Skeletal muscle glutathione is depleted in critically ill patients

Hammarqvist, Folke; Luo, Jiali; Cotgreave, Ian A.; Andersson, Kerstin; Wernerman, Jan

doi:10.1097/00003246-199701000-00016

Cited by 120 publications

(64 citation statements)

References 29 publications

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“…Oxidative stress, caused by augmented ROS or reactive nitrogen species (RNS) generation, is characteristic of many diseases that are associated with NTIS. Patients usually have reduced plasma and intracellular levels of antioxidant scavenging molecules, including GSH, as well as decreased activity of the antioxidant enzymatic system involved in ROS detoxification (41)(42)(43). The increased production of proinf lammatory cytokines such as IL-6, a typical feature in NTIS, has been implicated in this process, since it leads to a significant increase in superoxide radical production through the enzyme complex of the NADPH oxidase pathway (40).…”

Section: Discussionmentioning

confidence: 99%

IL-6 promotes nonthyroidal illness syndrome by blocking thyroxine activation while promoting thyroid hormone inactivation in human cells

Wajner¹,

Goemann²,

Bueno³

et al. 2011

J. Clin. Invest.

129

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Nonthyroidal illness syndrome (NTIS) is a state of low serum 3,5,3′ triiodothyronine (T 3 ) that occurs in chronically ill patients; the degree of reduction in T 3 is associated with overall prognosis and survival. Iodothyronine deiodinases are enzymes that catalyze iodine removal from thyroid hormones; type I and II deiodinase (D1 and D2, respectively) convert the prohormone thyroxine T 4 to active T 3 , whereas the type III enzyme (D3) inactivates T 4 and T 3 . Increased production of cytokines, including IL-6, is a hallmark of the acute phase of NTIS, but the role of cytokines in altered thyroid hormone metabolism is poorly understood. Here, we measured the effect of IL-6 on both endogenous cofactor-mediated and dithiothreitol-stimulated (DTT-stimulated) cell sonicate deiodinase activities in human cell lines. Active T 3 generation by D1 and D2 in intact cells was suppressed by IL-6, despite an increase in sonicate deiodinases (and mRNAs). N-acetylcysteine (NAC), an antioxidant that restores intracellular glutathione (GSH) concentrations, prevented the IL-6-induced inhibitory effect on D1-and D2-mediated T 3 production, which suggests that IL-6 might function by depleting an intracellular thiol cofactor, perhaps GSH. In contrast, IL-6 stimulated endogenous D3-mediated inactivation of T 3 . Taken together, these results identify a single pathway by which IL-6-induced oxidative stress can reduce D1-and D2-mediated T 4 -to-T 3 conversion as well as increasing D3-mediated T 3 (and T 4 ) inactivation, thus mimicking events during illness.

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Section: Discussionmentioning

confidence: 99%

IL-6 promotes nonthyroidal illness syndrome by blocking thyroxine activation while promoting thyroid hormone inactivation in human cells

Wajner¹,

Goemann²,

Bueno³

et al. 2011

J. Clin. Invest.

129

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“…They highlighted the importance of glutathione and c-GCS in protecting against the cytotoxic effects of various agents and that most of the actions of TNF-a are regulated by the glutathione-controlled redox status of the cell. Modulation of GSH synthesis in organs such as the skeletal muscle of critically ill patients, in whom GSH synthesis is markedly affected, would be another means of targeting GSH synthesis by gene transfer [259,266]. Thus the induction of c-GCS by molecular means to increase cellular GSH levels or c-GCS gene therapy holds great promise in protection against chronic inflammation and oxidant-mediated injury in various inflammatory diseases.…”

