Imaging and Targeting Lung Proteolysis in ARDS

ARDS 中的成像和靶向肺蛋白水解

• 批准号: 10475272
• 负责人: Albert J Sinusas
• 金额: $ 72.26万
• 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/10475272
• 关键词: Acute Lung Injury; Acute 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 Imaging; Diffuse; Disease; Disease Progression; Dose; Doxycycline; Drug Delivery Systems; Elastin; Endothelium; Enzyme Activation; Enzyme Inhibition; Evaluation; Extracellular Matrix; Extracellular Matrix Degradation; 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; Recovery; Research Personnel; Resistance; Resources; Respiratory Failure; Right Ventricular Dysfunction; Risk; Role; Scheme; Scientist; Stress; Structure of parenchyma of lung; Testing; Therapeutic; Tissues; Treatment Efficacy; Ventilator; Ventilator-induced lung injury; Ventricular; X-Ray Computed Tomography; base; clinical application; clinically relevant; complement pathway; contrast enhanced computed tomography; cytokine; diagnostic strategy; experience; first-in-human; imaging approach; imaging biomarker; imaging modality; improved; individual patient; inhibitor; ischemic injury; lung injury; lung vascular 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 arterial pressure; pulmonary function; pulmonary vascular disorder; radiotracer; respiratory; right ventricular failure; 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）是急性肺损伤（ALI）的最严重形式 和以弥漫性肺泡和内皮损伤为特征的呼吸衰竭。ARDS可能是 并发肺血管功能障碍（PVD）和右心室（RV）衰竭， 增加死亡率。目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和并发心脏病的风险相关， 功能障碍ARDS患者可能需要不同的通气方案， 通气可导致叠加的呼吸机诱导的肺损伤， 肺循环和肺泡腔之间组织界面的完整性。的 包括细胞外基质（ECM）的肺结构在ARDS中可被破坏。 基质金属蛋白酶激活发生在ARDS的设置，是一个关键的分子机制， 与疾病进展相关，因此代表治疗靶点。MMPs的抑制 也显示出保护与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 和进行性ARDS以及并发PVD和RV功能障碍。早期和系列靶向MMP 成像可以确定潜在的病理，并指导靶向介入治疗的时机。 缓解危及生命的疾病进展的策略。该项目将测试中央 在猪ARDS模型中，MMP活化可以被可视化、定量 更重要的是，通过局部治疗递送方法成功抑制， ARDS进展与血管和心肌损伤。我们将评估MMP激活， 猪的肺实质、肺血管和右心室心肌 采用局部支气管灌洗法建立急性呼吸窘迫综合征模型。我们将评估 MMP抑制剂通过静脉内或通过新型水凝胶制剂递送， 局部高剂量的抑制剂MMP激活的作用也将在通气中进行评价。 死于ARDS的患者。该项目将联合收割机诊断和治疗结合起来 战略，并联合一个医生和科学家团队，以推进新的诊断和 与ARDS管理高度相关的治疗策略，反过来将改善 患者从ARDS中的恢复和医疗资源的利用。