Abstract
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.
Highlights
Sepsis and major trauma often develop into multi-organ failure and persistent critical illness, which have a mortality rate of 20%–40% [1,2]
Increased inflammation, impaired coagulation, endothelial dysfunction leading to microvascular dysfunction [4], and mitochondrial dysfunction leading to increased oxidative stress [5], appear to be involved in this process, but are unable to fully explain the observed multi-organ failure and persistent critical illness [3,6]
An in vivo model in non-diabetic mice showed that the knockout of glyoxalase-1, modifies glomerular proteins and oxidative stress in a way that leads to an impaired renal function [19]
Summary
Sepsis and major trauma often develop into multi-organ failure and persistent critical illness, which have a mortality rate of 20%–40% [1,2]. Novel underlying potential mechanisms, linking increased inflammation, impaired coagulation, endothelial dysfunction, and increased oxidative stress, on the one hand, and multi-organ failure and persistent critical illness, on the other, to mortality, should be investigated. This may reveal new therapeutic targets which can be used in critical care. The reactive dicarbonyls—i.e., methylglyoxal, glyoxal, and 3-deoxyglucosone—are produced by several metabolic pathways, such as anaerobic glycolysis, gluconeogenesis, and lipid peroxidation [14] These dicarbonyls react with the amino groups of both intracellular and extracellular proteins, in a way that contributes to cell and tissue dysfunction [13,14,15]. Increased metabolic stress and an impaired glyoxalase system, increases the dicarbonyl stress that impairs cellular function and interacts on multiple levels
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