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

Neutrophils have been implicated as the cause of vascular injury that can lead to organ dysfunction and organ failure following a variety of initiating events. In particular, neutrophils have been shown to be necessary for vascular or tissue damage to occur in ischemia-reperfusion injuries of some organs and in the generalized ischemia-reperfusion injury resulting from hemorrhagic shock. Adherence of neurotrophils to endothelium or homotypic aggregation of neutrophils is thought to be necessary for injuries of this type to occur and these cell-cell interactions are mediated by adhesion molecules on both endothelial cells and leukocytes. In our completed studies, monoclonal antibodies that recognize functional epitopes of the leukocyte CD11/CD18 provided protection from ischemia-reperfusion injury. In addition, preliminary studies investigating leukocyte L-selectin and endothelial P-selectin appear to provide protection from ischemia-reperfusion injury.
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PMID:Monoclonal antibodies to leukocyte and endothelial adhesion molecules attenuate ischemia-reperfusion injury. 825 Aug 13

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

Leukocytes can produce vascular injury following ischemia and reperfusion of tissue resulting in thrombosis, edema and necrosis. Leukocyte adhesion to endothelial cells allows formation of a protected microenvironment where inflammatory molecules can exceed anti-inflammatory molecules thus resulting in injury. Blocking adherence with monoclonal antibodies to adherence molecules can prevent reperfusion injury to a variety of organs. In particular, antibodies to CD18 and P-selectin have been shown to be effective in ameliorating injury.
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PMID:The role of adhesion molecules in reperfusion injury. 831 35

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

Modulation of neutrophil responses by adenosine may have an important role in limiting tissue injury during inflammation or ischemia-reperfusion. Mac-1 (CD11/CD18), a member of the leukocyte integrin family, participates in neutrophil adhesion to endothelium, in transendothelial migration, and in phagocytosis. Using monoclonal antibodies and flow cytometry, we investigated the effect of adenosine on the increase in plasma membrane expression of Mac-1 which occurs following stimulation of neutrophils with the chemotactic peptide N-formylmethionylleucylphenylalanine (FMLP). Adenosine and 5'N-ethylcarboxamido-adenosine, a potent A2 agonist, each produced a dose-dependent inhibition of as much as 50% of the increase in Mac-1 expression on neutrophils stimulated with FMLP, with an IC50 of approximately 1 nM. The effect of adenosine was blocked by 8-p-sulfophenyltheophylline, an adenosine-receptor antagonist, N6-cyclopentyl-adenosine, an A1-selective agonist, had no effect on FMLP-stimulated Mac-1 expression in the concentration range expected for its action on neutrophil adenosine receptors of the A1 type. We also found that dibutyryl cyclic adenosine monophosphate inhibited the upregulation of Mac-1, and that the effect of adenosine on Mac-1 expression was not reversed by colchicine or vinblastine. We conclude that adenosine acts via A2 receptors to inhibit the upregulation of Mac-1 expression of FMLP-stimulated neutrophils, and that A1 receptors are not involved. This effect of adenosine may help to limit Mac-1-dependent neutrophil exudation at sites of inflammation or ischemia-reperfusion.
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PMID:Acting via A2 receptors, adenosine inhibits the upregulation of Mac-1 (Cd11b/CD18) expression on FMLP-stimulated neutrophils. 839 28

