Extracellular histones induce tissue factor expression in vascular endothelial cells via TLR and activation of NF-κB and AP-1

Yang, Xinyu; Li, Lin; Liu, Jin; Lv, Ben; Chen, Fangping

doi:10.1016/j.thromres.2015.10.012

Cited by 96 publications

(81 citation statements)

References 36 publications

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“…Sustained inflammation in the presence of a xenograft can also induce histone release by cell/tissue injury and activation, which can promote coagulation dysfunction. Exhaustion of coagulation factors and platelets may occur through thrombin generation by (i) inducing tissue factor (TF) expression, 18 (ii) reducing expression of coagulation-regulatory proteins, 9 or (iii) through direct platelet activation and aggregation. 15,16,43 …”

Section: Discussionmentioning

confidence: 99%

“…14 When extracellular histones bind to TLR2 and TLR4 on platelets, they induce platelet activation and aggregation 15,16 that in turn induces NETosis. 17 Extracellular histones enhance thrombin generation by (i) inducing tissue factor expression on endothelial cells potentially through the NF-κB pathway, 18 (ii) releasing von Willebrand Factor (vWF), 19,20 and (iii) reducing expression of coagulation-regulatory proteins (eg, thrombomodulin). 9 …”

Section: Introductionmentioning

confidence: 99%

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An Investigation of Extracellular Histones in Pig-To-Baboon Organ Xenotransplantation

Lee

Hara

et al. 2017

Transplantation

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Background Serum (extracellular) histone levels are increased in inflammatory states and in the presence of coagulation dysfunction, eg, trauma, chemical/ischemic injury, infection. There is increasing evidence of a systemic inflammatory response associated with the presence of a pig xenograft in a nonhuman primate. We evaluated extracellular histone levels in baboons with various pig xenografts. Methods We measured serum histones in baboons with pig heterotopic heart (n=8), life-supporting kidney (n=5), orthotopic liver (n=4), and artery patch (n=9) grafts by ELISA. C-reactive protein (CRP), free triiodothyronine (fT3), serum amyloid A (SAA), and platelet counts were also measured, all of which may provide an indication of an inflammatory state. We investigated the effect of histones on platelet aggregation and on cytotoxicity of pig cells in vitro. Results Serum histones increased when baboons developed consumptive coagulopathy (CC) (eg, thrombocytopenia) or infection. CRP levels tended to be higher and fT3 levels lower when CC developed. Measurement of SAA correlated fairly well with CRP and indicated the state of inflammation. Treatment of the recipient with tocilizumab reduced the level of serum histones, CRP, and SAA, and increased the level of fT3 and platelet counts. In vitro, histone-induced platelet aggregation and endothelial cell apoptosis were both significantly reduced by the NF-kB pathway inhibitor, parthenolide. Conclusions These noninvasive assays may be useful for monitoring the health status of nonhuman primate recipients of pig organ grafts and may help in management after xenotransplantation. Tocilizumab and NF-κB inhibitors might prove valuable in reducing the inflammatory response to a pig xenograft.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

An Investigation of Extracellular Histones in Pig-To-Baboon Organ Xenotransplantation

Lee

Hara

et al. 2017

Transplantation

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“…4647 In addition, histones, elastase, and MPO-generated hypochlorous acid each induce endothelial TF production. 48495036 Supporting these in vitro studies, clinical data implicate NETs in coronary disease, venous thrombosis, and other thrombotic conditions. 51525354 Thrombi retrieved from the culprit arteries of ACS patients show higher levels of NET markers.…”

Section: A Special Role For Granulocytes and Neutrophil Extracellularmentioning

confidence: 92%

Mechanisms of erosion of atherosclerotic plaques

Quillard

Franck²,

Mawson³

et al. 2017

Current Opinion in Lipidology

132

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Purpose of review This review explores the mechanisms of superficial intimal erosion, a common cause of thrombotic complications of atherosclerosis. Recent findings Human coronary artery atheroma that give rise to thrombosis due to erosion differ diametrically from those associated with fibrous cap rupture. Eroded lesions characteristically contain few inflammatory cells, abundant extracellular matrix, and neutrophil extracellular traps (NETs). Innate immune mechanisms such as engagement of Toll-like receptor 2 (TLR2) on cultured endothelial cells (EC) can impair their viability, attachment, and ability to recover a wound. Hyaluronan fragments may serve as endogenous TLR2 ligands. Mouse experiments demonstrate that flow disturbance in arteries with neointimas tailored to resemble features of human eroded plaques disturbs EC barrier function, impairs EC viability, recruits neutrophils, and provokes EC desquamation, NET formation, and thrombosis in a TLR2-dependent manner. Summary Mechanisms of erosion have received much less attention than those that provoke plaque rupture. Intensive statin treatment changes the characteristic of plaques that render them less susceptible to rupture. Thus, erosion may contribute importantly to the current residual burden of risk. Understanding the mechanisms of erosion may inform the development and deployment of novel therapies to combat the remaining atherothrombotic risk in the statin era.

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Section: Toll-like Receptorsmentioning

confidence: 99%

“…80 In addition to inducing TF expression, TLR2 and TLR4 also mediate platelet activation and increase coagulation in response to extracellular histones. 80,81 Fibrinogen may act as a ligand for TLR-mediated signaling. TLR9 has also been implicated as an initiator of TF expression in vitro by human coronary artery endothelial cells and in mice, 82 illustrating that TLR-mediated inflammation augments coagulation through more than just TLR2 and TLR4.…”

Section: Toll-like Receptorsmentioning

confidence: 99%

Cross Talk Pathways Between Coagulation and Inflammation

Foley

Conway

2016

Circulation Research

426

376

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Anatomic pathology studies performed over 150 years ago revealed that excessive activation of coagulation occurs in the setting of inflammation. However, it has taken over a century since these seminal observations were made to delineate the molecular mechanisms by which these systems interact and the extent to which they participate in the pathogenesis of multiple diseases. There is, in fact, extensive cross talk between coagulation and inflammation, whereby activation of one system may amplify activation of the other, a situation that, if unopposed, may result in tissue damage or even multiorgan failure. Characterizing the common triggers and pathways are key for the strategic design of effective therapeutic interventions. In this review, we highlight some of the key molecular interactions, some of which are already showing promise as therapeutic targets for inflammatory and thrombotic disorders. (Circ Res.

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Extracellular histones induce tissue factor expression in vascular endothelial cells via TLR and activation of NF-κB and AP-1

Cited by 96 publications

References 36 publications

An Investigation of Extracellular Histones in Pig-To-Baboon Organ Xenotransplantation

An Investigation of Extracellular Histones in Pig-To-Baboon Organ Xenotransplantation

Mechanisms of erosion of atherosclerotic plaques

Cross Talk Pathways Between Coagulation and Inflammation

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