UMLS:C0022116 - FACTA Search

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Query: UMLS:C0022116 (ischemia)
91,303 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Reperfusion of the ischemic heart is necessary to prevent irreversible injury of the myocardium, which leads to permanent organ dysfunction. However, reperfusion in itself leads to myocardial ischemia/reperfusion (I/R) injury, which is characterized by an acute inflammatory response mediated by activated inflammatory cells, chemokines, cytokines, and adhesion molecules. The molecular mechanisms of myocardial I/R injury are not completely known. Tissue factor (TF) and thrombin, two potent procoagulant and proinflammatory mediators, are recognized to play significant roles in myocardial I/R injury. To investigate the role of TF and thrombin in myocardial I/R injury, we used rabbit and murine in situ coronary artery ligation models. Increased TF mRNA, antigen, and activity were found in ischemic cardiomyocytes. Administration of an inhibitory antirabbit TF monoclonal antibody before or during the onset of ischemia resulted in a significant reduction in infarct size. Functional inhibition of thrombin with hirudin also reduced the infarct size. However, defibrinogenating rabbits with ancrod had no effect on infarct size, suggesting a requirement of thrombin generation but not fibrin deposition in myocardial I/R injury.
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PMID:Tissue factor and thrombin mediate myocardial ischemia-reperfusion injury. 1260 7

Abnormal uterine bleeding is the major reason for discontinuing long-term progesterone-only contraceptives (LTPOCs). Prior studies demonstrated that endometria exposed to the LTPOC, Norplant, display aberrant angiogenesis, leukocyte infiltration, and hypoxia-associated impaired blood flow. Paradoxically, human endometrial stromal cells (HESCs) of these specimens exhibit elevated expression of tissue factor (TF), the primary initiator of hemostasis via thrombin generation. The current study demonstrates that TF levels are also elevated in HESCs that are decidualized after insertion of Mirena, an intrauterine system that releases levonorgestrel directly into the endometrial canal and produces elevated perivascular levels of the proinflammatory and angiognenic cytokine IL-8. Because bleeding, inflammation, and ischemia-associated increased vascular permeability enhance access of plasma factor VII to HESC-expressed TF to generate thrombin, we evaluated the effects of steroids, thrombin, and hypoxia on HESC expression of IL-8. Confluent HESCs were incubated in a serum-containing medium for 7 d with vehicle control or estradiol (E(2)) plus medroxyprogesterone acetate (MPA). The medium was then exchanged for corresponding defined medium with and without thrombin, and the cultures were incubated in parallel for up to 48 h in a standard incubator (normoxia) or a sealed chamber at 0-1% O(2) (hypoxia). Under normoxia, immunoreactive IL-8 levels in the conditioned medium were reduced to one-third of control levels during decidualization with E(2)+MPA (P < 0.05; n = 5). In E(2)+MPA-treated cultures, thrombin (0.1 U/ml to 2.5 U/m) elicited a dose-dependent reversal of this inhibition, elevating IL-8 up to 60-fold (P < 0.05; n = 5) for more than 24 h and steady-state IL-8 mRNA levels by 3-fold for 3 h. The specific inactivator, hirudin, blocked most of the effects of thrombin, whereas TRAP-14, an agonist of the protease-activated receptor for thrombin, enhanced IL-8 output. In the absence of thrombin, hypoxia elevated IL-8 output 5-fold in E(2)+MPA-treated HESCs (P < 0.02, n = 4), with thrombin exerting additive effects. In contrast to its effects in progestin-treated HESCs, hypoxia did not elevate IL-8 output in control cultures. This study suggests that inhibition of IL-8 expression in decidualized HESCs contributes to the antiinflammatory milieu of the luteal phase. However, LTPOC-induced hypoxia and excess thrombin generation enhance IL-8 expression in decidualized HESCs, thereby eliciting aberrant angiogenesis and inflammation that promote the onset of abnormal uterine bleeding.
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PMID:Effects of thrombin, hypoxia, and steroids on interleukin-8 expression in decidualized human endometrial stromal cells: implications for long-term progestin-only contraceptive-induced bleeding. 1500 49

