator of increased microvascular permeability that (1) is released into the circulation in over
80% of patients with severe sepsis, (2) is independently associated with mortality in patients with severe
sepsis, (3) has potent effects on pulmonary microvascular permeability across our model systems, (4) can be
oxidized in clinical and experimental sepsis to highly reactive ferryl (4+) hemoglobin, a potent oxidant, and (5)
can be mechanistically targeted by the hemoprotein reductant acetaminophen. Furthermore, preliminary
studies suggest that oxidant-mediated mitochondrial injury and activation of apoptosis in endothelial cells are
key mechanisms through which CFH mediates its effects on microvascular permeability. The studies in this
proposal will build on this preliminary work to characterize the mechanisms by which CFH triggers increased
pulmonary microvascular permeability in sepsis. Our primary goal is to translate these findings to new targeted
therapies that will be tested in our novel human lung model as preparation for rapid translation to clinical trials
in sepsis. In Aim 1, we will study the cellular and physiologic mechanisms by which CFH increases
microvascular permeability and acute lung injury in the isolated human lung and clinically relevant models of
sepsis-induced ARDS. In Aim 2 we will study primary pulmonary microvascular endothelial cells along with our
in vivo models to define the molecular mechanisms by which CFH induces endothelial apoptosis. In Aim 3, we
will test the therapeutic potential of targeting oxidized CFH with acetaminophen in pulmonary microvascular
endothelial cells and clinically relevant models of human and murine sepsis-induced ARDS. The studies
proposed in these aims have the potential for major and sustained scientific impact. Targeting CFH for early
prevention and treatment of ARDS in sepsis is a new approach that could ...

## Key facts

- **NIH application ID:** 9922349
- **Project number:** 5R01HL135849-04
- **Recipient organization:** VANDERBILT UNIVERSITY MEDICAL CENTER
- **Principal Investigator:** Julie A. Bastarache
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $511,205
- **Award type:** 5
- **Project period:** 2017-08-01 → 2021-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9922349

## Citation

> US National Institutes of Health, RePORTER application 9922349, Targeting cell-free hemoglobin in sepsis to reduce lung microvascular permeability: mechanistic and translational studies (5R01HL135849-04). Retrieved via AI Analytics 2026-05-29 from https://api.ai-analytics.org/grant/nih/9922349. Licensed CC0.

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