van Bussel Bas C T, van de Poll Marcel C G, Schalkwijk Casper G, Bergmans Dennis C J J
Department of Intensive Care, Maastricht University Medical Centre +, Maastricht 6229 HX, The Netherlands.
Department of Surgery, and NUTRIM School for Nutrition and Translational Research, Maastricht University Medical Centre +, Maastricht 6229 HX, The Netherlands.
Int J Mol Sci. 2017 Feb 7;18(2):346. doi: 10.3390/ijms18020346.
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.
导致危重病患者多器官功能衰竭的分子病理途径正逐渐被揭示。然而，调节这些途径的尝试尚未改善临床结局。因此，应研究新的可靶向机制。我们假设二羰基应激增加就是这样一种机制。二羰基应激是二羰基代谢产物（即甲基乙二醛、乙二醛和3-脱氧葡萄糖醛酮）的积累，这些代谢产物会损害细胞内蛋白质、修饰细胞外基质蛋白并改变血浆蛋白。已证明二羰基应激增加会损害肾脏、心血管和中枢神经系统功能，也可能损害肝脏和呼吸功能。除高血糖外，缺氧和炎症也可导致二羰基应激增加，而这些情况在危重病中很常见。已证明缺氧和炎症会促使活性二羰基化合物在细胞内快速积累，即通过降低乙二醛酶-1活性，而乙二醛酶-1是二羰基解毒酶系统中的关键酶。因此，在危重病中，无论有无高血糖，缺氧和炎症都可能以某种方式增加二羰基应激，进而导致多器官功能衰竭。因此，我们假设在脓毒症和重大创伤等危重病中，二羰基应激增加会促使多器官功能衰竭的发生。这种机制具有在重症监护中进行新的治疗干预的潜力。
