# Restoring Endothelial Function After Traumatic Injury to Reduce ARDS and Multi-Organ Dysfunction

> **NIH NIH K23** · UNIVERSITY OF COLORADO DENVER · 2024 · $189,783

## Abstract

PROJECT SUMMARY
Trauma is the leading cause of death worldwide for people under 45 years old, and hemorrhagic shock
remains the primary cause of early death after trauma. Later trauma deaths are frequently attributable to
endotheliopathy of trauma (EOT), a systemic response to activated endothelial cells characterized by impaired
blood flow, barrier integrity, and coagulation. Clinically, EOT manifests as a pro-inflammatory state of
microcirculation leak and tissue edema, contributing to acute respiratory distress syndrome (ARDS), multi-
organ dysfunction, and, eventually, death. Fibrinogen replacement restores the endothelial glycocalyx in vitro
and in mice via stabilization of syndecan-1, a glycocalyx-based proteoglycan. Fibrinogen stabilization of
syndecan-1 then mitigates EOT and restores microcirculation barrier integrity. However, it is unclear if
fibrinogen-based restoration of endothelial integrity translates to improved clinical outcomes in humans.
Further, current transfusion protocols in trauma provide fibrinogen too little or too late. This is a problem
because trauma patients who develop EOT are twice as likely to die than those who do not. Therefore,
restoring endothelial barrier integrity is essential to mitigating late morbidity and mortality in trauma.
Accordingly, there is a critical need to determine the effect of early fibrinogen replacement on endothelial and
organ dysfunction in critically ill trauma patients. Our preliminary data indicate improved patient-centered
outcomes when fibrinogen is replaced within 6 hours of hospital arrival. However, we do not know whether
endothelial restoration was the primary mechanism. To address this gap, we will test our overarching
hypothesis that preserving endothelial function with early fibrinogen replacement will prevent ARDS and multi-
organ dysfunction after trauma. We will test this hypothesis with the following specific aims: 1) determine the
association between early fibrinogen replacement and multi-organ dysfunction; 2) determine the effect of early
fibrinogen replacement on endothelial function; and 3) determine the cumulative effect of endotheliopathy on
supplemental oxygen-free days. To achieve these aims, the candidate, David Douin, MD, will leverage his
background in clinical research and the existing research infrastructure within the emergency medicine, trauma
surgery, and anesthesiology departments. As an anesthesiologist and surgical intensivist, Dr. Douin is uniquely
positioned to accomplish the proposed K23 research and career development aims. His long-term goal is to
become an expert in novel interventions to prevent and treat multi-organ dysfunction and improve outcomes in
critically ill trauma patients. Dr. Douin has assembled a multidisciplinary team of mentors with extensive clinical
and translational research experience and topical expertise in traumatic injury, critical care, clinical trials,
endothelial function, and lung injury to ensure his success in achiev...

## Key facts

- **NIH application ID:** 10920493
- **Project number:** 5K23HL165107-02
- **Recipient organization:** UNIVERSITY OF COLORADO DENVER
- **Principal Investigator:** David J. Douin
- **Activity code:** K23 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $189,783
- **Award type:** 5
- **Project period:** 2023-09-05 → 2028-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10920493

## Citation

> US National Institutes of Health, RePORTER application 10920493, Restoring Endothelial Function After Traumatic Injury to Reduce ARDS and Multi-Organ Dysfunction (5K23HL165107-02). Retrieved via AI Analytics 2026-05-28 from https://api.ai-analytics.org/grant/nih/10920493. Licensed CC0.

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