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

Neutrophils play an important role in ischemia-reperfusion (I/R)-induced vascular injury in the small intestine. Monoclonal antibodies against the leukocyte adhesion glycoprotein CD11/CD18 afford protection against I/R-induced microvascular injury. It has been suggested that the response to I/R differs between the various layers of the bowel wall, with relatively few granulocytes accumulating in the mucosa compared with the serosa or mesentery. The objectives of this study were to determine whether I/R-induced neutrophil accumulation is 1) homogenous in the different layers of intestine (mucosa, submucosa, muscle, and mesentery) and 2) dependent on the expression and/or activation of the leukocyte adhesion glycoprotein CD11/CD18. Neutrophil infiltration was monitored by measuring myeloperoxidase activity in mucosa, submucosa, muscle, and mesentery of cat small intestine subjected to 3 h ischemia (blood flow reduced to 20% of control) and reperfusion. I/R elicited a comparable degree of polymorphonuclear (PMN) infiltration in mucosa, submucosa, and mesentery, with the muscularis exhibiting a greater response. Pretreatment with the CD18-specific monoclonal antibody (IB4) significantly attenuated the I/R-induced PMN accumulation in all layers of the bowel wall and mesentery, indicating that the granulocyte accumulation elicited by I/R is dependent on the expression and/or activation of the leukocyte adhesion molecule CD11/CD18.
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PMID:Granulocyte accumulation in postischemic intestine: role of leukocyte adhesion glycoprotein CD11/CD18. 135 Apr 22

This study tested the hypothesis that preventing neutrophil adhesion during reperfusion, by blocking either the neutrophil membrane CD18 integrin complex or its endothelial and myocyte ligand, intercellular adhesion molecule-1 (ICAM-1), would reduce myocardial inflammation and edema and improve reflow and ventricular function after heart preservation and transplantation. After cardioplegia and insertion of a left ventricular balloon, rabbit hearts were heterotopically transplanted into recipient rabbits either immediately (immediate, n = 12) or after preservation in 4 degrees C saline (3 hours of ischemia, n = 33). Forty-five minutes before reperfusion, recipients of preserved hearts received intravenous infusions of either saline (vehicle, n = 13), anti-CD18 monoclonal antibody (Mab) R15.7 (2 mg/kg) (anti-CD18, n = 10), or anti-ICAM-1 Mab R1.1 (2 mg/kg) (anti-ICAM, n = 10). During 3 hours of reperfusion the slope of the peak-systolic pressure-volume relation and its volume-axis intercept, the exponential elastic coefficient of the end-diastolic pressure-volume relation, the unstressed ventricular volume, and the time constant of the exponential left ventricular pressure decay after dP/dtmin were serially measured. Myocardial blood flow was measured with microspheres from which coronary vascular resistance was calculated. After explanation, the degree of myocardial inflammation, estimated by tissue neutrophil sequestration (myeloperoxidase assay) and myocardial water content were determined. Within each group no significant differences in measurements made at 1, 2, and 3 hours of reperfusion were noted. Compared with the immediate transplantation group, the vehicle group demonstrated a significant increase in myeloperoxidase activity (3380 +/- 456 versus 1712 +/- 552 microU/gm, p < 0.05), coronary vascular resistance (115.5 +/- 13.4 versus 70.5 +/- 10.6 U/gm, p < 0.05), and myocardial water content (79.8% +/- 0.4% versus 75.6% +/- 1.3%, p < 0.05), a significant decrease in unstressed ventricular volume (a leftward shift in the end-diastolic pressure-volume relation) (-0.49 +/- 0.24 versus 0.28 +/- 0.21 ml, p < 0.05), and a marked prolongation in exponential left ventricular pressure delay after dP/dtmin (156.64 +/- 3.81 versus 37.25 +/- 3.34 msec, p < 0.01).(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Complete prevention of myocardial stunning, contracture, low-reflow, and edema after heart transplantation by blocking neutrophil adhesion molecules during reperfusion. 136 May 56

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 molecules mediating tissue injury which act synergistically with other molecules and cells. The aim of our investigation was to evaluate the granulocyte function in patients affected by coronary artery disease (CAD) and during coronary angioplasty (PTCA). We studied 20 patients suffering from CAD. The PMN's aggregating activity was greater in the coronary sinus than in the aorta (P < 0.01). The increase in aggregating activity was evident in patients who were smokers: their cells release significantly lower quantities of leukotriene C4 (P < 0.025). In the 20 patients who underwent coronary angioplasty we analyzed superoxide release after stimulation with phorbol-myristate-acetate (PMA). The results showed a greater decrease of PMN's superoxide production in the coronary sinus than in the aorta (P < 0.05). In all patients affected by CAD we evaluated the PMN's expression of CD11b/CD18 membrane integrins. In these patients the increase in expression of CD11b/CD18 was statistically significant in comparison with the controls (P < 0.01). This increase in expression correlates with a higher aggregation (r = 0.87, P < 0.001). 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 paper presents studies carried out in vivo which have been instrumental in demonstrating the role of granulocytes as mediators of myocardial ischemia.
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PMID:Phagocyte activation in coronary artery disease. 136 45

