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)

During their life span, leukocytes adhere transiently to one another, to other cell types, such as vascular endothelial cells, and to extracellular matrix proteins. This adhesiveness is mediated by families of specific cell surface adhesion molecules, namely, integrins, immunoglobulin superfamily molecules, and selectins. Adhesion is required for leukocyte-mediated cytotoxicity, phagocytosis, chemotaxis, and induction of lymphocyte proliferation and maturation. It also participates in recirculation and homing of lymphocytes into lymphoid organs and in leukocyte migration from the vascular compartment to extravascular tissues. Adhesion underlies the beneficial or detrimental role of leukocytes in immune and inflammatory responses. In animals, blocking monoclonal antibodies to adhesion molecules dramatically reduce vascular and tissue injury in several organs following ischemia-reperfusion, and delay renal allograft rejection. Moreover, expression of particular adhesion molecules is induced or increased in cells which are targets for allergic or autoimmune reactions and in inflamed tissues. On the other hand, a congenital deficiency of the CD11/CD18 integrins (Leu-CAMs) leads to recurrent, and sometimes fatal, bacterial infections, and lack of particular cell-adhesion molecules on Burkitt's lymphoma cells may enable these cells to escape immunosurveillance.
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PMID:Leukocyte adhesion in host defense and tissue injury. 183 Aug 30

Tissue injury resulting from ischemia and reperfusion forms the basis of several important disorders including myocardial infarction, stroke, and circulatory shock. To examine the role of neutrophils in this process and to determine the extent to which injury is a consequence of reperfusion, we utilized the monoclonal antibody 60.3, directed to CD18, the human leukocyte adherence glycoprotein, to block intravascular neutrophil aggregation and neutrophil adherence to endothelium in a rabbit model of tissue ischemia and reperfusion. Antibody treatment either before ischemia or after ischemia, but prior to reperfusion, resulted in the same degree of significant protection against endothelial, microvascular, and tissue injury. We conclude that neutrophils and increased neutrophil adhesiveness are important in the development of microvascular and tissue injury after ischemia and reperfusion and that under these circumstances, injury is primarily a consequence of reperfusion.
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PMID:Inhibition of leukocyte adherence by anti-CD18 monoclonal antibody attenuates reperfusion injury in the rabbit ear. 196 37

Monoclonal antibodies (MAbs) that recognize the neutrophil (PMN) adherence complex CD11/CD18 inhibit PMN adherence to endothelium and attenuate PMN-mediated ischemia-reperfusion injury. One consideration regarding the clinical usefulness of such therapy is whether transient inhibition of PMN adherence or function will impede host defense and increase susceptibility to infection and sepsis. We studied susceptibility to sepsis in New Zealand white rabbits with an appendiceal devascularization model to answer the question: Does inhibition of PMN adherence with the anti-CD18 MAb 60.3 increase morbidity and mortality rates in abdominal sepsis? Four treatment groups of 10 animals each were studied: group 1 (controls) received no treatment, group 2 received MAb 60.3, group 3 was given the antibiotic cefazolin alone, and group 4 received both cefazolin and MAb 60.3. PMN emigration into the peritoneum was inhibited significantly in MAb 60.3-treated animals (groups 2 and 4). There was no difference in weight loss, incidence of infectious complications, or mortality rates when MAb 60.3-treated animals were compared with untreated animals. These results demonstrate that transient inhibition of PMN adherence does not increase morbidity or mortality rates in this model of abdominal sepsis. These results suggest that if MAb 60.3 or similar antibodies are used to prevent PMN-mediated injury, they will not increase susceptibility to sepsis.
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PMID:Transient inhibition of neutrophil adherence with the anti-CD18 monoclonal antibody 60.3 does not increase mortality rates in abdominal sepsis. 200 54

The activation and accumulation of leukocytes during inflammatory processes such as that initiated by myocardial ischemia and reflow appear to be major determinants of irreversible tissue injury. Myocardial salvage by dual cyclooxygenase/lipoxygenase inhibitors and selective 5-lipoxygenase inhibitors has suggested a role for lipoxygenase (LOX) products, such as the potent chemotactic factor leukotriene B4, in ischemia-reflow injury. However, many LOX inhibitors are antioxidants and several have been shown to directly inhibit neutrophil function in vitro, thereby questioning the role of LOX products in reperfusion injury. To clarify further the protective mechanism of lipoxygenase inhibitors, we have examined the effects of two nonantioxidant inhibitors, SK&F 86002 and REV-5901, on human neutrophil activation and function in vitro. The antioxidant LOX inhibitor nordihydroguiaretic acid, which served as a positive control, exhibited a concentration-dependent inhibition of N-formyl-methionyl-leucyl-phenylalanine (fMLP) and recombinant C5a-induced neutrophil bipolarization, fMLP-induced upregulation of the adherence glycoprotein Mac-1 (CD11b/CD18), fMLP-induced aggregation and neutrophil adherence to and migration through interleukin-1-stimulated human endothelial monolayers. In contrast, neither SK&F 86002 nor REV-5901 (in concentrations up to 50 microM) had any effect on these functions, nor did they inhibit neutrophil oxidative metabolism (phorbol myristate acetate-induced chemiluminescence). Inasmuch as both of these agents have been observed to reduce myocardial ischemia-reflow injury in vivo, their failure to directly inhibit neutrophil function further supports an important role for chemotactic LOX products in the pathogenesis of reperfusion injury.
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PMID:Comparison of antioxidant and nonantioxidant lipoxygenase inhibitors on neutrophil function. Implications for pathogenesis of myocardial reperfusion injury. 215 49

