Control of lung permeability by oxidized phospholipids

氧化磷脂控制肺通透性

• 批准号: 10408752
• 负责人: Konstantin Birukov
• 金额: $ 57.45万
• 依托单位: UNIVERSITY OF MARYLAND BALTIMORE
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-06-01 至 2024-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10408752
• 关键词: Acute Lung Injury; Acute Respiratory Distress Syndrome; Agonist; Animal Model; Anti-Inflammatory Agents; Antiinflammatory Effect; Apoptosis; Apoptotic; Attenuated; Blood Vessels; CD44 gene; Caveolins; Cell model; Cells; Cessation of life; Choline; Complex; Development; Disease; Down-Regulation; Endothelium; Event; Exhibits; Experimental Models; Extravasation; Functional disorder; Guanine Nucleotide Exchange Factors; Guanosine Triphosphate Phosphohydrolases; Iloprost; In Vitro; Inflammasome; Inflammation; Injury; Knowledge; Lead; Link; Lipid Peroxidation; Lipids; Lung; Maintenance; Mediating; Modeling; Molecular; Morbidity - disease rate; Oxidative Stress; Oxides; Permeability; Pharmacology; Phospholipase; Phospholipids; Pilot Projects; Pneumonia; Positioning Attribute; Property; Prostaglandin D2; Prostaglandins; Prostaglandins I; Proteins; Recovery; Resistance; Resolution; Role; Sepsis; Signal Pathway; Signal Transduction; Staphylococcus aureus; Structure; TNFRSF10B gene; TXNIP gene; Testing; Therapeutic; Up-Regulation; Vascular Endothelium; analog; base; effective therapy; improved; in vivo Model; lung injury; lung repair; lung vascular inflammation; mortality; novel; oxidation; oxidized lipid; prevent; protective effect; receptor; recruit; sepsis induced ARDS; septic; transcription factor; vascular endothelial dysfunction

Project Summary/Abstract Control of lung permeability by oxidized phospholipids Oxidative stress during pneumonia or septic lung injury generates a spectrum of bioactive oxidized lipids and proteins. While terminal products of lipid peroxidation exhibit deleterious effects, other groups, such as cyclopenthenone-containing products of phosphatidyl choline oxidation (OxPAPC) exhibited anti-inflammatory and vasoprotective properties in experimental models of inflammation. We have previously described potent effects of OxPAPC in preventing the lung injury and vascular barrier dysfunction. Products of phospholipid oxidation are unstable and may convert to barrier disruptive fragmented phospholipids. To overcome this problem, we developed and successfully tested a new class of synthetic phosholipase-resistant OxPAPC analogs based on structure-function analysis of barrier protective OxPAPC products. Testing synthetic OxPL compounds generated on our lab revealed that D-ring prostanoids not only showed barrier-protective and anti- inflammatory effects, but also effectively attenuated inflammation-associated apoptosis/necroptosis of lung vascular endothelium. In pilot studies, phospholipase resistant phospholipid containing D-ring prostanoid (D2PC) showed strong protective effects in the in vitro and in vivo models of Staphylococcus aureus (SA)- induced ALI. Pilot analysis of anti-inflammatory mechanisms triggered by D2PC revealed increased expression of KLF2 and KLF4, the two transcription factors regulating anti-inflammatory defense in vascular endothelium. Our pilot studies also suggest a link between D2PC-induced KLF2/4 upregulation and inhibition of inflammation-induced expression of thioredoxin interacting protein (TXNIP) involved in activation of NLRP3 inflammasome. In addition, D2PC upregulated guanine nucleotide exchange factor Epac1. Besides the documented role of Epac1-Rap1 GTPase signaling in the maintenance of lung EC barrier, our pilot studies show that D2PC suppressed SA-induced EC apoptosis/necroptosis via Epac1-dependent inhibition of death receptor 5 (DR5) within the caveolin enriched microdomains (CEM). The overall hypothesis of this study is that synthetic phospholipid D2PC mitigates SA-induced ALI and promotes lung recovery by protecting lung barrier function, attenuating inflammation and endothelial apoptosis via mechanisms that involve: a) KLF2/4- dependent downregulation of TXNIP and inactivation of NLRP3 inflammasome; and b) Epac1-mediated inhibition of DR5-dependent apoptotic/necroptotic signaling caused by SA. Aim-1 will investigate protective effects of synthetic D2PC in cell and animal models of SA–induced injury and evaluate CEM-associated receptors mediating D2PC effects. Aim-2 will study the anti-inflammatory mechanism of D2PC via KLF2/4- dependent suppression of TXNIP/NLRP3 cascade. Aim-3 will investigate anti-apoptotic/necroptotic properties of D2PC via Epac1-mediated inhibition of DR5 signaling. Characterization of a novel synthetic lipid compound and identification of molecular mechanisms governing its anti-inflammatory and cytoprotective properties may open a new avenue for treatment of ARDS and sepsis by mitigating lung injury and promoting lung repair.

