Angry macrophages patrol for fibrin

Miles, Lindsey A.; Parmer, Robert J.

doi:10.1182/blood-2016-01-687673

Cited by 5 publications

(4 citation statements)

References 8 publications

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“…Previous studies have also found that knockout mice for GXP-3, the enzyme that uses GSH to lower ROS, demonstrate increased platelet-induced microthrombosis [ 29 ]. GSH also can reduce fibrin clot formation by assisting macrophages in removing fibrin [ 40 ]. With immunothrombosis being one of the proposed mechanisms in COVID-19 infection, we wanted to investigate this process and hypothesized that L-GSH supplementation would reduce fibrin clot formation within the PBMC cultures by reducing ROS and assisting in fibrin clearance.…”

Section: Discussionmentioning

confidence: 99%

Evaluation of Glutathione in Spike Protein of SARS-CoV-2 Induced Immunothrombosis and Cytokine Dysregulation

Norris,

Chorbajian,

Dawi

et al. 2024

Antioxidants

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Thrombotic microangiopathy has been identified as a dominant mechanism for increased mortality and morbidity in coronavirus disease 2019 (COVID-19). In the context of severe COVID-19, patients may develop immunothrombosis within the microvasculature of the lungs, which contributes to the development of acute respiratory distress syndrome (ARDS), a leading cause of death in the disease. Immunothrombosis is thought to be mediated in part by increased levels of cytokines, fibrin clot formation, and oxidative stress. Glutathione (GSH), a well-known antioxidant molecule, may have therapeutic effects in countering this pathway of immunothrombosis as decreased levels of (GSH) have been associated with increased viral replication, cytokine levels, and thrombosis, suggesting that glutathione supplementation may be therapeutic for COVID-19. GSH supplementation has never been explored as a means of treating COVID-19. This study investigated the effectiveness of liposomal glutathione (GSH) as an adjunctive therapy for peripheral blood mononuclear cells (PBMC) treated with SARS CoV-2 spike protein. Upon the addition of GSH to cell cultures, cytokine levels, fibrin clot formation, oxidative stress, and intracellular GSH levels were measured. The addition of liposomal-GSH to PBMCs caused a statistically significant decrease in cytokine levels, fibrin clot formation, and oxidative stress. The addition of L-GSH to spike protein and untreated PBMCs increased total intracellular GSH, decreased IL-6, TGF-beta, and TNF-alpha levels, decreased oxidative stress, as demonstrated through MDA, and decreased fibrin clot formation, as detected by fluorescence microscopy. These findings demonstrate that L-GSH supplementation within a spike protein-treated PBMC cell culture model reduces these factors, suggesting that GSH supplementation should be explored as a means of reducing mediators of immunothrombosis in COVID-19.

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Section: Discussionmentioning

confidence: 99%

Evaluation of Glutathione in Spike Protein of SARS-CoV-2 Induced Immunothrombosis and Cytokine Dysregulation

Norris,

Chorbajian,

Dawi

et al. 2024

Antioxidants

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“…These areas also showed a further increase in elastin fibres in the alveolar walls, CXCR4 upregulation and, interestingly also no sign of relevant fibrinolytic gene expression. It is known that there are alternative, non‐proteolytic mechanisms for the digestion of fibrin . However, it is unclear how this alternative clearance affects phagocyte behaviour, especially with respect to pro‐fibrotic signalling, since there was also increasing accumulation of fibroblasts and an increase in collagen expression. The fully developed AFE phase; hallmarks of this phase are increased amounts of ECM taking up the alveolar lumen, some incorporated myofibroblasts, derived from the host, as indicated by exemplary XY‐chromosome FISH and decreasing numbers of local inflammatory cells/histiocytes.…”

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Comparative analysis of morphological and molecular motifs in bronchiolitis obliterans and alveolar fibroelastosis after lung and stem cell transplantation

