Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0243026 (sepsis)
 52,417 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Sepsis is a common and serious complication of major burn injury and accounts for over 54% of deaths in burn patients. Burns are associated with high levels of circulating pro-inflammatory cytokines and immunosuppression, promoting systemic inflammatory response syndrome (SIRS) and sepsis, for which no effective treatment is currently available. Defensins, a family of cationic, naturally occurring, antimicrobial peptides are important components of the innate immune system, playing a major role in the body's defence by inhibiting activities of bacteria, fungi and enveloped viruses. These natural antimicrobials also chemoattract immature dendritic cells, some types of T and B-lymphocytes, neutrophils and macrophages, and act as an adjuvant, enhancing adaptive immunity. Our prior studies suggested a decreased expression of human beta defensin 2 (HBD2) in burn wounds. Here we have identified HBD2 protein in skin samples of partial and full thickness burns and in normal skin using fluorescence deconvolution microscopy. Images showed that in normal skin the majority of HBD2 is located in the Malpighian layer and, in smaller amounts, in the more superficial layers, a pattern that is absent in burned skin in which the epidermis is destroyed or damaged. However, surviving dermal and subcutaneous layers revealed the presence of HBD2 in a number of other cell types and structures, such as hair follicles and sweat gland acini, but not in vascular endothelium and fat cells. The results of these studies further contribute to an understanding of the role of antimicrobial peptides in the pathophysiology of burn injury, associated immunosuppression and sepsis and the possibility of using these other sites of HBD2 deposition for upregulation of antimicrobial synthesis in the treatment of burns.
 ...
PMID:Expression of human beta defensin 2 in thermal injury. 1547 36

Activated protein C (APC) has anti-inflammatory and vascular protective effects independent of anticoagulation. We previously identified the prototypical thrombin receptor, protease-activated receptor-1 (PAR1), as part of a novel APC-endothelial cell protein C receptor (EPCR) signaling pathway in endothelial cells. Experiments in wild-type and PAR1(-/-) mice demonstrated that intravenous injection of APC leads to PAR1-dependent gene induction in the lung. The vascular endothelium undergoes profound changes in severe sepsis, the approved therapeutic indication for APC. Similar to PAR1, APC activated PAR2 through canonical cleavage. Although PAR2 was up-regulated in cytokine-stimulated endothelial cells, APC signaling remained PAR1-dependent. Large scale gene expression profiling documented marked differences in both up- and down-regulated genes between APC and thrombin signaling in cytokine-stimulated cells. APC down-regulated transcripts for proapoptotic proteins including p53 and thrombospondin-1, but p53 was unchanged, and thrombospondin was even up-regulated by thrombin. Concordant PAR1-dependent effects on protein levels were found. Thus, by signaling through the same receptor PAR1, APC, and thrombin can exert distinct biological effects in perturbed endothelium. These data may explain how APC can be therapeutically protective through the EPCR-PAR1 signaling despite ongoing thrombin generation due to disseminated intravascular coagulopathy.
 ...
PMID:Protease-activated receptor-1 signaling by activated protein C in cytokine-perturbed endothelial cells is distinct from thrombin signaling. 1576 47

For many years the vascular endothelium was believed simply to provide a passive lining between circulating blood and extravascular tissue. It is now clear, however, that this monolayer of cells on the luminal surface of all blood vessels, provides a selective barrier that responds dynamically to various stimuli, and controls a complex series of cellular reactions and interactions. The current presentation describes the use of computer enhanced video recording to study interactions between endothelial cells and circulating blood cells, especially leucocytes. Subsequently, modern assays for soluble cell adhesion molecules and other cell receptors were assessed for potential use in routine clinical practice. The results demonstrated that adhesive mechanisms involving leucocytes and endothelial cells involve a range of interrelationships that cut across conventional views of haemostasis and leucocyte function. The findings also suggest that interplay between the vascular lumen and circulating blood cells might be vitally important in clinically demanding pathologies, such as life-threatening sepsis, ischaemic heart disease, atherosclerosis and cancer. The concepts provide challenging strategies for further investigation.
 ...
PMID:Soluble adhesion molecules in inflammatory and vascular diseases. 1578 16

