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

Acute inflammation has been suggested as a potential mechanism for some of the injury associated with reperfusion of the ischemic myocardium. This hypothesis implies that viable myocardial cells adjacent to the lethally injured cells are vulnerable to injury induced by the neutrophil influx observed to attend reperfusion. In our previous work, we demonstrated that the presence of ICAM-1 on the surface of cardiac myocytes is required for neutrophils to directly damage them; blocking monoclonal antibodies to either ICAM-1 on cardiac myocytes or Mac-1 on activated neutrophils completely precluded neutrophil-induced myocyte injury. We also demonstrated that postischemic cardiac lymph (cardiac extracellular fluid) contained leukotactic factors (primarily C5a) and cytokines present in concentrations sufficient to maximally induce Mac-1 on the surface of neutrophils and ICAM-1 on the surface of isolated dog cardiac myocytes. The present study sought to further these observations by examining the site of potential ICAM-1 induction as a function of time of reperfusion, degree of ischemia, and viability of myocardial cells. Our evidence suggests that ICAM-1 mRNA is induced very early after reperfusion only in the previously ischemic myocardium and is not seen in the nonischemic myocardium during the early hours of reperfusion. Moreover, ICAM-1 mRNA induction is seen most intensely in the ischemic area directly bordering the necrotic area (which, after 1-hr reperfusion, does not contain any ICAM-1 mRNA) and immediately abutting the site of maximal influx of neutrophils. Thus, the induction of ICAM-1 and the influx of neutrophils (presumably activated by the chemotactic factors that guided their migration) exists on the border between viable and necrotic cells. This provides the first direct molecular evidence for a jeopardized border zone on the edge of myocardial infarction during reperfusion. As previously demonstrated, this reaction is wholly dependent upon tissue injury of the ischemic myocardium and therefore represents an example of a mechanism of injury extension induced as a reaction to a primary injury. The degree of specificity of this reaction demonstrated by the subendocardial sparing directly adjacent to ischemic cells suggests finely modulated mechanisms by which this process is controlled.
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PMID:Molecular evidence for a border zone vulnerable to inflammatory reperfusion injury. 791 64

Immunological events are implicated in the brain damages after ischemia. Neutrophils have been implicated in the pathogenesis of ischemia-reperfusion injury. We showed beneficial effect of antineutrophol monoclonal antibody RP3, which depletes circulationing neutrophils, on brain edema formation and infarct size. In addition, marked increase in IL-8 concentration was detected in brain and serum during early reperfusion. Time course of IL-8 production precedes brain edema formation and neutrophil infiltration. It is reported that IL-1 induces IL-8 production and anti-IL-1 antibody significantly reduced ischemic brain damages. Neutralizing antibodies against cell adhesion molecules (ICAM-1 and LFA-1) regulate neutrophil: endothel adhesion and monoclonal antibodies against these adhesion molecules reduced the size of infarction. These results indicate that neutrophil infiltration into the ischemic brain is implicated in postischemic brain injury.
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PMID:[Ischemia and neuroimmunology--ischemia/reperfusion injury]. 799

We evaluated the effect of antibodies directed against a leukocyte adhesion molecule (ICAM-1) in an embolic model of stroke followed by thrombolysis with tissue plasminogen activator (tPA). To test whether reperfusion injury after ischemia was related to white cell adhesion, microclots were injected into carotid circulation. The conditions examined were control, alpha-ICAM 5 min following ischemia, tPA 30 min after ischemia, and the combination of alpha-ICAM and tPA. alpha-ICAM and tPA both increased the amount of clot necessary to produce permanent neurological damage. Combined therapy was no more effective than either substance alone. A similar outcome was obtained when tPA was delayed until 90 min postischemia. When thrombolysis was delayed 3 h following embolism, neither tPA nor the tPA/alpha-ICAM combination reduced neurological damage. Thus, the alpha-ICAM antibody and tPA each effectively reduced neurological damage but the interaction was not significant.
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PMID:Monoclonal antibody to the ICAM-1 adhesion site reduces neurological damage in a rabbit cerebral embolism stroke model. 809 42

