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

The coagulant and inflammatory exacerbation in sepsis is counterbalanced by the protective protein C (PC) pathway. Activated PC (APC) was shown to use the endothelial cell PC receptor (EPCR) as a coreceptor for cleavage of protease activated receptor 1 (PAR1) on endothelial cells. Gene profiling demonstrated that PAR1 signaling could account for all APC-induced protective genes, including the immunomodulatory monocyte chemoattractant protein-1 (MCP-1), which was selectively induced by activation of PAR1, but not PAR2. Thus, the prototypical thrombin receptor is the target for EPCR-dependent APC signaling, suggesting a role for this receptor cascade in protection from sepsis.
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PMID:Activation of endothelial cell protease activated receptor 1 by the protein C pathway. 1205 63

Cellular signaling by proteases of the blood coagulation cascade through members of the protease-activated receptor (PAR) family can profoundly impact on the inflammatory balance in sepsis. The coagulation initiation reaction on tissue factor expressing cells signals through PAR1 and PAR2, leading to enhanced inflammation. The anticoagulant protein C pathway has potent anti-inflammatory effects, and activated protein C signals through PAR1 upon binding to the endothelial protein C receptor. Activation of the coagulation cascade and the downstream endothelial cell localized anticoagulant pathway thus have opposing effects on systemic inflammation. This dichotomy is of relevance for the interpretation of preclinical and clinical data that document nonuniform responses to anticoagulant strategies in sepsis therapy.
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PMID:Science review: role of coagulation protease cascades in sepsis. 1272 May 55

The anti-inflammatory effects of activated protein C (APC) have lead to its recent approval for the treatment of sepsis. Although the endothelial cell protein C receptor (EPCR) plays a crucial role in APC's protective roles in septicemia, the precise signaling mechanism of the protease APC remains unclear. In fibroblast overexpression systems, we find that APC activates protease activated receptors (PAR) 1 and 2 in an EPCR-dependent manner. Human endothelial cells (HUVECs) express PAR1, PAR2 and EPCR. Stimulation of HUVECs with either APC, or specific receptor activating peptides for PAR1 or PAR2, show that all three agonists induce a very similar set of early response genes as assessed by high density microarray analysis. Only the transcript for monocyte chemo-attractant protein-1 (MCP-1) was selectively induced by APC and the PAR1 agonist, but not by the PAR2 agonist. APC-mediated MAP kinase phosphorylation and gene induction were inhibited by cleavage blocking antibodies to PAR1, demonstrating that APC signals exclusively through PAR1 in endothelial cells. MCP-1 is protective in animal models of endotoxemia, suggesting that APC may prevent lethality in sepsis by inducing MCP-1 expression through EPCR-dependent activation of endothelial cell PAR1. These data demonstrate unexpected protective functions of the major thrombin receptor PAR1 in endothelial cells.
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PMID:Activated protein C signals through the thrombin receptor PAR1 in endothelial cells. 1457 49

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.
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PMID:Protease-activated receptor-1 signaling by activated protein C in cytokine-perturbed endothelial cells is distinct from thrombin signaling. 1576 47

Coagulation and inflammation are intimately linked and cellular signaling by coagulation proteases through protease-activated receptors (PARs) may affect pro- and anti-inflammatory responses. Permeability of the endothelial cell barrier at the blood-tissue interface plays a key role in inflammatory disorders such as sepsis. We have recently shown that PAR1 signaling by activated protein C or low concentrations of thrombin can enhance endothelial barrier integrity. In the present study, we analyzed effects of coagulation factor Xa (FXa), which is known to activate both endothelial cell PAR1 and PAR2, on monolayer integrity using a transformed human umbilical vein endothelial cell (HUVEC) line in a dual-chamber system. Preincubation with FXa potently reduced high-dose thrombin-mediated hyperpermeability and basal permeability. FXa was protective at concentrations of 5 nm or higher and proteolytic activity was required. Barrier protective FXa signaling was not affected by cleavage-blocking anti-PAR1 antibodies or by a PAR1 antagonist. Similarly, cleavage-blocking anti-PAR2 alone had no effect, but blocking both PAR1 and PAR2 inhibited barrier protection by FXa. Incubation of the cell layer with a PAR2-specific agonist peptide reduced thrombin-mediated hyperpermeability and basal permeability similar to FXa. In conclusion, not only PAR1, but also PAR2 can mediate barrier protection in endothelial cells and FXa can use either receptor to enhance barrier integrity. Although it is currently unknown whether PAR signaling by FXa has a physiological role, the results suggest a potential protective effect of FXa and other agonists of endothelial PAR2, which should be explored in models of local and systemic inflammation in vivo.
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PMID:Protease-activated receptors-1 and -2 can mediate endothelial barrier protection: role in factor Xa signaling. 1635 18

