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)

Three major cytokines, namely, tumor necrosis factor (TNF-alpha), interleukin (IL)-1, and IL-6 are produced by cultured brain cells after various stimuli such as ischemia. Neurones, astrocytes, microglia and oligodendrocytes can produce inflammatory mediators, and cytokine receptors are expressed constitutionally throughout the Central Nervous System (CNS), albeit at low levels. Cytokines are involved in virtually every facet of stroke and they have numerous pro-inflammatory and pro-coagulant effects on endothelium. TNF-alpha expression after stroke stimulates expression of tissue factor and adhesion molecules for leukocytes, release of interleukin-1 (IL-1), nitric oxide, factor VIII/von Willebrand factor, platelet-activating factor and endothelin, suppression of the thrombomodulin-protein C-protein S system, reduction of tissue-plasminogen activator and release of plasminogen activator inhibitor-1. Research into the actions of IL-1beta in the brain initially focused on its role in host defence responses to systemic disease. IL-1beta can also elicit an array of responses which could either inhibit, exacerbate or induce neuronal damage and death. IL-6 can be induced by a variety of molecules including IL-1, TNF-alpha, transforming growth factor-beta and prostaglandins (PGs), and many other mediators such as b-amyloid, interferon-g (IFNg) and IL-4 can potentiate these primary inducers, highlighting the complex nature of IL-6 modulation. Several studies reported that plasma levels of TNF-alpha and IL-6 are associated with prognosis after ischemic stroke and our group showed that plasma levels of cytokines such as TNF-alpha, IL-1beta are different in every diagnostic subtype of ischemic stroke, and how plasma levels of some immunoinflammatory markers and thrombotic-phybrinolitic markers are predictive of acute ischemic stroke diagnosis in the acute setting.
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PMID:Inflammatory cytokines in acute ischemic stroke. 1907 34

Altered coagulation and inflammation contribute to the pathogenesis of ischemic renal injury. Thrombomodulin is a necessary factor in the anticoagulant protein C pathway and has inherent anti-inflammatory properties. We studied the effect of soluble thrombomodulin (sTM) in a hypoperfusion model of ischemic kidney injury. To markedly reduce infrarenal aortic blood flow and femoral arterial pressures, we clamped the suprarenal aorta of rats, occluding them 90%, for 60 min. Reversible acute kidney injury (AKI) occurred at 24 h in rats subjected to hypoperfusion. Histologic analysis at 24 h revealed acute tubular necrosis (ATN), and intravital two-photon microscopy showed flow abnormalities in the microvasculature and defects of endothelial permeability. Pretreatment with rat sTM markedly reduced both I-R-induced renal dysfunction and tubular histologic injury scores. sTM also significantly improved microvascular erythrocyte flow rates, reduced microvascular endothelial leukocyte rolling and attachment, and minimized endothelial permeability to infused fluorescence dextrans, assessed by intravital quantitative multiphoton microscopy. Furthermore, sTM administered 2 h after reperfusion protected against ischemia-induced renal dysfunction at 24 h and improved survival. By using an sTM variant, we also determined that the protective effects of sTM were independent of its ability to generate activated protein C. These data suggest that sTM may have therapeutic potential for ischemic AKI.
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PMID:Soluble thrombomodulin protects ischemic kidneys. 1917 99