Extravasation of leukocytes at the sites of ischemia-reperfusion is thought to exacerbate the tissue injury. It has been proposed that leukocyte accumulation is a secondary effect of the ischemic damage, mediated by inflammatory cytokines. We have recently demonstrated that physiologically low levels of oxygen tension alone can have a direct effect on the adhesive characteristics of mesenchymal cells for lymphocytes. We now report that decrease of oxygen tension in the environment induces the adhesion of neutrophils to human endothelial cells in culture. Adhesion of human neutrophils to human umbilical vein, bovine aortic, and mouse microvascular endothelial cell monolayers, which had been incubated at pO2 of 50 torr for 3 hours, increased 2.5-fold, 2-, and 1.5-fold, respectively. The effects of decreased oxygen concentration on adhesion were not mediated by a soluble factor elaborated by the hypoxic cells. Low oxygen tension upregulates a saturable, endothelial cell-associated adhesion mechanism, capable of withstanding centrifugation forces greater than 160g. Hypoxia-induced adhesion was inhibited by LFA-1-specific (CD11a/CD18 integrin) antibodies, but not by antibodies directed against the ICAM-1 ligand for the LFA-1 receptor. These studies demonstrate that decreases in oxygen tension alone increase the adhesive properties of endothelial cells for leukocytes. In addition, they provide evidence for the existence of a new ligand for the LFA-1 molecule on endothelial cells which can be affected by hypoxic environments.
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PMID:Oxygen tension regulates neutrophil adhesion to human endothelial cells via an LFA-1-dependent mechanism. 825 69

Ischemia followed by reperfusion of the rat hind limb resulted in local evidence of injury, as reflected in increased vascular permeability and hemorrhage in skeletal muscle as well as distant organ injury, as reflected by increased vascular permeability and hemorrhage in lung. These changes were proportional to the duration of reperfusion and were associated with neutrophil accumulation in tissue, as quantitated by myeloperoxidase (MPO) content. There was corresponding evidence of complement depletion and increases in plasma IL-1 and IL-6. On the basis of interventional approaches, limb and lung vascular injury was neutrophil and complement dependent and was attenuated by treatment with antioxidants. Products of L-arginine were involved in the development of vascular injury since antagonists of L-arginine were protective. Based on the use of blocking antibodies, the cytokines TNF alpha and IL-1 were also involved in the development of tissue injury. Finally, both LFA-1 (CD11a/CD18) and Mac-1 (CD11b/CD18) beta 2 integrins were required as well as the endothelial adhesion molecules E-selectin and ICAM-1. Protective interventions were more protective that both local and remote organ injury following ischemia-reperfusion is in lung than in skeletal muscle. There were, in general, parallel effects when tissue protection was related to reduction in MPO content. These data suggest dependent on toxic oxygen and L-arginine products of neutrophils, the accumulation of which can be linked to cytokines (TNF alpha, IL-1), beta 2 integrins and endothelial adhesion molecules.
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PMID:Ischemia-reperfusion injury. 831 38