The last few years have clarified the tight link between inflammation and coagulation. In addition to the identification of new regulatory mechanisms of the coagulation system and of an explosive number of mediators of inflammation, it is now clear that the existence of a positive feed-back between inflammation and coagulation leads to reciprocal activation of both pathways. Plasma levels of acute phase proteins involved in coagulation and fibrinolysis are elevated during inflammation, while natural anticoagulant mechanisms are depressed. Pro-inflammatory cytokines "activate" cell membranes exposed to flowing blood (endothelium, platelets, monocytes, neutrophils) which from physiologically inert or anticoagulant become procoagulant. Increased tissue factor expression results in increased thrombin formation within the microcirculation. Thrombin is central to fibrin deposition but it also plays a key role in cell-mediated mechanisms involving inflammation, cell proliferation and activation of the natural anticoagulant protein C. Depression of natural anticoagulant mechanisms, occurring in severe sepsis, results in uncontrolled thrombin formation, with pro-inflammatory activity prevailing, and the feed-back loop of inflammation and coagulation ultimately leading to multi-organ failure. However, both in the clinical setting and in animal experiments, heparin or direct anticoagulants have shown no effect on survival even if blocking fibrin deposition. Organ failure is only partially due to the thrombotic occlusion of the microcirculation, while other mechanisms of endothelial damage are probably more relevant in the development of ischemia. The endothelium is central to the maintenance of the natural anticoagulant mechanisms (TFPI, antithrombin, protein C). The protein C system, in addition to dumping thrombin formation, specifically modulates inflammation by cell signaling. This system is markedly depressed in severe sepsis. The infusion of activated protein C, or restoring normal levels of protein C within the circulation - depending on the individual bleeding risk are powerful tools to treat the endothelitis responsible for the clinical sequelae of severe sepsis.
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PMID:[Protein C and coagulation in sepsis]. 1518 14

This article focuses on the role of the tissue factor (TF)-thrombin pathway in cardiac ischemia-reperfusion (I/R) injury. We and others have used rabbit models of cardiac I/R injury to show that anti-TF therapy prevents the transient decrease in regional myocardial blood flow, reduces platelet and fibrin(ogen) accumulation, and reduces infarct size. At present, the mechanism by which TF-initiated coagulation contributes to myocardial injury is not established. Inhibition of TF may decrease intravascular fibrin deposition and thrombosis. However, immunohistochemical studies demonstrated that fibrin deposition was predominantly within the myocardium and depletion of fibrinogen did not reduce infarct size. In contrast, inhibition of thrombin reduced infarct size to a similar extent as anti-TF therapy. We propose that the TF-thrombin pathway may contribute to myocardial injury by an additional mechanism that is not dependent on fibrin deposition but involves activation of protease activated receptor 1 (PAR-1) on vascular endothelial cells and cardiac myocytes. Anti-TF therapy would inhibit both thrombin-dependent fibrin deposition and thrombin-dependent PAR-1 signaling.
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PMID:The role of the tissue factor-thrombin pathway in cardiac ischemia-reperfusion injury. 1519 82

Following vessel wall injury, tissue factor (TF) is exposed and forms complexes with already activated factor VII (FVIIa) present in the circulating blood, thereby initiating the hemostatic process. After the first FXa is formed, the TF pathway inhibitor (TFPI) forms a complex with FXa, and a quaternary complex is formed, TF/FVIIa/ FXa/TFPI, which inhibits the first step of the hemostatic pathway. Recombinant activated FVII (rFVIIa) has been developed for use as a hemostatic agent (NovoNordisk A/S, Denmark). Active site-inactivated rFVIIa (rFVIIai) has also been prepared and was shown to have a faster association to and a slower dissociation from TF than rFVIIa, resulting in a lower calculated Kd of rFVIIai compared with rFVIIa. In various animal models rFVIIai has been demonstrated to prevent or diminish immediate thrombus formation at the site of vessel wall injury (athroplasty or other forms of mechanical injury) as well as the development of long-term intima thickening. The inflammatory response following endotoxin-induced sepsis was shown to decrease after administration of rFVIIai. Also, survival increased in the rFVIIai-treated animals in this study. In addition, ischemia-reperfusion injury was mitigated by rFVIIai. In a limited number of patients undergoing percutaneous transluminal coronary angioplasty (PTCA), rFVIIai was observed to allow PTCA to be performed at lower doses of heparin than what has been reported previously.
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PMID:rFVIIai in Acute Coronary Syndromes. 1519 83

