Methylglyoxal-related carbonyl stress in sepsis

脓毒症中甲基乙二醛相关的羰基应激

• 批准号: 392046647
• 负责人: Professor Dr. Thorsten Brenner
• 金额: --
• 依托单位: Klinik für Anästhesiologie und Intensivmedizin
• 依托单位国家: 德国
• 项目类别: Research Grants
• 财政年份: 2017
• 资助国家: 德国
• 起止时间: 2016-12-31 至 2021-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/392046647?language=en
• 关键词: Methylglyoxal; related; carbonyl; stress; sepsis

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.

脓毒症是由宿主对感染的反应失调引起的。脓毒症早期阶段的特征是先天免疫系统效应细胞（巨噬细胞、单核细胞、中性粒细胞）的大量激活，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）物质的形成。反应性羰基物质（RCS）形成了第三组关键的高反应性代谢物，直到今天它们还不是脓毒症的关注焦点。然而，我们之前在一项前瞻性观察性临床试验中表明，患有感染性休克的患者具有明显的甲基乙二醛（MG）衍生的羰基应激。甲基乙二醛（MG）是一种高反应性RCS。它是通过作为糖酵解中间代谢物的磷酸丙糖、磷酸甘油醛和磷酸二羟基丙酮（= MG 的内源性来源）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 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）有关，尽管可以通过施用特殊的清除剂（=富含精氨酸的肽/GERP10）来降低此类并发症的严重程度。此外，细菌似乎也能够通过酶促方式产生 MG（= MG 的外源来源）。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征。此外，在该研究中，在早期有效检测脓毒症方面，MG 优于既定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 (IL)-6。此外，我们确定 MG 是败血症死亡率的独立预测因子。在动物试验中，额外给予 MG 与存活率呈负相关。然而，潜在的机制和潜在的治疗选择尚未确定。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以及潜在的调节机制是什么？（2.）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？总而言之，本转化项目的重点是 阐明临床试验中观察到的现象背后的病理生理学机制。结果将用于确定治疗脓毒症的潜在治疗靶点。