Increased Dicarbonyl Stress as a Novel Mechanism of Multi-Organ Failure in Critical Illness.
Molecular pathological pathways leading to multi-organ failure in critical illness are progressively being unravelled. However, attempts to modulate these pathways have not yet improved the clinical outcome. Therefore, new targetable mechanisms should be investigated. We hypothesize that increased dicarbonyl stress is such a mechanism. Dicarbonyl stress is the accumulation of dicarbonyl metabolites (i.e., methylglyoxal, glyoxal, and 3-deoxyglucosone) that damages intracellular proteins, modifies extracellular matrix proteins, and alters plasma proteins. Increased dicarbonyl stress has been shown to impair the renal, cardiovascular, and central nervous system function, and possibly also the hepatic and respiratory function. In addition to hyperglycaemia, hypoxia and inflammation can cause increased dicarbonyl stress, and these conditions are prevalent in critical illness. Hypoxia and inflammation have been shown to drive the rapid intracellular accumulation of reactive dicarbonyls, i.e., through reduced glyoxalase-1 activity, which is the key enzyme in the dicarbonyl detoxification enzyme system. In critical illness, hypoxia and inflammation, with or without hyperglycaemia, could thus increase dicarbonyl stress in a way that might contribute to multi-organ failure. Thus, we hypothesize that increased dicarbonyl stress in critical illness, such as sepsis and major trauma, contributes to the development of multi-organ failure. This mechanism has the potential for new therapeutic intervention in critical care.
Department of Intensive Care, Maastricht University Medical Centre +, Maastricht 6229 HX, The Netherlands. bas.van.bussel@mumc.nl.
Bas C T
BC
van Bussel
Department of Intensive Care, Maastricht University Medical Centre +, Maastricht 6229 HX, The Netherlands. marcel.vande.poll@mumc.nl.|Department of Surgery, and NUTRIM School for Nutrition and Translational Research, Maastricht University Medical Centre +, Maastricht 6229 HX, The Netherlands. marcel.vande.poll@mumc.nl.
Marcel C G
MC
van de Poll
Department of Internal Medicine, and CARIM School for Cardiovascular Diseases, Maastricht University Medical Centre +, Maastricht 6229 HX, The Netherlands. c.schalkwijk@maastrichtuniversity.nl.
Casper G
CG
Schalkwijk
Department of Intensive Care, Maastricht University Medical Centre +, Maastricht 6229 HX, The Netherlands. d.bergmans@mumc.nl.
Dennis C J J
DC
Bergmans
D015415:Biomarkers; D015897:Comorbidity; D003422:Critical Care; D016638:Critical Illness; D003847:Deoxyglucose / Q000031:analogs & derivatives / Q000378:metabolism; D006037:Glyoxal / Q000378:metabolism; D006801:Humans; D000860:Hypoxia / Q000378:metabolism; D007249:Inflammation / Q000378:metabolism; D009102:Multiple Organ Failure / Q000453:epidemiology / Q000209:etiology* / Q000378:metabolism* / Q000628:therapy; D011765:Pyruvaldehyde / Q000378:metabolism; D013312:Stress, Physiological
D015415:Biomarkers; D006037:Glyoxal; D011765:Pyruvaldehyde; D003847:Deoxyglucose; C016350:3-deoxyglucosone
critical care; dicarbonyl stress; glyoxalase; methylglyoxal; multi-organ failure; persistent critical illness