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)

Reperfusion of ischemic skeletal muscle is associated with neutrophil (PMN) adherence to damaged endothelium and PMN-mediated tissue destruction. Neutrophils may attach to endothelium through surface adhesive molecules, such as CD18. The purpose of this study was to determine whether monoclonal antibody blockade of CD18 would reduce skeletal muscle necrosis associated with ischemia and reperfusion. In rabbits, an entire hindlimb was rendered ischemic for 4 hr, followed by 48 hr of in vivo reperfusion. Animals were allocated to one of five treatment groups: ischemia/reperfusion without treatment (I/R controls), I/R plus treatment with the anti-CD18 antibody IB4 (end-ischemic 2 mg/kg dose), I/R plus treatment with an identical dose of isotype-matched control Ig, I/R plus anterior compartment fasciotomy, or I/R plus both IB4 and fasciotomy. After 48 hr of reperfusion anterior tibial muscle necrosis was assessed (by tetrazolium staining and computerized planimetry), wet:dry muscle weights (W:D) were determined, and muscle PMN sequestration was measured by myeloperoxidase (MPO) activity. IB4-treated animals exhibited markedly reduced muscle MPO activity, compared to untreated animals. Although all interventions reduced edema formation (W:D ratios), none did so significantly. IB4 treatment reduced muscle necrosis when used alone (to 28 +/- 7%, vs. 48% +/- 6% in untreated controls), however this was not statistically significant (P = 0.06).2+ Fasciotomy significantly reduced necrosis (to 22 +/- 2%, P < 0.05); however, the addition of IB4 to fasciotomy resulted in necrosis that was significantly lower than that after fasciotomy alone (12 +/- 4%, P < 0.05 vs fasciotomy group) and the least necrosis of any group.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Salvage of postischemic skeletal muscle by monoclonal antibody blockade of neutrophil adhesion molecule CD18. 790 92

The progressive nature of dermal ischemia and subsequent tissue destruction within the "zone of stasis" is a central focus in burn research. To examine the role of neutrophils and neutrophil adherence within the zone of stasis, we utilized the monoclonal antibody (MAb) 60.3, directed to the human leukocyte adherence glycoprotein CD18 to block neutrophil adherence to endothelium and intravascular aggregation in a rabbit model of partial-thickness burn. Burns were created by applying an 80 degrees C brass template to the dorsal rabbit skin for 5 or 10 seconds. Animals treated with MAb 60.3 thirty minutes following a 5-second burn had less edema, thinner eschar, and earlier elevation of the eschar than control animals. Histologic analysis revealed an eightfold increase in live hair follicles (p < 0.05) and 43 percent greater reepithelialization at 8 days (p < 0.05) and a 15 percent reduction in burn surface area at 24 hours (p < 0.0001) in the antibody-treated group. There was no significant difference between treatment and control groups exposed to 10-second burns. We conclude that neutrophils and increased neutrophil adherence play important roles in the progressive tissue destruction within the zone of stasis in burns. Furthermore, moderate burn injury may be significantly attenuated by blocking neutrophil adherence functions with a CD18 MAb.
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PMID:Reduction of burn injury by inhibiting CD18-mediated leukocyte adherence in rabbits. 791 82

