Intra- and extra-cellular signaling by Cardiolipin in Lung injury

肺损伤中心磷脂的细胞内和细胞外信号传导

• 批准号: 8643330
• 负责人: Valerian E Kagan
• 金额: $ 38.03万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-01-03 至 2018-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8643330
• 关键词: Acute Lung Injury; Adult Respiratory Distress Syndrome; Antibodies; Apoptosis; Apoptotic; Autophagocytosis; Bacteria; Bacterial Infections; Bacterial Pneumonia; Binding; Blood Circulation; Blood Vessels; Cardiolipins; Cell Death; Cells; Data; Development; Diphosphates; Distal; Epithelial; Epithelial Cells; Epithelium; Evolution; Homeostasis; Human; Immune response; Infection; Inflammation; Label; Life; Ligand Binding; Lipids; Liquid substance; Lung; Mediating; Mediator of activation protein; Microinjections; Mitochondria; Molecular; Mus; Outer Mitochondrial Membrane; Oxidative Stress; Pathogenesis; Pathway interactions; Pattern; Phospholipids; Phosphotransferases; Plasma; Pneumonia; Protective Agents; Proteins; Pseudomonas aeruginosa; Role; Signal Transduction; Staphylococcus aureus; Structure; Testing; Therapeutic; Therapeutic Intervention; Virulent; annexin A5; base; cell injury; cellular imaging; cytochrome c; cytotoxic; design; inhibitor/antagonist; injured; innovation; liquid chromatography mass spectrometry; lung injury; novel; novel therapeutic intervention; pathogen; peroxidation; protective effect; research study; small molecule

Bacterial pneumonia triggers an exuberant host response with excessive inflammation, oxidative stress, and epithelial cell damage culminating in ARDS. At present, therapeutic interventions to treat ARDS remain limited to lung-protective strategies, as newer molecular mechanism-driven therapeutic interventions have not yet emerged. The specific pathways involved in the evolution of epithelial damage remain elusive. In preliminary experiments, we discovered that a mitochondria-specific phospholipid, cardiolipin (CL), is a critical damage signal that produces severe epithelial lung injury. We observed that after bacterial infection of murine lung epithelial cells or mice, CL transmigrates from the inner to the outer mitochondrial membrane where it acts as a novel signal for autophagy of mitochondria, mitophagy. We also showed that bacterial infection induces cytochrome c (cyt c)-mediated CL peroxidation as a pivotal step in apoptosis. Thus peroxidation of externalized CL acts as a molecular switch that triggers the apoptotic machinery. Finally, we demonstrate that CL and oxidized CL (Clox) are released from injured host cells into circulation and act as mitochondria-derived damage associated molecular patterns (DAMP-CL) triggering innate and adaptive immune responses. Our central hypothesis is that bacterial infection stimulates the unmasking and release of mitochondrial Cls that are indispensible intracellular signals in accelerating mitophagy and apoptosis; upon release into circulation, Cls act as DAMP-CL inducing innate and adaptive immune responses. The Specific Aims of the proposed studies are to determine the: 1. Mechanisms and signaling role of CL asymmetry and its collapse in bacterial-induced mitophagy in distal lung epithelia. 2. Molecular pathways of CL peroxidation and the design and application of small-molecule regulators that protect against bacterial¿ induced distal lung epithelial apoptosis. 3. Molecular identity of species of CUCLox as DAMP-CL in circulation. Based on the highly innovative concept that CL is a unique intra- and extra-cellular signal in mitophagy, apoptosis, and innate/adaptive immune responses in pulmonary epithelium, we will explore four new classes of regulators of CL signaling for the development of pulmonary protective drugs

细菌性肺炎会引发强烈的宿主反应，导致过度炎症、氧化应激和上皮细胞损伤，最终导致急性呼吸窘迫综合征 (ARDS)。目前，治疗 ARDS 的治疗干预措施仍然仅限于肺保护策略，因为新的分子机制驱动的治疗干预措施尚未出现。参与上皮损伤演变的具体途径仍然难以捉摸。在初步实验中，我们发现线粒体特异性磷脂心磷脂（CL）是产生严重上皮性肺损伤的关键损伤信号。我们观察到，小鼠肺上皮细胞或小鼠被细菌感染后，CL 从线粒体内膜迁移到线粒体外膜，在那里它充当线粒体自噬（线粒体自噬）的新信号。我们还表明，细菌感染会诱导细胞色素 c (cyt c) 介导的 CL 过氧化，这是细胞凋亡的关键步骤。因此，外化CL的过氧化作用充当触发细胞凋亡机制的分子开关。最后，我们证明CL和氧化CL（Clox）从受损的宿主细胞释放到循环中，并作为线粒体衍生损伤相关分子模式（DAMP-CL）触发先天性和适应性免疫反应。我们的中心假设是，细菌感染会刺激线粒体 Cls 的暴露和释放，这些线粒体 Cls 是加速线粒体自噬和细胞凋亡不可或缺的细胞内信号。释放到循环中后，Cls 充当 DAMP-CL 诱导先天性和适应性免疫反应。拟议研究的具体目标是确定： 1. CL 不对称性的机制和信号传导作用及其在远端肺上皮细菌诱导的线粒体自噬中的崩溃。 2.CL过氧化的分子途径以及防止细菌诱导的远端肺上皮细胞凋亡的小分子调节剂的设计和应用。 3. 循环中的 CUCLox 物种与 DAMP-CL 的分子特性。基于CL是肺上皮线粒体自噬、细胞凋亡和先天/适应性免疫反应中独特的细胞内和细胞外信号这一高度创新的概念，我们将探索四类新的CL信号调节剂，用于肺保护药物的开发