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

Accumulating evidence during the last decade has shown that the CNS can mount a well-defined inflammatory reaction to a variety of insults including trauma, ischemia, transplantation, viral infections as well as neurodegeneration. Many aspects of this centrally derived inflammatory response parallel to some extent the nature of such a reaction in the periphery. Through the recent application of molecular genetic techniques including PCR, utilization of cDNA probes in conjuncture with the availability of highly specific antibodies, new concepts are rapidly emerging as to the molecular mechanisms associated with the development of brain injury. In particular, the importance of cytokines, especially TNFalpha and IL-1beta, is emphasized in the propagation and maintenance of a CNS inflammatory response. This review summarizes evidence in support of a case for ischemia and trauma eliciting an inflammatory condition in the injured brain. The inflammatory condition consists of cells (neutrophils early after the onset of brain injury and subsequently monocyte infiltration) and mediators (cytokines, chemokines and adhesion molecules). It is clear that de novo up-regulation of pro-inflammatory cytokines, chemokines and endothelial-leukocyte adhesion molecules in the brain occurs soon following focal ischemia and trauma and at a time when the tissue injury is evolving. The significance of the inflammatory response and its contribution to brain injury are now becoming better understood. Evidence has emerged in support of the role of cytokines in driving the inflammatory response and that this process is causally related to the degree of brain injury. Evidence reviewed includes: (1) the capacity of specific cytokines to exacerbate brain damage; (2) the capacity of specific cytokine blockade to reduce ischemic brain damage; (3) depletion of circulating neutrophils reduces ischemic brain injury, and (4) antagonists of the endothelial-leukocyte adhesion interactions (e.g. anti-ICAM-1) reduce ischemic brain injury. Targeting the cytokines that drive the brain inflammatory response to injury provides opportunities to intervene with novel therapeutics in stroke and neurotrauma.
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PMID:The role of cytokines in the neuropathology of stroke and neurotrauma. 973 Jun 80

The role of neutrophils in acute renal failure is controversial. Acute renal failure can clearly occur in the absence of neutrophils. However, recent studies using specific neutrophil markers indicate that neutrophils accumulate in postischemic kidneys. Moreover, reperfusion of ischemic kidneys with neutrophils worsens ischemic injury and causes kidney neutrophil retention. Neutrophil retention is dependent on the state of neutrophil activation and the duration of renal ischemia. This interaction could account for the high frequency of acute renal failure in conditions associated with prolonged prerenal asotemia and neutrophil priming such as the adult respiratory distress syndrome, or sepsis. Neutrophil retention is mediated by interaction of neutrophil integrins and endothelial cell ICAM-1 because maneuvers reducing the expression and/or function of these adhesion molecules is protective in experimental models of ischemia. Nitric oxide is a key modulator of neutrophil worsening of ischemic injury because maneuvers that decrease nitric oxide production worsen and those which increase nitric oxide protect ischemic kidneys from neutrophil effects. The clinical significance of neutrophils may relate to the observation that bioincompatible membranes activate complement, and retard recovery from acute renal failure. In conclusion, neutrophils are an important contributor to ischemic acute renal failure. It remains to be determined whether decreasing neutrophil function accelerates recovery in acute renal failure.
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PMID:The role of neutrophils in acute renal failure. 975 2

Neutrophils are known to mediate injury in acute ischemic stroke especially during reperfusion. Migration of neutrophils into regions of ischemic injury involves binding to the endothelial cell's intercellular adhesion molecule (ICAM-1) through the leukocyte integrin, CD11/CD18. We studied the potential for neuroprotection with a humanized antibody that binds to and blocks the functions of the CD11/CD18 integrin in a rabbit model of transient focal ischemia. Fifteen New Zealand White rabbits underwent transorbital occlusion of the left middle cerebral, anterior cerebral, and internal carotid arteries using aneurysm clips for 2 h, followed by 6 h of reperfusion. Treatment with a maximally saturating dose (4 mg/kg) of a humanized CD11/CD18 monoclonal antibody (Hu23F2G, ICOS Corp., Bothell, WA) (n = 8) or placebo (n = 7) was administered 20 min after occlusion and given as a single intravenous bolus. Hemispheric ischemic neuronal damage (IND) as seen on hematoxylin- and eosin-stained sections was significantly reduced in Hu23F2G-treated animals by 57% (Hu23F2G: 15 +/- 6.9%; placebo: 35 +/- 5%; mean +/- SEM, P < 0.05, t-test). Immunohistochemical staining with neutrophil elastase confirmed the presence of neutrophils within regions of IND in control brains. Treatment with Hu23F2G resulted in marked reduction of neutrophil infiltration. (No. of neutrophils/IND area: Hu23F2G 36.1 +/- 36.7 cm-2, placebo 460.6 +/- 101.8 cm-2, P = 0.001. ) Antagonism of neutrophil migration at the level of the CD11/CD18 integrin reduces ischemic injury in experimental stroke.
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PMID:Hu23F2G, an antibody recognizing the leukocyte CD11/CD18 integrin, reduces injury in a rabbit model of transient focal cerebral ischemia. 978 82