The Kunitz-type proteinase inhibitor, tissue factor pathway inhibitor (TFPI), is the only endogenous inhibitor of the tissue factor (TF)-mediated coagulation pathway that plays a dominant role in normal haemostasis. TFPI exerts its action by binding to factor Xa (FXa) forming a TFPI-FXa complex that then, in a second step, binds and effectively inhibits the TF-factor VIIa (FVIIa) complex. Both full-length TFPI and chemically modified forms (e.g., truncated, glycosylated or phosphorylated TFPI variants) exert various pharmacological effects. The anticoagulant and antiplatelet actions of TFPI, its potency in inhibiting thrombin and FXa generation, as well as its favourable antithrombotic effectiveness seen in different animal models of venous and arterial thrombosis make this inhibitor a promising agent that could be potentially useful in several clinical indications. The inhibitory action of TFPI is accelerated by heparin. Heparin, as well as low molecular weight heparin (LMWH) derivatives, release TFPI from the vascular endothelium, an effect which seems to contribute mainly to the antithrombotic effectiveness of these drugs. The clinical relevance of TFPI is still undefined. Based on the beneficial actions in animal studies, as well as on the results obtained in first clinical investigations, TFPI is expected to be effective in the treatment of various diseases, such as disseminated intravascular coagulation, sepsis, coronary syndromes, stroke and acute respiratory distress syndrome (ARD). Further clinical trials should clarify the role of TFPI and more importantly define its potential usefulness as a prophylactic and/or therapeutic agent.
 ...
PMID:Recombinant TFPI and variants: potential implications in the treatment of cardiovascular disorders. 1599 20

This article reviews the major role that the vascular endothelium plays in pathophysiological processes related to metabolism, vascular function, and blood coagulation. Normally an antithrombotic surface, inflammation activates endothelium to become a prothrombotic and pro-inflammatory interface that is critically involved in multi-organ failure in patients with severe systemic diseases including sepsis. Improving endothelial functions in sepsis is a major therapeutic challenge.
 ...
PMID:The endothelium in intensive care. 1599 64

Exogenous activated protein C combines a marked anti-inflammatory effect on the vascular endothelium and anticoagulative and profibrinolytic activities. The total results of this action are better multiple organ microcirculation and, as a result, elimination and even prevention of irreversible changes in the vitally important organs. The many-sidedness and potency of this effect make the agent essential for intensive therapy of severe sepsis of various etiology. The Russian cooperative study of the efficacy of the exogenous activated protein C--drotrecogine alpha (activated)--has shown that its inclusion into therapy for sepsis with multiple organ dysfunction and septic shock results in longer estimated survival. With this, the best results are observed when therapy is initiated within 48 hours since the development of multiple organ deficiency.
 ...
PMID:[Exogenous activated protein C in severe sepsis]. 1607 46

Protein C is a plasma protease that when activated plays a central role in modulating the function of the vascular endothelium and its interface with the innate immune system. A recombinant form of human activated protein C (APC), drotrecogin alfa (activated), has shown efficacy in a number of preclinical models of thrombosis and ischemia and reduces mortality in patients that have a high risk of dying from severe sepsis. Studies have begun to elucidate the mechanism for the multifunctional role of APC in modulating not only coagulation, but also inflammation and apoptotic processes. From gene profiling to pharmacology studies, drotrecogin alfa (activated) appears to directly modulate endothelial dysfunction by blocking cytokine signaling, functional cell adhesion expression, vascular permeability and preventing the induction of apoptosis. Moreover, APC, via endothelial protein C receptor/protease activated receptor-1 mediated mechanisms, also appears to directly modulate leukocyte migration and adhesion. The ability of APC to suppress pro-inflammatory pathways and enhance cellular survival suggests that APC has a role in the adaptive response at the vessel wall, in which it protects the wall from vascular insult and prolongs endothelial, cellular, and organ survival. The emerging data further suggest that APC effectively modulates the complex changes that occur during multi-system activation and dysfunction in sepsis.
 ...
PMID:Activated protein C and sepsis. 1614 61

