Scientific and Clinical Challenges in Sepsis

Ulloa, Luis; Brunner, Michael; Ramos, Laura; Deitch, Edwin A.

doi:10.2174/138161209788453248

Cited by 55 publications

(49 citation statements)

References 203 publications

(312 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Yet, in addition to coagulation activation and the downregulation of endogenous anticoagulant pathways, impairment of the fibrinolytic system plays a central role in the pathogenesis of microvascular thrombosis and organ dysfunction in sepsis. 8,9,12,13 To date, the mechanisms that modulate fibrinolysis in sepsis remain incompletely understood.…”

Section: Discussionmentioning

confidence: 99%

“…8,9,12,13 To date, the mechanisms that modulate fibrinolysis in sepsis remain incompletely understood.…”

Section: Dna Impairs Fibrinolysis In Sepsis 2549mentioning

confidence: 99%

“…5,8,10,11 Clinical management of patients with sepsis is challenging and largely limited to supportive therapies, which is in part related to a limited understanding of the underlying pathophysiology. 12,13 Recently, cell-free DNA (CFDNA) has emerged as an important link between innate immunity, coagulation, and inflammation. [14][15][16] Furthermore, we have previously demonstrated that the plasma levels of CFDNA have high discriminative power to predict intensive care unit mortality in patients with severe sepsis.…”

mentioning

confidence: 99%

See 2 more Smart Citations

Cell-Free DNA Modulates Clot Structure and Impairs Fibrinolysis in Sepsis

Gould

Stafford

et al. 2015

ATVB

134

144

View full text Add to dashboard Cite

Objectives-Sepsis is characterized by systemic activation of inflammation and coagulation in response to infection. In sepsis, activated neutrophils extrude neutrophil extracellular traps composed of cell-free DNA (CFDNA) that not only trap pathogens but also provide a stimulus for clot formation. Although the effect of CFDNA on coagulation has been extensively studied, much less is known about the impact of CFDNA on fibrinolysis. To address this, we (1) investigated the relationship between CFDNA levels and fibrinolytic activity in sepsis and (2) determined the mechanisms by which CFDNA modulates fibrinolysis. Approach and Results-Plasma was collected from healthy and septic individuals, and CFDNA was quantified. Clot lysis assays were performed in plasma and purified systems, and lysis times were determined by monitoring absorbance. Clot morphology was assessed using scanning electron microscopy. Clots formed in plasma from septic patients containing >5 µg/mL CFDNA were dense in structure and resistant to fibrinolysis, a phenomenon overcome by deoxyribonuclease addition. These effects were recapitulated in control plasma supplemented with CFDNA. In a purified system, CFDNA delayed fibrinolysis but did not alter tissue-type plasminogen activator-induced plasmin generation. Using surface plasmon resonance, CFDNA bound plasmin with a K d value of 4.2±0.3 µmol/L, and increasing concentrations of CFDNA impaired plasmin-mediated degradation of fibrin clots via the formation of a nonproductive ternary complex between plasmin, CFDNA, and fibrin. Conclusions-Our studies suggest that the increased levels of CFDNA in sepsis impair fibrinolysis by inhibiting plasmin-mediated fibrin degradation, thereby identifying CFDNA as a potential therapeutic target for sepsis treatment. Gould et al DNA Impairs Fibrinolysis in Sepsis 2545patients increase thrombin generation by activating the intrinsic pathway of blood coagulation, 26 whereas DNA-histone complexes trigger platelet activation and aggregation by signaling through toll-like receptor-2 and toll-like receptor-4. [26][27][28] In addition, recent evidence suggests that fibrin, along with von Willebrand factor and chromatin, form a colocalized network within the thrombus that provides a scaffold for localized coagulation activation coupled with platelet and red blood cell adhesion, thereby promoting thrombus formation. 16,20,29 Although the contributions of CFDNA to coagulation activation and thrombus formation have been well characterized, studies on the influence of CFDNA on the fibrinolytic system are limited. NETs have previously been shown to intercalate with fibrin to form a structural network that is resistant to lysis by tissue-type plasminogen activator (tPA) or degradation by DNase. 20 Conversely, CFDNA has been shown to facilitate the recruitment of profibrinolytic enzymes, such as tPA, urokinase plasminogen activator, plasminogen, and plasmin, and their endogenous inhibitors, plasminogen activator inhibitor-1 (PAI-1) and α2-antiplasmin.30 Thus, although CFDNA may...

show abstract

Section: Discussionmentioning

confidence: 99%

“…8,9,12,13 To date, the mechanisms that modulate fibrinolysis in sepsis remain incompletely understood.…”

