Role of intravascular ERO1@ in acute lung injury

血管内ERO1@在急性肺损伤中的作用

• 批准号: 10027023
• 负责人: Jaehyung Cho
• 金额: $ 39.38万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-21 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10027023
• 关键词: Acute; Acute Lung Injury; Address; Adhesions; Adhesives; Admission activity; Adult Respiratory Distress Syndrome; Affect; Alveolar; Antibodies; Attenuated; Binding; Biochemical; Biological; Biological Markers; Blood; Blood Cells; Blood Platelets; Blood Vessels; Cell Aggregation; Cell Communication; Cells; Complex; Complication; Data; Disease; Disease Progression; Endoplasmic Reticulum; Endothelial Cells; Estrogen receptor positive; Extracellular Protein; Genetic; Glycoproteins; Goals; Hematological Disease; Hypoxia; Imaging Techniques; Impairment; Inflammation; Inflammatory; Integrins; Intensive Care Units; Leukocytes; Life; Ligand Binding; Ligands; Light; Lung; Lung Inflammation; Macrophage-1 Antigen; Mediating; Molecular; Mus; Natural Immunity; Neutrophil Infiltration; Organ failure; Oxidases; Pathogenesis; Pathologic; Pathology; Patients; Peptides; Plasma; Pneumonia; Process; Protein Disulfide Isomerase; Pulmonary Edema; Pulmonary Valve Insufficiency; Role; Sepsis; Severities; Severity of illness; Signal Transduction; Site; Sulfhydryl Compounds; Supporting Cell; Surface; Testing; Tissues; Trauma; Treatment Efficacy; adhesion receptor; base; design; disulfide bond; extracellular; imaging approach; improved; inhibitor/antagonist; insight; intravital imaging; lung imaging; mouse model; neutrophil; novel; novel therapeutics; receptor; recruit; septic; small molecule; thromboinflammation; vascular inflammation

Project Summary Acute lung injury (ALI) is a life-threatening condition, which affects > 200,000 patients annually in the U.S. It is associated with pneumonia, sepsis, and trauma, leading to pulmonary insufficiency and eventually multisystem organ failure. Since excessive recruitment of activated neutrophils to lung microvessels is a primary cause of ALI, a better understanding of the mechanism mediating neutrophil-endothelial cell interactions will provide insight into developing an effective therapeutic for treating ALI. We previously demonstrated that intravascular protein disulfide isomerase (PDI) enhances the ligand-binding activity of neutrophil and platelet surface receptors and leads to intravascular cell-cell interactions during vascular inflammation. To elucidate how extracellular PDI activity is regulated and whether the regulatory mechanism contributes to the pathology of ALI, we have found that endoplasmic reticulum oxidoreductin 1α (ERO1α, a key oxidase of PDI in the ER) promotes neutrophil recruitment during vascular inflammation. In this proposal, we will test the hypothesis that intravascular ERO1α enhances the ligand-binding function of neutrophil adhesion receptors by modifying disulfide bonds, inducing neutrophil recruitment to sites of acute lung inflammation. In Aim 1, we will determine the mechanism by which ERO1α regulates neutrophil-endothelial cell interactions. In Aim 2, we will utilize lung live imaging techniques to investigate the pathological role of intravascular ERO1α in ALI. In Aim 3, using the blood of patients with acute respiratory distress syndrome (ARDS), we will determine the contribution of ERO1α to the disease progression and severity in patients with ARDS. These studies will employ biochemical, cell biological, genetic, and confocal intravital imaging approaches. Since little is known about extracellular thiol-modifying machinery, the proposed studies will identify an essential, yet unexplored, mechanism that promotes the pathogenesis of ALI/ARDS.

项目概要 急性肺损伤 (ALI) 是一种危及生命的疾病，在美国每年影响超过 200,000 名患者。 与肺炎、败血症和创伤有关，导致肺功能不全并最终导致多系统 器官衰竭。由于肺微血管过度募集活化的中性粒细胞是肺微血管的主要原因 ALI，更好地理解介导中性粒细胞-内皮细胞相互作用的机制将提供 深入了解开发治疗 ALI 的有效疗法。我们之前证明了血管内 蛋白质二硫键异构酶 (PDI) 增强中性粒细胞和血小板表面受体的配体结合活性 并导致血管炎症期间血管内细胞间相互作用。阐明细胞外 PDI 如何 我们发现，活动是否受到调节以及调节机制是否有助于 ALI 的病理学 内质网氧化还原素 1α（ERO1α，ER 中 PDI 的关键氧化酶）促进中性粒细胞 血管炎症期间的募集。在本提案中，我们将检验血管内 ERO1α 的假设 通过修饰二硫键增强中性粒细胞粘附受体的配体结合功能，诱导 中性粒细胞募集到急性肺部炎症部位。在目标 1 中，我们将确定机制 ERO1α 调节中性粒细胞与内皮细胞的相互作用。在目标 2 中，我们将利用肺部实时成像技术 研究血管内 ERO1α 在 ALI 中的病理作用。在目标 3 中，使用急性重症患者的血液 呼吸窘迫综合征 (ARDS)，我们将确定 ERO1α 对疾病进展的贡献 以及 ARDS 患者的严重程度。这些研究将采用生物化学、细胞生物学、遗传学和共聚焦 活体成像方法。由于对细胞外硫醇修饰机制知之甚少，因此建议 研究将确定促进 ALI/ARDS 发病机制的重要但尚未探索的机制。