Abstract
242007
Introduction: Acute respiratory distress syndrome (ARDS) is the major cause of death from systemic inflammatory diseases or viral infections such as coronavirus. Early and accurate diagnosis of ARDS in patients presenting with dyspnea and/or hypoxia is of great importance for effective treatment and improved prognosis. Although lung imaging has been a fundamental tool for evaluating lung injury, early image detection of inflammatory changes in the lung has been challenging. The activation of matrix metalloproteinases (MMP) contributes to the early inflammatory response in ARDS. Imaging technologies targeting the activation of MMP would provide a potential for early detection of inflammation. We developed a novel imaging approach for the early detection of ARDS using dynamic single photon emission computed tomography/computed tomography (SPECT/CT) with a 99mTc-labeled radiotracer targeting MMP (RP805).
Methods: We investigated the early activation of MMPs in lung in a pig model of ARDS and performed MMP-targeted imaging using dynamic 99mTc-RP805 SPECT/CT for differentiating the injured from the non-injured regions of lung. Anesthetized Yorkshire pigs (n=8) underwent unilateral surfactant depletion by repeated bronchoalveolar lavage with normal saline on the left lung protecting the right lung. The pig was then mechanically ventilated for 4 hours inducing ventilator-induced lung injury. Serial dynamic 99mTc-RP805 SPECT/CT scans were acquired starting one-hour post-lavage at 5-15 minutes interval up to 120 minutes after radiotracer injection using CZT SPECT 64-slice CT scanner. Time activity curves were obtained from different lung regions and were also corrected for the tissue fraction effect from the blood component using kinetic modeling. The SPECT images were analyzed by using semi-automatic lobar segmentation of the lungs. The ratio of radiotracer uptake was compared between injured vs non-injured lung dynamically and in select regions that were biopsied. The pigs were euthanized after dynamic in vivo imaging and lungs were excised for ex vivo SPECT/CT, and tissues processed for well counting for 99mTc radioactivity and immunohistochemical analysis of MMP-9 activity.
Results: The 99mTc-RP805 total lung uptake ratio (injured/non-injured) after lavage and mechanical ventilation was 0.92±0.11, 1.02±0.08 and 1.08±0.08 at 5, 60 and 120 minutes after radiotracer injection, respectively. The blood fraction-corrected (BFC) total lung uptake ratio was 0.90±0.37, 1.08±0.12 and 1.17±0.13 at same times. The BFC upper lung uptake ratio was 1.20±0.63, 1.12±0.07 and 1.20±0.11 while the lower lung uptake ratio was 0.83±0.23, 1.06±0.15 and 1.17±0.17 (after 5, 60 and 120 minutes, respectively). The ex vivo 99mTc-RP805 uptake was higher in the regions from the injured lung compared to non-injured lung (P = 0.013), and correlated with well counting radioactivity in matched tissue samples (Spearman’s rho = 0.500, P=0.005). Immunohistochemistry showed an early increase in MMP-9 activity from the injured lung.
Conclusions: Quantification of MMP-targeted 99mTc-RP805 SPECT/CT imaging is a potential method to identify early inflammation in ARDS. 99mTc-RP805 activity was initially low in the injured lung and increased and was retained in injured lung on serial SPECT/CT images in the early phase of ARDS. 99mTc-RP805 imaging provides an early biomarker of MMP activation in the lung for early noninvasive diagnosis of ARDS and could be used to evaluate treatment of ARDS with MMP inhibitors or other modulators of inflammation.
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