PAD2 and CitH3 in Pathogenesis of Sepsis-induced ALI

PAD2 和 CitH3 在脓毒症引起的 ALI 发病机制中的作用

• 批准号: 10293158
• 负责人: HASAN B ALAM
• 金额: $ 53.4万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-01 至 2025-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10293158
• 关键词: Acute Lung Injury; Animal Model; Antibodies; Antibody Response; Arginine deiminase; Bacteria; Binding; Biological; Biological Markers; Biological Process; Biology; Blood Circulation; Bone Marrow; Bronchoalveolar Lavage Fluid; CASP1 gene; Cause of Death; Cell Death; Cells; Cellular biology; Cessation of life; Chemicals; Cleaved cell; Clinical; Clinical Research; Clinical Trials; Clustered Regularly Interspaced Short Palindromic Repeats; Data; Dose; Drug Kinetics; Endocytosis; Endotoxins; Enzymes; Foundations; Functional disorder; Future; Genes; Goals; Histone H3; Histones; Human; Immune response; Infection; Inflammation Mediators; Inflammatory; Injections; Injury; Interleukin-1 beta; Interleukin-18; Investigation; Knock-out; Knowledge; Label; Life; Link; Lung; Manuscripts; Mediating; Membrane; Membrane Potentials; Molecular Biology; Monoclonal Antibodies; Morbidity - disease rate; Mus; Nuclear; Organ; Pathogenesis; Pathologic; Pathway interactions; Patients; Peptides; Phagocytes; Pharmaceutical Preparations; Phenotype; Physiological; Play; Protein-arginine deiminase; Proteomics; Pseudomonas aeruginosa; Pseudomonas aeruginosa pneumonia; Publishing; Reaction Time; Reporting; Research; Resistance; Role; Safety; Sepsis; Serum; Serum Markers; Signal Transduction; Signaling Molecule; Therapeutic; Tissues; Translating; Wild Type Mouse; base; cecal ligation puncture; effective therapy; experimental study; improved; inflammatory marker; inhibitor/antagonist; insight; intravenous injection; macrophage; mortality; mouse model; multidisciplinary; neutrophil; new therapeutic target; novel; novel strategies; organ injury; receptor; response; septic; septic patients; success; therapeutic target; tool; uptake

PROJECT SUMMARY ABSTRACT Sepsis is a life-threatening organ dysfunction caused by dysregulated host response to infection, and acute lung injury (ALI) is a leading cause of death associated with sepsis. An emerging mechanism of sepsis induced-ALI (sepsis-ALI) involves neutrophils/macrophages undergoing cell death, releasing nuclear histones and citrullinated histone H3 (CitH3) to cause tissue damage and exacerbate pulmonary injury. CitH3 is catalyzed by peptidylarginine deiminase 2 and 4 (PAD2 and PAD4). We found that CitH3 is elevated in serum of patients with sepsis-ALI, but not in ALI patients due to non-infectious causes, suggesting that CitH3 could be a biomarker, as well as a potential causative factor for sepsis-ALI. Significant elevations of CitH3 and PAD2 in bronchoalveolar lavage fluid (BALF), not PAD4, are detected in septic patients. While Pad4-/- mice do not show a clear septic phenotype compared with wild type littermates, the Pad2-/- mice are strikingly more resistant to sepsis-ALI and other organ dysfunctions. The improved survival of the Pad2-/- septic mice is linked to enhanced bacterial clearance due to enhanced function of macrophages. We have data to show that chemical inhibition of PAD2 and antibody sequestration of CitH3 have therapeutic benefits to treat sepsis- ALI in mice. Combining our expertise in cell and molecular biology, animal models of and clinical research in sepsis, and chemical biology, our team-based research aims to dissect the physiological actions of PAD2 and CitH3 in modulating macrophage function associated with sepsis (Aim 1), and to conduct proof-of-concept studies targeting PAD2 and CitH3 as novel means to treat sepsis-ALI in mice (Aim 2). Circulating CitH3 could act as a signaling molecule and bind to membrane receptor(s) to fulfill its biological function; or CitH3 can enter the host cells via endocytosis to directly interfere with their survival or death pathways. Thus, knowledge on the membrane delimited interaction between CitH3 and macrophages will add significant insight into the pathogenesis and potential treatment of sepsis-ALI and other multi-organ dysfunctions.

项目摘要摘要 败血症是一种威胁生命的器官功能障碍。 感染和急性肺损伤（ALI）是与败血症有关的主要死亡原因。一个 败血症诱导-ALI（败血症）的新兴机制涉及中性粒细胞/巨噬细胞 经历细胞死亡，释放核组蛋白和瓜氨酸组蛋白H3（CITH3）引起 组织损伤和恶化的肺损伤。 CITH3被肽基金氨酸催化 脱脂酶2和4（PAD2和PAD4）。我们发现Cith3在患者的血清中升高 败血症ALI，但由于非感染原因而在ALI患者中没有，这表明Cith3可能是 生物标志物以及败血症ALI的潜在因子。显着的海拔 在化粪池中检测到支气管肺泡灌洗液（BALF）而非PAD4的CITH3和PAD2 患者。虽然PAD4 - / - 小鼠与野生类型相比没有显示清晰的化粪池表型 窝窝，PAD2 - / - 小鼠对败血症和其他器官的耐药性更高 功能障碍。 PAD2 - / - 化粪池小鼠的生存率提高与增强的细菌有关 由于巨噬细胞功能增强而导致的清除。我们有数据表明化学 抑制PAD2和CITH3的抗体隔离具有治疗益处，可以治疗败血症 阿里在小鼠中。结合我们在细胞和分子生物学，动物模型和临床方面的专业知识 败血症研究和化学生物学研究，我们的基于团队的研究旨在剖析 PAD2和CITH3在调节巨噬细胞功能中的生理作用 败血症（AIM 1），并进行针对PAD2和CITH3作为新颖的概念验证研究 用于治疗小鼠败血症的手段（AIM 2）。循环Cith3可以充当信号分子 并结合膜受体以实现其生物学功能；或Cith3可以输入主机 细胞通过内吞作用直接干扰其生存或死亡途径。因此，知识 在膜上划界的相互作用上，Cith3和巨噬细胞将增加显着的 深入了解败血症和其他多器官的发病机理和潜在处理 功能障碍。