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

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

We investigated the effects of F(ab')2 fragments of anti-CD11b and anti-CD18 monoclonal antibodies on ischemic cell damage in the rat when administered upon reperfusion and at 2 h of reperfusion after transient (2 h) middle cerebral artery (MCA) occlusion. 2 h of MCA occlusion was induced by intraluminal insertion of a monofilament. The following groups of animals were investigated. Anti-CD11b groups (n = 15): an intact anti-CD11b antibody (1B6c) and an anti-CD11b F(ab')2 fragment of 1B6c were infused upon reperfusion (4 mg/kg i.v.). Anti-CD18 group (n = 8): an anti-CD18 F(ab')2 fragment of CL26 was infused upon reperfusion (2 mg/kg i.v.), and at 22 h of reperfusion (1 mg/kg i.v.). Anti-CD11b delayed group (n = 9): an anti-CD11b F(ab')2 fragment of 1B6c was infused at 2 h of reperfusion (4 mg/kg i.v.), and at 22 h after reperfusion (2 mg/kg i.v.). Control groups (n = 18): an isotype-matched control antibody (mouse IgG1) was administered: (a) upon reperfusion (n = 13), and (b) at 2 h and 22 h of reperfusion (n = 5). Rats were sacrificed at 7 days of reperfusion. In a separate population of rats subjected to 2 h of MCA occlusion (n = 9), brain myeloperoxidase (MPO) activity was measured at 46 h of reperfusion. The vehicle groups had infarct volumes of 35.21 +/- 2.82% to 41.39 +/- 2.73% of the contralateral hemisphere, respectively. Infarct volume was significantly reduced after treatment with: the intact anti-CD11b antibody upon reperfusion (19.0 +/- 6.6%) (P < 0.05), the fragments of mAbs of anti-CD11b administered upon reperfusion (19.7 +/- 2.7%) (P < 0.05), and at 2 h of reperfusion (22.2 +/- 4.8%) (P < 0.05), and anti-CD18 administered upon reperfusion (20.4 +/- 4.8%) (P < 0.05). Anti-CD11b treatment significantly (P < 0.05) inhibited the increase of MPO activity in the ischemic hemisphere. Our data demonstrate that anti-CD11b and anti-CD18 mAb fragments significantly reduce infarct volume and inhibit the increase of MPO activity in the ischemic lesion; administration of anti-CD11b mAb fragment even at 2 h of reperfusion significantly reduces infarct volume. These data support importance of the beta 2 integrin CD11b/CD18 in ischemia/reperfusion injury and indicate that the therapeutic window for intervention to reduce ischemic cell damage in this model is at least 4 h from the onset of MCA occlusion.
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PMID:Postischemic treatment (2-4 h) with anti-CD11b and anti-CD18 monoclonal antibodies are neuroprotective after transient (2 h) focal cerebral ischemia in the rat. 858 6

This study was performed to determine effects of atrial and brain natriuretic peptides (ANP, BNP) on neutrophils-induced endothelial injury which is known to play a role in the pathophysiology of ischemia/reperfusion myocardial injury and to examine whether the effects of ANP and BNP on neutrophils are modulated by neutral endopeptidase 24.11 (NEP) in neutrophils themselves. The incubation of human neutrophils with ANP and BNP inhibited the neutrophils-induced detachment of cultured human endothelial cells (HEC). The inhibitory effect of ANP and BNP was associated with the suppressions of the neutrophils adhesiveness to HEC, CD18 expression on the neutrophils and elastase release from the neutrophils. Coincubation with UK73967 or phosphoramidon, inhibitors of NEP, potentiated all of the effects of ANP and BNP on the neutrophil functions, and the NEP inhibitors protected degradation of ANP and BNP by the neutrophils. NEP enzymatic activity in the particulate fractions and immunoreactive NEP expression were found to increase in the neutrophils from patients with early phase of acute myocardial infarction (AMI) by 5.2- and by 4.2-fold of the neutrophils from patients with late phase of AMI, respectively. In an in vivo canine model of myocardial ischemia/reperfusion, the intravenous administration of UK73967 suppressed the neutrophil adherence to endothelium and the neutrophil accumulation in the ischemic/reperfused myocardium. The results indicate that ANP and BNP, which are known to increase in AMI, modulate the neutrophil functions and exert protective effects against the neutrophils-induced endothelial cytotoxity. But the effects are suppressed due to their degradation by the neutrophil own NEP. Thus, neutrophil NEP, which also increases in AMI, may play a role in the pathophysiology of neutrophils-mediated ischemia/reperfusion endothelial and myocardial injury.
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PMID:Neutral endopeptidase 24.11 in neutrophils modulates protective effects of natriuretic peptides against neutrophils-induced endothelial cytotoxity. 863 98


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