Increased Dicarbonyl Stress as a Novel Mechanism of Multi-Organ Failure in Critical Illness

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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.

Original languageEnglish
Article number346
Number of pages9
JournalInternational journal of molecular sciences
Volume18
Issue number2
DOIs
Publication statusPublished - Feb 2017

Keywords

  • dicarbonyl stress
  • glyoxalase
  • methylglyoxal
  • critical care
  • multi-organ failure
  • persistent critical illness
  • ADVANCED GLYCATION ENDPRODUCTS
  • RANDOMIZED CLINICAL-TRIAL
  • SEPTIC SHOCK
  • GLYOXALASE 1
  • INTENSIVE-CARE
  • SEVERE SEPSIS
  • END-PRODUCTS
  • D-LACTATE
  • METHYLGLYOXAL
  • DYSFUNCTION

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