项目摘要/摘要 通过氧化磷脂控制肺通透性 肺炎或败血性肺损伤期间的氧化应激会产生一系列生物活性氧化物脂质和 蛋白质。而脂质过氧化的末端产物暴露了有害影响，但其他群体，例如 磷脂酰胆碱氧化（OXPAPC）暴露于抗炎的含环丙酮的产物 和炎症实验模型中的血管保护特性。我们以前已经描述了有效的 OXPAPC在防止肺损伤和血管屏障功能障碍方面的影响。磷脂的产物 氧化是不稳定的，可能会转换为屏障破坏性碎片磷脂。克服这一点 问题，我们开发并成功测试了一类新的合成磷脂酶的OXPAPC 基于屏障保护OXPAPC产物的结构功能分析的类似物。测试合成OXPL 我们实验室产生的化合物表明，D形前列腺素不仅显示出屏障保护和抗 - 炎症作用，但也有效地减弱了与炎症相关的凋亡/肺坏死作用 血管内皮。在初步研究中，含有D环类动物的磷脂酶耐磷脂 （D2PC）在体外和体内模型（SA） - 诱导的阿里。 D2PC触发的抗炎机制的试验分析显示，表达增加了 KLF2和KLF4，这两个转录因子控制了血管森林的抗炎防御。 我们的试点研究还表明，D2PC诱导的KLF2/4上调和抑制之间的联系 炎症引起的硫氧还蛋白相互作用蛋白（TXNIP）的表达参与NLRP3的激活 炎症。此外，D2PC更新了鸟嘌呤核丁基交换因子EPAC1。除了 EPAC1-RAP1 GTPase信号在维持肺EC屏障中的作用，我们的试点研究 表明D2PC通过EPAC1依赖死亡抑制SA诱导的EC凋亡/坏死性抑制 富含小域中（CEM）内的受体5（DR5）。这项研究的总体假设是 合成磷脂D2PC减轻SA诱导的ALI并通过保护肺屏障来促进肺恢复 功能，通过涉及的机制减弱炎症和内皮细胞凋亡：a）KLF2/4-- txnip的依赖下调和NLRP3炎性体的失活； b）EPAC1介导的 SA引起的DR5依赖性凋亡/坏死信号传导的抑制。 AIM-1将调查受保护 合成D2PC在SA诱导损伤的细胞和动物模型中的影响，并评估CEM相关 介导D2PC效应的受体。 AIM-2将通过KLF2/4-研究D2PC的抗炎机制 TXNIP/NLRP3级联的依赖抑制。 AIM-3将研究抗凋亡/坏死性能 D2PC通过EPAC1介导的DR5信号传导的抑制作用。新型合成脂质化合物的表征 以及鉴定有关其抗炎和细胞保护特性的分子机制 通过减轻肺损伤并促进肺修复，为治疗ARD和败血症打开新的途径。