Role of JNK and BNP in Septic Hypotension

JNK 和 BNP 在脓毒性低血压中的作用

• 批准号: 10389857
• 负责人: Konstantinos Drosatos
• 金额: $ 7.7万
• 依托单位: TEMPLE UNIV OF THE COMMONWEALTH
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-20 至 2022-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10389857
• 关键词: Accident and Emergency department; Acute; Address; Adenoviruses; Administrative Supplement; Antibiotics; Automobile Driving; Biochemical; Biological Markers; Blood Pressure; Blood Pressure Monitors; Blood Volume; Brain natriuretic peptide; Cardiac; Cardiac Myocytes; Cardiac Output; Cardiomyopathies; Cessation of life; Clinical; Clinical Data; Clinical Research; Clinical Trials; Critical Illness; Data; Disease; Disease Marker; Disease Progression; EFRAC; Enrollment; Equipment; Experimental Models; Fiber; Functional disorder; Future; Genes; Genetic; Goals; Heart; Heart failure; Hospital Mortality; Hospitals; Hour; Human; Hypotension; Image; Immune response; Impairment; Infection; Intervention; Life; Liquid substance; Low Cardiac Output; MAPK8 gene; Measurement; Mechanical ventilation; Mediating; Modality; Monoclonal Antibodies; Mus; Muscle Cells; Myocardial; Myocardial dysfunction; N-terminal; Natriuresis; Organ; Organ failure; Pathway interactions; Patients; Peptide Signal Sequences; Performance; Perfusion; Phase; Phosphotransferases; Physiological; Plasma; Principal Investigator; Production; Prognosis; Refractory; Reporting; Resolution; Resuscitation; Role; Sepsis; Severities; Severity of illness; Signal Pathway; Source; Stress; Supportive care; Therapeutic; Time; Tissues; Translating; Two-Dimensional Echocardiography; Up-Regulation; Vasoconstrictor Agents; Vasodilation; Ventricular; clinical application; design; heart function; heart output disorder; hypoperfusion; improved; insight; mortality; mouse model; neutralizing monoclonal antibodies; novel; novel strategies; novel therapeutic intervention; patient biomarkers; pressure; response; septic; septic patients; targeted treatment; translational impact; treatment duration; treatment guidelines; treatment strategy

ABSTRACT Sepsis is the body's overwhelming immune response to infection that leads to organ failure and death. Refractory hypotension despite administration of vasopressors and fluid resuscitation is the most severe consequence of sepsis with a ~50% in-hospital mortality rate. Currently, there are no targeted therapies to treat sepsis. Existing treatment guidelines focus on source control and supportive care, including early administration of antibiotics and fluid resuscitation. Thus, novel genes and pathways that are involved in the pathophysiology of sepsis are actively sought with the goal to identify new targets that may offer novel therapeutic approaches. Cardiac dysfunction and hypotension in sepsis are associated with poor prognosis and increased mortality. Elevated circulating levels of B-type natriuretic peptide (BNP) correlate with myocardial stress in sepsis, as well as in other types of heart failure. Our data identified a signaling pathway that increases BNP production, which leads to lower cardiac output. We have shown that activation of cJun N- terminal kinase (JNK) contributes in the pathophysiology of sepsis. Our previous studies and new data show that cardiac JNK activation, which we have shown to be involved in sepsis pathophysiology, increases BNP expression in septic miceI. Our new data show that JNK inhibition increases blood pressure and tissue perfusion in septic mice and this is associated with lower plasma BNP levels. Thus, our central hypothesis is that activation of cardiomyocyte JNK and cJun mediates BNP upregulation in sepsis, and that inhibition of circulating BNP will alleviate septic hypotension and improve survival. To address our hypothesis we have designed the following specific aims: Aim 1 - To investigate the mechanism(s) that mediate plasma BNP increase in sepsis. Aim 2 - To assess the role of BNP in reducing CO and promoting hypotension in septic mice and patients. In summary, our goal is to elucidate the role of BNP in the pathophysiology of septic hypotension and explore the therapeutic potential of treatment strategies aimed at regulating BNP expression or neutralizing circulating BNP. Simultaneously, we will pursue clinical studies to evaluate the translational impact of our findings. Thus, we anticipate our findings to constitute the basis for designing future clinical applications aiming to alleviate septic hypotension and organ hypo-perfusion.

抽象的 败血症是人体对感染的压倒性免疫反应，导致器官衰竭和死亡。 尽管给予血管加压药和液体复苏，但难治性低血压是最严重的 败血症的后果，院内死亡率约为 50%。目前尚无靶向治疗方法 治疗败血症。现有的治疗指南侧重于源头控制和支持性护理，包括早期治疗 给予抗生素和液体复苏。因此，参与该过程的新基因和途径 人们正在积极探索脓毒症的病理生理学，目标是确定可能提供新靶点的新靶点 治疗方法。脓毒症患者的心脏功能障碍和低血压与不良预后相关 并增加死亡率。 B 型利尿钠肽 (BNP) 循环水平升高与 败血症以及其他类型的心力衰竭中的心肌应激。我们的数据确定了信号通路 这会增加 BNP 的产生，从而导致心输出量降低。我们已经证明 cJun N- 的激活 末端激酶 (JNK) 参与脓毒症的病理生理学。我们之前的研究和新数据显示 我们已证明心脏 JNK 激活与脓毒症病理生理学有关，可增加 BNP 脓毒症小鼠中的表达I.我们的新数据表明 JNK 抑制会增加血压和组织 脓毒症小鼠的灌注与较低的血浆 BNP 水平有关。因此，我们的中心假设是 心肌细胞 JNK 和 cJun 的激活介导脓毒症中 BNP 上调，并且抑制 循环 BNP 将缓解脓毒性低血压并提高生存率。为了解决我们的假设，我们有 设计了以下具体目标： 目标 1 - 研究介导血浆 BNP 的机制 败血症增加。目标 2 - 评估 BNP 在脓毒症患者中减少 CO 和促进低血压的作用 老鼠和病人。总之，我们的目标是阐明 BNP 在脓毒症病理生理学中的作用 低血压并探索旨在调节 BNP 表达的治疗策略的治疗潜力 或中和循环BNP。同时，我们将进行临床研究来评估转化效果 我们的研究结果的影响。因此，我们预计我们的发现将构成设计未来临床的基础 旨在缓解脓毒性低血压和器官灌注不足的应用。

项目成果

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• DOI: 10.3390/ijms24054682
• 发表时间: 2023-02-28
• 期刊: International journal of molecular sciences
• 影响因子: 5.6

1821-2021: Contributions of physicians and researchers of Greek descent in the advancement of clinical and experimental cardiology and cardiac surgery.

• DOI: 10.3389/fcvm.2023.1231762
• 发表时间: 2023
• 期刊: FRONTIERS IN CARDIOVASCULAR MEDICINE
• 影响因子: 3.6
• 作者: Gerontas, Apostolos;Avgerinos, Dimitrios;Charitakis, Konstantinos;Maragou, Helena;Drosatos, Konstantinos
• 通讯作者: Drosatos, Konstantinos