Role of JNK and BNP in Septic Hypotension

JNK 和 BNP 在脓毒性低血压中的作用

基本信息

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
项目类别：
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

项目摘要

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

期刊论文数量（4）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

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
作者：
通讯作者：

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