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.

摘要 脓毒症是身体对感染的压倒性免疫反应，导致器官衰竭和死亡。 尽管使用了血管加压药和液体复苏，但顽固性低血压是最严重的 败血症的后果，约50%的住院死亡率。目前，还没有靶向治疗， 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 给予抗生素和液体复苏。因此，新的基因和途径，涉及在 脓毒症的病理生理学正在积极寻求，目的是鉴定可以提供新的靶点， 治疗方法。脓毒症时心功能不全和低血压与预后不良有关 和死亡率的增加。B型利钠肽（BNP）循环水平升高与以下因素相关： 败血症以及其他类型心力衰竭中的心肌应激。我们的数据确定了一个信号通路 这会增加脑钠肽的产生，从而导致心输出量降低。我们已经证明，激活cJun N- 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 心脏JNK激活，我们已经证明它参与了脓毒症的病理生理学， 在脓毒症小鼠中的表达我们的新数据表明，JNK抑制会增加血压和组织 在脓毒症小鼠中，这与较低的血浆BNP水平有关。因此，我们的中心假设是 心肌细胞JNK和cJun激活介导脓毒症中BNP上调， 循环BNP将减轻脓毒性低血压并提高存活率。为了验证我们的假设， 目的1 -研究血浆BNP的调节机制 败血症增加。目的2 -评估BNP在脓毒症患者中降低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在脓毒症的病理生理学中的作用， 低血压，并探讨旨在调节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，以评估翻译 我们的调查结果的影响。因此，我们期望我们的研究结果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

Specificity Proteins (SP) and Krüppel-like Factors (KLF) in Liver Physiology and Pathology.

• 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