The diagnosis of disseminated intravascular coagulation (DIC) should encompass both clinical and laboratory information. The International Society for Thrombosis and Haemostasis (ISTH) DIC scoring system provides objective measurement of DIC. Where DIC is present the scoring system correlates with key clinical observations and outcomes. It is important to repeat the tests to monitor the dynamically changing scenario based on laboratory results and clinical observations. The cornerstone of the treatment of DIC is treatment of the underlying condition. Transfusion of platelets or plasma (components) in patients with DIC should not primarily be based on laboratory results and should in general be reserved for patients who present with bleeding. In patients with DIC and bleeding or at high risk of bleeding (e.g. postoperative patients or patients due to undergo an invasive procedure) and a platelet count of <50 x 10(9)/l transfusion of platelets should be considered. In non-bleeding patients with DIC, prophylactic platelet transfusion is not given unless it is perceived that there is a high risk of bleeding. In bleeding patients with DIC and prolonged prothrombin time (PT) and activated partial thromboplastin time (aPTT), administration of fresh frozen plasma (FFP) may be useful. It should not be instituted based on laboratory tests alone but should be considered in those with active bleeding and in those requiring an invasive procedure. There is no evidence that infusion of plasma stimulates the ongoing activation of coagulation. If transfusion of FFP is not possible in patients with bleeding because of fluid overload, consider using factor concentrates such as prothrombin complex concentrate, recognising that these will only partially correct the defect because they contain only selected factors, whereas in DIC there is a global deficiency of coagulation factors. Severe hypofibrinogenaemia (<1 g/l) that persists despite FFP replacement may be treated with fibrinogen concentrate or cryoprecipitate. In cases of DIC where thrombosis predominates, such as arterial or venous thromboembolism, severe purpura fulminans associated with acral ischemia or vascular skin infarction, therapeutic doses of heparin should be considered. In these patients where there is perceived to be a co-existing high risk of bleeding there may be benefits in using continuous infusion unfractionated heparin (UFH) due to its short half-life and reversibility. Weight adjusted doses (e.g. 10 mu/kg/h) may be used without the intention of prolonging the APTT ratio to 1.5-2.5 times the control. Monitoring the APTT in these cases may be complicated and clinical observation for signs of bleeding is important. In critically ill, non-bleeding patients with DIC, prophylaxis for venous thromboembolism with prophylactic doses of heparin or low molecular weight heparin is recommended. Consider treating patients with severe sepsis and DIC with recombinant human activated protein C (continuous infusion, 24 microg/kg/h for 4 d). Patients at high risk of bleeding should not be given recombinant human activated protein C. Current manufacturers guidance advises against using this product in patients with platelet counts of <30 x 10(9)/l. In the event of invasive procedures, administration of recombinant human activated protein C should be discontinued shortly before the intervention (elimination half-life approximately 20 min) and may be resumed a few hours later, dependent on the clinical situation. In the absence of further prospective evidence from randomised controlled trials confirming a beneficial effect of antithrombin concentrate on clinically relevant endpoints in patients with DIC and not receiving heparin, administration of antithrombin cannot be recommended. In general, patients with DIC should not be treated with antifibrinolytic agents. Patients with DIC that is characterised by a primary hyperfibrinolytic state and who present with severe bleeding could be treated with lysine analogues, such as tranexamic acid (e.g. 1 g every 8 h).
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PMID:Guidelines for the diagnosis and management of disseminated intravascular coagulation. British Committee for Standards in Haematology. 1922 77

Thrombomodulin (TM), a cell surface-expressed glycoprotein predominantly synthesized by vascular endothelial cells, is a critical cofactor for thrombin-medicated activation of protein C. TM thus has an impact on coagulation, inflammation, and fibrinolysis. In this study, we investigated expression of endothelial TM in the dorsal skin of the rat as an ischemic flap model. Twenty male Wistar rats weighing between 250 and 350 g were used in the study. Nine by 3-cm, full-thickness, caudally based random pattern dorsal skin flaps were elevated. The rats were randomized into 2 subgroups according to the evaluation time. Tissue blood flow of the skin flaps was measured 4 times (before the operation and on days 1, 3, and 7) at 1, 3, and 5 cm distal to the baseline of the skin flap. Skin flap samples including subcutaneous tissue were taken from killed rats at day 3 (n = 10) and 7 (n = 10) for histologic assessment. These samples were also taken from the midline at 1, 3, and 5 cm distal to the baseline of the skin flaps. The survival rate of the skin flaps was measured on day 7. According to the blood flow rate change, we found that there were significant differences between the 1-, 3-, and 5-cm samples throughout the experiment. The most profound change was that it was at 5 cm in which there was an initial pattern of reduced perfusion followed by cessation of perfusion. On the third day, positive immunoperoxidase staining specific for TM was detected in all the specimens of the skin biopsies taken from 1 and 3 cm. The 5-cm samples demonstrated very little evidence of necrosis and had negative immunoperoxidase staining for TM. The 1-cm samples were found to have preserved morphologic features present on days 3 and 7. The 3-cm samples showed no evidence of necrosis, though some of the capillary vessels were filled with aggregated blood cells. The vascular wall had negative peroxidase staining for endothelial TM. At 5 cm, there was clear evidence of necrosis, some found within the capillary vessels, which were filled with aggregated blood cells. These samples also had negative peroxidase staining for TM. On day 7, the survival rate of skin flaps was 45.35%. In this study, we demonstrate that tissue ischemia is an important factor, particularly in down-regulating TM transcription. TM depletion from the vascular cells and microthrombus formation occurred in the ischemic areas, playing an important role in secondary aggravation of tissue ischemia.
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PMID:Expression of the endothelial thrombomodulin (TM) on the ischemic rat flap model: preliminary study. 1946 Dec 88

