Systemic inflammation down-regulates glyoxalase-1 expression: an experimental study in healthy males. Issue 7 (30th July 2021)

• Record Type: Journal Article
• Authors: G.H. Driessen, Rob; Kiers, Dorien; G. Schalkwijk, Casper; L.J.M. Scheijen, Jean; Gerretsen, Jelle; Pickkers, Peter; C.G. van de Poll, Marcel; C.C. van der Horst, Iwan; C.J.J. Bergmans, Dennis; Kox, Matthijs; C.T. van Bussel, Bas
• Is Part Of: Bioscience reports. Volume 41:Issue 7(2021)
• Publication Date: 2021-07-30
• Subjects: dicarbonyl -- glyoxalase -- hypoxia -- inflammation -- methylglyoxal -- sepsis; Molecular biology -- Periodicals; Cytology -- Periodicals; 572.8
• DOI: 10.1042/BSR20210954
• Languages: English
• ISSNs: 0144-8463

Abstract

Abstract: 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 down-regulation 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 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 (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.