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

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.

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“…Due to these insufficient amounts of glutathione, the authors had suggested that TamR cells were more sensitive to dicarbonyl stress. Dicarbonyl stress can result in damage to intracellular proteins, mitochondrial dysfunction and oxidative stress, which eventually leads to cell death [ 51 , 52 ].…”

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“…Experimental data have shown that dicarbonyl stress contributes to the impairment of both micro- and macro-vascular dysfunction, also independently of hyperglycemia [12].…”

“…Most glycation reactions of MGO occur in the unhydrated form [11], and this probably accounts for its short half-life. The percentage of MGO in its unhydrated form is hundreds of times higher than GO [12], which makes MGO the most reactive dicarbonyl.…”

Дикарбонільний Стрес: Гіпотеза Клітинного Пошкодження В Умовах Гіпоксії. Пусковий Механізм Розвитку Мультиорганної Дисфункції

“…В свою очередь, измененные протеины активируют клетки сосудистого эндотелия, мезангиальные клетки и макрофаги, продуцирующие активные формы кислорода. Таким образом, дикарбонильные соединения принимают участие в формировании механизмов окислительного стресса [7,8,10].…”

“…Эти вещества обладают значительной цитотоксичностью, повреждая протеины и нарушая процессы тканевого дыхания, инициируют воспаление. Неблагоприятное интегративное действие на организм химических соединений, несущих в себе пару карбонильных групп, в ситуациях, характеризующихся их усиленной продукцией и нарушением инактивации, получило название «дикарбонильный стресс» [7][8][9].…”