When activated neutrophils are recruited and bind to endothelial tissues, they release leukotrienes, proteolytic enzymes, and free radicals. The latter has been implicated in myocardial stunning following periods of ischemia and reperfusion, as may occur following cardiopulmonary bypass (CPB). The neutrophil surface complex CD11/CD18 promotes the neutrophil-endothelial adhesion process. Monoclonal antibodies have been developed that can block neutrophil adhesion to the endothelium by preventing CD11/CD18 binding to adhesion molecules (ICAM-1 or ELAM-1) located on endothelial cells. We used monoclonal IgG antibody 60.3 to block neutrophil adherence and thereby potentially reduce myocardial stunning. Pretreatment of rabbits subjected to myocardial ischemia/reperfusion with either monoclonal 60.3 or saline resulted in only a small increase in the rate of recovery of preload recruitable stroke work index during reperfusion. More severe occlusion may have been needed to see significant results. We also evaluated the effects of anti-neutrophil therapy in animal models of CPB. Rhesus monkeys were subjected to deep hypothermia and CPB, followed by 24 hours of fluid resuscitation. Animals receiving monoclonal 60.3 (N = 3) showed less weight gain, less infused resuscitative fluid, and higher terminal hematocrit and PaO2 than controls (N = 3). Antineutrophil therapy may prevent multiorgan system failure in certain high risk patients.
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PMID:Potential role of neutrophil anti-adhesion therapy in myocardial stunning, myocardial infarction, and organ dysfunction after cardiopulmonary bypass. 846 23

This article reviews the evidence that myocardial stunning during surgical reperfusion after coronary revascularization or heart transplantation is not strictly due to myocardial injury sustained during ischemia, but results from pathophysiological events triggered by reperfusion (reperfusion injury). In sheep, left ventricular (LV) dP/dt and stroke work were reduced up to 50%, and 60% to 70% necrosis was observed in the area at risk during 3 hours reperfusion following coronary occlusion and cardioplegic arrest on bypass. Reperfusion with leukocyte depleted blood, or pharmacological blockade of either thromboxane or leukotriene receptors, provided significant improvements in LV function and myocardial blood flow, with a 40% to 50% reduction in necrosis. Similar results have been obtained using animal heart subjected to 2 to 3 hours arrest at either 4 degrees C or 15 degrees C, simulating cardiac preservation and reperfusion after transplantation. Diastolic pressure was significantly elevated, and increases in the time constant for relaxation of LV pressure and coronary vascular resistance were noted. These indices of myocardial stunning were reversed after blocking neutrophil-endothelial cell interaction with monoclonal antibodies against CD18 or ICAM-1 receptors, and significant improvements were also obtained after either thromboxane or leukotriene receptor blockade. We conclude that immediate postoperative myocardial stunning results largely from reperfusion injury that occurs due to an acute inflammatory response to ischemia and reperfusion, and that stunning can be largely reversed with appropriate pharmacological intervention.
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PMID:Myocardial stunning and reperfusion injury in cardiac surgery. 846 24

Recent studies suggest that graft microvascular endothelia may play an important role in the regulation of rejection. Alloantigen-dependent changes in microvascular endothelial phenotype may be associated with differences in infiltrate function in allografts vs. isografts, as reflected in alloantigen-specific CTL accumulation and cytokine production. To correlate cytokine production with differences in microvascular endothelial phenotype during allograft inflammation, we used PCR to identify cytokine mRNAs isolated from pooled cardiac isografts and allografts on days 1, 3, and 5 after transplantation. Graft microvascular endothelia express an inflamed phenotype associated with wound healing and the repair of tissue damage due to mechanical trauma, ischemia, and/or reperfusion injury--i.e., high levels of ICAM-1 expression and MECA-32 mAb reactivity. By day 1 in both isografts and allografts, mRNAs for the cytokines IL1 alpha, IL6, TNF, LT, and TGF beta are upregulated or induced. By the third day in cardiac allografts, an antigen-dependent endothelial phenotype is expressed, characterized by the presence of cell surface VCAM-1. Concomitantly, mRNAs for the lymphokines IL2 and IFN gamma are detected, followed by IL4 mRNA by day 5. The expression of VCAM-1 by allograft endothelia may influence the inflammatory process, by physically recruiting specific T cell subpopulations into the response and/or by delivering additional signals to the infiltrating cells. Eventually, these and other regulatory events occurring at these early times initiate a process that later results in alloreactive tissue destruction.
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PMID:Alloantigen-dependent endothelial phenotype and lymphokine mRNA expression in rejecting murine cardiac allografts. 847 68