The liver can be injured and its functions altered by activation of the coagulation and inflammatory processes in sepsis. The objective of the present study was to investigate the pattern of protease- activated receptors (PARs) over time in a model of acute liver injury induced by lipopolysaccharide (LPS); and whether PARs play a role in this process and exert their effects through inflammation and coagulation. Levels of tumor necrosis factor-a (TNF-a) were significantly expressed 1 h after LPS administration followed by: i) an increase in levels of tissue factor, factor VIIa, thrombin and plasminogen activator inhibitor-1; ii) unchanged or steady levels of tissue factor pathway inhibitor; and iii) subsequent deposition of fibrin in the liver tissue, that led to the elevation of aspartate aminotransferase (AST) and alanine aminotransferase (ALT), which are associated with liver injury. The expression of all PAR isoforms (1-4) was elevated, and each isoform had a distinct cellular localization (hepatocytes, Kupffer cells, the portal triad area, and central veins) and a time-dependent pattern of expression. The immuno-reactivity of PAR2 and 4 in Kupffer cells was intense. Interestingly, PAR2 blocking peptide improved the healing of liver injuries, an effect that was associated with suppression of TNF-a elevation, and normalization of coagulation and fibrinolysis. This ultimately led to decreased fibrin formation in the injured liver. The present study reveals a distinct chronological expression and cellular localization of PARs in LPS-mediated liver injury and shows that blockade of PAR2 may play a crucial role in treating liver injury, via normalization of inflammation, coagulation and fibrinolytic pathways.
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PMID:Chronological expression of PAR isoforms in acute liver injury and its amelioration by PAR2 blockade in a rat model of sepsis. 1713 80

Tissue factor (TF) is the primary initiator of coagulation, and the TF pathway mediates signaling through protease-activated receptors (PARs). In sepsis, TF is up-regulated as part of the proinflammatory response in lipopolysaccharide (LPS)-stimulated monocytes leading to systemic coagulation activation. Here we demonstrate that TF cytoplasmic domain-deleted (TF(Delta CT)) mice show enhanced and prolonged systemic coagulation activation relative to wild-type upon LPS challenge. However, TF(Delta CT) mice resolve inflammation earlier and are protected from lethality independent of changes in coagulation. Macrophages from LPS-challenged TF(Delta CT) mice or LPS-stimulated, in vitro-differentiated bone marrow-derived macrophages show increased TF mRNA and functional activity relative to wild-type, identifying up-regulation of macrophage TF expression as a possible cause for the increase in coagulation of TF(Delta CT) mice. Increased TF expression of TF(Delta CT) macrophages does not require PAR2 and is specific for toll-like receptor, but not interferon gamma receptor, signaling. The presence of the TF cytoplasmic domain suppresses ERK1/2 phosphorylation that is reversed by p38 inhibition leading to enhanced TF expression specifically in wild-type but not TF(Delta CT) mice. The present study demonstrates a new role of the TF cytoplasmic domain in an autoregulatory pathway that controls LPS-induced TF expression in macrophages and procoagulant responses in endotoxemia.
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PMID:Regulation of macrophage procoagulant responses by the tissue factor cytoplasmic domain in endotoxemia. 1733 47

Sepsis is a deadly disease characterized by considerable derangement of the proinflammatory, anti-inflammatory and coagulation responses. Protease-activated receptor 1 (PAR1), an important regulator of endothelial barrier function and blood coagulation, has been proposed to be involved in the lethal sequelae of sepsis, but it is unknown whether activation of PAR1 is beneficial or harmful. Using a cell-penetrating peptide (pepducin) approach, we provide evidence that PAR1 switched from being a vascular-disruptive receptor to a vascular-protective receptor during the progression of sepsis in mice. Unexpectedly, we found that the protective effects of PAR1 required transactivation of PAR2 signaling pathways. Our results suggest therapeutics that selectively activate PAR1-PAR2 complexes may be beneficial in the treatment of sepsis.
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PMID:'Role reversal' for the receptor PAR1 in sepsis-induced vascular damage. 1796 15

Tissue factor (TF) is a member of the cytokine receptor superfamily and binds FVII/VIIa. The TF:FVIIa complex has both procoagulant and signaling activities. It functions in many biological processes, including hemostasis, thrombosis, inflammation, angiogenesis and tumor growth. Importantly, TF is essential for hemostasis. However, increased TF expression within atherosclerotic plaques and elevated levels of circulating TF-positive micro particles promote thrombosis. TF increases inflammation by enhancing intravascular fibrin deposition, by increasing the formation of pro-inflammatory fragments of fibrin and by generating coagulation proteases, including FVIIa, FXa and thrombin, that activate protease-activated receptors (PARs). In endotoxemia and sepsis, TF-dependent thrombin generation and activation of PAR1 on dendritic cells enhance inflammation. Finally, the TF:FVIIa complex contributes to tumor growth by activating PAR2.
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PMID:The many faces of tissue factor. 1963 Jul 86