Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0022116 (ischemia)
 91,303 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Exposure of the vessel wall to hypoxemia is a central feature of ischemic cardiovascular disease. This led us to examine the perturbation of endothelial cell properties under hypoxia. An atmosphere of pO2 of 12 mmHg is not lethal to the endothelial cells for up to five days, but barrier function was impaired. Increased passage of macromolecule tracers were observed in time- and dose-dependent manner and electron microscopy demonstrated small gaps (0.5-1.0 micron) between cells. Expression of the anticoagulant cofactor thrombomodulin was also perturbed: thrombomodulin activity and antigen decreased in parallel. Northern blots showed almost complete suppression of thrombomodulin in hypoxic culture. Furthermore, synthesis of other proteins, such as fibronectin, was slightly enhanced under hypoxia. In addition to the suppression of these anticoagulant cofactor, hypoxic endothelial cell displayed a noval procoagulant activity distinct from tissue factor. Further study revealed that hypoxic endothelial cultures directly activated Factor X, as assessed by functional assays and SDS-PAGE. In addition to this no activation of Factor IX or prothrombin was observed. The hypoxia-induced Factor X activator was membrane-associated, required calcium to form Factor Xa, was inhibited by HgCl2 but not by PMSF, and had Km approximately 25 micrograms/ml. Co-incubation of hypoxic cultures with cycloheximide prevented the expression of this activity, suggesting that protein synthesis is required for its expression. These functional perturbations of endothelial cells were reversible following reoxygenation. These data indicate that hypoxia imposes a selective perturbation on endothelial cell function, suggesting the possible contribution of hypoxemia to vascular dysfunction in ischemia.
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PMID:Modulation of endothelial function by hypoxia: perturbation of barrier and anticoagulant function, and induction of a novel factor X activator. 196 56

Yucatan miniature swine were the experimental model used to examine the effect of ischemia-injury on post-ischemic monocyte (MO) and immune function. Monocyte plasminogen activator (PA) was depressed while MO tissue factor activity was increased. The ability of porcine monocytes to generate a primary in vitro antibody forming cell (AFC) response to sheep red blood cells (SRBC) also was depressed by ischemic injury. The mechanism by which ischemic injury modulated immunosuppression appeared to be through generation of immunosuppressive serum substances.
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PMID:Post-ischemia immunosuppression in a miniature swine model. 377 45

Alveolar and interstitial fibrin deposition is a prominent pathologic feature in many acute lung injury syndromes. Previous studies have suggested that ischemic lung preservation has a stimulatory effect on donor alveolar macrophages (Mphis) during transplantation. An animal model of lung preservation was developed to examine the hypothesis that ischemia enhances Mphi procoagulant activity (PCA) as a potential mechanism contributing to lung reperfusion injury. Histologic examination of ischemic lungs reperfused ex vivo revealed evidence of alveolar fibrin deposition. Mphis lavaged from lungs stored for at least 8 h at 21 degrees C exhibited increased PCA. The use of factor-deficient human plasma characterized this Mphi procoagulant as tissue factor (TF). Since increased PCA correlated with decreased airspace pO2 at the end of preservation, the effect of various O2 concentrations on PCA induction in vivo and in vitro was examined. Lung inflation during ischemia with decreasing O2 concentrations confirmed that hypoxia was associated with a rise in Mphi PCA in situ. However, in vitro exposure of Mphis to hypoxia did not increase Mphi PCA, suggesting that hypoxia alone was not responsible for induction of this procoagulant effect. Northern blot analysis demonstrated an increase in TF mRNA levels from in situ but not in vitro Mphis, thereby confirming transcriptional TF induction in this group. In addition, enhanced PCA was observed when Mphis were suspended in the bronchoalveolar lavage supernatant from the ischemic lungs stored at 21 degrees C. This suggests that in situ lung ischemia and hypoxia may produce soluble factors that either directly or indirectly stimulate Mphi TF expression. These factors may contribute to Mphi-mediated ischemic lung injury.
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PMID:In situ ischemia and hypoxia enhance alveolar macrophage tissue factor expression. 791 12