Section: Dna Impairs Fibrinolysis In Sepsis 2549mentioning

confidence: 99%

mentioning

confidence: 99%

See 1 more Smart Citation

Cell-Free DNA Modulates Clot Structure and Impairs Fibrinolysis in Sepsis

Gould

Stafford

et al. 2015

ATVB

134

144

View full text Add to dashboard Cite

show abstract

“…These treatments, however, have yielded variable effects on the resolution of sepsis complications and survival. Drotrecogin alfa (recombinant human-activated protein C) is currently the only treatment for sepsis approved by the Food and Drug Administration ( 27 ). The PROWESS study showed that this treatment improved survival in high-risk patients ( 28 ).…”

Section: Vessel Reactivity Studiesmentioning

confidence: 99%

The apolipoprotein A-I mimetic peptide 4F prevents defects in vascular function in endotoxemic rats

Dai

Datta

Zhang

et al. 2010

Journal of Lipid Research

View full text Add to dashboard Cite

Sepsis is a major cause of death in hospitalized patients. Approximately 50% of patients in intensive care units develop sepsis, and the overall mortality rate is 29% ( 1 ). Mortality is due, in large part, to the cytotoxic actions of lipopolysaccharide (LPS), an endotoxic component of the outer membrane of Gram-negative bacteria. LPS is released from bacterial membranes and activates Toll-like receptors (TLR) on monocytes, neutrophils, and other target cells ( 2-5 ). TLRs transduce LPS action by activating nuclear factor (NF)-B-dependent signaling ( 4-6 ). By this mechanism, LPS stimulates the synthesis/release of infl ammatory cytokines, which play an important role in the innate immune response ( 7,8 ). Dysregulation of this infl ammatory response can lead to intravascular coagulation and multiple organ failure. LPS-induced cytokine production also increases expression of nitric oxide synthase 2 (NOS2) and cyclooxygenase 2 (COX-2), thus enhancing the synthesis of nitric oxide (NO) and arachidonic acidderived vasoactive prostanoids. These products have been implicated in hemodynamic disturbances in sepsis by reducing peripheral vascular resistance ( 9-14 ). Cardiovascular (CV) failure, characterized by severe hypotension and cardiac dysfunction, is linked to increased mortality in patients with severe sepsis ( 15-17 ).Lipoproteins are thought to play a role in the neutralization/detoxifi cation of endotoxin (18)(19)(20). Low-density lipoprotein (LDL), very low-density lipoprotein (VLDL), and high-density lipoprotein (HDL) bind to LPS and direct it to the liver for metabolism and excretion (18)(19)(20). HDL is most effective in clearing endotoxin, a property attributed to its relatively high phospholipid content compared with LDL and VLDL ( 18,21 ). With increasing Abstract High density lipoprotein (HDL) and apolipoprotein A-I (apoA-I) reduce infl ammatory responses to lipopolysaccharide (LPS). We tested the hypothesis that the apoA-I mimetic peptide 4F prevents LPS-induced defects in blood pressure and vascular reactivity. Systolic blood pressure (SBP) was measured in rats at baseline and 6 h after injection of LPS (10 mg/kg) or saline vehicle. Subgroups of LPStreated rats also received 4F (10 mg/kg) or scrambled 4F (Sc-4F). LPS administration reduced SBP by 35% compared with baseline. 4F attenuated the reduction in SBP in LPStreated rats (17% reduction), while Sc-4F was without effect. Ex vivo studies showed a reduced contractile response to phenylephrine (PE) in aortae of LPS-treated rats (ED 50 = 459 ± 83 nM) compared with controls (ED 50 = 57 ± 6 nM). This was associated with nitric oxide synthase 2 (NOS2) upregulation. 4F administration improved vascular contractility (ED 50 = 60 ± 9 nM), reduced aortic NOS2 protein, normalized plasma levels of NO metabolites, and reduced mortality in LPS-treated rats. These changes were associated with a reduction in plasma endotoxin activity. In vivo administration of , , GM-082952 (C.R.W. and G.D.) and HL-85282 (H.G.) Abbreviations: apoA-I, apolipoprotein A-I; COX-2,...

show abstract

“…While recombinant activated protein C (APC, also known as Drotrecogin alpha-activated) is currently the only FDA-approved therapy for sepsis, it is only indicated in patients at the late stage of severe sepsis [134]. Ultimately, the most successful therapies will in all probability be those that can be implemented as early as possible.…”

Section: Sepsis Therapiesmentioning

confidence: 99%

Nitrite and Nitric Oxide as Potential Diagnostic Markers in Acute Vascular Diseases

Silver¹

2011

J Neurol Neurophysiol

View full text Add to dashboard Cite

Scientific and Clinical Challenges in Sepsis

Cited by 55 publications

References 203 publications

Cell-Free DNA Modulates Clot Structure and Impairs Fibrinolysis in Sepsis

Cell-Free DNA Modulates Clot Structure and Impairs Fibrinolysis in Sepsis

The apolipoprotein A-I mimetic peptide 4F prevents defects in vascular function in endotoxemic rats

Nitrite and Nitric Oxide as Potential Diagnostic Markers in Acute Vascular Diseases

Contact Info

Product

Resources

About