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死亡的主要原因之一。根据定义，它是由感染引起的全身炎症反应。根据严重程度，它会影响器官。脓毒症心肌病是脓毒症的一种令人担忧的并发症，并将在本项目中作为多器官衰竭的例子进行研究。全身性炎症反应尤其是由脓毒症期间释放的损伤相关分子模式（DAMP）诱导。DAMP是内源性细胞内分子，从受损或死亡细胞释放并引起炎症反应。细胞外RNA（eRNA）属于DAMPS组，已被证明对心脏有有害影响。eRNA的这些有害作用可以通过其被天然存在的核糖核酸酶（RNase）降解来限制。RNA酶是先天免疫系统的组分，属于内源性抗微生物肽组，并且调节由病原体相关分子模式（PAMP）和DAMP诱导的局部和全身炎症反应。人RNA酶抑制剂1（RNH 1）在多种组织中广泛表达并抑制RNA酶。在我们自己的初步研究中，我们可以表明，与健康志愿者相比，脓毒症患者的RNase 1，3和7以及RNH 1升高。此外，在多微生物脓毒症的小鼠模型中，我们证明了RNase 1的应用减少了体内心功能障碍和细胞凋亡。然而，RNase 1、3和7血清水平的过程及其与脓毒症患者临床过程的相关性以及各种DAMP和PAMP对其分泌的影响仍不清楚。RNH 1在体外和体内心脏功能障碍中的作用也未得到解决。该翻译项目的目的是进一步研究RNase A家族及其抑制剂RNH 1在脓毒性心肌病中的作用。将在脓毒症患者中评价蛋白质的血清水平，并在体外进一步分析潜在的分泌机制。RNase A家族和RNH 1的影响将在鼠多微生物脓毒症模型中进一步研究其对心功能障碍的影响。在最后一个项目点中，将研究核糖核酸酶的机制，除了它们的溶核功能以及它们在心肌细胞中的抗炎活性。此外，将研究RNH 1本身在心肌细胞中PAMP/DAMP诱导的炎症反应中发挥抗炎作用的程度。

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.