Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0036690 (sepsis)
 59,461 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Human endothelial cells respond to bacterial endotoxin (lipopolysaccharide [LPS]) with changes that transform the endothelium into a surface with prominent procoagulant properties. Production of tissue factor (TF) in response to LPS is a major alteration that favors coagulation. Biologic activities of LPS have previously been shown to be enhanced by the presence of hemoglobin. Therefore, the ability of human hemoglobin (Hb) to modulate TF production by cultured human umbilical vein endothelial cells (HUVEC) was investigated. Cell-free Hb (10 mg/mL), either purified native (HbAo) or chemically cross-linked (alpha alpha Hb), was incubated with LPS (0.1 microgram/mL), and the mixtures then were added to HUVEC in culture. TF activity was quantified with a clotting assay and TF protein was measured with an enzyme-linked immunosorbent assay. Hb preparations greatly enhanced the production of TF activity (11- to 25-fold greater than TF produced by HUVEC alone) compared with minimal TF activity generated by LPS alone (only twofold greater than HUVEC alone). The enhancement of LPS-induced TF activity was Hb concentration-dependent over a range of 1 to 100 mg/mL. Cross-linked alpha alpha Hb also greatly enhanced the production of TF protein compared with TF protein generated by LPS alone (12-fold greater v 3.5-fold greater than HUVEC alone, respectively). The enhancement of LPS-induced TF protein was Hb concentration-dependent over a range of 0.1 to 2 mg/mL. Enhancement of TF activity by Hb required new protein synthesis. These results show that human Hb can augment the ability of LPS to induce endothelial cell TF and suggest that hemolysis associated with disseminated intravascular coagulation during sepsis may further stimulate coagulation. In addition, these results suggest a potential mechanism for generalized thrombosis in animals that has been associated with the infusion of cell-free Hb for resuscitation.
 ...
PMID:Hemoglobin enhances the production of tissue factor by endothelial cells in response to bacterial endotoxin. 818 Mar 81

Induction of tissue factor (TF) expression on monocytes and endothelial cells is central to the development of septic coagulopathy. Serum concentrations of endotoxin in septic patients who develop disseminated intravascular coagulation (DIC) do not, however, reach the levels that would directly stimulate TF expression on either monocytes or endothelium. We show, using an in vitro coculture system, that the interaction of monocytes with endothelium induces the expression of significant levels of TF. Unstimulated cocultures of monocytes (2 x 10(4)/well) and endothelial cells (2 x 10(4)/well) produced 35.3 +/- 8.5 mU of PCA/well, representing a 5-fold increase over the combined PCA of each cell type cultured alone (7.1 +/- 1.5 mU, n = 6, P < 0.001). Significant enhancement was also found in the presence of low concentrations of LPS. Induction of TF protein was confirmed by Western blotting. Fixation of monocytes with paraformaldehyde completely abolished TF induction in cocultures, whereas fixation of endothelium had no effect, suggesting that TF induction occurred in monocytes rather than endothelial cells. Induction of TF in cocultures could be further augmented by preincubating the endothelial cells with IFN-gamma. When endothelium was prestimulated with 500 U/ml IFN-gamma there was 142 +/- 11% increase over unstimulated cocultures (n = 5, P < 0.01). TF induction was inhibited by 32 +/- 6% in the presence of anti-ICAM-1 mAb (n = 5, P < 0.01). Our results suggest that monocyte interactions with vascular endothelium, regulated by inflammatory cytokines, and mediated by adhesive ligand binding, leads to the induction of functional monocyte TF protein, which may be responsible for the initiation of DIC in sepsis.
 ...
PMID:Induction of tissue factor expression in human monocyte/endothelium cocultures. 854 49

It is generally accepted that the initial event in coagulation and intravascular thrombus formation is the exposure of cell-surface protein, such as tissue factor (TF). TF is exposed to the flowing blood as a consequence of vascular injury induced, for instance, by PTCA, or by spontaneous rupture of an atherosclerotic plaque. Expression of TF may also be induced in monocytes and endothelial cells in several conditions such as sepsis and cancer, causing a more generalized activation of clotting. In addition to its essential role in hemostasis, TF may be also implicated in several pathophysiological processes, such as intracellular signaling, cell proliferation, and inflammation. For all these reasons, TF has been the subject of intense research focus. Many experimental studies have demonstrated that inhibition of TF:factor VIIa procoagulant activity is a powerful inhibitor of in vivo thrombosis and that this approach usually results in a less-pronounced bleeding tendency compared with other "more classical" antithrombotic interventions. Alternative approaches may be represented by antibodies directed against TF, by transfection of the arterial wall with natural inhibitors of the TF:factor VIIa complex, such as the TF pathway inhibitor, or with catalytic RNA (ribozyme), which could inhibit the expression of the TF protein by the disruption of cellular TF mRNA. All these approaches seem particularly attractive because they may result in complete inhibition of local thrombosis without incurring potentially harmful systemic effects. Further studies are warranted to determine the efficacy and safety of such approaches in patients.
 ...
PMID:Targeting tissue factor as an antithrombotic strategy. 1519 84