The objective of the present study was to assess the role of lipid mediators and adhesion molecule expression in exacerbation of ischemia-reperfusion-induced inflammatory response in diabetes. Leukocyte-endothelial cell interactions were studied in mesenteric venules by intravital microscopy. Endothelial expression of intercellular adhesion molecule (ICAM)-1 was measured by the double-radiolabeled monoclonal antibody technique, and beta2-integrin expression was measured by flow cytometry. Ischemia-reperfusion elicited significantly larger increases in leukocyte adhesion and emigration in diabetic rats that were prevented by a platelet-activating factor (PAF)-receptor antagonist or a leukotriene synthesis inhibitor. Leukotriene B4 (LTB4) superfusion induced similar leukocyte recruitment in diabetic and control rats, whereas PAF elicited larger increases in diabetic rats. CD11a, but not CD11b, expression was higher in leukocytes from diabetic animals. Endothelial ICAM-1 in mesentery and in intestine did not differ between diabetic and control rats. These results indicate that diabetes is associated with an enhanced response to ischemia-reperfusion that depends on both PAF and leukotrienes. An increased sensitivity to PAF, along with an increased CD11a expression, may account for the exaggerated inflammatory response to ischemia-reperfusion in diabetes.
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PMID:Mechanisms responsible for enhanced inflammatory response to ischemia-reperfusion in diabetes. 981 85

Recent evidence indicates that thrombolysis may be an effective therapy for the treatment of acute ischemic stroke. However, the reperfusion of ischemic brain comes with a price. In clinical trials, patients treated with thrombolytic therapy have shown a 6% rate of intracerebral hemorrhage, which was balanced against a 30% improvement in functional outcome over controls. Destruction of the microvasculature and extension of the infarct area occur after cerebral reperfusion. We have reviewed the existing data indicating that an inflammatory response occurring after the reestablishment of circulation has a causative role in this reperfusion injury. The recruitment of neutrophils to the area of ischemia, the first step to inflammation, involves the coordinated appearance of multiple proteins. Intercellular adhesion molecule-1 and integrins are adhesion molecules that are up-regulated in endothelial cells and leukocytes. Tumor necrosis factor-alpha, interleukin-1, and platelet-activating factor also participate in leukocyte accumulation and subsequent activation. Therapies that interfere with the functions of these factors have shown promise in reducing reperfusion injury and infarct extension in the experimental setting. They may prove to be useful adjuncts to thrombolytic therapy in the treatment of acute ischemic stroke.
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PMID:Reperfusion injury after focal cerebral ischemia: the role of inflammation and the therapeutic horizon. 984 53

Recent evidence has shown crucial roles for cell-adhesion molecules in inflammation-induced rolling, adhesion, and accumulation of neutrophils in tissue. Intercellular adhesion molecule-1 (ICAM-1) is one of these adhesion molecules. Previous studies have shown marked reduction in the size of infarction after focal cerebral ischemia by depletion of granulocytes and administration of the antibody against ICAM-1. In the present study we investigated the role of ICAM-1 in the size of ischemic lesions, accumulation of granulocytes, and microcirculatory compromise in focal cerebral ischemia by using ICAM-1-knockout mice. Ischemic lesions were significantly mitigated in knockout mice after permanent and transient focal ischemia, even though the number of granulocytes in the infarcted tissue was almost the same between knockout and wild-type mice. Depletion of granulocytes further decreased the size of ischemic lesions after transient focal ischemia in ICAM-1-knockout mice. Microcirculation was reduced after focal ischemia, but it was better preserved in the cerebral cortex of knockout mice than that of wild-type mice. The present study demonstrated that ICAM-1 played a role in microcirculatory failure and subsequent development and expansion of infarction after focal cerebral ischemia. However, it is highly unlikely that ICAM-1 played a key role in accumulation of granulocytes after focal cerebral ischemia.
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PMID:Deficiency of intercellular adhesion molecule 1 attenuates microcirculatory disturbance and infarction size in focal cerebral ischemia. 985 Jan 46

