Methylglyoxal-related carbonyl stress in sepsis

• Applicant: Professor Dr. Thorsten Brenner
• Subject Area: Anaesthesiology
• Term: from 2017 to 2022
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 392046647

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.

• DFG Programme: Research Grants
• Co-Investigators: Ute Krauser; Dr. Karsten Schmidt; Dr. Thomas Schmoch