Targeted thrombotic eradication of solid tumors is a novel therapeutic strategy. The feasibility, efficacy, selectivity, and safety are dependent on multiple variables of protein design, molecular assembly, vascular target, and exclusive restriction of function to the tumor vasculature. To advance this strategy, we describe a design of an integrin targeting selective tumor vascular thrombogen. We adopted the fibronectin structural motif of tandem repeating modules with four type III repeat modules of fibronectin followed by two structurally homologous modules of the extracellular domain of tissue factor. This hybrid protein of six tandem modules recognizes integrins and selectively docks and initiates the thrombogenic protease cascade locally on the target cell surfaces. The protein is inactive in blood but is functionally active once assembled on integrin-positive cells. When administered i.v. to tumor-bearing mice, it selectively induces extensive local microthrombosis of the tumor microvasculature. The principles are addressed from the perspective of protein structural design for a class of selective tumor vascular thrombogen proteins that, through interaction with tumor angiogenic endothelium, elicit thrombotic occlusion rather than apoptosis or arrest of angiogenesis. This response can produce local tumor infarction followed by intratumoral ischemia-reperfusion injury, inflammation, and a local host tumor eradicative response.
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PMID:A hybrid fibronectin motif protein as an integrin targeting selective tumor vascular thrombogen. 1525 40

Inflammation and platelet activation are critical phenomena in the setting of acute coronary syndromes. Platelets may contribute to increase ischemic injury by enhancing the inflammatory response of leukocytes and endothelial myocardial cells. Pharmacological inhibition of platelet activation prevents ischemic complications in patients with coronary diseases. Agents directed against the integrin glycoprotein IIb/IIIa (GP IIb/IIIa) receptor not only inhibit platelet aggregation but also have been demonstrated to limit the inflammatory response in acute coronary syndromes. The question then raised is if the inhibition of platelet activation by other mechanisms than the blockade of GP IIb/IIIa may also exert anti-inflammatory effects. The aim of the present study was to analyze if clopidogrel may exert anti-inflammatory effects during the acute phase of myocardial infarction. A ligature was placed around the left anterior descending coronary artery of New Zealand White rabbits. After 15 min of ischemia, the myocardium was reperfused and the ischemic coronary artery was isolated 24 h after the ischemia. A group of ischemic rabbits was given a single oral dose of clopidogrel (20 mg kg(-1)) just after the arterial occlusion and the animal was recovered. Sham-operated animals served as control. P-selectin expression was significantly increased in infarcted rabbits with respect to control rabbits. Clopidogrel administration reduced P-selectin expression with respect to untreated infarcted rabbits. CD40 ligand and tissue factor expression was increased in the ischemic coronary artery and reduced after clopidogrel administration. Clopidogrel also protected endothelial nitric oxide synthase protein expression in the ischemic coronary artery, a protein that has been found downregulated under inflammatory conditions. In conclusion, inhibition of platelet activation by clopidogrel exerted anti-inflammatory effects on the ischemic coronary artery.
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PMID:Effect of clopidogrel on the expression of inflammatory markers in rabbit ischemic coronary artery. 1604 1

