Imaging and Targeting Lung Proteolysis in ARDS

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。ARD可以是 合并肺血管功能不全(PVD)和右室(RV)衰竭 死亡率上升。目前的成像技术依赖于对解剖特征的评估 ALI的评估，它对检测首发肺脏和 血管损伤。我们提出了一种分子成像方法，可以发现早期的亚临床 心肺损伤的表现及基质金属蛋白酶的确定条件 激活与进展为ARDS和心脏并发症的风险相关 功能障碍。患有ARDS的患者可能需要不同的通风方案，并且不适合 通风可导致叠加呼吸机所致的肺损伤，并伴有结构的破坏 肺循环和肺泡腔之间的组织界面的完整性。这个 ARDS患者的肺结构，包括细胞外基质(ECM)可被破坏。 基质金属蛋白酶的激活发生在急性呼吸窘迫综合征的发病过程中，是一种重要的分子机制 与疾病的进展有关，因此代表了一个治疗目标。对MMPs的抑制有 也被证明可以预防与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影像生物标志物来检测ALI患者 进展性ARDS和并发PVD和RV功能障碍。早期和连续的靶向基质金属蛋白酶 影像可以定义潜在的病理并指导靶向介入治疗的时机 减缓向危及生命的疾病发展的战略。该项目将测试中央 在ARDS猪模型中的假设是，可以可视化、量化和 更重要的是，通过局部治疗提供方法成功地抑制了 ARDS进展与血管和心肌损伤。我们将评估基质金属蛋白酶的激活情况 猪肺实质、肺血管和右室心肌的研究 区域支气管灌洗致急性呼吸窘迫综合征模型。我们将评估其治疗效果。 一种基质金属蛋白酶抑制剂，通过静脉或通过新型水凝胶配方传递，将产生 局部高剂量的抑制剂。在呼吸机治疗中，还将评估基质金属蛋白酶的激活作用 死于急性呼吸窘迫综合征的患者。该项目将把诊断和治疗结合起来 战略和联合医生和科学家团队，以推进新的诊断和 治疗策略与ARDS的管理高度相关，并反过来将得到改善 ARDS患者的康复和医疗资源的利用。

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.