Deranged Bioenergetics and Defective Redox Capacity in T Lymphocytes and Neutrophils Are Related to Cellular Dysfunction and Increased Oxidative Stress in Patients with Active Systemic Lupus Erythematosus

Li, Ko-Jen; Wu, Cheng-Han; Hsieh, Song-Chou; Lu, Ming‐Chi; Tsai, Chang-Youh; Yu, Chia‐Li

doi:10.1155/2012/548516

Cited by 28 publications

(25 citation statements)

References 46 publications

(65 reference statements)

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“…Additionally, ROS can be generated by NADPH oxidase in lysosomes and microsomes , polymononuclear cells and phagocytic cells (Fig. ) . Moreover, reduced intracellular GSH levels and increased ROS levels were found in different blood components in SLE patients .…”

Section: Clinical Conditions Stimulating Eryptosis By Generation Of Omentioning

confidence: 98%

Oxidative stress, eryptosis and anemia: a pivotal mechanistic nexus in systemic diseases

et al. 2018

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The average lifespan of circulating erythrocytes usually exceeds hundred days. Prior to that, however, erythrocytes may be exposed to oxidative stress in the circulation which could cause injury and trigger their suicidal death or eryptosis. Oxidative stress activates Ca -permeable nonselective cation channels in the cell membrane, thus, stimulating Ca entry and subsequent cell membrane scrambling resulting in phosphatidylserine exposure and activation of Ca -sensitive K channels leading to K exit, hyperpolarization, Cl exit, and ultimately cell shrinkage due to loss of KCl and osmotically driven water. While the mechanistic link between oxidative stress and anemia remains ill-defined, several diseases such as diabetes, hepatic failure, malignancy, chronic kidney disease and inflammation have been identified to display both increased oxidative stress as well as eryptosis. Recent compelling evidence suggests that oxidative stress is an important perpetrator in accelerating erythrocyte loss in different systemic conditions and an underlying mechanism for anemia associated with these pathological states. In the present review, we discuss the role of oxidative stress in reducing erythrocyte survival and provide novel insights into the possible use of antioxidants as putative antieryptotic and antianemic agents in a variety of systemic diseases.

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Section: Clinical Conditions Stimulating Eryptosis By Generation Of Omentioning

confidence: 98%

Oxidative stress, eryptosis and anemia: a pivotal mechanistic nexus in systemic diseases

et al. 2018

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“…The rationale for reversing oxidative stress with NAC is supported by several observations. Intracellular GSH levels are decreased in PBLs and T cells from patients with SLE 30,192–195 , and GSH depletion and oxidative stress contribute to T-cell dysfunction in these patients 189,192,196 . Additionally, NAC and GSH-sparing antioxidants improve the clinical outcome of lupus in mice 197–199 , and the fact that large dosages (up to 8 g daily) of NAC can be safely administered to humans 200 (and that similar dosages of NAC improve fatigue in healthy individuals 201 ) further supports the use of NAC in this context.…”

Section: Mtor As a Therapeutic Target In Rheumatic Diseasementioning

confidence: 99%

Activation of mTOR (mechanistic target of rapamycin) in rheumatic diseases

2015

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Mechanistic target of rapamycin (mTOR, also known as mammalian target of rapamycin) is a ubiquitous serine/threonine kinase that regulates cell growth, proliferation and survival. These effects are cell-type-specific, and are elicited in response to stimulation by growth factors, hormones and cytokines, as well as to internal and external metabolic cues. Rapamycin was initially developed as an inhibitor of T-cell proliferation and allograft rejection in the organ transplant setting. Subsequently, its molecular target (mTOR) was identified as a component of two interacting complexes, mTORC1 and mTORC2, that regulate T-cell lineage specification and macrophage differentiation. mTORC1 drives the proinflammatory expansion of T helper (TH) type 1, TH17, and CD4−CD8− (double-negative, DN) T cells. Both mTORC1 and mTORC2 inhibit the development of CD4+CD25+FoxP3+ T regulatory (TREG) cells and, indirectly, mTORC2 favours the expansion of Tfollicular helper (TFH) cells which, similarly to DN T cells, promote B-cell activation and autoantibody production. In contrast to this proinflammatory effect of mTORC2, mTORC1 favours, to some extent, an anti-inflammatory macrophage polarization that is protective against infections and tissue inflammation. Outside the immune system, mTORC1 controls fibroblast proliferation and chondrocyte survival, with implications for tissue fibrosis and osteoarthritis, respectively. Rapamycin (which primarily inhibits mTORC1), ATP-competitive, dual mTORC1/mTORC2 inhibitors and upstream regulators of the mTOR pathway are being developed to treat autoimmune, hyperproliferative and degenerative diseases. In this regard, mTOR blockade promises to increase life expectancy through treatment and prevention of rheumatic diseases.

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“…Further, a piHDL phenotype, including the detection of oxidized forms of HDL, has been appreciated in murine models of SLE [42,43]**, where treatment with apoA1 mimetics has shown promise [44]. In general, interplay between oxidative stress and lupus CVD will surely receive increased attention in the coming years [45–47]. …”

Section: Epidemiology Risk Factors and Biomarkersmentioning

confidence: 99%

Cardiovascular disease in lupus

Knight

Kaplan

2013

Current Opinion in Rheumatology

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Purpose of review With improved management of the classical disease manifestations of systemic lupus erythematosus (SLE), cardiovascular disease (CVD) has emerged as one of the most important causes of morbidity and mortality. This review in particular focuses on progress over the past year in clinical and basic aspects of SLE-driven accelerated atherosclerosis. Recent findings Both subclinical CVD and CV events continue to be recognized at increased frequency in previously unstudied lupus cohorts and populations. Novel associations have been identified between lupus CVD and cognitive impairment, depression, and low income status. In terms of pathogenesis, there is an ever-increasing focus on the innate immune system and, in particular, type I interferons (IFNs). Recent studies have drawn connections in both human and murine models between neutrophils, plasmacytoid dendritic cells, type I IFNs, and endothelial dysfunction. Whether treatments such as mycophenolate mofetil or statins have a role in prevention of lupus CVD is an area of intensive study. Summary CVD is a major complication of lupus and is now a leading cause of death among people living with this disease. As such, additional studies are needed in order to identify the most effective preventive strategies and most predictive vascular risk biomarkers. Type I IFNs may play a critical role in lupus CVD pathogenesis, and it is recommended that vascular outcomes be included in ongoing trials testing the efficacy of anti-IFN biologics.

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Deranged Bioenergetics and Defective Redox Capacity in T Lymphocytes and Neutrophils Are Related to Cellular Dysfunction and Increased Oxidative Stress in Patients with Active Systemic Lupus Erythematosus

Cited by 28 publications

References 46 publications

Oxidative stress, eryptosis and anemia: a pivotal mechanistic nexus in systemic diseases

Oxidative stress, eryptosis and anemia: a pivotal mechanistic nexus in systemic diseases

Activation of mTOR (mechanistic target of rapamycin) in rheumatic diseases

Cardiovascular disease in lupus

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