Imaging and Targeting Lung Proteolysis in ARDS

ARDS 中的成像和靶向肺蛋白水解

• 批准号: 10289990
• 负责人: Albert J Sinusas
• 金额: $ 77.7万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-08-26 至 2025-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10289990
• 关键词: Acute Lung Injury; Adult Respiratory Distress Syndrome; Alveolar; Anatomy; Angiography; Animal Model; Animals; Architecture; Autopsy; Biophysics; Blood; Blood Vessels; Bronchial Lavages; COVID-19 pandemic; COVID-19/ARDS; Cardiac; Cardiac Myocytes; Cardiopulmonary; Cardiopulmonary Physiology; Cardiovascular Diseases; Cardiovascular Models; Chemical Injury; Complement Activation; Complication; Coupled; Cytokine Activation; Detection; Diagnostic; Diagnostic Imaging; Diffuse; Disease; Disease Progression; Dose; Doxycycline; Drug Delivery Systems; Elastin; Endothelium; Enzyme Activation; Enzyme Inhibition; Evaluation; Extracellular Matrix; Extracellular Matrix Degradation; Failure; Family; Fibrillar Collagen; Formulation; Future; Heart; Human; Hybrids; Hydrogels; Image; Imaging technology; Impairment; Inflammation; Inflammatory; Inhibition of Matrix Metalloproteinases Pathway; Injury; Intensive Care Units; Interruption; Intervention; Intravenous; Lead; Life; Lung; Lung Compliance; Lung diseases; Matrix Metalloproteinase Inhibitor; Matrix Metalloproteinases; Measurement; Medical; Molecular; Multimodal Imaging; Myocardial dysfunction; Myocardium; Outcome Study; Pathology; Pathway interactions; Patients; Peptide Hydrolases; Perfusion; Physicians; Play; Positioning Attribute; Proteolysis; Pulmonary Circulation; Pulmonary artery structure; Recovery; Research Personnel; Resistance; Resources; Respiratory Failure; Right Ventricular Dysfunction; Risk; Role; Scheme; Scientist; Stress; Structure; Structure of parenchyma of lung; Testing; Therapeutic; Tissues; Treatment Efficacy; Vascular Diseases; Ventilator; Ventilator-induced lung injury; Ventricular; X-Ray Computed Tomography; base; clinical application; clinically relevant; complement pathway; cytokine; experience; first-in-human; imaging approach; imaging biomarker; imaging modality; improved; individual patient; inhibitor/antagonist; ischemic injury; lung injury; molecular imaging; mortality; multidisciplinary; myocardial injury; novel; novel diagnostics; novel therapeutic intervention; novel therapeutics; porcine model; pre-clinical; pressure; prevent; pulmonary arterial hypertension; pulmonary function; radiotracer; respiratory; single photon emission computed tomography; targeted treatment; therapeutic evaluation; therapeutic target; treatment strategy; validation studies; vascular injury; ventilation

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.

急性呼吸窘迫综合征 (ARDS) 是最严重的急性肺损伤 (ALI) 以及以弥漫性肺泡和内皮损伤为特征的呼吸衰竭。急性呼吸窘迫综合征 (ARDS) 可以是 并发肺血管功能障碍（PVD）和右心室（RV）衰竭 死亡率增加。当前的成像技术依赖于对解剖特征的评估 ALI 的评估，其对于检测初始肺部和肺损伤的敏感性有限 血管损伤。我们提出了一种分子成像方法，可以检测早期、亚临床 心肺损伤的表现和基质金属蛋白酶（MMP）的定义条件 激活与进展为 ARDS 和心脏并发症的风险相关 功能障碍。 ARDS 患者可能需要不同的通气方案，并且不合适 通气可导致叠加呼吸机诱发的肺损伤，并破坏结构 肺循环和肺泡腔之间组织界面的完整性。这 肺结构，包括细胞外基质 (ECM)，在 ARDS 中可能会被破坏。 MMP 激活发生在 ARDS 的情况下，是相关的关键分子机制 随着疾病进展，因此代表了治疗靶点。 MMP 的抑制作用 还被证明可以防止与 ARDS 相关的 RV 心肌细胞损伤。有一个 迫切需要临床相关的诊断成像生物标志物来检测 ALI 患者 进行性 ARDS 以及使 PVD ​​和 RV 功能障碍复杂化。早期和系列靶向 MMP 影像学可以明确潜在的病理并指导有针对性的介入治疗的时机 减缓发展为危及生命的疾病的策略。该项目将测试中央 在 ARDS 猪模型中假设 MMP 激活可以可视化、量化和 更重要的是，通过局部治疗递送方法成功抑制了 ARDS 进展以及血管和心肌损伤。我们将评估 MMP 激活情况 猪的肺实质、肺血管系统和右心室心肌 局部支气管灌洗诱发ARDS模型。我们将评估治疗效果 MMP 抑制剂通过静脉注射或通过新型水凝胶制剂输送，可产生 局部高剂量的抑制剂。 MMP 激活的作用也将在通气条件下进行评估 死于 ARDS 的患者。该项目将结合诊断和治疗 战略并联合医生和科学家团队来推进新的诊断和治疗 治疗策略与 ARDS 的管理高度相关，反过来会改善 ARDS 患者的康复和医疗资源的利用。