# Imaging and Targeting Lung Proteolysis in ARDS

> **NIH NIH R01** · YALE UNIVERSITY · 2023 · $712,213

## Abstract

Acute respiratory distress syndrome (ARDS) is the most severe form of acute lung injury (ALI)
and respiratory failure characterized by diffuse alveolar and endothelial damage. ARDS can be
complicated by pulmonary vascular dysfunction (PVD) and right ventricular (RV) failure and
increased mortality. Current imaging technology relies on assessment of anatomic features for
the assessment of ALI, which has limited sensitivity for detecting the initial pulmonary and
vascular injury. We propose a molecular imaging approach that would detect early, subclinical
manifestations of cardiopulmonary injury and define conditions of matrix metalloproteinase (MMP)
activation associated with the risk for advancement to ARDS and complicating cardiac
dysfunction. Patients with ARDS may require different ventilation schemes, and inappropriate
ventilation can lead to superimposed ventilator induced lung injury with disruption of the structural
integrity of the tissue interface between the pulmonary circulation and alveolar space. The
pulmonary architecture, which includes the extracellular matrix (ECM) can be disrupted in ARDS.
MMP activation occurs in the setting of ARDS and is a critical molecular mechanism associated
with disease progression and therefore represents a therapeutic target. Inhibition of MMPs has
also been shown to protect against RV cardiomyocyte injury associated with ARDS. There is an
urgent need for clinically relevant diagnostic imaging biomarkers for detection of patients with ALI
and progressive ARDS and complicating PVD and RV dysfunction. Early and serial targeted MMP
imaging can define the underlying pathology and guide the timing of targeted interventional
strategies to mitigate the progression to life-threatening disease. This project will test the central
hypothesis in a porcine model of ARDS that MMP activation can be visualized, quantified, and
more importantly successfully inhibited with a localized therapeutic delivery approach to mitigate
ARDS progression and vascular and myocardial injury. We will evaluate MMP activation within
the lung parenchyma, pulmonary vasculature, and right ventricular myocardium in a porcine
model of ARDS induced by regional bronchial lavage. We will evaluate the therapeutic efficacy of
an MMP inhibitor delivered intravenously or via a novel hydrogel-based formulation that will yield
localized high doses of the inhibitor. The role of MMP activation will also be evaluated in ventilated
patients that have died with ARDS. This project will combine both diagnostic and treatment
strategies and coalesce a team of physicians and scientists to advance novel diagnostic and
therapeutic strategies with high relevance to management of ARDS, and in turn will improve
patient recovery from ARDS and utilization of medical resources.

## Key facts

- **NIH application ID:** 10686292
- **Project number:** 5R01HL159459-03
- **Recipient organization:** YALE UNIVERSITY
- **Principal Investigator:** Albert J Sinusas
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2023
- **Award amount:** $712,213
- **Award type:** 5
- **Project period:** 2021-08-26 → 2025-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10686292

## Citation

> US National Institutes of Health, RePORTER application 10686292, Imaging and Targeting Lung Proteolysis in ARDS (5R01HL159459-03). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10686292. Licensed CC0.

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