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Tissue factor-dependent coagulation is preferentially up-regulated within arterial branching areas in a baboon model of Escherichia coli sepsis.

ABSTRACT: Endothelium plays a critical role in the pathobiology of sepsis by integrating systemic host responses and local rheological stimuli. We studied the differential expression and activation of tissue factor (TF)-dependent coagulation on linear versus branched arterial segments in a baboon sepsis model. Animals were injected intravenously with lethal doses of Escherichia coli or saline and sacrificed after 2 to 8 hours. Whole-mount arterial segments were stained for TF, TF-pathway inhibitor (TFPI), factor VII (FVII), and markers for endothelial cells (ECs), leukocytes, and platelets, followed by confocal microscopy and image analysis. In septic animals, TF localized preferentially at branches, EC surface, leukocytes, and platelet aggregates and accumulated in large amounts in the subendothelial space. FVII strongly co-localized with TF on ECs and leukocytes but less so with subendothelial TF. TFPI co-localized with TF and FVII on endothelium and leukocytes but not in the subendothelial space. Focal TF increases correlated with fibrin deposition and increased endothelial permeability to plasma proteins. Biochemical analysis confirmed that aortas of septic baboons expressed more TF mRNA and protein than controls. Branched segments contained higher TF protein levels and coagulant activity than equivalent linear areas. These data suggest that site-dependent endothelial heterogeneity and rheological factors contribute to focal procoagulant responses to E. coli.

SUBMITTER: Lupu C

PROVIDER: S-EPMC1415276 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:BackgroundDuring sepsis, gram-negative bacteria induce robust inflammation primarily via lipopolysacharride (LPS) signaling through TLR4, a process that involves the glycosylphosphatidylinositol (GPI)-anchored receptor CD14 transferring LPS to the Toll-like receptor 4/myeloid differentiation factor 2 (TLR4/MD-2) complex. Sepsis also triggers the onset of disseminated intravascular coagulation and consumptive coagulopathy.ObjectivesWe investigated the effect of CD14 blockade on sepsis-induced coagulopathy, inflammation, organ dysfunction, and mortality.MethodsWe used a baboon model of lethal Escherichia (E) coli sepsis to study two experimental groups (n = 5): (a) E coli challenge; (b) E coli challenge plus anti-CD14 (23G4) inhibitory antibody administered as an intravenous bolus 30 minutes before the E coli.ResultsFollowing anti-CD14 treatment, two animals reached the 7-day end-point survivor criteria, while three animals had a significantly prolonged survival as compared to the non-treated animals that developed multiple organ failure and died within 30 hours. Anti-CD14 reduced the activation of coagulation through inhibition of tissue factor-dependent pathway, especially in the survivors, and enhanced the fibrinolysis due to strong inhibition of plasminogen activator inhibitor 1. The treatment prevented the robust complement activation induced by E coli, as shown by significantly decreased C3b, C5a, and sC5b-9. Vital signs, organ function biomarkers, bacteria clearance, and leukocyte and fibrinogen consumption were all improved at varying levels. Anti-CD14 reduced neutrophil activation, cell death, LPS levels, and pro-inflammatory cytokines (tumor necrosis factor, interleukin (IL)-6, IL-1β, IL-8, interferon gamma, monocyte chemoattractant protein-1), more significantly in the survivors than non-surviving animals.ConclusionsOur results highlight the crosstalk between coagulation/fibrinolysis, inflammation, and complement systems and suggest a protective role of anti-CD14 treatment in E coli sepsis.

Project description:Shifting markets can cause unexpected, stochastic changes in rural landscapes that may take local communities by surprise. Preferential siting of new industrial facilities in poor areas or in areas with few regulatory restrictions can have implications for environmental sustainability, human health, and social justice. This study focuses on frac sand mining-the mining of high-quality silica sand used in hydraulic fracturing processes for gas and oil extraction. Frac sand mining gained prominence in the 2000s in the upper midwestern United States where nonmetallic mining is regulated primarily by local zoning. I asked whether frac sand mines were more commonly sited in rural townships without formal zoning regulations or planning processes than in those that undertook zoning and planning before the frac sand boom. I also asked if mine prevalence was correlated with socioeconomic differences across townships. After creating a probability surface to map areas most suitable for frac sand mine occurrence, I developed neutral landscape models from which to compare actual mine distributions in zoned and unzoned areas at three different spatial extents. Mines were significantly clustered in unzoned jurisdictions at the statewide level and in 7 of the 8 counties with at least three frac sand mines and some unzoned land. Subsequent regression analyses showed mine prevalence to be uncorrelated with land value, tax rate, or per capita income, but correlated with remoteness and zoning. The predicted mine count in unzoned townships was over two times higher than that in zoned townships. However, the county with the most mines by far was under a county zoning ordinance, perhaps indicating industry preferences for locations with clear, homogenous rules over patchwork regulation. Rural communities can use the case of frac sand mining as motivation to discuss and plan for sudden land-use predicaments, rather than wait to grapple with unfamiliar legal processes during a period of intense conflict.

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Tissue factor-dependent coagulation is preferentially up-regulated within arterial branching areas in a baboon model of Escherichia coli sepsis.

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