Recent studies implicate a role for granulocytes in the genesis of the microvascular and parenchymal cell dysfunction, which occurs upon reperfusion of ischemic tissues. Although the molecular mechanisms underlying this neutrophil-mediated injury are not completely understood, it is clear that an essential first step in granulocyte migration from the vascular lumen to the interstitial space is adherence to vascular endothelium. The purpose of this study was to determine whether prevention of neutrophil adherence with monoclonal antibody IB4 directed against the neutrophil CD11/CD18 glycoprotein adherence complex or neutrophil depletion with a specific polyclonal antineutrophil serum would attenuate the microvascular dysfunction seen in postischemic skeletal muscle. Changes in vascular permeability were assessed by measurement of the solvent drag reflection coefficient for total plasma proteins (sigma) in isolated canine gracilis muscle subjected to ischemia/reperfusion, ischemia/reperfusion plus antineutrophil serum, or ischemia/reperfusion plus IB4. Estimates of sigma averaged 0.83 +/- 0.04 in nonischemic, control gracilis muscles, while ischemia/reperfusion was associated with a marked increase in vascular permeability (decrease in sigma to 0.54 +/- 0.04) and vascular resistance (increased by 135 +/- 41% over the control value). Prevention of neutrophil adherence or neutrophil depletion prevented this increase in vascular permeability (sigma = 0.80 +/- 0.03 and 1.01 +/- 0.06, respectively) and resistance (decrease of 16.51 +/- 8.0% and increase of 2.4 +/- 4.6% over control values, respectively). The results of this study suggest that neutrophils play a critical role in the genesis of microvascular dysfunction in postischemic skeletal muscle. Furthermore, neutrophil adherence to vascular endothelium appears to be a prerequisite for the production of this injury.
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PMID:Neutrophil-mediated microvascular dysfunction in postischemic canine skeletal muscle. Role of granulocyte adherence. 215 91

Cardiac lymph from a canine model of myocardial ischemia and reperfusion was examined for evidence of chemotactic activity. Lymph was continuously collected from awake animals before and during a 60-minute coronary artery occlusion and up to 6 hours after the initiation of reperfusion. It was assessed for the ability to activate the following proinflammatory functions in neutrophils isolated from the blood of healthy dogs: 1) morphological changes characteristic of chemotactic stimulation, which were assessed by phase contrast microscopy, 2) orientation of canine neutrophils in a gradient of cardiac lymph, which was assessed in Zigmond chambers, 3) the binding of monoclonal antibodies reactive with CD11b and CD18 adherence glycoproteins, which was assessed by flow cytometry, and 4) adherence of canine neutrophils to monolayers of canine jugular vein endothelium, which was assessed in vitro by a visual assay. Lymph samples collected after 1 hour of reperfusion in animals demonstrating ECG evidence of ischemia and histological evidence of infarction exhibited significant stimulatory activity for each of the functions tested. Shape change-inducing activity was evaluated at more frequent intervals than other functions and was found to peak at 1 hour after initiation of reperfusion and to disappear by 6 hours. In addition, the CD11b/CD18 levels on neutrophils isolated from cardiac lymph collected during reperfusion were significantly greater than neutrophils obtained before or during occlusion. Animals that failed to exhibit evidence of infarction also failed to exhibit increased stimulatory activity in lymph collected during reperfusion, and surface levels of CD11b/CD18 on neutrophils collected from reperfusion lymph were not elevated. This study provides direct evidence supporting the hypothesis that chemotactic activity is generated in ischemic and reperfused myocardium.
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PMID:Canine neutrophil activation by cardiac lymph obtained during reperfusion of ischemic myocardium. 257 38

Recent studies suggest that neutrophils are an important factor in the organ injury associated with ischemia and shock. Increased neutrophil-endothelial adhesiveness is essential for neutrophil-mediated vascular injury. To examine the role of neutrophils and neutrophil adhesiveness in the development of injury after hypovolemic shock, and to determine whether this injury is a consequence of reperfusion, we used the monoclonal antibody (MAb) 60.3 (directed to the primary human neutrophil adherence glycoprotein, CD18) to block neutrophil adherence functions at the time of resuscitation in a rabbit model of hemorrhagic shock. None of the unanesthetized control animals subjected to 2 hours of shock (cardiac output, 30% of baseline) followed by resuscitation survived 5 days. All had gross and histologic evidence of injury to lungs, liver, and gastrointestinal mucosa. In contrast, 71% of the animals that received MAb 60.3 immediately before resuscitation survived 5 days (p less than 0.005), and visceral organ injury was absent or markedly attenuated. We conclude that a significant proportion of injury resulting from shock and resuscitation occurs after the ischemic insult and that increased neutrophil adhesiveness plays an important role in the development of multiple organ injury and death following shock and resuscitation (in this model). This injury may be significantly reduced by blocking neutrophil adherence functions with the MAb 60.3--even if administration is delayed until resuscitation.
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PMID:Role of neutrophils in generalized reperfusion injury associated with resuscitation from shock. 277 26

