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）是急性肺损伤最严重的形式（ALI） 和呼吸衰竭，其特征是弥漫性肺泡和内皮损伤。可以是 由于肺血管功能障碍（PVD）和右心（RV）衰竭而复杂 死亡率增加。当前的成像技术依赖于评估解剖特征 对ALI的评估，ALI的敏感性有限，用于检测初始肺和 血管损伤。我们提出了一种分子成像方法，该方法将早期检测到亚临床 心肺损伤的表现和定义基质金属蛋白酶（MMP）的条件 激活与促进ARD和心脏复杂的风险相关 功能障碍。 ARDS患者可能需要不同的通风方案，并且不适当 通风会导致叠加的呼吸机诱发肺损伤，并破坏结构 肺循环和肺泡空间之间组织界面的完整性。这 包括细胞外基质（ECM）的肺结构可以在ARDS中破坏。 MMP激活发生在ARDS的环境中，是一种关键的分子机制 随着疾病的进展，代表了治疗靶标。抑制MMP的 还显示可防止与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 以及进行性弧度，使PVD和RV功能障碍复杂化。早期和串行针对的MMP 成像可以定义潜在的病理并指导目标介入的时间安排 减轻威胁生命的疾病的策略。该项目将测试中央 在ARDS的猪模型中，MMP激活可以可视化，定量，并且 更重要的是通过局部治疗方法成功地抑制以减轻 ARDS进展，血管和心肌损伤。我们将评估MMP激活 肺部肺实质，肺脉管系统和右心心肌在猪中 由区域支气管灌洗引起的ARDS模型。我们将评估 MMP抑制剂静脉注射或通过新型水凝胶的配方递送，该配方将产生 局部高剂量的抑制剂。 MMP激活的作用也将在通风中评估 死于ARDS的患者。该项目将结合诊断和治疗 策略和融合了一组医生和科学家团队，以推进新颖的诊断和 与ARD的管理高度相关的治疗策略，进而将改善 患者从ARDS中恢复和医疗资源的利用。