mAb blockade of CD18-mediated neutrophil adherence has previously been shown to reduce tissue injury in the rabbit ear as a result of ischemia followed by reperfusion. Similar injury reduction has been demonstrated whether treatment is given before ischemia or at the time of reperfusion. We examined the effects of delayed treatment with blocking CD18 mAb (60.3) after reperfusion of ischemic rabbit ears. The central neurovascular bundle of rabbit ears was isolated by microsurgery, the remainder of the ear devascularized, and all nerves cut to render the ear anesthetic. Arterial blood flow was occluded with a microvascular clamp for 6 h at an ambient temperature of 23 to 24 degrees C. The clamp was then removed and the ear allowed to reperfuse. Rabbits were divided into five treatment groups: 1) i.v. saline at reperfusion, 2) i.v. mAb 60.3 (2 mg/kg) at reperfusion, 3) i.v. mAb 60.3 1 h after reperfusion, 4) i.v. mAb 60.3 4 h after reperfusion, and 5) i.v. mAb 60.3 12 h after reperfusion. Ear edema (measured by volume displacement) was determined daily for 7 days. Edema in the immediate, 1 h, and 4 h mAb-treated groups was significantly less than in saline-treated controls, although less pronounced in the 4-h treatment group. Tissue necrosis measured at 7 days was significantly reduced in the same three mAb-treated groups compared with controls. However, edema and tissue necrosis in the 12 h mAb-treated group were similar to controls. We conclude that mAb blockade of CD18 at 1 h after reperfusion is as effective as immediate treatment in reducing ischemia reperfusion injury in the rabbit ear. Delaying treatment for 4 h is also effective but less so, whereas delaying treatment for 12 h results in no beneficial effects.
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PMID:Ischemia reperfusion injury in the rabbit ear is reduced by both immediate and delayed CD18 leukocyte adherence blockade. 791 18

We examined the influence of transient myocardial ischemia on the number and function of neutrophils in patients with effort angina (EA). We tested fluorometrically the expression of neutrophil membrane molecules (CD11b, CD11c, CD18) and neutrophil oxidative burst using a chemiluminescence (CL) generation system. The estimations were conducted before, 1 min after and 20 min after percutaneous transluminal coronary angioplasty (PTCA) in 15 patients qualified for the treatment because of single-vessel disease. Eight EA patients subjected to coronary arteriography (CA) comprised a control group. We did not observe any marked changes in leucocytosis or lymphocyte number in peripheral blood (PB) or in coronary sinus blood (CSB) after the procedure. The percentage of granulocytes in coronary blood decreased significantly 20 min after reperfusion. No significant changes in white blood cell count were noted in peripheral blood of PTCA patients or in control CA subjects. Oxidative burst of nonstimulated and fMLP, PMA and zymosan stimulated sinus blood neutrophils was significantly depressed 1 min after inflation, and enhanced 20 min after reperfusion. We found a significant increase in the percentage of the CD11c+ neutrophils from 56.7 +/- 7.4% to 64 +/- 6.5% 20 min after inflation and postischemic decrease in the CD11c molecule expression on CSB neutrophils. Significant positive linear correlation (Rval = 0.71) between inflation time and the CD11c molecule expression on CSB immediately after reperfusion was also noted. The results may reflect local activation of neutrophils in ischemic myocardium as a response to ischemia induced increase of activating stimuli.
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PMID:The effect of short-term myocardial ischemia on the expression of adhesion molecules and the oxidative burst of coronary sinus blood neutrophils. 791 25

The neutrophil has been implicated as a pivotal player in the pathogenesis of adult respiratory distress syndrome (ARDS) and multiple organ failure. An important first step in the process of neutrophil-mediated organ injury involves the binding of neutrophils to endothelial cells. This process is largely regulated by complementary adhesion molecules, some of which are present constitutively on the cell surface and others that can be up-regulated in response to chemotactic and proinflammatory stimuli. Several different adhesion molecules have been described. The leukocyte integrins consist of a common beta 2 chain (CD18) covalently linked to one of three different alpha chains (CD11a, CD11b, CD11c). CD11a/CD18 is expressed on all leukocytes, whereas CD11b/CD18 and CD11c/CD18 are restricted to cells of myeloid origin. CD11b/CD18 is involved in transendothelial migration and adherence-dependent formation of reactive oxygen species. Recently, a relationship between CD11b/CD18 expression, as an indication of neutrophil activation, and the development of ARDS has been suggested. The potential for monoclonal antibodies to adhesion proteins to reduce vascular and tissue damage has been studied in a large number of experimental models. Protective effects with anti-CD18 antibodies have been observed in a wide variety of inflammatory, immune, and ischemia-reperfusion injuries. Blockage of CD18, however, would affect all leukocytes, as would antibodies to CD11a/CD18. Targeting CD11b/CD18 would affect cells of the myeloid lineage only, which could prove to be beneficial. Anti-CD11b treatment has been used effectively to reduce tissue injury initiated by ischemia-reperfusion, complement activation, and endotoxemia.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Neutrophils and neutrophil-endothelial cell adhesion in adult respiratory distress syndrome. 791 59