Tissue factor is a transmembrane protein that activates the extrinsic coagulation pathway by binding factor VII. Endothelial cells, being in contact with circulating blood, do not normally express tissue factor. Here we provide evidence that oxygen free radicals induce tissue factor messenger RNA transcription and expression of tissue factor procoagulant activity in endothelial cells in culture. Isolated, perfused rabbit hearts exposed to exogenous oxygen free radicals also showed a marked increase in tissue factor activity within the coronary circulation. Furthermore, in ex vivo and in vivo hearts subjected to ischemia and reperfusion, a condition associated with a production of oxygen free radicals in large amounts, a marked increase in tissue factor activity occurred. This phenomenon could be abolished by oxygen radical scavengers. This increase in tissue factor activity during postischemic reperfusion was accompanied by a significant decrease in coronary flow, suggesting that increase in tissue factor activity with the consequent activation of the coagulation cascade might impair coronary flow during reperfusion and possibly contribute to the occurrence of reperfusion injury.
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PMID:Effects of tissue factor induced by oxygen free radicals on coronary flow during reperfusion. 856 35

Tissue factor pathway inhibitor (TFPI) is a novel agent that binds to tissue factor/VIIa complex and factor-Xa, thereby reducing the effect of tissue factor (TF) on inflammation and the extrinsic pathway of coagulation. We hypothesize that systemic treatment with TFPI may limit ischemia-reperfusion (IR) injury. Our experiment was designed to evaluate the effects of TFPI on IR in the spinal cord. Twenty-three adult New Zealand white rabbits had snare occlusion devices placed circumferentially around the aorta and tunneled to a subcutaneous position. Forty-eight hours later, in the fully awake state, the animals were treated with either TFPI (1 mg/kg bolus followed by a 1-hr infusion of 20 microgram/kg/min), or heparin (100 U/kg bolus) followed by a 1-hr infusion of 10 ml/kg/hr of PBS while controls received phosphate buffered saline (20 ml followed by a 1-hr infusion of 10 ml/kg/hr). The infrarenal aorta was occluded for 21 min in all groups via the snare device. Animals were observed for 3 days and neurologic recovery was graded by the Tarlov criteria. Results were evaluated as percent of animals with hindlimb recovery (Tarlov 3 and 4). At 24 hr postocclusion, 88% of the TFPI-treated animals had recovered neurologic function versus only 20% of heparin-treated animals and 10% of the phosphate buffered saline group (P=0.031 and 0.009, respectively). At 72 hr, 63% of the TFPI animals retained neurologic function versus 20% of heparin-treated animals and 10% of phosphate buffered saline-treated animals (P=0.032, TFPI versus phosphate buffered saline). The mechanism of action of TFPI is not completely understood, yet this drug may hold promise in the prevention of IR injury of the spinal cord.
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PMID:Tissue factor pathway inhibitor protects the ischemic spinal cord. 866 Nov 93

Tissue factor pathway of coagulation plays a dominant role during normal haemostasis. Tissue factor pathway inhibitor (TFPI), expressed primarily by the microvascular endothelium, appears to be the major physiologic inhibitor of TF-induced coagulation. TF-initiated coagulation also plays an important role in the pathophysiology of many diseases including coronary thrombosis, sepsis, disseminated intravascular coagulation, stroke, cancer, acute respiratory distress syndrome, and ischemia-reperfusion injury. Several animal studies have found a beneficial effect of anti-TF monoclonal antibodies and, recombinant TFPI in some of the above clinical conditions. rTFPI is presently being used in clinical trials in patients with sepsis and in those following microvascular surgery. This article discusses many of the animal studies addressing inhibition of TF-induced coagulation, as well as potential therapeutic uses of rTFPI in humans.
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PMID:Tissue factor pathway inhibitor: potential therapeutic applications. 919 99

Polymorphonuclear neutrophils (PMN) and monocytes play a role in vascular diseases. Animal experimental models, using deleukocytation or injection of anti-CD11b-anti-CD18 monoclonal antibodies (inhibition of leukocytic adhesion and of interaction with the endothelial cell) have confirmed this role in the ischemia-reperfusion syndrome and in myocardial infarction. In man, increased production of oxygen radicals, PMN release of elastase, increased monocyte formation of tissue factor (TF) and integrins have been noted in coronary artery disease, in chronic arteriopathy of the lower limbs and in association with vascular risk factors such as diabetes. Pharmacological alteration of leukocyte hyperactivity therefore seems to be justified. Pentoxifylline, used with good effect in arteriopathy of the lower limbs, affects numerous leukocytic functions: diminution in adherence and in PMN production of free radicals, diminution in the formation of TF and cytokines (TNF). Gingkolides reduce leukocytic interactions and platelet activation through an anti-PAF (Platelet Activation Factor) action. Aspirin may interfere with free radicals and inhibit TF formation. alpha-tocopherol blocks the activation, by free radicals, of the transcription factor NF k B. By altering the TNF and IL-1 cytokines, leukocytic activation can be controlled. Other cytokines (IL-4, IL-10) have an immunosuppressive action and reduce the formation of TF. The pharmacological targets are therefore multiple. Their use in vascular diseases is only at a very preliminary stage.
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PMID:[Modulators of leukocytic functions]. 960 25