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.
 ...
PMID:Tissue factor-dependent coagulation is preferentially up-regulated within arterial branching areas in a baboon model of Escherichia coli sepsis. 1619 50

Tissue factor (TF) is a transmembrane protein, which is essential for initiation of the coagulation cascade. TF has been reported to play an important role in the progression of endotoxin (lipopolysaccharide, LPS)-mediated endotoxemia, being induced in numerous tissues, such as kidney, spleen and lung. We developed and validated a rabbit anti-murine TF peptide antiserum to localize TF protein in a murine sepsis model. TF protein distribution was compared to localization of TF mRNA and fibrin deposits, the ultimate resultant of procoagulant TF activity. Evident LPS mediated TF mRNA induction was observed in the tubular area at the cortico-medullar junction in the kidney, and TF activity was increased after 6 hours of endotoxemia. In the spleen, however, TF mRNA was induced in the interfollicular region upon LPS injection, corresponding to increased TF protein in the same area. The clusters of TF-protein positive cells in the spleen are predominantly granulocytes, but no TF mRNA expression was observed within these cells. Based on these observations and the presence of TF-protein positive granulocytes after splenectomy, we hypothesize that granulocytes take-up TF for transport to other locations in order to initiate fibrin formation or to induce pro-inflammatory gene expression upon interaction with factor VIIa.
 ...
PMID:Differential expression of tissue factor mRNA and protein expression in murine sepsis. The role of the granulocyte revisited. 1649 99

Tissue factor (TF), which is expressed on the surface of activated monocytes, is the major procoagulant that initiates thrombus formation in sepsis. Two endogenous neuropeptides, vasoactive intestinal peptide (VIP) and pituitary adenylate cyclase-activating polypeptide (PACAP), are attractive candidates for the development of therapies against septic shock. The purpose of this study was to examine whether VIP or PACAP inhibit the LPS-induced TF expression in monocytes. Treatment of freshly isolated human monocytes or cultured monocytic THP-1 cells with VIP or PACAP leads to reduced LPS-induced TF protein, mRNA expression and activity, as demonstrated by Western blot, real-time polymerase chain reaction, and TF activity assay, respectively. In an endotoxemic model, VIP blunts the increase of LPS-induced TF expression in blood cells at the transcriptional level, as demonstrated by real-time polymerase chain reaction. However, neither neuropeptide affects the expression of TF pathway inhibitor in monocytes. In vitro, LPS increases the migration of c-Rel/p65 into the nucleus and the phosphorylation of p38 and JNK, all of which are essential for LPS-induced TF expression. In addition, interestingly, VIP and PACAP block both the migration of c-Rel/p65 and the phosphorylation of p38 and JNK, as demonstrated by Western blot analysis. These data indicate that VIP and PACAP inhibit LPS-induced TF expression in monocytes in vitro and in vivo, confirming these peptides as candidates for the multitarget therapy of septic shock.
 ...
PMID:Vasoactive Intestinal Peptide and pituary adenylate cyclase-activating polypeptide inhibit tissue factor expression in monocyte in vitro and in vivo. 1865 Jul 85

During severe sepsis, microvesicles that are positive for tissue factor (TF) are at increased levels within blood and in pulmonary lavage. These microvesicles potentially disperse TF, the major initiator of the coagulation cascade, throughout multiple organ systems, initiating fibrin deposition and resultant ischemia. The source of these microvesicles has remained incompletely defined. Although TF(+) microvesicles are shed from cells that express nascent TF transcript in response to injury, recent findings revealed that circulating, full-length TF protein is detectable prior to these nascent transcripts. This finding suggested that the protein is released from constitutive sources as an acute response. We examined whether Staphylococcus aureus, the Gram-positive bacteria that is emerging as one of the most common etiologic agents in sepsis, is capable of stimulating the release of TF(+) microvesicles from a pulmonary cell line that constitutively expresses TF protein. We found that host cell invasion stimulated an acute release of TF(+) microvesicles and that these microvesicles mediated the transfer of the protein to TF-negative endothelial cells. We also found that transfer was inhibited by cholesterol-lowering simvastatin. Taken together, our findings reveal that S. aureus pathogenesis extends to the acute release of TF(+) microvesicles and that inhibiting dispersal by this mechanism may provide a therapeutic target.
 ...
PMID:Host cell invasion by Staphylococcus aureus stimulates the shedding of microvesicles. 2341 Jul 54