Activation of endothelial intrinsic NF-κB pathway impairs protein C anticoagulation mechanism and promotes coagulation in endotoxemic mice

Song, Dongmei; Ye, Xiaobing; Xu, Hao; Liu, Shu Fang

doi:10.1182/blood-2009-02-205914

Cited by 80 publications

(86 citation statements)

References 34 publications

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“…31,32,44 TNF-␣ has been reported to down-regulate TM and KLF2 expression by activating NF-B. 49 An IL-6-mediated pathway has been demonstrated to play a critical role in PM-induced thrombotic events.…”

Section: Discussionmentioning

confidence: 99%

“…31 Briefly, after fixation, lung sections were permeabilized, blocked, and incubated with antibodies against Sirt1 CD31, fibrin, or thrombomodulin, followed by fluorescence-conjugated secondary antibodies. Images were captured at room temperature using Nikon Elipse TE-2000-U microscope with a 40ϫ/1.30 NA objective and NIS Elements software (Nikon).…”

Section: Collection Of Mouse Lung Samplesmentioning

confidence: 99%

“…45,46 NF-B also physically interacts with p300, a transcriptional coactivator required for many transcription factors including those controlling TM expression. 31,32,49,50 NF-B has been reported to down-regulate TM expression indirectly by competing for the limited pool of p300 in the nucleus. 31,32,49,50 Acetylation has recently been demonstrated as a key mechanism for NF-B activation.…”

Section: Sirt1 Controls Lung Inflammation and Coagulation 2427mentioning

confidence: 99%

“…[27][28][29][30] It has been reported that Sirt1 deacetylates NF-B, thereby inhibiting its activity in several in vitro and in vivo systems. [27][28][29][30] NF-B activation has been reported to suppress TM expression, 31,32 implying that Sirt1 may be involved in protection against both inflammation and coagulation.…”

Section: Introductionmentioning

confidence: 99%

“…[27][28][29][30] It has been reported that Sirt1 deacetylates NF-B, thereby inhibiting its activity in several in vitro and in vivo systems. 27-30 NF-B activation has been reported 31,32 implying that Sirt1 may be involved in protection against both inflammation and coagulation.For personal use only. on April 8, 2019. by guest www.bloodjournal.org From to suppress TM expression,…”

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confidence: 99%

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Sirt1 protects against thrombomodulin down-regulation and lung coagulation after particulate matter exposure

Liu

Liang

et al. 2012

Blood

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Exposure to ambient particulate matter (PM) air pollution has been reported to trigger inflammation and thrombosis. However, molecular mechanisms underlying the modulation of coagulation pathways in PM-induced thrombosis remain largely unknown. We report here that Sirt1, a member of class III histone deacetylase, controls lung inflammation and coagulation after PM exposure. Sirt1 knock-out mice exhibited aggravated lung vascular leakage and inflammation after PM exposure, which was correlated with increased NF-B acetylation and activation. Furthermore, Sirt1 knock-out mice were highly susceptible to PM-induced lung coagulation as demonstrated by increased fibrin formation. The increased fibrin formation was associated with reduced tissue factor pathway inhibitor (TFPI) expression and increased plasminogen activator inhibitor-1 (PAI-1) activity in the lungs, thus favoring elevated coagulation and disrupted fibrinolysis responses. Thrombomodulin (TM), a central player of the anticoagulant protein C system, is regulated by Kruppel-like factor 2 (KLF2) at the transcriptional level. IntroductionExposure to ambient particulate matter (PM) air pollution has been associated with impaired pulmonary function and increased cardiovascular disease-related mortality including inflammation and thrombosis. 1-5 Acute exposure to increased ambient fine particulate matter Ͻ 2.5 m in diameter (PM 2.5 ) was estimated to cause the premature deaths of tens of thousands of people each year in the United States. 6 Urban particulate matter (UPM) PM 2.5, one of the major air pollutants closely monitored by the US Environmental Protection Agency (EPA), is a complex mixture of substances that are directly emitted into the air from dust, soot, smoke, and combustion. 6 To protect public health, the EPA issued the current 24-hour PM 2.5 standard at 35 g/m 3 . 6 Despite the enormous health problems caused by PM 2.5 exposure, there have been few studies performed to explore the molecular mechanisms of PM 2.5 -induced lung vascular dysfunction. PM 2.5 can reach deep in the lung to the small airway and alveoli, 6 and directly cause lung inflammation and injury. [7][8][9][10][11][12][13] The pulmonary complications may lead to detrimental effects on other organs, particularly cardiovascular dysfunction such as systemic microvascular dysfunction and thrombosis. 1,2,4,5,13 A recent study demonstrated that short-term UPM exposure triggered the activation of primary hemostasis in healthy mice, with no substantial secondary hemostasis activation, leading to arterial but not venous thrombosis. 5 Whereas another study showed that short-term UPM exposure may cause activation of coagulation responses and fibrin formation in the lung. 14 Tissue factor pathway inhibitor (TFPI) and plasminogen activator inhibitor-1 (PAI-1) play important roles in coagulation and fibrinolysis cascades, respectively. TFPI is an inhibitor of tissue factor (TF)-mediated coagulation responses. 15 PAI-1, on the other hand, is a major regulator of fibrinolysis, which functions by in...

