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)

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

L-selectin on leukocyte surfaces mediates cell rolling on endothelium. L-selectin blockade with antibodies attenuated ischemic-reperfusion injury (IRI) in heart and skeletal muscle, but its role in renal IRI is unknown. We evaluated the role of L-selectin in renal IRI using L-selectin-deficient mice. Neutrophil migration to chemically inflamed peritoneum was reduced by 47% (P < 0.01) in L-selectin-deficient mice. Ischemia was induced by bilateral renal pedicle clamping for 30 min. Control and L-selectin groups had similar elevations of serum creatinine (1.8 +/- 0.3 vs. 1.7 +/- 0.2 mg/dl) and blood urea nitrogen (111 +/- 17 vs. 128 +/- 12 mg/dl) 24 h postischemia. Pathological assessment showed comparable degrees of tubular necrosis at 24 h. The postischemic increase in peritubular neutrophils per 10 high-power field was similar in control and L-selectin-deficient groups at 4 (28 +/- 10 vs. 22 +/- 5), 12 (245 +/- 80 vs. 236 +/- 78), and 24 h (130 +/- 12 vs. 156 +/- 18). These data argue against a significant role for L-selectin in renal IRI. Patho-physiological roles of L-selectin in vivo appear to be more complex than in vitro data would suggest.
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PMID:Renal ischemic-reperfusion injury in L-selectin-deficient mice. 877 Jan 73

We investigated the role of adhesion molecules in the early phase of reperfusion following cold ischemia. Livers of male Lewis rats were preserved for 0 h (group A) or 24 h in University of Wisconsin (UW) solution without additives (group B) or in UW solution with anti-ICAM-1 antibody (group C) or anti-E-selectin-1, SLe(x) and SLe(a) antibodies (group D). The livers were then reperfused with diluted rat whole blood (DWB; groups A and B). DWB containing anti-ICAM-1 and LFA-1 antibodies (group C) or DWB containing anti-L-selectin, SLe(x) and SLe(a) antibodies (group D). The reperfusion was performed at 37 degrees C for 1 h at 5 cm H2O of perfusion pressure. During reperfusion, hepatic microcirculation was assessed by monitoring portal and peripheral tissue blood flow. Bile production was significantly reduced in group B livers compared with those in group A. Anti-ICAM-1 and LFA-1 antibodies failed to improve hepatic microcirculation, whereas anti-LECAM-1, SLe(x) and SLe(a) antibodies significantly improved the microcirculation. Bile production in group C and D livers was comparable to that in group B livers. Preservation for 24 h significantly increased the release of TNF-alpha from 0.207 to 43.7 pg/g per hour during reperfusion. Monoclonal antibodies to the adhesion molecules did not suppress the release of TNF-alpha in groups C and D. Histological examination demonstrated a lack of leukocyte infiltration or thrombus in hetapic microvessels. The extent of hepatocyte necrosis did not differ among groups B, C, and D. We conclude that the microcirculatory disturbance in the early phase of reperfusion occurs as a result of the tethering of leukocytes through the interaction of the selectin family and their ligands, and that the ICAM-1-LFA-1 pathway is not involved in this step. The lack of improvement in bile production with antibodies to the selectin family and their ligands strongly suggests that other mechanisms participate in the deterioration of hepatic function.
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PMID:Impact of adhesion molecules of the selectin family on liver microcirculation at reperfusion following cold ischemia. 887 87

Polymorphonuclear leukocytes (PMN), atrial natriuretic peptide (ANP) and leukotriene B4 (LTB4) reportedly play a major role in ischemia/reperfusion states of coronary artery disease. We sought to determine whether ANP and LTB4 cooperate in inducing PMN activation with consequent modulation of membrane molecules required for adherence to endothelium and myocardial cells, namely CD11b and L-selectin and the release of toxic oxygen radicals. ANP (from 10(-16) to 10(-8) M), LTB4 (from 10(-10) to 10(-6) M) and combinations of the two were incubated with normal PMN at 37 degrees C for 15 minutes. Membrane molecules modulation was measured by flow cytometry using specific monoclonal antibodies. Hydrogen peroxide production, an indicator of the capacity of PMN to release toxic oxygen species was quantified by flow cytometry using the peroxide-sensitive fluorescent probe dichlorofluorescein diacetate. ANP, uneffective when used alone, dose-dependently potentiated the PMN response to LTB4 (10(-9) M) as evidenced by an up-regulation of CD11b expression and peroxide production, and a down-regulation of L-selectin expression. These effects were prevented dose-dependently by the protein kinase C (PKC) inhibitor staurosporine (from 10 to 160 microM). Two carnitine congeners, palmytoylcarnitine (tested from 125 pg to 2 micrograms/ml) that also possesses an established ability to antagonise PKC and L-carnitine (tested from 12 to 200 ng/ml) were also effective. These data indicate that ANP potentiates LTB4 in inducing PMN mobilization and activation with a possible consequent detrimental effect on cardiac tissue and evisages the usefulness of PMN metabolism modulators.
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PMID:Potentiation of human polymorphonuclear leukocyte activation by atrial natriuretic peptide. Inhibitory effect of carnitine congeners. 892 47

