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Molecular characterization of pulmonary edema: a window to an injured lung

肺水肿的分子特征：了解受损肺部的窗口

基本信息

批准号：
10650385
负责人：
ANGELA J ROGERS
金额：
$ 76.77万
依托单位：
STANFORD UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-08-09 至 2025-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10650385
关键词：
Acute Respiratory Distress Syndrome Address Alveolar Bilateral Bioinformatics Biology Bronchoscopy Cessation of life Characteristics Classification Classification Scheme Clinical Clinical Research Clinical Trials Collection Data Development Disease Edema Electrons Enrollment Epithelium Failure Fingerprint Functional disorder Future Goals Heterogeneity Hour Individual Inflammation Inflammatory Informatics Intensive Care Life Lipids Liquid substance Lung Machine Learning Mass Spectrum Analysis Measures Mechanical ventilation Methods Minority Modeling Molecular Molecular Profiling Outcome Patients Pharmaceutical Preparations Pharmacotherapy Phenotype Plasma Population Proteins Proteomics Pulmonary Edema Qualifying Reporting Research Research Personnel Respiratory Failure Risk Sample Size Sampling Severities System Technology Testing Ventilator alveolar epithelium cohort effective therapy epithelial injury high risk innovation ionization lung injury metabolomics mortality mortality risk multidisciplinary novel peripheral blood primary outcome prognostic prognostic value prospective protein profiling receptor for advanced glycation endproducts recruit risk stratification secondary outcome systemic inflammatory response therapeutic target treatment strategy

项目摘要

Acute respiratory distress syndrome (ARDS) is a heterogeneous, life-threatening condition defined by poor oxygenation and bilateral pulmonary edema that carries a mortality rate >40% in most studies. Every ARDS drug trial to date has failed, perhaps because the clinical criteria defining ARDS include a substantial subset of low-risk patients. Clinical scoring systems poorly predict which ARDS patients will develop prolonged respiratory failure and are at increased risk of death. Molecular profiling of pulmonary edema fluid could serve as a window on the alveolar microenvironment, enabling identification of high-risk patients. Pulmonary edema directly reflects lung pathobiology including loss of barrier integrity, inflammation, and epithelial damage. Unfortunately, free-flowing pulmonary edema has limited clinical utility because it can only be captured in a minority of patients. Molecular characterization of pulmonary edema is now possible in every patient with ARDS because of two critical innovations. First, we discovered that edema fluid condensing in the HME (heat and moisture exchanger) filter of the ventilator circuit, usually discarded as trash, closely reflects free-flowing edema. Second, we developed a non-targeted metabolomic fingerprinting method using mass spectroscopy that characterizes molecular components in trace quantities of fluid. Together, these innovations make it possible to test the central hypothesis that molecular features of edema fluid reflect pathobiology and enable ARDS risk stratification. To address the prognostic enrichment potential of HME edema fluid, 300 early ARDS patients will be recruited at 3 US centers, with protocolized HME edema fluid collection. Aim 1 is to study whether high HME edema fluid total protein and lung-injury specific proteins predict prolonged respiratory failure ≥48h in ARDS. Aim 2 is to test whether hypermetabolic edema fluid and inflammatory lipids predict prolonged respiratory failure ≥48h in ARDS. In Aim 3, LASSO machine learning will be used to integrate all proteomic and metabolomic edema features into a prolonged mechanical ventilation classifier. The robustness of the classifier will be assessed by measuring whether it adds prognostic value to clinical ARDS severity scores, identifying how well key molecular features are reflected in plasma, and testing for replication in an independent cohort. The goal of these studies is to examine to what extent a novel and readily available lung-specific sample, obtained early in the course of ARDS, reflects biology and can predict ARDS outcomes, thus offering prognostic enrichment for future clinical trials. Successful completion of the Specific Aims offers the potential for a much-needed classification scheme to better refine, understand, and therapeutically-target ARDS.

急性呼吸窘迫综合征（ARDS）是一种异质性的、危及生命的疾病，氧合不良和双侧肺水肿，在大多数研究中死亡率>40%。每迄今为止，ARDS药物试验失败了，可能是因为定义ARDS的临床标准包括大量的低风险患者的子集。临床评分系统不能很好地预测哪些ARDS患者会发展为长期性ARDS。呼吸衰竭，死亡风险增加。肺水肿液的分子谱可以作为肺泡微环境的窗口，从而能够识别高风险患者。肺水肿直接反映了肺病理学，包括损失屏障完整性、炎症和上皮损伤。不幸的是，自由流动性肺水肿临床实用性有限，因为它只能在少数患者中捕获。的分子特征由于两个关键的创新，肺水肿现在可能发生在每一个患有ARDS的患者身上。一是发现水肿液在呼吸机的HME（热湿交换器）过滤器中冷凝通常被当作垃圾丢弃的回路密切反映了自由流动的水肿。其次，我们开发了一种非目标性的代谢组学指纹法，使用质谱法表征痕量中的分子组分大量的液体。总之，这些创新使人们有可能测试的核心假设，分子水肿液的特征反映了病理生物学并使ARDS危险分层成为可能。为了解决HME水肿液的预后富集潜力，将对300例早期ARDS患者进行在3个美国中心招募，采集方案规定的HME水肿液。目的1是研究高HME是否水肿液总蛋白和肺损伤特异性蛋白预测ARDS患者呼吸衰竭时间≥48h。目的2是检测高代谢水肿液和炎性脂质是否预测呼吸延长 ARDS失败≥ 48 h。在目标3中，LASSO机器学习将用于整合所有蛋白质组学和将代谢组学水肿特征转化为延长的机械通气分类器。分类器的鲁棒性将通过测量它是否增加了临床ARDS严重程度评分的预后价值，关键分子特征在血浆中的反映情况，以及在独立队列中进行复制测试。这些研究的目的是检查在何种程度上新的和容易获得的肺特异性样品，在ARDS早期获得，反映了生物学，可以预测ARDS的结果，因此提供了预后富集用于未来的临床试验。成功完成特定目标提供了潜力一个急需的分类方案，以更好地完善，理解和治疗目标的ARDS。