# Haptoglobin 2 variant and endothelial glycocalyx shedding in sepsis-induced ARDS

> **NIH NIH R01** · VANDERBILT UNIVERSITY MEDICAL CENTER · 2024 · $549,637

## Abstract

ABSTRACT
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. Sepsis-associated ARDS is characterized by pathologic degradation of the pulmonary
endothelial glycocalyx—a glycosaminoglycan-enriched endovascular layer necessary for pulmonary vascular
homeostasis. There is a vital need to identify early triggers of endothelial glycocalyx degradation 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 published and preliminary data suggest that (1)
cell-free hemoglobin (CFH) is released into the circulation in sepsis and contributes to oxidant-mediated organ
dysfunction and death; (2) CFH can directly injure the lung endothelial glycocalyx, causing degradation and
shedding; (3) haptoglobin, an endogenous scavenger for cell-free hemoglobin that limits its ability to cause
oxidative injury has a common genetic variant, HP-2, that increases the risk of ARDS in both humans and mice
with sepsis; and (4) patients and mice with sepsis and the HP-2 variant have increased degradation of the
endothelial glycocalyx and evidence of increased oxidative stress. The studies in this proposal will build on
these preliminary findings to characterize the mechanisms by which CFH-mediated endothelial glycocalyx
degradation is modified by the HP-2 genotype. Our primary goal is to translate these findings to new targeted
therapies that will be tested in our novel isolated human lung model as preparation for rapid translation to
targeted clinical trials in sepsis. In Aim 1, we will use state-of-the-art mass spectrometry analyses of circulating
glycosaminoglycan fragments to determine the extent and signature of endothelial glycocalyx shedding in
patients with the HP-2 variant, study the association with ARDS and determine downstream mechanisms of
endothelial injury. In Aim 2 we will use genetically manipulated mouse models to determine the contribution of
heparanase and oxidative injury to glycocalyx degradation in mice with the HP-2 genotype. In Aim 3, we will
test the therapeutic potential of targeting oxidant mediated injury in the HP-2 genotype to preserve the
endothelial glycocalyx in the isolated perfused human lung as a translational bridge to future patient studies.
The studies proposed in these aims have the potential for major and sustained scientific impact. Since HP-2 is
the most common allele of the HP gene and over 40% of people of European or African ancestry are
homozygous for this allele, targeting patients with the HP2 genotype with therapies to prevent endothelial
glycocalyx degradation is a new approach that could have a major impact on clinical outcomes.

## Key facts

- **NIH application ID:** 10907623
- **Project number:** 5R01HL158906-04
- **Recipient organization:** VANDERBILT UNIVERSITY MEDICAL CENTER
- **Principal Investigator:** Lorraine B Ware
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $549,637
- **Award type:** 5
- **Project period:** 2021-09-01 → 2025-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10907623

## Citation

> US National Institutes of Health, RePORTER application 10907623, Haptoglobin 2 variant and endothelial glycocalyx shedding in sepsis-induced ARDS (5R01HL158906-04). Retrieved via AI Analytics 2026-05-21 from https://api.ai-analytics.org/grant/nih/10907623. Licensed CC0.

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