Leukocytes have been shown to play an important role in the development of isolated organ injury after experimental ischemia and reperfusion. To examine the role of leukocytes in generalized ischemia-reperfusion injury we used the MAb 60.3 (directed to the human leukocyte adherence glycoprotein, CD18) to block leukocyte adherence functions in a rabbit model of hemorrhagic shock and resuscitation. In control animals subjected to 1 h of shock (mean blood pressure 45 torr and mean cardiac output 30% of baseline) followed by resuscitation, only 29% survived 5 d. All had gross and histologic evidence of injury to lungs, liver, and gastrointestinal mucosa. In contrast, 100% of the MAb 60.3-treated animals survived 5 d (P less than 0.01) and organ injury was absent or markedly attenuated. The control animals also had a persistent acidosis, lost more weight, and had evidence of continued gastrointestinal bleeding in contrast to MAb 60.3-treated animals. We conclude that increased leukocyte adhesiveness plays an important role in the development of multiple organ injury and death after generalized ischemia-reperfusion and that this injury may be significantly reduced by blocking leukocyte adherence functions with the MAb 60.3.
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PMID:A monoclonal antibody to the adherence-promoting leukocyte glycoprotein, CD18, reduces organ injury and improves survival from hemorrhagic shock and resuscitation in rabbits. 327 7

A monoclonal antibody (904) that binds to a leukocyte cell adhesion-promoting glycoprotein, (Mo1; CD11b/CD18) was administered (1 mg/kg, iv.) to open chest anesthetized dogs 45 min after the induction of regional myocardial ischemia. Ischemia was produced by occluding the left circumflex coronary artery (LCX) for 90 min and then reperfusing for 6 h. There was no difference between control and antibody treated groups with respect to arterial blood pressure, heart rate, or LCX blood flow. Administration of antibody produced no observable effect on circulating neutrophil counts, suggesting that antibody-bound neutrophils were not cleared from the circulation. The mean size of myocardial infarct expressed as percentage of the area at risk of infarction that resulted was reduced by 46% with anti-Mo1 treatment (25.8 +/- 4.7%, n = 8) compared to control (47.6 +/- 5.7%, n = 8; P less than 0.01). The area at risk of infarction was similar between groups. Circulating (serum) antibody excess was confirmed in all 8 anti-Mo1 treated dogs by immunofluorescence analysis. Analysis of ST segment elevation on the electrocardiogram as an indicator of the severity of ischemia suggests that the anti-Mo1 reduces infarct size independent of the severity of ischemia. An additional group of dogs (n = 5) was tested with a control monoclonal antibody of the same subtype (murine IgG1) and was found to produce no significant reduction in myocardial infarct size. Accumulation of neutrophils within the myocardium was significantly attenuated with 904 treatment when analyzed by histological methods. These data demonstrate that administration of anti-Mo1 monoclonal antibody after the induction of regional myocardial ischemia results in reduced myocardial reperfusion injury as measured by ultimate infarct size.
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PMID:Reduction of experimental canine myocardial reperfusion injury by a monoclonal antibody (anti-Mo1, anti-CD11b) that inhibits leukocyte adhesion. 333 35

Recent studies indicate that polymorphonuclear neutrophils (PMNs) infiltrate the intestinal mucosa during ischemia and after reperfusion. To determine whether PMNs mediate the increased microvascular permeability produced by ischemia-reperfusion (I/R) we treated cats with either saline, antineutrophil serum (ANS), or a monoclonal antibody specific for the beta-chain of the CD18 complex (MoAb 60.3) that prevents neutrophil adherence and extravasation. Intestinal microvascular permeability to plasma proteins was measured in control preparations (0.08 +/- 0.007), in preparations subjected to 1 h of ischemia then reperfusion (I/R, 0.32 +/- 0.02), I/R preparations treated with ANS (0.13 +/- 0.01), and I/R preparations treated with MoAb (0.12 +/- 0.003). Our results indicate that both PMN depletion (to less than 10% control) and prevention of PMN adherence significantly attenuate the increased microvascular permeability induced by I/R. These findings, coupled to previous results obtained from this model, support the hypothesis that neutrophils, which accumulate in the mucosa in response to xanthine oxidase activation, mediate the oxyradical-dependent injury produced by reperfusion of the ischemic bowel.
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PMID:Role of neutrophils in ischemia-reperfusion-induced microvascular injury. 363 3


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