Hepatic ischemia and reperfusion (IR) injury is a major clinical problem often leading to acute kidney injury characterized by early endothelial cell apoptosis, subsequent neutrophil infiltration, proximal tubule necrosis/inflammation, impaired vascular permeability, and disintegration of the proximal tubule filamentous actin cytoskeleton. Activated protein C is a major physiological anticoagulant with anti-inflammatory and anti-apoptotic activities in endothelial cells. Here we tested if activated protein C would attenuate hepatic and renal injury caused by hepatic ischemia and reperfusion. Both liver and kidney injury were significantly reduced when activated protein C was given immediately before and 2 h after liver reperfusion, in that there was reduced renal endothelial and hepatocyte apoptosis, as well as reduced hepatic and renal tubular necrosis. Further, the administration of activated protein C also reduced the expression of several pro-inflammatory genes, liver and kidney filamentous-actin degradation, and neutrophil infiltration, and resulted in better preservation of vascular permeability of both the liver and kidney than is normally seen after liver ischemia and reperfusion. These protective effects of activated protein C were due to protease-activated receptor-1 modulation since administration of a selective receptor antagonist dose-dependently inhibited its ameliorative effects in both organs after liver ischemia and reperfusion. Our results suggest the powerful multi-organ protective effects of activated protein C may improve outcome in those patients at significant risk of developing acute kidney injury following liver ischemia and reperfusion during transplantation.
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PMID:Human activated protein C attenuates both hepatic and renal injury caused by hepatic ischemia and reperfusion injury in mice. 1962 89

Thrombin can amplify inflammation induced by other stimuli, either through ischemia (consequent upon thrombosis), indirectly through generation of downstream mediators such as activated protein C, or directly via signals through protease activated receptors (PAR). This paper will summarize recent data from our laboratory indicating that thrombin is required to initiate CCR2-dependent leukocyte recruitment and that it is the principal determinant of the outcome after vascular injury, via PAR-1 activation of a distinct subset of smooth muscle cell progenitors. In both, tissue factor (TF) initiates thrombin generation and the thrombin acts locally, exemplifying that the initiation phase can generate autocrine or paracrine signalling molecules. Thrombin is an important constituent of innate immunity, able to amplify and modify responses to invading pathogens or tissue damage. With novel anti-thrombin therapeutics and agents to target PAR, a new understanding of the importance of thrombin may allow the development of innovative anti-inflammatory strategies.
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PMID:Critical roles for thrombin in acute and chronic inflammation. 1963 Jul 83

Sepsis associated Acute Kidney Injury (SA-AKI) is the leading cause of AKI in the hospital setting and its incidence is increasing. Although the exact pathophysiology and phenotype of SA-AKI are not known, it is widely accepted that SA-AKI has a multi-injury pathway. This form of AKI has components of ischemia-reperfusion injury, direct inflammatory injury, coagulation and endothelial cell dysfunction, and apoptosis. As such, multiple agents have been shown in pre-clinical studies to ameliorate SA-AKI, but there are no interventions currently available for the treatment of SA-AKI. Promising agents that are in development include toll-like receptor inhibition, IL-10 augmentation, modulators of the protein C pathway, and mesenchymal stem cell mediated therapeutics. The aim of this review is to review the pathophysiology of SA-AKI and the therapeutic interventions that are under development to treat this complex and morbid disease.
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PMID:Novel therapeutic targets for prevention and therapy of sepsis associated acute kidney injury. 1971 36

