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.

项目总结