Novel mechanisms of endothelial Injury in the pathogenesis of ARDS

ARDS发病机制中内皮损伤的新机制

基本信息

批准号：
10618326
负责人：
YOU-YANG ZHAO
金额：
$ 56.78万
依托单位：
LURIE CHILDREN'S HOSPITAL OF CHICAGO
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：
2020-05-01 至 2025-04-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10618326
关键词：
Acute Lung Injury Acute Respiratory Distress Syndrome Adherens Junction Alveolar Animal Model Animals Apoptosis Attenuated Binding Blood Vessels CASP4 gene CD14 Antigen CD14 gene CXC Chemokines CXCR4 gene Caspase Cells Chemotactic Factors Complex Data Diagnosis Disease Edema Endothelial Cells Endothelium Epithelium Extravasation Functional disorder G-Protein-Coupled Receptors Goals Human Hypoxemia Inflammation Inflammatory Inflammatory Infiltrate Injury Intervention Liposomes Lung Mediating Mediator Molecular Mus Necrosis Outcome Pathogenesis Patients Phase Plasma Play Prevention Prevention approach Prognostic Marker Proteins Publishing Pulmonary Edema Recombinants Reporter Resistance Role Sampling Sepsis Severities Signal Pathway Signal Transduction Stromal Cell-Derived Factor 1 Syndrome Therapeutic Transduction Gene Vascular Endothelium chemokine early onset effective therapy endothelial regeneration endothelial repair epithelial repair epithelial stem cell in vivo innovation lung injury lung regeneration lung repair mortality mouse model novel novel strategies novel therapeutic intervention pharmacologic plasmid DNA polymicrobial sepsis receptor coupling recruit repaired sepsis induced ARDS septic severe injury therapeutic gene therapeutically effective translational potential

项目摘要

Acute respiratory distress syndrome (ARDS) is a complex, multi-factorial syndrome which manifest itself by leaky lung microvessels, protein rich edema, and intractable hypoxemia. Given that recent studies from both human and animal studies has demonstrated the key role of microvascular leakage in determining the outcome of sepsis and ARDS, maintaining the endothelial barrier integrity represents a novel, effective therapeutic approach for the prevention and treatment of ARDS. However, the molecular mechanisms mediating endothelial barrier disruption after sepsis remain poorly understood, especially, little is known about the key molecules and signaling pathways responsible for endothelial barrier dysfunction resulting in high mortality in ARDS patients. Our Supporting Data show that higher levels of plasma SDF1 in ARDS patients are positively associated with high mortality. In mice, we observed that SDF1 treatment augmented sepsis-induced lung injury and mortality, which were attenuated in mice with inducible EC-specific disruption of Cxcr4 (Cxcr4iEC). Importantly, our mechanistic studies demonstrate that SDF1 treatment induces endothelial cell pyroptosis leading to severe endothelial barrier dysfunction. Thus, we hypothesize that elevated plasma SDF1 levels is a prognostic biomarker of severe lung injury and greater mortality of ARDS patients which is ascribed to SDF1-induced overwhelming endothelial pyroptosis and resultant severe endothelial barrier dysfunction following sepsis. The proposed studies will address the following Specific Aims. Studies in Aim 1 will validate circulating SDF1 level as a prognostic biomarker of ARDS patients and define the signaling pathway mediating SDF1-exaggerated lung injury and mortality following sepsis challenge. Studies in Aim 2 will delineate the molecular and cellular mechanisms of SDF1 in augmenting sepsis-induced lung injury through activation of endothelial pyroptosis and explore the therapeutic potential of inhibiting pyroptosis for treatment of ARDS. With the data from these comprehensive studies, we will delineate the fundamental mechanisms of endothelial injury, identify a prognostic biomarker for the severity and mortality of ARDS, and provide novel therapeutic approaches for effective treatment of ARDS and promotion of survival. Thus, these innovative mechanistic studies have high translational potential.

急性呼吸窘迫综合征（ARDS）是一种复杂的多因素综合征，表现出来通过漏水的肺微血管，富含蛋白质的水肿和顽固性低氧血症。考虑到最近的研究从人类和动物研究中都表明，微血管泄漏的关键作用确定败血症和ARD的结果，保持内皮屏障完整性代表新颖的，有效的治疗方法，用于预防和治疗ARDS。但是，分子脓毒症后介导内皮屏障中断的机制，尤其是理解的机制，尤其是关于负责内皮屏障的关键分子和信号通路知之甚少功能障碍导致ARDS患者死亡高。我们的支持数据表明，较高的水平 ARDS患者的血浆SDF1与高死亡率呈正相关。在小鼠中，我们观察到 SDF1治疗增强了败血症诱导的肺损伤和死亡率，这些肺损伤和死亡率在小鼠中衰减 CXCR4（CXCR4IEC）的诱导EC特异性破坏。重要的是，我们的机械研究表明 SDF1治疗诱导内皮细胞凋亡导致严重的内皮屏障功能障碍。因此，我们假设血浆SDF1水平升高是严重肺损伤的预后生物标志物以及归因于SDF1诱导的压倒性内皮的ARDS患者的更大死亡率败血症后的凋亡和导致的严重内皮屏障功能障碍。提出的研究将解决以下特定目标。 AIM 1的研究将验证循环SDF1水平为一个 ARDS患者的预后生物标志物并定义了介导SDF1夸大的信号传导途径败血症挑战后的肺损伤和死亡率。 AIM 2中的研究将描绘分子和 SDF1的细胞机制在增强败血症诱导的肺损伤方面通过激活内皮激活凋亡并探索抑制凋亡治疗ARD的治疗潜力。与来自这些综合研究的数据，我们将描述内皮的基本机制伤害，确定ARDS严重性和死亡率的预后生物标志物，并提供新颖有效治疗ARD和促进生存的治疗方法。因此，这些创新机械研究具有很高的转化潜力。

项目成果

期刊论文数量（2）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Macrophage-derived IGF-1 protects the neonatal intestine against necrotizing enterocolitis by promoting microvascular development.

DOI：
10.1038/s42003-022-03252-9
发表时间：
2022-04-06
期刊：
Communications biology
影响因子：
5.9
作者：
Yan X;Managlia E;Zhao YY;Tan XD;De Plaen IG
通讯作者：
De Plaen IG

Rabeprazole Promotes Vascular Repair and Resolution of Sepsis-Induced Inflammatory Lung Injury through HIF-1α.

DOI：
10.3390/cells11091425
发表时间：
2022-04-22
期刊：
CELLS
影响因子：
6
作者：
Evans, Colin E.;Peng, Yi;Zhu, Maggie M.;Dai, Zhiyu;Zhang, Xianming;Zhao, You-Yang
通讯作者：
Zhao, You-Yang