Imaging and Targeting Lung Proteolysis in ARDS

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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.