Role of JNK and BNP in Septic Hypotension

摘要 败血症是人体对感染的压倒性免疫反应，会导致器官衰竭和死亡。 尽管使用了血管增压剂和液体复苏，顽固性低血压是最严重的 败血症的后果，住院死亡率约为50%。目前，还没有针对性的治疗方法 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 使用抗生素和液体复苏。因此，新的基因和途径参与了 脓毒症的病理生理学被积极研究，目的是确定新的靶点，可能提供新的 治疗方法。脓毒症患者的心功能不全和低血压与预后不良有关 并增加了死亡率。循环中B型利钠肽(BNP)水平升高与 败血症以及其他类型心力衰竭时的心肌应激。我们的数据确定了一条信号通路 这会增加BNP的产生，从而导致较低的心输出量。我们已经证明，cJun N-的激活 末端激酶(JNK)参与了脓毒症的病理生理过程。我们之前的研究和新的数据表明 心脏JNK的激活，我们已经证明参与了脓毒症的病理生理，增加了BNP 在败血症小鼠中的表达。我们的新数据显示，抑制JNK会增加血压和组织 脓毒症小鼠的血流灌注，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的激活介导BNP在脓毒症中的上调，并抑制 循环BNP将缓解感染性低血压，提高存活率。为了解决我们的假设，我们有 设计了以下具体目标：目的1-探讨脑钠素的调节机制(S) 败血症增多。目的2：评价脑钠素在脓毒症患者降低一氧化碳和促进低血压中的作用 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。 并探索旨在调节BNP表达的治疗策略的治疗潜力 或中和循环中的BNP。同时，我们将继续进行临床研究，以评估翻译的 我们发现的影响。因此，我们预期我们的发现将构成未来临床设计的基础。 旨在缓解感染性低血压和器官低灌注的应用。

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.