Systemic inflammation down-regulates glyoxalase-1 expression: an experimental study in healthy males

Background: Hypoxia and inflammation are hallmarks of critical illness, related to multi-ple organ failure. A possible mechanism leading to multiple organ failure is hypoxia-or inflammation-induced down-regulation of the detoxifying glyoxalase system that clears di-carbonyl stress. The dicarbonyl methylglyoxal (MGO) is a highly reactive agent produced by metabolic pathways such as anaerobic glycolysis and gluconeogenesis. MGO leads to protein damage and ultimately multi-organ failure. Whether detoxification of MGO into D-lactate by glyoxalase functions appropriately under conditions of hypoxia and inflamma-tion is largely unknown. We investigated the effect of inflammation and hypoxia on the MGO pathway in humans in vivo.Methods: After prehydration with glucose 2.5% solution, ten healthy males were exposed to hypoxia (arterial saturation 80-85%) for 3.5 h using an air-tight respiratory helmet, ten males to experimental endotoxemia (LPS 2 ng/kg i.v.), ten males to LPS+hypoxia and ten males to none of these interventions (control group). Serial blood samples were drawn, and glyoxalase-1 mRNA expression, MGO, methylglyoxal-derived hydroimidazolone-1 (MG-H1), D-lactate and L-lactate levels, were measured serially.Results: Glyoxalase-1 mRNA expression decreased in the LPS (beta (95%CI);-0.87 (-1.24;-0.50) and the LPS+hypoxia groups;-0.78 (-1.07;-0.48) (P<0.001). MGO was equal between groups, whereas MG-H1 increased over time in the control group only (P=0.003). D-Lactate was increased in all four groups. L-Lactate was increased in all groups, except in the control group.Conclusion: Systemic inflammation downregulates glyoxalase-1 mRNA expression in hu-mans. This is a possible mechanism leading to cell damage and multi-organ failure in critical illness with potential for intervention.