Role of JNK and BNP in Septic Hypotension

修改项目摘要/摘要部分 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。尽管给予血管加压药和液体复苏，顽固性低血压是脓毒症最严重的后果，院内死亡率约为50%。目前，没有靶向疗法来治疗脓毒症。现有的治疗指南侧重于源头控制和支持性护理，包括早期使用抗生素和液体复苏。因此，积极寻找参与脓毒症病理生理学的新基因和途径，目的是鉴定可提供新治疗方法的新靶点。脓毒症患者的心功能不全和低血压与预后不良和死亡率增加有关。B型利钠肽（BNP）循环水平升高与脓毒症以及其他类型心力衰竭的心肌应激相关。我们的数据确定了一个信号通路，增加BNP产生导致心输出量降低。我们以前的研究和新的数据表明，心脏JNK激活，我们已经表明，参与脓毒症的病理生理，增加脑钠肽的表达在脓毒症小鼠。我们的新数据表明，JNK抑制增加脓毒症小鼠的血压和组织灌注，这与较低的血浆BNP水平有关。因此，我们的中心假设是，抑制循环BNP将减轻感染性低血压，提高生存率。为了解决我们的假设，我们设计了以下具体目标：目标1 -评估BNP在脓毒症小鼠和患者中降低CO和促进低血压的作用。总之，我们的目标是阐明BNP在感染性低血压的病理生理学中的作用，并探索旨在调节BNP表达或中和循环BNP的治疗策略的治疗潜力。同时，我们将进行临床研究，以评估我们的研究结果的转化影响。因此，我们期望我们的研究结果构成设计未来临床应用的基础，旨在减轻感染性低血压和器官灌注不足。

Modified Project Summary/Abstract Section 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 increased BNP production leads to lower cardiac output. 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 mice. 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 inhibition of circulating BNP will alleviate septic hypotension and improve survival. To address our hypothesis we have designed the following specific aim: Aim 1 - 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.