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

基本信息

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
项目类别：
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

项目摘要

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.

项目概要摘要脓毒症是一种危及生命的器官功能障碍，由宿主反应失调引起感染和急性肺损伤（ALI）是脓毒症相关死亡的主要原因。一个脓毒症引起的 ALI（脓毒症-ALI）的新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) 导致组织损伤，加剧肺损伤。 CitH3 由肽基精氨酸催化脱亚氨酶 2 和 4（PAD2 和 PAD4）。我们发现患有以下疾病的患者血清中 CitH3 升高脓毒症-ALI，但由于非感染原因而没有出现在 ALI 患者中，这表明 CitH3 可能是一种生物标志物，也是脓毒症-ALI 的潜在致病因素。显着海拔在脓毒症中检测到支气管肺泡灌洗液 (BALF) 中的 CitH3 和 PAD2，而不是 PAD4 患者。虽然 Pad4-/- 小鼠与野生型相比没有表现出明显的败血症表型同窝小鼠中，Pad2-/- 小鼠对脓毒症-ALI 和其他器官的抵抗力显着增强功能障碍。 Pad2-/-脓毒症小鼠的存活率提高与细菌的增强有关由于巨噬细胞功能增强而清除。我们有数据表明化学抑制 PAD2 和隔离 CitH3 抗体对治疗脓毒症具有治疗益处小鼠急性肺损伤。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在脓毒症和化学生物学方面的研究中，我们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脓毒症（目标 1），并针对 PAD2 和 CitH3 作为新型药物进行概念验证研究治疗小鼠败血症-ALI 的方法（目标 2）。循环中的 CitH3 可以充当信号分子并与膜受体结合以实现其生物学功能；或者CitH3可以进入宿主细胞通过内吞作用直接干扰其生存或死亡途径。因此，知识膜上 CitH3 和巨噬细胞之间的相互作用将显着增加深入了解脓毒症-ALI 和其他多器官疾病的发病机制和潜在治疗方法功能障碍。