Carbon monoxide (CO), an endogenous cytoprotective product of heme oxygenase type-1 regulates target thrombotic and inflammatory genes in ischemic stress. Regulation of the gene encoding early growth response 1 (Egr-1), a potent transcriptional activator of deleterious thrombotic and inflammatory cascades, may govern CO-mediated ischemic lung protection. The exact signaling mechanisms underlying CO-mediated cytoprotection are not well understood. In this study we tested the hypothesis that inhibition of mitogen-activated protein kinase-dependent Egr-1 expression may be pivotal in CO-mediated ischemic protection. In an in vivo isogeneic rat lung ischemic injury model, inhaled CO not only diminished fibrin accumulation and leukostasis and improved gas exchange and survival but also suppressed extracellular signal-regulated kinase (ERK) activation, Egr-1 expression, and Erg DNA-binding activity in lung tissue. Additionally, CO-mediated inhibition of Egr-1 reduced expression of target genes, such as tissue factor, serpine-1, interleukin-1, and TNF-alpha. However, CO failed to inhibit serpine-1 expression after unilateral lung ischemia in mice null for the Egr-1 gene. In RAW macrophages in vitro, hypoxia-induced Egr-1 mRNA expression was ERK-dependent, and CO-mediated suppression of ERK activation resulted in Egr-1 inhibition. Furthermore, CO suppression of ERK phosphorylation was reversed by the guanylate cyclase inhibitor 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one but was insensitive to cAMP-dependent protein kinase A inhibition with H89 and NO synthase inhibition with l-nitroarginine methyl ester. This finding indicates that CO suppresses ERK in a cGMP-dependent but cAMP/protein kinase A- and NO-independent manner. Together, these data identify a unifying molecular mechanism by which CO interrupts proinflammatory and prothrombotic mediators of ischemic injury.
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PMID:Carbon monoxide rescues ischemic lungs by interrupting MAPK-driven expression of early growth response 1 gene and its downstream target genes. 1655 42

Ischemia/reperfusion (IR) injury is a leading cause of acute renal failure and an important contributor to allograft damage. Tissue factor (TF) is up-regulated during IR, and TF inhibition reduces renal injury. However, the underlying mechanisms by which TF contributes to injury have not been elucidated. We postulated that TF contributes to IR injury by production of coagulation proteases and subsequent signaling by protease activated receptor (PARs). We compared renal injury after 25 minutes of bilateral renal ischemia and varying periods of reperfusion in C57BL/6 mice, those expressing low levels of TF (low-TF), hirudin-treated C57BL/6, and mice lacking either PAR-1 or PAR-2. C57BL/6 mice developed severe renal failure and died within 48 hours of reperfusion. In contrast, low-TF, hirudin-treated C57BL/6, and PAR-1-/- mice were protected from renal failure and had reduced mortality, tubular injury, neutrophil accumulation, and lower levels of the chemokines KC and MIP-2. Importantly, PAR-1-/- mice had lower chemokine levels despite up-regulation of TF and fibrin deposition. In addition, treating PAR-1-/- mice with hirudin conferred no additional benefit. Somewhat surprisingly, PAR-2 deficiency did not protect from renal failure. These experiments indicate that increased TF activity after renal IR leads to increased CXC chemokine expression and subsequent neutrophil-mediated injury predominantly by thrombin-dependent PAR-1 signaling.
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PMID:Tissue factor deficiency and PAR-1 deficiency are protective against renal ischemia reperfusion injury. 1699 Jun 8

Adenosine is an endogenous purine nucleoside that, following its release into the extracellular space, binds to specific adenosine receptors expressed on the cell surface. Adenosine appears in the extracellular space under metabolically stressful conditions, which are associated with ischemia, inflammation, and cell damage. There are 4 types of adenosine receptors (A(1), A(2A), A(2B) and A(3)) and all adenosine receptors are members of the G protein-coupled family of receptors. Adenosine receptors are expressed on monocytes and macrophages and through these receptors adenosine modulates monocyte and macrophage function. Since monocytes and macrophages are activated by the same danger signals that cause accumulation of extracellular adenosine, adenosine receptors expressed on macrophages represent a sensor system that provide monocytes and macrophages with information about the stressful environment. Adenosine receptors, thus, allow monocytes and macrophages to fine-tune their responses to stressful stimuli. Here, we review the consequences of adenosine receptor activation on monocyte/macrophage function. We will detail the effect of stimulating the various adenosine receptor subtypes on macrophage differentiation/proliferation, phagocytosis, and tissue factor (TF) expression. We will also summarize our knowledge of how adenosine impacts the production of extracellular mediators secreted by monocytes and macrophages in response to toll-like receptor (TLR) ligands and other inflammatory stimuli. Specifically, we will delineate how adenosine affects the production of superoxide, nitric oxide (NO), tumor necrosis factor-alpha, interleukin (IL)-12, IL-10, and vascular endothelial growth factor (VEGF). A deeper insight into the regulation of monocyte and macrophage function by adenosine receptors should assist in developing new therapies for inflammatory diseases.
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PMID:Shaping of monocyte and macrophage function by adenosine receptors. 1705 21

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