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

Rob G.H Driessen,Dorien Kiers,Casper G Schalkwijk,Iwan C.C Van Der Horst,Marcel C.G Van De Poll,Peter Pickkers,Jelle Gerretsen,Bas C.T Van Bussel,Matthijs Kox,Dennis C.J.J Bergmans,Jean L.J.M Scheijen

doi:10.1042/bsr20210954

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.

Highlights

Severe inflammatory conditions, such as sepsis, leading to multiple organ failure (MOF), are still a major challenge in intensive care units (ICUs) [1,2]
Data from the hypoxia group (n=10) were obtained from the study registered under NCT01889823 [21], data from the LPS (n=10) and LPS+hypoxia (n=10) groups from the study registered under NCT01978158 [21], and data from the control group (n=10) from the study registered under NCT02642237 [22]
After adjustment for age and BMI, GLO1 expression decreased in the LPS (β (95%CI); -0.87 (-1.24; -0.50)) and LPS+hypoxia (-0.78 (-1.07; -0.48)) groups over time, compared with the hypoxia group (P

Summary

Introduction

Severe inflammatory conditions, such as sepsis, leading to multiple organ failure (MOF), are still a major challenge in intensive care units (ICUs) [1,2]. It has been postulated that increased formation of the dicarbonyls methylglyoxal (MGO), glyoxal (GO) and 3-deoxyglucosone (3-DG), induced by inflammation and hypoxia, may contribute to multi-organ failure in critical illness [8]. These reactive dicarbonyls are produced by several metabolic pathways, such as anaerobic glycolysis and gluconeogenesis [9]. A possible mechanism leading to multiple organ failure is hypoxia- or inflammation-induced down-regulation of the detoxifying glyoxalase system that clears dicarbonyl stress. 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

Methods

Results

Conclusion