The role of ribonuclease A superfamily as a therapeutic target in septic cardiomyopathy.

脓毒症是德国重症监护病房的主要死亡原因之一。根据定义，它是由感染引起的全身性炎症反应。根据严重程度的不同，它会影响器官。败血症心肌病是脓毒症的一种可怕的并发症，在本项目中将作为多器官衰竭的一个例子进行研究。全身炎症反应是由脓毒症期间释放的损伤相关分子模式(DAMP)等诱导的。DAMP是一种内源性细胞内分子，从受损或濒临死亡的细胞中释放出来，引起炎症反应。细胞外RNA(ERNA)属于湿性物质，已被证明对心脏有有害影响。Erna的这些有害作用可以被其自然产生的核糖核酸酶(RNase)降解所限制。核糖核酸酶是天然免疫系统的组成部分，属于内源性抗菌肽的一类，调节病原体相关分子模式(PAMPs)和DAMPS诱导的局部和全身炎症反应。人核糖核酸酶抑制因子1(RNH1)广泛表达于多种组织中，对核糖核酸酶具有抑制作用。在我们自己的初步研究中，我们可以显示，与健康志愿者相比，败血症患者的RNase1、RNase3和RNase7以及RNH1都升高了。此外，在多菌素脓毒症的小鼠模型中，我们证明了RNase1的应用减少了体内的心功能障碍和细胞凋亡。然而，血清核糖核酸酶1、3和7水平的变化过程及其与脓毒症患者临床病程的关系以及各种湿气和PAMP对其分泌的影响仍不清楚。此外，RNH1在体外和体内心脏功能障碍中的作用也尚未解决。这个翻译项目的目的是进一步研究RNaseA家族及其抑制物RNH1在感染性心肌病中的作用。脓毒症患者的血清蛋白质水平将被评估，潜在的分泌机制将在体外进一步分析。RNase A家族和RNH1的影响将在小鼠多菌败血症模型中进一步研究它们对心功能障碍的影响。在最后一个项目中，除了核糖核酸酶的核溶解功能和抗炎活性外，还将研究核糖核酸酶在心肌细胞中的作用机制。此外，RNH1本身在PAMPS/DAMPS诱导的心肌细胞炎症反应中的抗炎作用的程度也将被研究。

Sepsis is one of the leading causes of death in german intensive care units. According to the definition, it is a systemic inflammatory reaction resulting from an infection. Depending on the severity, it affects the organs. Septic cardiomyopathy is a feared complication of sepsis and will be studied as an example of multi-organ failure in this project. The systemic inflammatory response is induced, among others, by Damage Associated Molecular Patterns (DAMPs) that are released during sepsis. DAMPs are endogenous intracellular molecules that are released from injured or dying cells and cause an inflammatory response. Extracellular RNA (eRNA) belongs to the group of DAMPS and has been shown to have harmful effects on the heart. These deleterious effects of eRNA can be limited by its degradation by naturally occurring ribonuclease (RNases). RNases are components of the innate immune system, belong to the group of endogenous antimicrobial peptides and modulate the local and systemic inflammatory response induced by Pathogen Associated Molecular Patterns (PAMPs) and DAMPs. Human RNase inhibitor 1 (RNH1) is ubiquitously expressed in a variety of tissues and inhibits RNases. In our own preliminary studies we could show that in septic patients RNase 1, 3 and 7 as well as RNH1 are elevated compared to healthy volunteers. In addition, in a murine model of polymicrobial sepsis, we demonstrated that application of RNase 1 reduces cardiac dysfunction and apoptosis in vivo. However, the course of RNases 1, 3, and 7 serum levels and their associations with the clinical course of patients with sepsis and the influence of various DAMPs and PAMPs on their secretion remain unclear. Also unresolved is the role of RNH1 in cardiac dysfunction in vitro and in vivo. The aim of this translational project is to further investigate the role of the RNase A family and its inhibitor RNH1 in septic cardiomyopathy. Serum levels of the proteins will be evaluated in patients with sepsis and the underlying secretion mechanisms will be further analyzed in vitro. The influence of the RNase A family and RNH1 will be further investigated in vivo in a murine polymicrobial sepsis model with respect to their impact on cardiac dysfunction. In the last program point, mechanisms of RNases apart from their nucleolytic function as well as their anti-inflammatory activity in cardiomyocytes will be investigated. In addition, the extent to which RNH1 itself plays an anti-inflammatory role in the PAMPs/DAMPs-induced inflammatory response in cardiomyocytes will be investigated.