Cell migration plays important roles in embryonic development and inflammation, and this process is highly regulated to ensure tissue homeostasis. A number of barriers exist to prevent the inappropriate migration of leukocytes into healthy peripheral tissues, including retention of these cells in the inactive state and maintenance of the integrity and charge of the vascular endothelium. However, active signals also are likely to exist that can repulse cells or abolish existing cell migration. One such paradigm exists in the developing nervous system, where neuronal migration is mediated by a balance between chemoattractive and chemorepulsive signals. The ability of the guidance molecule netrin-1 to repulse or abolish attraction of neuronal cells expressing the UNC5b receptor makes it an attractive candidate for the regulation of inflammatory cell migration. Here, we show that netrin-1 is expressed on vascular endothelium, where it is regulated by infection and inflammatory cytokines. The netrin-1 receptor UNC5b is strongly expressed by leukocytes, upon which netrin-1 acts as a potent inhibitor of migration to different chemotactic stimuli both in vivo and in vitro. These data suggest that endothelial expression of netrin-1 may inhibit basal cell migration into tissues and that its down-regulation with the onset of sepsis/inflammation may facilitate leukocyte recruitment.
 ...
PMID:Netrin-1 inhibits leukocyte migration in vitro and in vivo. 1620 81

Lung inflammatory disease is characterized by increased polymorphonuclear leukocyte (PMN) infiltration and vascular permeability. PMN infiltration into tissue involves signaling between endothelial cells and migrating PMNs, which leads to alterations in the organization of adherens junctions (AJs). We addressed the possible role of the protein constituents of AJs, endothelium-specific vascular-endothelial (VE)-cadherin, in the migration of PMNs. Studies were made using VE-cadherin mutant constructs lacking the extracellular domain (DeltaEXD) or, additionally, lacking the COOH-terminus beta-catenin-binding domain (DeltaEXDDeltabeta). Either construct was transduced in pulmonary microvessel endothelia of mice using cationic liposome-encapuslated cDNA constructs injected intravenously. Optimal expression of constructs was seen by Western blot analysis within 24 h. Vessel wall liquid permeability measured as the lung microvessel capillary filtration coefficient increased threefold in DeltaEXD-transduced lungs, indicating patency of interendothelial junctions, whereas the control DeltaEXDDeltabeta construct was ineffective. To study lung tissue PMN recruitment, we challenged mice intraperitoneally with LPS (3 mg/kg) for 6 h and measured PMN numbers by bronchoalveolar lavage and their accumulation morphometrically in lung tissue. DeltaEXD expression markedly reduced the PMN sequestration and migration seen in nontransfected (control wild type) or DeltaEXDDeltabeta-transfected (negative control) mice challenged with LPS. In addition, DeltaEXD transfection suppressed LPS-induced activation of NF-kappaB and consequent ICAM-1 expression. These results suggest that disassembly of VE-cadherin junctions serves as a negative signal for limiting transendothelial PMN migration secondary to decreased ICAM-1 expression in the mouse model of LPS-induced sepsis.
 ...
PMID:Regulation of lung neutrophil recruitment by VE-cadherin. 1678 51

Tumor necrosis factor (TNF)-alpha is a key mediator of sepsis-associated multiorgan failure, including the acute respiratory distress syndrome. We examined the role of protein tyrosine phosphorylation in TNF-alpha-induced pulmonary vascular permeability. Postconfluent human lung microvascular and pulmonary artery endothelial cell (EC) monolayers exposed to human recombinant TNF-alpha displayed a dose- and time-dependent increase in transendothelial [(14)C]albumin flux in the absence of EC injury. TNF-alpha also increased tyrosine phosphorylation of EC proteins, and several substrates were identified as the zonula adherens proteins vascular endothelial (VE)-cadherin, and beta-catenin, gamma-catenin, and p120 catenin (p120(ctn)). Prior protein tyrosine kinase (PTK) inhibition protected against the TNF-alpha effect. TNF-alpha activated multiple PTKs, including src family PTKs. Prior PTK inhibition with the src-selective agents PP1 and PP2 each protected against approximately 60% of the TNF-alpha-induced increment in [(14)C]albumin flux. PP2 also blocked TNF-alpha-induced tyrosine phosphorylation of VE-cadherin, gamma-catenin, and p120(ctn). To identify which src family kinase(s) was required for TNF-alpha-induced vascular permeability, small interfering RNA (siRNA) targeting each of the three src family PTKs expressed in human EC, c-src, fyn, and yes, were introduced into the barrier function assay. Only fyn siRNA protected against the TNF-alpha effect, whereas the c-src and yes siRNAs did not. These combined data suggest that TNF-alpha regulates the pulmonary vascular endothelial paracellular pathway, in part, through fyn activation.
 ...
PMID:TNF-alpha increases tyrosine phosphorylation of vascular endothelial cadherin and opens the paracellular pathway through fyn activation in human lung endothelia. 1689 93


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>