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Section: Discussionmentioning

confidence: 99%

Section: Collection Of Mouse Lung Samplesmentioning

confidence: 99%

Section: Sirt1 Controls Lung Inflammation and Coagulation 2427mentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

mentioning

confidence: 99%

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Sirt1 protects against thrombomodulin down-regulation and lung coagulation after particulate matter exposure

Liu

Liang

et al. 2012

Blood

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Acute Lung Injury and Pulmonary Vascular Permeability: Use of Transgenic Models

Parker

2011

Comprehensive Physiology

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Acute lung injury is a general term that describes injurious conditions that can range from mild interstitial edema to massive inflammatory tissue destruction. This review will cover theoretical considerations and quantitative and semi-quantitative methods for assessing edema formation and increased vascular permeability during lung injury. Pulmonary edema can be quantitated directly using gravimetric methods, or indirectly by descriptive microscopy, quantitative morphometric microscopy, altered lung mechanics, high-resolution computed tomography, magnetic resonance imaging, positron emission tomography, or x-ray films. Lung vascular permeability to fluid can be evaluated by measuring the filtration coefficient (Kf) and permeability to solutes evaluated from their blood to lung clearances. Albumin clearances can then be used to calculate specific permeability-surface area products (PS) and reflection coefficients (σ). These methods as applied to a wide variety of transgenic mice subjected to acute lung injury by hyperoxic exposure, sepsis, ischemia-reperfusion, acid aspiration, oleic acid infusion, repeated lung lavage, and bleomycin are reviewed. These commonly used animal models simulate features of the acute respiratory distress syndrome, and the preparation of genetically modified mice and their use for defining specific pathways in these disease models are outlined. Although the initiating events differ widely, many of the subsequent inflammatory processes causing lung injury and increased vascular permeability are surprisingly similar for many etiologies.

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Neutrophil, neutrophil extracellular traps and endothelial cell dysfunction in sepsis

Zhang

Wang

et al. 2023

Clinical & Translational Med

103

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Sepsis is a persistent systemic inflammatory condition involving multiple organ failures resulting from a dysregulated immune response to infection, and one of the hallmarks of sepsis is endothelial dysfunction. During its progression, neutrophils are the first line of innate immune defence against infection. Aside from traditional mechanisms, such as phagocytosis or the release of inflammatory cytokines, reactive oxygen species and other antibacterial substances, activated neutrophils also release web‐like structures composed of tangled decondensed DNA, histone, myeloperoxidase and other granules called neutrophil extracellular traps (NETs), which can efficiently ensnare bacteria in the circulation. In contrast, excessive neutrophil activation and NET release may induce endothelial cells to shift toward a pro‐inflammatory and pro‐coagulant phenotype. Furthermore, neutrophils and NETs can degrade glycocalyx on the endothelial cell surface and increase endothelium permeability. Consequently, the endothelial barrier collapses, contributing to impaired microcirculatory blood flow, tissue hypoperfusion and life‐threatening organ failure in the late phase of sepsis.

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Activation of endothelial intrinsic NF-κB pathway impairs protein C anticoagulation mechanism and promotes coagulation in endotoxemic mice

Cited by 80 publications

References 34 publications

Sirt1 protects against thrombomodulin down-regulation and lung coagulation after particulate matter exposure

Sirt1 protects against thrombomodulin down-regulation and lung coagulation after particulate matter exposure

Acute Lung Injury and Pulmonary Vascular Permeability: Use of Transgenic Models

Neutrophil, neutrophil extracellular traps and endothelial cell dysfunction in sepsis

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