Endothelial dysfunction is an important early-recurring phenomenon in virtually all forms of ischemia-reperfusion, including a variety of circulatory shock states. The dysfunction appears to be triggered within 2.5 min of the endothelial generation of a large burst of superoxide radicals. However, the initial dysfunction may be amplified by neutrophil-generated factors including oxygen-derived free radicals, cytokines, proteases, and lipid mediators. Moreover, adhesive molecules on the surface of the PMN, along with their ligands on the endothelial cell membrane, appear to promote endothelial dysfunction in ways that may go beyond the adherence of neutrophils on the endothelial surface. These interactions remain to be elucidated but may involve intricate cell signaling pathways. A variety of pharmacologic agents exert endothelial protective effects in ischemia-reperfusion and circulatory shock states. Table 1 summarizes these agents and indicates the major mechanism of preservation of the endothelium. These substances can be classified into three broad categories: (a) substances replacing endogenous cytoprotective agents of endothelial origin including prostacyclin (PGI2), endothelium-derived relaxing factor (EDRF), and adenosine: the endothelium protecting agents include these substances as well as stable analogs of PGI2, and nitric oxide donors; (b) substances that inhibit pro-inflammatory mediators of endothelial origin: the pro-inflammatory agents are primarily platelet activating factor (PAF) and oxygen-derived free radicals (e.g. superoxide radicals) although other mediators may be involved. The therapeutic agents useful in this area are PAF receptor antagonists and free radical scavengers (e.g. superoxide dismutase); (c) substances that inhibit neutrophils or neutrophil-derived mediators: the major neutrophil-derived mediators are oxygen-derived free radicals, cytokines (e.g. TNF alpha and IL-1 beta), proteases (e.g. elastase), and lipid mediators (e.g. LTB4). In addition, adhesive molecules on the neutrophil surface and their endothelial ligands promote endothelial dysfunction and the action of adherent neutrophils. Agents that inhibit some of these mediators are transforming growth factor-beta (TGF-beta), elastase inhibitors, leukotriene B4 (LTB4) receptor antagonists and monoclonal antibodies to adhesive proteins (e.g. anti-CD18, anti-ICAM-1). Further work is needed to clarify these findings and to determine the physiologic and pathophysiologic interactions among these diverse agents. This topic of endothelial dysfunction represents a fertile area for further investigation to elucidate the complex mechanisms of neutrophil-endothelial interactions. These interactions lead to neutrophil adherence to the endothelium, neutrophil migration into the underlying tissues, and subsequent tissue injury (e.g. myocardial reperfusion injury).(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Pharmacology of the endothelium in ischemia-reperfusion and circulatory shock. 849 55

Although treatment with agents that block leukocyte function, including anti-ICAM-1 and doxycycline, reduces experimental central nervous system (CNS) ischemic injury, it is not known how leukocyte subset accumulation is affected by these agents. Using the rat two-vessel occlusion model and immunohistochemistry, we investigated granulocyte (PMN) and monocyte/macrophage (M phi) accumulation at 1 and 4 d postischemia. A total of 24 animals were randomized to sham surgery, or to ischemia with saline, anti-ICAM-1, or doxycycline treatments. No leukocytes were observed in sham animals. At 24 h postischemia, there was a moderate infiltration of PMN and M phi in untreated animals that was significantly decreased with either treatment. At 4 d after ischemia no PMN were identified, with extensive M phi accumulation occurring in untreated animals that was only partially reduced with doxycycline treatment. These results confirm that both anti-ICAM-1 and doxycycline treatments reduce PMN and M phi infiltration at 24 h. Delayed M phi accumulation occurs despite treatment, suggesting that some of these cells represent transformed resident microglia.
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PMID:The influence of antiadhesion therapies on leukocyte subset accumulation in central nervous system ischemia in rats. 856 19


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