The leukocyte beta 2-integrin Mac-1 (CD11b/CD18) and its endothelial ligand intercellular adhesion molecule 1 (ICAM-1) are involved in leukocyte adhesion to and macromolecular leakage from postcapillary venules during inflammatory reactions. Both events are also encountered after ischemia-reperfusion of striated muscle, suggesting a central role of both adhesion proteins in reperfusion injury. Using intravital fluorescence microscopy and a microcirculation model in awake BALB/C mice, we investigated the effects of monoclonal antibodies (MAb) and Fab fragments to Mac-1 and MAb to ICAM-1 on leukocyte-endothelium interaction and macromolecular leakage of fluorescein isothiocyanate-dextran (1.5 x 10(5) mol wt) in striated skin muscle after 3 h of ischemia followed by reperfusion. We demonstrated that administration of MAb and Fab to Mac-1 before reperfusion was as effective as administration of MAb to ICAM-1, which was found to be significantly upregulated in the postischemic tissue by immunohistochemical analysis, in preventing postischemic leukocyte adhesion to and macromolecular leakage from postcapillary venules, whereas postischemic leukocyte rolling was not affected after MAb administration. Postischemic capillary perfusion was efficiently preserved in animals treated with anti-Mac-1 and anti-ICAM-1 MAb compared with animals receiving the isotype-matched control antibodies.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Role of Mac-1 and ICAM-1 in ischemia-reperfusion injury in a microcirculation model of BALB/C mice. 794 77

The aim of this study was to determine whether the formation of edema that occurs secondary to the neutrophil-dependent increase in microvascular permeability contributes to the genesis of no-reflow in postischemic skeletal muscle. To address this issue, four experimental approaches were used. In the first group, capillary perfusion was assessed in nonischemic canine gracilis muscles in which interstitial fluid volume was increased to a level similar to that in postischemic muscle. In the second and third groups, edema formation was prevented in postischemic skeletal muscles by administration of phalloidin or a hypertonic hyperosmotic saline-dextran solution (HSD; 7.5% saline-6% Dextran 70), and the extent of capillary no-reflow was assessed. In the final group of experiments, a monoclonal antibody (MAb) that binds to the common beta-subunit of the leukocyte integrin CD11/CD18 (MAb IB4) was administered after the development of postischemic edema, and capillary perfusion was determined. Formation of edema in nonischemic preparations and ischemia-reperfusion (I-R) were associated with marked reduction in the number of patent capillaries per fiber (1.2 +/- 0.1 and 0.4 +/- 0.1, respectively) compared with nonedematous nonischemic controls (2.5 +/- 0.3). Treatment with phalloidin or HSD prevented edema formation and attenuated the reduction in the number of patent capillaries per fiber (1.62 +/- 0.2 and 1.71 +/- 0.2, respectively) induced by I-R, whereas administration of MAb IB4 after the formation of edema in reperfused muscles failed to limit capillary no-reflow (0.5 +/- 0.1 patent capillaries/fiber).(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Leukocyte adhesion, edema, and development of postischemic capillary no-reflow. 794 78