Granulocytes play an important role in increasing the infarct size after ischemia and reperfusion by the release of oxygen-derived free radicals (ODFR) and lysosomal enzymes. It has been shown that the number of granulocytes adhering to the vascular endothelium increases after occlusion of the coronary artery, and that the area of myocardial damage can be reduced by preventing granulocyte adherence with monoclonal antibodies directed against adhesion receptors. The underlying mechanism of granulocyte activation under these conditions is not yet known. We have investigated whether granulocytes can be activated directly by reduced oxygen tensions. Granulocytes were suspended in a hypoxic buffer and incubated on fibronectin and gelatin coated microtitre plates at 1-3% ambient oxygen to study their ability to adhere to these matrices. The results showed that the adherence of granulocytes to fibronectin was dependent on the duration of hypoxia. After 30 min of incubation under hypoxia granulocyte adherence increased 1.3 to 1.8 fold compared to the normoxic control. The adherence to fibronectin could be inhibited partially by anti-CD18 antibody, a monoclonal antibody to the common beta chain of a class of extracellular matrix receptors. This direct activation of granulocytes due to hypoxic conditions may have implications for the interaction of these cells with the vascular endothelium in vivo.
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PMID:Studies on the interaction of leucocytes and the myocardial vasculature. I. Effect of hypoxia on the adherence of blood granulocytes. 136 46

The objective of this study was to compare the leukocyte-endothelial cell adhesive interactions elicited in postcapillary venules by either local ischemia-reperfusion or hemorrhage-reperfusion. Leukocyte rolling, adherence, and emigration were monitored in cat mesenteric venules exposed to an 85% reduction in blood flow (induced by either hemorrhage or local restriction of arterial inflow) for 1 h, followed by 1 h reperfusion. Leukocyte-endothelial cell interactions, venular diameter, and red blood cell velocity were measured during baseline, ischemia, and reperfusion periods. Both local and hemorrhage-induced ischemia reperfusion caused a reduction in leukocyte rolling velocity and increases in leukocyte adherence and emigration. Quantitatively, the adherence and emigration responses in both ischemia models were nearly identical. However, the two models differed in their response to immunoneutralization of the leukocyte adhesion glycoprotein CD11/CD18 with monoclonal antibody (MAb) IB4. The MAb had a more profound effect in attenuating leukocyte adherence and emigration in the local ischemia model. These results indicate that different factors may contribute to leukocyte-endothelial cell adhesive interactions observed in local vs. systemic models of ischemia-reperfusion.
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PMID:Leukocyte adhesion in local versus hemorrhage-induced ischemia. 141 7

Reperfusion after transient tissue ischemia constitutes an irrevocable need to preserve tissue viability. However, release of prolonged ischemia will either result in failure of the microcirculation to reperfusion (no-reflow) and thus the prolongation of hypoxia, or in restoration of blood flow resulting in reoxygenation of the inflicted tissue. While ischemia damages the tissue primarily through hypoxia-induced depletion of energy stores, reoxygenation paradoxically contributes to tissue damage through the formation of oxygen radicals, the release of chemoattractant mediators (TNF, IL-1, LTB4), and the activation of circulating polymorphonuclear leukocytes (PMNs). Through the action of chemoattractant mediators and the upregulation of leukocytic (CD11/CD18) and endothelial adhesion receptors (ICAM, GMP-140), activated PMNs adhere to the endothelium, release further chemoattractants and oxygen radicals and undertain a vicious circle, which will ultimately result in further tissue damage. Both the no-reflow phenomenon and the events initiated by reflow--termed herein as the reflow-paradox--contribute to the failure of the nutritive microvascular perfusion and loss of tissue viability following ischemia and reperfusion.
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PMID:Role of oxygen radicals in the microcirculatory manifestations of postischemic injury. 166 84

Polymorphonuclear cells and monocytes (phagocytes) are a critical component of host defense against infections. However, these cells also play a significant role in host tissue damage in many noninfectious diseases, such as ischemia-reperfusion injury syndromes and rejection of transplanted organs. The leukocyte adhesion molecule family CD11/CD18 (beta 2 integrins) is critical to the function of polymorphonuclear cells and monocytes in inflammation and injury. Inherited deficiency of CD11/CD18 impairs phagocyte chemotaxis, adhesion and transmigration across endothelium, and clearance of invading microorganisms through phagocytosis and cell-mediated killing. Furthermore, murine monoclonal antibodies directed against the CD11b/CD18 (CR3) heterodimer have been shown to reduce, by 50%-80%, phagocyte-mediated ischemia-reperfusion injury in several organ systems, such as the myocardium, liver, and gastrointestinal tract and to inhibit development of insulin-dependent diabetes mellitus in nonobese diabetic (NOD) mice. Expression of CD11b/CD18 in a soluble and functional form might therefore be potentially useful as an anti-inflammatory agent. We have now expressed a recombinant soluble heterodimeric form of this human beta 2 integrin, normally expressed as two noncovalently associated membrane-bound subunits. The secreted receptor exhibited direct and specific binding to its ligand, iC3b, the major complement C3 opsonin, and inhibited binding of polymorphonuclear cells to recombinant interleukin 1-activated endothelium.
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PMID:Expression of a soluble and functional form of the human beta 2 integrin CD11b/CD18. 167 28

