Article

Plasminogen activator inhibitor-I potentiates LPS-induced neutrophil activation through a JNK-mediated pathway

Division of Pulmonary Sciences and Critical Care Medicine, University of Colorado Health Sciences Center, Colorado, USA.
Thrombosis and Haemostasis (Impact Factor: 5.76). 06/2006; 95(5):829-35. DOI: 10.1160/TH05-12-0782
Source: PubMed

ABSTRACT Plasminogen activator inhibitor-1 (PAI-1), a member of the serine protease inhibitor superfamily, modulates fibrinolysis by interacting with proteolytic mediators, including urokinase plasminogen activator (uPA). Although the roles of uPA and PAI-1 in plasmin generation and the degradation of fibrin are well known, recent evidence also suggests that they can participate in acute inflammatory conditions that involve neutrophil activation. In the present experiments, we found that the addition of PAI-1 to LPS- stimulated neutrophils resulted in enhanced nuclear translocation of NF-kappaB and increased production of the proinflammatory cytokines IL-1beta, Tnf-alpha, and Mip-2. uPA and the kringle domain (KD) of uPA potentiated cytokine expression and NF-kappaB activation by neutrophils cultured with LPS, and had additive effects when combined with PAI-1. The c-Jun N-terminal kinase (JNK) was activated after exposure of resting neutrophils to PAI-1 or the uPA KD. Enhanced JNK activation, but not that of other kinases induced by LPS, was present in neutrophils cocultured with PAI-1 or uPA KD. Inhibition of JNK activation prevented the potentiation of expression of proinflammatory cytokines induced by PAI-1 or uPA KD in LPS stimulated neutrophils. These results demonstrate that PAI-1 and uPA KD enhance LPS-induced neutrophil responses through their effects on JNK mediated pathways.

0 Bookmarks
 · 
197 Views
  • [Show abstract] [Hide abstract]
    ABSTRACT: This study is focused on the pertinence of the seismic reprocessing done in the North-East of Paris Basin in order to define the geometry of the Dogger and Trias reservoirs. The goal of this work was to evaluate the possibilities of storage of CO2 in the deep saline aquifers of the Paris Basin. This paper presents a new updated vision of the structural map and geology of North-East of Paris Basin.The preliminary phase involved reprocessing of 343 oil seismic lines recorded between 1981 and 1988, adding up to 303 kilometres coming from 10 different surveys. The quality of the existing data was not always good and work was performed to digitize original bands. Data consistency at the different scale was also analysed and checked.Particular attention was applied to the faults of the Dogger and Trias reservoirs and all shallower structure and aquifers up to the surface. The whole set of available data was harmonized through the establishment of a model of static multi-layer correction of the tertiary cover and by the use of adapted deconvolution. The crossings are thus homogeneous knowing that in-depth quality and definition remain dependent on the parameters of recording on the ground and in particular the length of the maximum offset and the distance between traces.Interpretation made it possible to identify the reflectors from the establishment of synthetic seismograms on 3 representative wells. The tops of the following layers were picked: Cenomanian, Gault, Oxfordian, Dogger, Aalenian, medio liassic sandstones, Triassic sandstones, and the metamorphic basement. The structure issued by this interpretation is notably different from that presented by the public sources because of the different density of the profiles taken into account. Explanations of the different interpretations are discussed in the paper. The isochrone maps were converted in-depth on the basis of 38 calibrations per well to illustrate the interpretation.The different layers show smooth deformations but also some faults where continuity and density increases with the depth because of the character inherited from the fault in the basement.Accidents visible are not continuous from the top of Cenomanian and to the top of the Gault, rather they correspond to the fault of Pays de Bray oriented N130 ° and to a meridian accident located in the western part of the study. From the top of Oxfordian, the continuity increases for these accidents. In addition, some oriented North-South faults appear. All the major faults are visible from the Sandstones in Medio Liasic. In addition to antithetic faults in relation with the accidents previously described, other meridian faults appear in the North of the fault of Pays de Bray.It should be indicated uncertainties in the picking of reflectors between the Trias and the basement, many multiples resistant to the processing programs interfering with these events.This project is based on an appropriated density of existing seismic 2D lines. The unequal quality of these acquisitions makes it possible to define structural aspects of the deep layers but does not allow to image possible lateral variations of rock types of the reservoir.
    Energy Procedia 01/2011; 4:4607-4616. DOI:10.1016/j.egypro.2011.02.420
  • [Show abstract] [Hide abstract]
    ABSTRACT: Toll-like receptor 4 (TLR4) and myeloid differentiation protein 2 (MD-2) are the main lipopolysaccharide (LPS) binding receptors that respond to inflammatory stimuli and mediate NF-kappa B (NF-κB) signaling pathway in macrophages. We have previously shown that plasminogen activator inhibitor-1 (PAI-1) deletion increased lung injury induced by intratracheal instillation of LPS through downregulation of TLR4 negative regulators. However, the mechanisms by which PAI-1 regulates lung inflammation are largely unknown. The aim of this study is to assess the relationship between PAI-1 and TLR4 signaling pathways in LPS-induced NR8383 cells inflammatory reaction. The results showed that the levels of PAI-1, TNF-α, and IL-1β protein were increased remarkably in NR8383 cell supernatants after LPS stimulation. PAI-1 gene knockdown reduced TNF-α and IL-1β levels in cell supernatants and inhibited the NF-κB p65 protein expression in NR8383 cells. The upregulated mRNA and protein expressions of TLR4, MD-2, and myeloid differentiation protein (MyD88) induced by LPS were attenuated after PAI-1 gene knockdown. Conversely, overexpression of PAI-1 in NR8383 cells not only resulted in additional mRNA and protein production of PAI-1, TLR4, MD-2, and MyD88, it also aggravated the inflammatory response induced by LPS. In conclusion, PAI-1 contributes to the regulation of LPS-induced inflammatory response in NR8383 cells, likely by affecting the TLR4-MD-2/NF-κB signaling transduction pathway.
    Inflammation 10/2014; DOI:10.1007/s10753-014-0042-8 · 1.92 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Neutrophil extracellular traps (NETs), which consist of neutrophil DNA and cytoplasmic proteins, have been shown to be involved in various infectious, inflammatory, and autoimmune diseases. Neutrophil extracellular traps are abundant at the site of infection and acute inflammation. Neutrophil extracellular trap formation can occur through various intracellular signaling pathways, including peptidylarginine deiminase 4, Raf-MEK-ERK, nitric oxide, Toll-like receptor 4, high mobility group box 1, pentraxin 3, and mammalian targets of rapamycin. A growing body of evidence indicates that NETs may play an important role in injury, and decreases in NETs could reduce tissue injury. Neutrophil extracellular traps are believed to modulate the inflammatory and immune responses of individuals after injury. In this review, the role of NETs in injury, including traumatic injury, ischemia-reperfusion-induced injury, and sepsis, as well as the potential markers and therapeutic targets of NET-related injury will be discussed.
    Shock (Augusta, Ga.) 06/2014; 41(6):491-498. DOI:10.1097/SHK.0000000000000146 · 2.87 Impact Factor