Section: Glutathione Therapeutic Perspectives In Inflammatory Lung DImentioning

confidence: 99%

Oxidative stress and regulation of glutathione in lung inflammation

Rahman¹,

MacNee²

2000

Eur Respir J

797

543

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Inflammatory lung diseases are characterized by chronic inflammation and oxidant/antioxidant imbalance, a major cause of cell damage. The development of an oxidant/antioxidant imbalance in lung inflammation may activate redox‐sensitive transcription factors such as nuclear factor‐κB, and activator protein‐1 (AP‐1), which regulate the genes for pro‐inflammatory mediators and protective antioxidant genes. Glutathione (GSH), a ubiquitous tripeptide thiol, is a vital intra‐ and extracellular protective antioxidant against oxidative/nitrosative stresses, which plays a key role in the control of pro‐inflammatory processes in the lungs. Recent findings have suggested that GSH is important in immune modulation, remodelling of the extracellular matrix, apoptosis and mitochondrial respiration. The rate‐limiting enzyme in GSH synthesis is γ‐glutamylcysteine synthetase (γ‐GCS). The human γ‐GCS heavy and light subunits are regulated by AP‐1 and antioxidant response elements and are modulated by oxidants, phenolic antioxidants, growth factors, and inflammatory and anti‐inflammatory agents in lung cells. Alterations in alveolar and lung GSH metabolism are widely recognized as a central feature of many inflammatory lung diseases such as idiopathic pulmonary fibrosis, acute respiratory distress syndrome, cystic fibrosis and asthma. The imbalance and/or genetic variation in antioxidant γ‐GCS and pro‐inflammatory versus antioxidant genes in response to oxidative stress and inflammation in some individuals may render them more susceptible to lung inflammation. Knowledge of the mechanisms of GSH regulation and balance between the release and expression of pro‐ and anti‐inflammatory mediators could lead to the development of novel therapies based on the pharmacological manipulation of the production as well as gene transfer of this important antioxidant in lung inflammation and injury. This review describes the redox control and involvement of nuclear factor‐κB and activator protein‐1 in the regulation of cellular glutathione and γ‐glutamylcysteine synthetase under conditions of oxidative stress and inflammation, the role of glutathione in oxidant‐mediated susceptibility/tolerance, γ‐glutamylcysteine synthetase genetic susceptibility and the potential therapeutic role of glutathione and its precursors in protecting against lung oxidant stress, inflammation and injury.

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“…In intensive-care (ICU) patients with septic complications following surgery, muscle free glutamine is depleted to less than 25 % of the normal concentration (Hammarqvist et al 1997). In parallel, during the first week in ICU muscle GSH concentration is reduced to the same level or greater compared with patients undergoing elective surgery.…”

Section: Glutathione In Human Musclementioning

confidence: 99%

Glutathione status in critically-ill patients: possibility of modulation by antioxidants

1999

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Muscle tissue serves as a protein reservoir which is mobilized to meet the specific metabolic needs associated with various catabolic conditions in human subjects, such as trauma and critical illness. Glutathione is one of the most abundant short-chain peptides and a major source of non-protein thiol in the body, and tissue glutathione concentration is related to its oxidative capacity. Skeletal muscle is relatively unique with respect to a variety of metabolic properties, such as oxidative potential, patterns of amino acid utilization, and antioxidant enzyme activity. The glutathione concentration is not influenced by food intake, or by food deprivation. Moreover, there is no diurnal variation on muscle glutathione levels. Following elective surgery the muscle concentration of GSH (the reduced form) decreases by 40 % 24 h post-operatively, while the concentration of GSSG (the oxidized form) remains unaltered. During critical illness a similar decrease in the GSH concentration is seen, but in addition a change in the redox status indicative of an elevated GSSG level occurs. Furthermore, correlations between the concentrations of glutamine as well as glutamate and GSH exist in these patients. From available evidence accumulated it is clear that glutathione plays a pivotal role in the maintenance of the intracellular redox status, the antioxidant vitamin levels, and the antioxidant enzyme functions under various metabolic conditions.

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Skeletal muscle glutathione is depleted in critically ill patients

Cited by 120 publications

References 29 publications

IL-6 promotes nonthyroidal illness syndrome by blocking thyroxine activation while promoting thyroid hormone inactivation in human cells

IL-6 promotes nonthyroidal illness syndrome by blocking thyroxine activation while promoting thyroid hormone inactivation in human cells

Oxidative stress and regulation of glutathione in lung inflammation

Glutathione status in critically-ill patients: possibility of modulation by antioxidants

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