Methylglyoxal-related carbonyl stress in sepsis

脓毒症是由宿主对感染的反应失调引起的。脓毒症的早期阶段的特征在于先天免疫系统的效应细胞（巨噬细胞、单核细胞、嗜中性粒细胞）的相当大的活化，导致促炎细胞因子的大量释放和活性氧（ROS;例如，超氧化物）以及氮（RNS;例如，一氧化氮）种类。反应性羰基物质（RCS）形成第三组关键的高反应性代谢物，直到今天还没有成为脓毒症的关注焦点。然而，我们先前在一项前瞻性观察性临床试验中发现，感染性休克患者的特征是显著的丙酮醛（MG）衍生的羰基应激。它是通过磷酸丙糖、磷酸甘油醛和磷酸二羟丙酮（= MG的内源性来源）作为糖酵解的中间代谢产物自发降解而非酶促形成的。因此，糖酵解通量增加的疾病与MG的血浆水平增加特别密切相关（例如糖尿病/DM）。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）相关，尽管这种并发症的严重程度可以通过施用特殊的清除剂（=富含精氨酸的肽/GERP 10）来降低。此外，细菌似乎也能够酶促产生MG（= MG的外源性来源）。然而，脓毒症中细菌MG产生的程度仍然未知。我们的初步工作清楚地表明，脓毒症患者的特点是由一个独特的MG衍生的羰基应激。此外，在该研究中，MG在早期和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）、可溶性分化抗原14亚型（sCD 14-ST）和白细胞介素（IL）-6。此外，我们确定MG是脓毒症死亡率的独立预测因子。在动物试验中，额外给予MG与生存率呈负相关。然而，潜在的机制和潜在的治疗方案尚未确定。因此，本项目在体外和体内解决了以下两个科学问题：（1）。脓毒症中MG衍生的羰基应激的来源是什么？潜在的调节机制是什么？（2.）MG衍生的羰基应激对脓毒症病程产生因果影响的机制是什么？由此产生的治疗选择是什么？总之，本翻译项目的重点是阐明病理生理机制，在临床试验中观察到的现象的基础。结果将用于确定脓毒症治疗中的潜在治疗靶点。

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.