Protein C is a plasma serine protease that when activated plays a central role in modulating the function of the vascular endothelium and its interface with the innate immune system. Activated protein C (APC) has a dual mechanism of action via the feedback inhibition of thrombin generation, and as an agonist of protease activated receptor-1 (PAR-1). Through different cofactor interactions, this dual mechanism of antithrombotic and cytoprotective activity results in the ability of APC to modulate endothelial dysfunction by blocking cytokine signaling, functional cell adhesion expression, vascular permeability, apoptosis, and modulating leukocyte migration and adhesion. Deficiency in protein C, which occurs during systemic inflammatory activation, is highly associated with organ dysfunction. APC has shown efficacy in a number of preclinical models of thrombosis and ischemia, and the recombinant human APC drotrecogin alfa (activated), reduces mortality in patients with high-risk severe sepsis. The ability of APC to suppress pro-inflammatory pathways and enhance cellular survival suggests that APC plays a key role in the adaptive response to protect the vessel wall from insult and to enhance endothelial, cellular, and organ survival. The focus of this review will be to summarize the emerging data suggesting the potential therapeutic benefit of APC and related members of the pathway in the prevention and treatment of acute kidney injury.
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PMID:Activated protein C and acute kidney injury: Selective targeting of PAR-1. 1971 37

Acute myocardial infarction (AMI) is a common cause of death for which effective treatments are available provided that diagnosis is rapid. The current diagnostic gold standards are circulating cardiac troponins I and T. However, their slow release delays diagnosis, and their persistence limits their utility in the identification of reinfarction. The aim was to identify candidate biomarkers of AMI. Isolated mouse hearts were perfused with oxygenated protein-free buffer, and coronary effluent was collected after ischemia or during matched normoxic perfusion. Effluents were analyzed using proteomics approaches based on one- or two-dimensional initial separation. Of the 459 proteins identified after ischemia with one-dimensional separation, 320 were not detected in the control coronary effluent. Among these were all classic existing biomarkers of AMI. We also identified the cardiac isoform of myosin-binding protein C in its full-length form and as a 40-kDa degradation product. This protein was not detected in the other murine organs examined, increased markedly with even trivial myocardial infarction, and could be detected in the plasma after myocardial infarction in vivo, a profile compatible with a biomarker of AMI. Two-dimensional fluorescence DIGE of ischemic and control coronary effluents identified more than 200 asymmetric spots verified by swapping dyes. Once again existing biomarkers of injury were confirmed as well as posttranslational modifications of antioxidant proteins such as peroxiredoxins. Perfusing hearts with protein-free buffers provides a platform of graded ischemic injury that allows detailed analysis of protein release and identification of candidate cardiac biomarkers like myosin-binding protein C.
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PMID:Identification of cardiac myosin-binding protein C as a candidate biomarker of myocardial infarction by proteomics analysis. 1972 Oct 77

Involvement of various neurotransmitters and neuromodulators have been shown to contribute to the ischemic injury and neuronal death associated with stroke Role of excitatory amino acid receptor activation, calcium overload, nitric oxide, and oxidative stress in the pathogenesis of ischemic brain damage is well established. Several new strategies are currently emerging, based on recent advances in our understanding of molecular pathways that could be considered as potential therapeutic targets. For example reactive oxygen species (ROS) are important contributors to the secondary injury cascade following traumatic brain injury (TBI), and ROS inhibition has consistently been shown to be neuroprotective following experimental TBI and brain ischemia. Furthermore, more recently, some authors concluded that nonanticoagulant 3K3A-APC exhibits greater neuroprotective efficacy with no risk for bleeding compared with drotrecogin-alfa activated, a hyperanticoagulant form of APC. Excessive calcium entry into depolarized neurons contributes significantly to cerebral tissue damage after ischemia. Included in the sequence of events leading to neuronal death in ischemic tissue following stroke is an excessive and toxic rise in the intracellular Ca(2+)-concentration, predominantly due to an influx of Ca2+ through nonselective cation-channels as well as Ca(2+)-channels.. Some authros conducted a study to investigate whether the enhancement of GABA receptor activity could inhibit NMDA receptor-mediated nitric oxide (NO) production by neuronal NO synthase (nNOS) in brain ischemic injury. The results showed that both the GABA(A) receptor agonist muscimol and the GABA(B) receptor agonist baclofen had neuroprotective effect, and the combination of two agonists could significantly protect neurons against death induced by ischemia/reperfusion. On this basis we conclude that neuroprotection for ischemic stroke refers to strategies, applied singly or in combination, that antagonize the injurious biochemical and molecular events that eventuate in irreversible ischemic injury. There has been a recent explosion of interest in this field, with over 1000 experimental papers and over 400 clinical articles appearing within the past 6 years. These studies, in turn, are the outgrowth of three decades of investigative work to define the multiple mechanisms and mediators of ischemic brain injury, which constitute potential targets of neuroprotection.
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PMID:Neuron protection as a therapeutic target in acute ischemic stroke. 1984 59


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