To evaluate the involvement of tissue factor (TF) in blood coagulation reflecting injury of the blood vessels induced by reperfusion following ischemic treatment in rat abdominal blood vessels in vivo, both TF expression and prothrombin time (PTT), which is used as a marker of coagulation, were measured after ischemic-reperfusion treatment. TF expression was significantly increased at 0 and 5 min after reperfusion following a 30 min period of vessel ligation, while the PTT was significantly shortened at 5 and 10 min. On the other hand, the change of TF expression and PTT were not detected in the animals ligated vessel for 15 min. These results suggest that TF plays an important role in the injury after reperfusion following ischemia.
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PMID:Enhancement of tissue factor following ischemic-reperfusion injury in rats. 1010 May 7

The adherence of activated neutrophils to endothelial cells during ischemia/reperfusion injury is mediated by inside-out signal transduction. Subsequently, outside-in signal transduction occurs following ligation of adhesion molecules with their ligands triggering respiratory bursts of neutrophils. In addition, neutrophil elastase enhances CC- and CXC-chemokine production by monocytes and macrophages. MCP-1, a CC-chemokine, enhances tissue factor production by macrophages and increases ICAM-1 expression on endothelial cells. Chemotaxis and respiratory bursts of neutrophils are augmented by CXC-chemokines. Furthermore, neutrophil elastase inactivates anticoagulants including antithrombin III, heparin cofactor II, and thrombomodulin, suggesting that neutrophil elastase aggravates microcirculatory disturbance after ischemia/reperfusion. Thus neutrophil elastase modulates the interation of neutrophils and endothelial cells during ischemia/reperfusion injury. Taken together with these observations, a therapeutic regimen with antibodies against adhesion molecules in combination with neutrophil elastase inhibitor and anticoagulants may attenuate ischemia/reperfusion injury.
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PMID:[Interaction between neutrophils and endothelial cells following ischemia/reperfusion]. 1041 50

The expression of tissue factor (TF), tissue factor pathway inhibitor (TFPI), von Willebrand factor (vWF), endothelial nitric oxide (NO) synthase (eNOS), tissue plasminogen activator (tPA), its inhibitor (PAI-1), and myosin, an indicator of local shear stress, was examined in the endothelium of cerebral vessels according to vessel size and location in human autopsy brains, using immunohistochemistry. Expression of TF, vWF, eNOS, tPA/PAI-1, and myosin was much greater in intracerebral perforating arteries and the microvasculature than the pial and carotid arteries. Expression of all antigens studied was normally faint or negative in the pial and carotid arteries. However, TF, vWF, myosin, tPA, and PAI-1 were strongly expressed in the endothelium of the inner wall of the carotid bifurcation where flowing blood collides, but not in the outer wall. In the endothelium of arteries with fibrillary hyperplasia, vWF, myosin, eNOS, tPA, and PAI-1 were strongly expressed. Within the brain, microvascular expression of TFPI was very faint or negative, whereas that of vWF was intense throughout all brain regions. However, expression of TF and myosin was more intense in the basal gray matter and white matter than in the cortex. eNOS was expressed more strongly in the basal gray matter and cortex than the white matter, whereas tPA and PAI-1 expression was more intense in the white matter than the gray matter. In addition to intrinsic properties of individual vessels, these local variations in expression of pro- and antithrombotic factors in cerebral vessels may in part be due to differences in hemorheological and humoral environments to which they are exposed, and may result in local difference in vulnerability to ischemia. The present findings may in part account for the propensity of thrombus generation in the carotid inner wall, an usual source of artery-to-artery microemboli, frequent development of lacunar (small) infarcts in deep brain regions, and diffuse white matter lesions as seen in Binswanger's leukoencephalopathy.
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PMID:Local variation in expression of pro- and antithrombotic factors in vascular endothelium of human autopsy brain. 1044 49


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