Systemic inflammation downregulates glyoxalase-1 expression: an experimental study in healthy males.

Driessen, Rob Gh; Kiers, Dorien; Schalkwijk, Casper; Scheijen, Jean Ljm; Gerretsen, Jelle; Pickkers, Peter; van de Poll, Marcel Cg; van der Horst, Iwan Cc; Bergmans, Dennis Cjj; Kox, Matthijs; van Bussel, Bas Ct

BACKGROUND Hypoxia and inflammation are hallmarks of critical illness, related to multiple organ failure. A possible mechanism leading to multiple organ failure is hypoxia- or inflammation-induced downregulation of the detoxifying glyoxalase system that clears dicarbonyl 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 inflammation 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 hours 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 (β (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 humans. This is a possible mechanism leading to cell damage and multi-organ failure in critical illness with potential for intervention.