Methylglyoxal-related carbonyl stress in sepsis

败血症是由宿主对感染的反应失调引起的。脓毒症的早期特征是先天免疫系统的效应细胞(巨噬细胞、单核细胞、中性粒细胞)大量激活，导致促炎细胞因子的大量释放，并形成活性氧(ROS；如超氧化物)和氮(RNS；如一氧化氮)物种。活性羰基物种(RCS)形成了第三类重要的高活性代谢物，直到今天，它们还不是脓毒症的研究重点。然而，我们先前在一项前瞻性观察临床试验中表明，感染性休克患者具有显著的甲基乙二醛(MG)衍生的羰基应激的特征。甲基乙二醛(MG)是一种高活性的RCS。它是由糖酵解中间代谢物磷酸三糖、磷酸甘油醛和磷酸二羟丙酮(MG的内源性来源)自发降解而成。因此，糖酵解通量增加的疾病与血浆MG水平升高(例如糖尿病/糖尿病)特别密切相关。此外，在糖尿病患者中，MG衍生的羰基应激与晚期糖尿病并发症(例如神经病变)有关，尽管这种并发症的严重程度可以通过给予特殊的清除剂(=富含精氨酸肽/GERP10)来减轻。此外，细菌似乎也能在酶作用下产生MG。然而，脓毒症中细菌MG产生的程度仍不清楚。我们的初步工作清楚地表明，脓毒症患者具有明显的MG衍生的羰基应激的特点。此外，在该研究中，MG在早期有效检测脓毒症方面优于已建立的炎症和感染标志物，如降钙素原(PCT)、C反应蛋白(CRP)、可溶性分化簇14亚型(sCD14-ST)和白细胞介素6(IL-6)。此外，我们发现MG是脓毒症死亡率的独立预测因子。在动物试验中，额外给药MG与存活率呈负相关。然而，潜在的机制和潜在的治疗选择还没有确定。因此，本项目在体外和体内解决了以下两个科学问题：(1)脓毒症时MG衍生的羰基应激的来源是什么？其潜在的调节机制是什么？关于MG衍生的羰基应激对脓毒症的病程产生因果影响的机制以及由此产生的治疗选择？综上所述，本翻译项目专注于阐明在临床试验中观察到的现象的病理生理机制。结果将用于确定脓毒症治疗的潜在治疗靶点。

Sepsis is caused by a dysregulated host response to infection. The early phase of sepsis is characterized by a considerable activation of effector cells of the innate immune system (macrophages, monocytes, neutrophils), resulting in a massive liberation of pro-inflammatory cytokines and the formation of reactive oxygen (ROS; e.g., superoxide) as well as nitrogen (RNS; e.g., nitric oxide) species. Reactive carbonyl species (RCS) form a third crucial group of highly reactive metabolites, which until today have not been the focus of interest in sepsis. However, we previously showed in a prospective observational clinical trial, that patients suffering from septic shock are characterized by significant methylglyoxal (MG)-derived carbonyl stress.Methylglyoxal (MG) is a highly reactive RCS. It is non-enzymatically formed by spontaneous degradation of the triose phosphates glycerinaldehyde phosphate and dihydroxyacetone phosphate (=endogenous source of MG) as an intermediate metabolite of glycolysis. Therefore, diseases with an increased glycolytic flux are particularly closely associated with increased plasma levels of MG (e.g. diabetes mellitus/DM). Moreover, in diabetic patients, MG-derived carbonyl stress is associated with late diabetic complications (e.g. neuropathy), although the severity of such complications can be reduced by the administration of a special scavenger (=arginine-rich peptide/GERP10). In addition, bacteria also seem to be able to produce MG enzymatically (=exogenous source of MG). However, the extent of bacterial MG production in sepsis remains unknown.Our preliminary works clearly demonstrate that patients with sepsis are hallmarked by a distinct MG-derived carbonyl stress. Moreover, MG outmatched the established markers of inflammation and infection, such as procalcitonin (PCT), C-reactive protein (CRP), soluble cluster of differentiation 14-subtype (sCD14-ST) and interleukin (IL)-6, with regards to early and effective detection of sepsis in that study. Furthermore, we identified MG as an independent predictor of mortality in sepsis. In animal trials the additional administration of MG was negatively correlated with survival. However, the underlying mechanisms, and potential therapeutic options, have not been identified yet. The present project therefore addresses the following two scientific questions in vitro and in vivo:(1.) What is the source of MG-derived carbonyl stress in sepsis and what are the underlying regulation mechanisms?(2.) About which mechanism does the MG-derived carbonyl stress exert causal influence on the course of the disease in sepsis and which therapeutic options arise out of this?In summary, the present translational project focusses on elucidating the pathophysiological mechanisms, that underlie a phenomena observed in a clinical trial. Results will be used to identify potential therapeutic targets in the treatment of sepsis.