Dysregulation of the NFkB/Sox18 Axis During Ventilator-Induced Lung Injury (VILI)

呼吸机引起的肺损伤 (VILI) 期间 NFkB/Sox18 轴失调

• 批准号: 10094246
• 负责人: Stephen M Black
• 金额: $ 43.35万
• 依托单位: UNIVERSITY OF ARIZONA
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-02-05 至 2021-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10094246
• 关键词: Acute Lung Injury; Adult Respiratory Distress Syndrome; Attenuated; Candidate Disease Gene; Capillary Endothelial Cell; Critical Care; Critical Illness; DNA Methylation; Data; Development; Down-Regulation; Endothelial Cells; Endothelium; Epigenetic Process; Event; Exhibits; Exposure to; Extravasation; Functional disorder; Genetic; Goals; Histone Deacetylase; Histone Deacetylase Inhibitor; Human; I Kappa B-Alpha; Inflammation Mediators; Inflammatory; Intercellular Junctions; Intervention; Life; Lipopolysaccharides; Liquid substance; Lung; Lung diseases; Mechanical Stress; Mechanical ventilation; Mediating; Mitochondria; Modification; Mus; Nuclear; Oxidative Stress; Patients; Peptides; Periodicity; Permeability; Phase; Phosphorylation; Post-Translational Protein Processing; Pre-Clinical Model; Predisposition; Proteins; Publishing; Reactive Oxygen Species; Reagent; Refractory; Regulation; Respiratory Failure; Role; SOX18 gene; Savings; Signal Transduction; Signaling Protein; Single Nucleotide Polymorphism; Stretching; Syndrome; Testing; Therapeutic; Tidal Volume; Tight Junctions; Transcriptional Regulation; Translating; Treatment Efficacy; United States; Ventilator-induced lung injury; cytokine; improved; individualized medicine; inflammatory lung disease; insight; lung injury; mechanical force; mortality; new therapeutic target; nicotinamide phosphoribosyltransferase; nitration; novel; preservation; prevent; promoter; receptor; recruit; response; shear stress; synergism; therapeutic target; transcription factor

PROJECT SUMMARY: Mechanical ventilation creates excessive mechanical stress that directly augments lung injury in critically ill patients with respiratory failure due to ARDS, a syndrome known as ventilator-induced lung injury (VILI). There have been little insights into the specific mechanisms involved in VILI-induced pulmonary capillary endothelial cell (EC) leakage, a key therapeutic target in ARDS/VILI. Project #1 will examine how excessive mechanical stress suppresses SOX18 expression, a transcription factor (TF) intimately involved in preservation of EC barrier integrity via transcriptional regulation of the tight junction protein, claudin 5 (CLDN5). We have shown that fluid shear stress increases Sox18 expression, however, EC exposed to 18% cyclic stretch (CS) or LPS exhibit decreased Sox18 expression. In addition, enhanced mouse lung Sox18 expression attenuates EC barrier disruption induced by exposure to high tidal volume mechanical ventilation or LPS. Project #1 will investigate mechanisms by which LPS and excessive mechanical stress reduce Sox18 expression in both human lung EC and the mouse lung. We will explore how the initial inflammatory phase of VILI, via inflammatory signaling evoked by nuclear factor (NF)-κB, suppresses SOX18 expression. Further, Project #1 will extend our published data and examine how excessive mechanical stress regulates NF-κB signaling proteins via increased ROS- mediated post-translational NF-κB modifications (PTMs) including nitration and phosphorylation. These events, in concert with recruitment of histone deacetylases, appear to be critical to suppressing SOX18 promoter activity. Specific Aim #1 (SA #1) will define the role of NF-κB signaling in mechanical stress-mediated downregulation of SOX18 and CLDN5 expression and loss of EC junctional integrity. SA #1 will also investigate the influence of ARDS/VILI related SOX18 and CLDN5 promoter SNPs on Sox18 and CLDN5 expression in response to mechanical stress. SA #2 will define the role of nitration-mediated PTMs in the mechanical stress- mediated activation of NF-κB signaling and investigate the involvement of the mechanosensitive receptor, TRPV4. SA #3 will translate SAs #1 & 2 data into actionable information and define the therapeutic efficacy of directly increasing Sox18 expression, preventing the epigenetic down-regulation of SOX18 (HDAC inhibitors), preventing nitration-mediated NF-κB activation (shielding peptides) and reducing mitochondrial-derived ROS (mitochondrial targeted peptides). Together with each PPG Project and the expertise residing in each PPG Core, these explorations will advance our understanding of the interplay between genetics, epigenetics and PTMs in regulating the SOX18-CLDN5 axis and EC barrier integrity. Further, our studies will promote a more thorough understanding of VILI pathobiology while highlighting the application of individualized therapies for the critically ill.

项目摘要： 机械通气会产生过多的机械应力，从而直接增加肺部损伤 由于ARDS引起的呼吸衰竭的患者，一种称为通风诱导的肺损伤（VILI）的综合征。那里 对VILI诱导的肺毛细管内皮涉及的特定机制几乎没有见解 细胞（EC）泄漏，ARDS/VILI中的关键治疗靶标。项目＃1将检查如何超越机械 应力抑制SOX18表达，这是一种与EC保持密切相关的转录因子（TF） 通过紧密连接蛋白Claudin 5（CLDN5）的转录调节的屏障完整性。我们已经表明 然而，流体剪切应力增加了Sox18表达，EC暴露于18％的环状拉伸（CS）或LPS表现出来 Sox18表达降低。此外，增强的小鼠肺Sox18表达减弱EC屏障 暴露于高潮汐体积机械通气或LPS引起的破坏。项目＃1将调查 LPS和过多的机械应力减少SOX18的机制 和小鼠肺。我们将通过炎症信号传导探索如何通过炎症的初始炎症阶段 被核因子（NF）-κB引起的诱发，可抑制SOX18的表达。此外，项目＃1将扩展我们已发布的 数据并检查如何通过增加ROS-的机械应力如何调节NF-κB信号传导蛋白 介导的翻译后NF-κB修饰（PTM），包括硝化和磷酸化。这些事件， 与募集组蛋白脱乙酰基酶的募集，对于抑制SOX18启动子至关重要 活动。特定的目标＃1（SA＃1）将定义NF-κB信号在机械应力介导的作用 SOX18和CLDN5表达的下调以及EC连接完整性的丧失。 SA＃1还将调查 ARDS/VILI相关的SOX18和CLDN5启动子SNP对Sox18和Cldn5表达的影响 对机械应力的反应。 SA＃2将定义硝化介导的PTM在机械应力中的作用 介导的NF-κB信号传导的激活，并研究机械敏感受体的参与， TRPV4。 SA＃3将将SAS＃1和2数据转化为可行的信息，并定义治疗效率 直接增加Sox18的表达，防止SOX18（HDAC抑制剂）的表观遗传下调， 防止硝化介导的NF-κB激活（屏蔽肽）并减少线粒体衍生的ROS （线粒体靶向肽）。以及每个PPG项目以及每个PPG中的专业知识 核心，这些探索将促进我们对遗传学，表观遗传学和 调节中的PTMS SOX18-CLDN5轴和EC屏障完整性。此外，我们的研究将促进更多 对VILI病理生物学的透彻理解，同时突出了个性化疗法的应用 重病。