Glutathione during stress in man

Glutathione, a tripeptide (gamma-glutamyl, -cysteinyl, -glycine), is quantitatively the most important antioxidant in man, protecting cells from the toxic effects of reactive oxygen species (ROS). These highly reactive molecules cause tissue damage and are produced at high rates during critical illness including sepsis [1-4]. Glutathione is mainly an intracellular acting substance and is continuously produced in almost all tissues [5]. Besides its antioxidant properties, it also has other important functions such as detoxification and metabolism of xenobiotics and counteracts the effects of radiation [6]. In septic patients, glutathione concentration is decreased in erythrocytes and in skeletal muscle by approximately 40 % within the first 24 hours after admission to the ICU [7]. Muscle glutathione depletion has been shown to correlate with mortality in septic ICU patients [8]. The consequences of glutathione depletion seen in septic patients are not fully understood. In this thesis work new insights into the glutathione status during sepsis are obtained.

Study 1. Glutamine is related to glutathione via glutamate which is a direct precursor for glutathione. Both glutathione and glutamine are depleted in skeletal muscle during sepsis and after major surgery. Patients (n = 18) undergoing major abdominal surgery were double blindly randomized to receive either glutamine enriched total parenteral nutrition (TPN) or conventional TPN. The results show that glutamine enriched TPN attenuates the decrease in skeletal muscle glutathione.

Study 2. The temporal changes of glutathione status in skeletal muscle were characterized. Samples were taken every 72 hours for 6 days in septic ICU patients (n = 10) with multiple organ failure. The results confirmed the initial glutathione depletion. However total glutathione was spontaneously restituted within a week of ICU treatment, despite low concentration of muscle glutamine. Although total glutathione concentration was restituted, the redox status of glutathione showed an increased oxidized state throughout the study period.

Study 3. The temporal changes of glutathione status in whole blood and plasma were investigated in septic ICU patients with multiple organ failure (n = 11), to elucidate whether erythrocytes were representative for skeletal muscle. Samples were taken every 72 hours for 15 days. The results showed an initial depletion of glutathione in whole blood that remained throughout the study, in contrast to what was seen in skeletal muscle. In parallel, the concentration of plasma glutathione increased, indicating a leakage of glutathione from the erythrocytes and/or other tissues via the endothelium.

Study 4. The changes occurring in glutathione status in whole blood and plasma during the initial phase (within the first hours) of sepsis have not been characterized in man. Glutathione status in whole blood, muscle and plasma was investigated in healthy volunteers (n = 8) using an endotoxin model, mimicking the physiological and metabolic changes seen in the initial phase of sepsis. The results showed a decrease of total glutathione concentration in plasma. In contrast, the whole blood and muscle concentrations remained unaltered. It was concluded that whole blood and muscle glutathione concentration was maintained in the initial phase of sepsis.

List of scientific papers

I. Flaring UB, Rooyackers OE, Wernerman J, Hammarqvist F (2003). Glutamine attenuates post-traumatic glutathione depletion in human muscle. Clin Sci. 104(3): 275-82.
https://pubmed.ncbi.nlm.nih.gov/12605586

II. Flaring UB, Rooyackers OE, Wernerman J, Hammarqvist F (2003). Temporal changes in muscle glutathione in ICU patients. Intensive Care Med. 29(12): 2193-8. Epub 2003 Oct 18.
https://pubmed.ncbi.nlm.nih.gov/14566458

III. Flaring UB, Rooyackers OE, Hebert C, Bratel T, Hammarqvist F, Wernerman J (2005). Temporal changes in whole-blood and plasma glutathione in ICU patients with multiple organ failure. Intensive Care Med. 31(8): 1072-8. Epub 2005 Jul 6
https://pubmed.ncbi.nlm.nih.gov/15999254

IV. Flaring UB, Rooyackers O, Hammarqvist F, Wernerman J (2006). Glutathione metabolism in human endotoxemia. [Manuscript]