Intercellular adhesion molecule-1 (ICAM-1) expression was studied with rat transient cerebral ischemic model. The results showed that the expression of ICAM-1 markedly increased after 1 h ischemia following 6 h reperfusion. Laser confocal microscope demonstrated that the FITC quantum on blood vessels after reperfusion was more than 47% compared to that of pure ischemia. MPO activity and light microscope observation showed that leukocytes accumulated in injured tissue 9 h after reperfusion. The local IL-1 content in brain tissue changed with different period of reperfusion time. Our data indicated that after brain ischemia-reperfusion injury ICAM-1 expression was in time-dependent increase, the local IL-1 secretion might up regulate the ICAM-1 expression, there were large amount of leukocytes accumulated in surrounding tissue, the increase of ICAM-1 expression was the prerequisite for leukocyte adhesion and migration.
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PMID:[The study of ICAM-1 expression after brain ischemia-reperfusion injury in rats]. 1007 95

Ischemia-reperfusion injury is an acute inflammatory process during which leukocytes are intimately involved. In this review, we summarize the current data on the leukocyte cell adhesion cascade in ischemia-reperfusion injury, focus upon studies which have demonstrated specific cell adhesion molecule interactions which mediate the leukocyte involvement in ischemia-reperfusion injury, and suggest future avenues of therapeutic interventions. The increased adhesion between activated vascular endothelium and peripheral blood leukocytes is central to the structural and the functional impairment in ischemia-reperfusion injury. Several families of adhesion molecules, namely the selectins, the intercellular adhesion molecules (ICAMs), and the integrins expressed either on the endothelium or on the leukocytes, are involved the cascade of events. Sequential and overlapping cellular interactions between the members of the three gene families of adhesion receptors result in adhesion of the leukocytes to the endothelium and extravasation at the site of ischemia. The functional importance of ICAM-1 and its beta2 integrin ligands in ischemia-reperfusion of the kidney has been demonstrated by monoclonal antibody blockade studies, in knockout mice and by treatment with antisense oligodeoxynulceotides (ODN). We have shown that antisense ODN for ICAM-1 protected the kidney against ischemic renal failure. In addition, in transplanted kidneys, ICAM-1 inhibition by antisense ODN ameliorates ischemia-reperfusion injury and prevents delayed graft function. Recent developments in antisense ODN technology make this a promising therapeutic approach, and antisense ODN treatment of donors or donor organs for ICAM-1 may be useful for the prevention of reperfusion injury in human renal transplantation and could influence acute and chronic graft function.
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PMID:Diapedesis of leukocytes: antisense oligonucleotides for rescue. 1021 72

Reactive oxygen metabolites (ROMs) have been implicated in the pathogenesis of the inflammatory response to ischemia/reperfusion (I/R), which is exacerbated in diabetes. This study revealed an increased (P < 0.01) ROMs production in mesenteric tissue (measured using the oxidant-sensitive fluorochrome dihydrorhodamine 123) after I/R in control and diabetic rats, with larger increments (P <0.0001) observed in the latter group, that was associated with an increased inflammatory response measured by intravital microscopy. Either xanthine oxidase inhibition, superoxide scavenging, ICAM-1 immunoneutralization, or blockade of platelet-activating factor or leukotrienes effectively reduced leukocyte recruitment and ROMs production in control and diabetic rats. Moreover, neutrophils from diabetic rats showed an enhanced production of ROMs in vitro in basal and stimulated conditions. We conclude that the oxidative stress during reperfusion is markedly enhanced in diabetes and this appears to result from increased leukocyte recruitment and a higher capacity of diabetic leukocytes to generate ROMs in response to stimulation.
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PMID:Reperfusion-induced oxidative stress in diabetes: cellular and enzymatic sources. 1041 Sep 90

The adherence of activated neutrophils to endothelial cells during ischemia/reperfusion injury is mediated by inside-out signal transduction. Subsequently, outside-in signal transduction occurs following ligation of adhesion molecules with their ligands triggering respiratory bursts of neutrophils. In addition, neutrophil elastase enhances CC- and CXC-chemokine production by monocytes and macrophages. MCP-1, a CC-chemokine, enhances tissue factor production by macrophages and increases ICAM-1 expression on endothelial cells. Chemotaxis and respiratory bursts of neutrophils are augmented by CXC-chemokines. Furthermore, neutrophil elastase inactivates anticoagulants including antithrombin III, heparin cofactor II, and thrombomodulin, suggesting that neutrophil elastase aggravates microcirculatory disturbance after ischemia/reperfusion. Thus neutrophil elastase modulates the interation of neutrophils and endothelial cells during ischemia/reperfusion injury. Taken together with these observations, a therapeutic regimen with antibodies against adhesion molecules in combination with neutrophil elastase inhibitor and anticoagulants may attenuate ischemia/reperfusion injury.
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PMID:[Interaction between neutrophils and endothelial cells following ischemia/reperfusion]. 1041 50


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