Intravital videomicroscopy was used to monitor the migration of leukocytes in rat mesenteric interstitium following exposure of the mesentery to either N-formylmethionyl-leucyl-phenylalanine (FMLP), leukotriene B4 (LTB4), platelet-activating factor (PAF), or ischemia-reperfusion (I-R). All inflammatory stimuli resulted in interstitial migration rates that were higher than those measured in unstimulated extravasated leukocytes. The median migration rate of cells stimulated with FMLP was significantly higher than those observed during superfusion with either LTB4 or PAF or following exposure to I-R. The enhanced leukocyte migration rates elicited by I-R were not attenuated by treatment with PAF- and LTB4-receptor antagonists, suggesting that these lipid mediators are not the inflammatory mediators responsible for I-R-induced leukocyte migration. Additional experiments revealed that the rate of leukocyte migration associated with FMLP stimulation was not significantly altered by either inhibitors of neutrophilic elastase and cathepsin G, a monoclonal antibody directed against the leukocyte adhesion glycoprotein CD11/CD18, or by altering interstitial hydration. This in vivo model provides a useful new approach for defining the factors that modulate leukocyte migration within the extravascular compartment.
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PMID:Modulation of leukocyte migration in mesenteric interstitium. 794 4

Paraplegia may occur after transient aortic occlusion as a consequence of primary ischemia to the spinal cord or injury during the reperfusion period. In animal models of ischemia/reperfusion there is evidence that reperfusion injury may be modulated partially by neutrophils. The efficacy of the neutrophil adherence blocking murine monoclonal antibody (MAb 60.3) was assessed in spinal cord ischemia/reperfusion in rabbits. Spinal cord ischemia was accomplished by balloon catheter occlusion of the infrarenal aorta. Neurologic assessment was graded as normal, partial neurologic deficit, or complete paralysis. Electrophysiologic monitoring with somatosensory evoked potentials was used to determine the optimal length of time of occlusion. Animals were treated randomly with 2 mg/kg of intravenous Mab 60.3 (n = 8) or saline solution (n = 9) with the investigator unaware of treatment. Mean occlusion times were no different between groups (control, 32.7 +/- 3.6 minutes versus MAb, 32.4 +/- 6.0 minutes). Five (55%) saline-treated and four (50%) MAb 60.3-treated animals became paraplegic. Animals with initial paraparesis all progressed to flaccid paraplegia within 24 hours. We conclude that spinal cord injury after transient aortic occlusion is independent of the CD11/CD18 glycoprotein complex of the neutrophil. Injury in this setting may occur during ischemia and thus may not be dependent on neutrophils or reperfusion.
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PMID:Inhibition of neutrophil adhesion does not prevent ischemic spinal cord injury. 794 51

Recent studies suggest that granulocytes (PMNs) play a role in the pathogenesis of acute and chronic myocardial ischemia and extension of myocardial injury. Granulocytes can release a variety of mediators tissue injury and synergize with these different mediators, cytokines and other cells resulting in amplification of neutrophil stimulation and rising to additional products with enhanced endothelial injury. Free radicals released by PMNs during ischemia or reperfusion produce deleterious effects on cell membranes, endothelial cells and myocardium. Experience in humans shows the modification of PMNs function in angina and during myocardial ischemia: upon reperfusion PMNs accumulate and produce an inflammatory response leading to endothelial injury. Rabbit derived antiserum dependent-reduction of circulating PMNs in the dog or using monoclonal antibody anti-CD11b/CD18 of PMNs resulted in smaller myocardial infarction. Another aspect of PMNs function is related to leukotriene C4 release; the vasoconstrictor effect of this leukotriene on coronary arteries is synergistic with that induced by platelet-released thromboxane A2, and the decrease in coronary flow produced by the combination of both substances is greater than the sum of changes caused by the two eicosanoids separately administered. The potential role of leukocytes, oxygen radicals, leukotrienes and granulocyte enzymes in the pathophysiology of myocardial injury due to regional ischemia and reperfusion is an area of intense investigation. This overview will not attempt to be exhaustive. Experimental and clinical studies to elucidate these events should not only provide insight into acute and chronic pathologic tissue damage, but may also lead to the identification of important new targets of pharmacologic intervention.
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PMID:[The role of the granulocytes in ischemic cardiopathy]. 807 42


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