Jonigk

Rath

Borchert

et al. 2016

The Journal of Pathology CR

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Chronic lung allograft dysfunction (CLAD) remains the major obstacle to long‐term survival following lung transplantation (LuTx). Morphologically CLAD is defined by obliterative remodelling of the small airways (bronchiolitis obliterans, BO) as well as a more recently described collagenous obliteration of alveoli with elastosis summarised as alveolar fibroelastosis (AFE). Both patterns are not restricted to pulmonary allografts, but have also been reported following haematopoietic stem cell transplantation (HSCT) and radio chemotherapy (RC). In this study we performed compartment‐specific morphological and molecular analysis of BO and AFE lesions in human CLAD (n = 22), HSCT (n = 29) and RC (n = 6) lung explants, utilising conventional histopathology, laser‐microdissection, PCR techniques and immunohistochemistry to assess fibrosis‐associated gene and protein expression. Three key results emerged from our analysis of fibrosis‐associated genes: (i) generally speaking, “BO is BO”. Despite the varying clinical backgrounds, the molecular characteristics of BO lesions were found to be alike in all groups. (ii) “AFE is AFE”. In all groups of patients suffering from restrictive changes to lung physiology due to AFE there were largely – but not absolutely ‐ identical gene expression patterns. iii) BO concomitant to AFE after LuTx is characterised by an AFE‐like molecular microenvironment, representing the only exception to (i). Additionally, we describe an evolutionary model for the AFE pattern: a non‐specific fibrin‐rich reaction to injury pattern triggers a misguided resolution attempt and eventual progression towards manifest AFE. Our data point towards an absence of classical fibrinolytic enzymes and an alternative fibrin degrading mechanism via macrophages, resulting in fibrous remodelling and restrictive functional changes. These data may serve as diagnostic adjuncts and help to predict the clinical course of respiratory dysfunction in LuTx and HSCT patients. Moreover, analysis of the mechanism of fibrinolysis and fibrogenesis may unveil potential therapeutic targets to alter the course of the eventually fatal lung remodelling.

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“…Just as low levels of GSH are associated with pro-inflammatory states, increasing levels of GSH has been shown to decrease inflammatory states by mechanisms like reducing IL-6 and TGF- β in HIV patients [ 12 , 39 , 40 ]. GSH can also assist in the prevention of thrombi formation by assisting macrophages in removing fibrin [ 41 ]. Therefore, GSH may serve as an adjunctive therapy for COVID-19 [ 11 ].…”

Section: Gsh Overviewmentioning

confidence: 99%

The Role of Glutathione in Prevention of COVID-19 Immunothrombosis: A Review

Glassman¹,

Le²,

Mirhosseini³

et al. 2023

Front. Biosci. (Landmark Ed)

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Immunothrombosis has emerged as a dominant pathological process exacerbating morbidity and mortality in acute-and long-COVID-19 infections. The hypercoagulable state is due in part to immune system dysregulation, inflammation and endothelial cell damage, as well as a reduction in defense systems. One defense mechanism in particular is glutathione (GSH), a ubiquitously found antioxidant. Evidence suggests that reduction in GSH increases viral replication, pro-inflammatory cytokine release, and thrombosis, as well as decreases macrophage-mediated fibrin removal. The collection of adverse effects as a result of GSH depletion in states like COVID-19 suggest that GSH depletion is a dominant mechanism of immunothrombosis cascade. We aim to review the current literature on the influence of GSH on COVID-19 immunothrombosis pathogenesis, as well as the beneficial effects of GSH as a novel therapeutic for acute-and long-COVID-19.

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Angry macrophages patrol for fibrin

Cited by 5 publications

References 8 publications

Evaluation of Glutathione in Spike Protein of SARS-CoV-2 Induced Immunothrombosis and Cytokine Dysregulation

Evaluation of Glutathione in Spike Protein of SARS-CoV-2 Induced Immunothrombosis and Cytokine Dysregulation

Comparative analysis of morphological and molecular motifs in bronchiolitis obliterans and alveolar fibroelastosis after lung and stem cell transplantation

The Role of Glutathione in Prevention of COVID-19 Immunothrombosis: A Review

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