# Novel mechanisms of endothelial Injury in the pathogenesis of ARDS

> **NIH NIH R01** · LURIE CHILDREN'S HOSPITAL OF CHICAGO · 2021 · $567,820

## Abstract

Acute respiratory distress syndrome (ARDS) is a complex, multi-factorial syndrome which manifest itself
by leaky lung microvessels, protein rich edema, and intractable hypoxemia. Given that recent studies
from both human and animal studies has demonstrated the key role of microvascular leakage in
determining the outcome of sepsis and ARDS, maintaining the endothelial barrier integrity represents a
novel, effective therapeutic approach for the prevention and treatment of ARDS. However, the molecular
mechanisms mediating endothelial barrier disruption after sepsis remain poorly understood, especially,
little is known about the key molecules and signaling pathways responsible for endothelial barrier
dysfunction resulting in high mortality in ARDS patients. Our Supporting Data show that higher levels of
plasma SDF1 in ARDS patients are positively associated with high mortality. In mice, we observed that
SDF1 treatment augmented sepsis-induced lung injury and mortality, which were attenuated in mice with
inducible EC-specific disruption of Cxcr4 (Cxcr4iEC). Importantly, our mechanistic studies demonstrate
that SDF1 treatment induces endothelial cell pyroptosis leading to severe endothelial barrier dysfunction.
Thus, we hypothesize that elevated plasma SDF1 levels is a prognostic biomarker of severe lung injury
and greater mortality of ARDS patients which is ascribed to SDF1-induced overwhelming endothelial
pyroptosis and resultant severe endothelial barrier dysfunction following sepsis. The proposed studies
will address the following Specific Aims. Studies in Aim 1 will validate circulating SDF1 level as a
prognostic biomarker of ARDS patients and define the signaling pathway mediating SDF1-exaggerated
lung injury and mortality following sepsis challenge. Studies in Aim 2 will delineate the molecular and
cellular mechanisms of SDF1 in augmenting sepsis-induced lung injury through activation of endothelial
pyroptosis and explore the therapeutic potential of inhibiting pyroptosis for treatment of ARDS. With the
data from these comprehensive studies, we will delineate the fundamental mechanisms of endothelial
injury, identify a prognostic biomarker for the severity and mortality of ARDS, and provide novel
therapeutic approaches for effective treatment of ARDS and promotion of survival. Thus, these innovative
mechanistic studies have high translational potential.

## Key facts

- **NIH application ID:** 10147153
- **Project number:** 5R01HL148810-02
- **Recipient organization:** LURIE CHILDREN'S HOSPITAL OF CHICAGO
- **Principal Investigator:** YOU-YANG ZHAO
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $567,820
- **Award type:** 5
- **Project period:** 2020-05-01 → 2024-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10147153

## Citation

> US National Institutes of Health, RePORTER application 10147153, Novel mechanisms of endothelial Injury in the pathogenesis of ARDS (5R01HL148810-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10147153. Licensed CC0.

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