Cardiolipin as a Novel Mediator of Acute Lung Injury

急性呼吸窘迫综合征（ARDS）最常见的原因是严重的细菌感染，包括肺炎。尽管进行了数十年的深入研究，但ARDS的死亡率仍然很高，而且基于全新分子病理生理驱动模型的新治疗策略尚未出现。PPG应用基于我们的开创性发现，即关键的细胞特异性脂质心磷脂在释放到细胞外环境中时深刻地产生ARDS样特征（Nat.Med.2010）。该计划的总体概念模型是心磷脂是一种新的“脂质组学相关分子模式”，编码细菌样分子特征，其通常被哺乳动物细胞线粒体内膜内的区室化所掩盖。然而，我们的初步数据表明，在肺炎模型中，发生了精液事件，其中心磷脂通过其失调的生物合成（项目1）或氧化迁移（项目2）从上皮细胞中的线粒体暴露于细胞外环境中，导致骨髓细胞的免疫抑制活性的严重不良后果（项目3）。因此，总的假设是心磷脂对ARDS中肺内稳态的不同影响是细胞特异性的和高度区室化的。为了执行该计划，我们组建了一个由世界级领导者组成的团队，他们具有互补的专业知识，以协同研究调节心磷脂可用性及其在线粒体完整性，上皮细胞凋亡和先天免疫功能中的作用的机制。为了评估这一假设，研究人员将采用最先进的分子、细胞和脂质组学工具，这些工具将被转化为肺损伤的补充体内模型，并在患有ARDS的人类受试者中进行分析。该计划将得到高度互动的核心支持，这些核心在氧化脂质组学，动物和人类储存库服务以及生物成像方面具有专业知识。这些研究的实施将为ARDS发病机制提供一个改变范式的概念模型，作为治疗干预的基础，并为肺生物学提供一个新的和持续的科学探究领域。

The acute respiratory distress syndrome (ARDS) is most commonly due to severe bacterial infection, including pneumonia. Despite decades of intense study, mortality rates for ARDS are still very high and yet newer therapeutic strategies based on fundamentally novel molecular-pathophysiologic-driven models have not emerged. This PPG application is based on our seminal discovery that a critical mitochondrial-specific lipid, cardiollpin, profoundly produces ARDS-like features when released into the extracellular environment (Nat. Med. 2010). The overall conceptual model underlying this Program is that cardiollpin is a new "lipidomic associated molecular pattern" encoding bacterial-like molecular signatures that is normally masked by its compartmentalization within the inner mitochondrial membrane of mammalian cells. However, in our preliminary data suggest that in pneumonia models there occur seminal events whereby cardiollpin is exposed into the extracellular environment through its dysregulated biosynthesis (Project 1) or oxidative transmigration (Project 2) from mitochondria in epithelia resulting in severe adverse consequences for immune suppressor activities of myeloid cells (Project 3). Thus, the overall hypothesis is that cardiollpin elicits differential efects on pulmonary homeostasis in ARDS that are cell specific and highly compartmentalized. To execute this Program, we have assembled a team of world-class leaders with complementary expertise to synergistically investigate mechanisms that modulate availability cardiollpin and its role in mitochondrial integrity, epithelial apoptosis, and innate immune function. To evaluate the hypothesis, investigators will employ state-of-art molecular, cell-based, and lipidomic tools that will be translated to complementary in vivo models of lung injury and analysis in human subjects with ARDS. The Program will be supported by highly interactive Cores with expertise in oxidative lipidomics, animal and human repository services, and bioimaging. Execution of these studies will provide a paradigm-changing conceptual model for ARDS pathogenesis that serves as a basis for therapeutic intervention and providing a new and sustained field of scientific inquiry in lung biology.