Activated leukocytes appear to be directly involved in ischemic central nervous system injury. A surface glycoprotein (CD18) on the leukocyte is required for endothelial adherence and subsequent function and can be blocked with leukocyte adhesion antibody treatment. We used two animal models to determine the efficacy of anti-CD18 antibody treatment in preserving neurologic function after central nervous system ischemia. We gave a dose of 1 mg/kg anti-CD18 to treatment rabbits 30 minutes before inducing irreversible ischemia in the brain with intraarterial microspheres or in the spinal cord using reversible aortic occlusion. Treatment with anti-CD18 produced a significant reduction in neurologic deficits in the reversible spinal cord model, but not in the irreversible microsphere model. This protective effect supports the active role of leukocytes in central nervous system reperfusion ischemic injury and offers potential for future therapy.
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PMID:Reduction of central nervous system ischemic injury in rabbits using leukocyte adhesion antibody treatment. 167 19

Intravital microscopic studies of the mesenteric microcirculation have demonstrated that leukocyte adherence and emigration in postcapillary venules are a characteristic feature of tissues exposed to ischemia-reperfusion. The objectives of this study were to determine whether: (1) neutrophils are the predominant leukocytes that adhere and emigrate in postischemic mesenteric venules, and (2) leukocyte adherence and/or emigration are a prerequisite for reperfusion-induced increases in venular permeability. Leukocyte kinetics in cat mesenteric venules (25-35 microns diameter) were evaluated using both intravital microscopy and quantitative morphometry. The intestine and mesentery were exposed to 60 min of ischemia, followed by 60 min reperfusion. Some animals were pretreated with a monoclonal antibody (MoAb IB4) against the leukocyte adhesion glycoprotein, CD11/CD18. Vessels observed by intravital microscopy and adjacent venules of similar diameter were excised and processed for light (LM) and electron microscopy (EM). Horseradish peroxidase (HRP), administered intravenously, was used to assess vascular permeability by EM. By LM, the control (nonischemic) mesentery is sparsely populated by plasma cells, mast cells, and leukocytes; 30-50% of the resident population is neutrophils. Ischemia-reperfusion led to a significant increase in the number of extravascular cells, with neutrophils accounting for greater than 80% of the total cell population. Control and ischemic venules demonstrated no leakage of HRP into the interstitium. However, venules exposed to ischemia and reperfusion demonstrated HRP leakage between endothelial cells and into the surrounding interstitium; neutrophils were adherent to the luminal surface of the endothelium, transmigrating the vessel wall, and in the surrounding interstitium. Animals pretreated with MoAb IB4 presented the same cell profile as nonischemic controls, with no adherent or transmigrating neutrophils. However, some HRP leakage was noted following reperfusion in venules treated with MoAb IB4. The results of this study indicate that: (1) neutrophils are the predominate leukocytes that adhere and emigrate in postischemic venules, and (2) inhibition of leukocyte adhesion does not completely prevent the venular dysfunction associated with ischemia-reperfusion.
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PMID:Morphologic assessment of leukocyte-endothelial cell interactions in mesenteric venules subjected to ischemia and reperfusion. 168 73

Recent studies suggest that granulocytes (PMNs) play a role in the pathogenesis of acute and chronic myocardial ischemia and extension of myocardial injury. A positive correlation was also found between leukocyte count and severity of coronary artery disease. Rabbit derived antiserum dependent-reduction of circulating PMNs in the dog or using monoclonal antibody anti-CD11b/CD18 of PMNs resulted in smaller myocardial infarcts. Granulocytes can release a variety of mediators tissue injury and synergize with these different mediators and other cells resulting in amplification of neutrophil stimulation and rising to additional products with enhanced endothelial injury. This paper reviews "in vivo" studies that have been instrumental in demonstrating this role of granulocytes as a mediator of myocardial ischemia. Experience in humans shows the modification of PMNs function in angina and during myocardial ischemia, and data from our group demonstrated that their aggregability is increased in the coronary sinus of patients with angiographically documented coronary disease. Upon re-perfusion PMNs accumulate and produce an inflammatory response resulting in endothelial injury. Free radicals formed during ischemia or re-perfusion produce deleterious effects on cell membranes, endothelial cell and myocardium. On the other hand the PMNs activation occurring during coronary angioplasty (PTCA) by the release of proteolytic enzymes and the generation of oxygen-free radicals, may aggravate the endothelial damage induced by PTCA and further stimulate platelets having potential implications in subsequent development of restenosis. An other 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, as well as 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 pathophysiology of myocardial injury due to a regional ischemia and reperfusion is an area of intense investigation. Experimental and clinical studies to elucidate these events should not only provide insights 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:Role of granulocytes in endothelial injury in coronary heart disease in humans. 181 45


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