Leukocyte adhesion molecule (LAM) blockade reduces ischemia-reperfusion injury. We tested the hypothesis that a monoclonal antibody (MAb) that recognizes a functional epitope of L-selectin would decrease hemorrhagic shock-induced reperfusion injury. Anesthetized rabbits were subjected to 2 h of hemorrhagic shock (cardiac output reduced to 30% of baseline), then given one of the following treatments: MAbs that recognize functional domains of L-selectin (LAM1-3), CD18 (60.3), MAbs that recognize a nonfunctional domain on L-selectin (LAM1-14), or saline, immediately before resuscitation with shed blood. Additional fluids were administered as needed to maintain cardiac output at baseline levels for 6 h. The cumulative fluid resuscitation after MAb LAM1-3 (58 +/- 34 ml/kg) was not significantly different from after MAb 60.3 (21 +/- 24 ml/kg) or MAb LAM1-14 (66 +/- 51 ml/kg), but it was significantly less than saline-treated controls (142 +/- 142 ml/kg). However, two animals treated with MAb LAM1-14 died before 6 h. If their resuscitation volumes are projected to 6 h by linear regression, then the LAM1-14-treated group required significantly greater volume (101 +/- 99 ml/kg) than the MAb LAM1-3-treated group. We conclude that MAbs to a functional domain on L-selectin are protective against reperfusion-injury following hemorrhagic shock.
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PMID:Blocking L-selectin function attenuates reperfusion injury following hemorrhagic shock in rabbits. 894 3

Previous studies have implicated the selectins (P- and L-selectin) in the acute phase of myocardial reperfusion injury. However, it is unclear whether these adhesion molecules are involved in the pathogenesis of myocardial reperfusion associated with longer periods of reperfusion. Dogs (n = 8/group) were subjected to 90 min of coronary ischemia and 48 h of reperfusion. Animals were initially treated with a 35 mg/kg intravenous bolus of a sialyl Lewis(x) oligosaccharide (SLe(x)-OS) 10 min before reperfusion, followed by a 1.75 mg.kg-1.h-1 infusion for the first 24 h of reperfusion. A control group of dogs received a normal saline bolus followed by saline infusion for the first 24 h of reperfusion. In a subsequent group of dogs treatment consisted of only the 35 mg/kg bolus of SLe(x)-OS to help elucidate the time course of selectin involvement. The saline control group exhibited marked decreases in blood flow in the ischemic-reperfused myocardium, sustained depression of left ventricular function, an average infarct size of 29 +/- 5% of the myocardial area at risk, and excessive polymorphonuclear leukocyte accumulation in the infarcted myocardium after 48 h of reperfusion. Dogs that received a bolus followed by an infusion of SLe(x)-OS exhibited significant preservation of myocardial blood flow and left ventricular function at 4.5 and 48 h of reperfusion, dramatic attenuation (56%) of infarct size (P < 0.05), and a 55% reduction (P < 0.05) in polymorphonuclear leukocyte accumulation compared with the saline group. Interestingly, SLe(x)-OS bolus treatment alone exerted early (i.e., at 4.5 h) cardioprotective effects that waned by 48 h of reperfusion. These results demonstrate that the selectin family of adhesion molecules plays an extended role in myocardial reperfusion injury and is not only involved in the acute phase of this disease process.
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PMID:A sialyl Lewis(x)-containing carbohydrate reduces infarct size: role of selectins in myocardial reperfusion injury. 894 29

Leukocyte infiltration is an important step in postischemic tissue damage. This study aimed to determine the expression of adhesion molecules and their relationship with leukocyte infiltration in the postischemic gastric mucosa. Gastric tissue was obtained from rats subjected to 30 min gastric ischemia followed by reperfusion. Sections were stained with specific antibodies against (1) L-selectin and (2) LFA-1 on leukocytes, (3) ICAM-1 on endothelial cells, (4) PMNs, and (5) monocytes. Stained cells or blood vessels in mucosal tissue were counted using image analysis. Results showed that from 5 min of reperfusion, numbers of L-selectin-positive cells decreased, whereas LFA-1-positive cells and PMNs increased compared with controls. ICAM-1 expression did not increase until 60 min of reperfusion. Monocyte numbers were unaffected by reperfusion. We conclude that gastric ischemia-reperfusion results in a rapid influx of LFA-1-positive cells, the majority of which are PMN. L-Selectin is shed from these cells allowing them to adhere to the microvasculature via constitutively expressed ICAM-1.
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PMID:Expression of adhesion molecules and leukocyte recruitment into gastric mucosa following ischemia-reperfusion. 905 14

Definition of the elements governing leukocyte adhesion to the microvascular endothelium may lead to new forms of treatment for reperfusion injury. The objectives of this study, employing a porcine latissimus dorsi flap reperfusion model, were (1) to characterize the expression of E- and L-selectin adhesion molecules and (2) to test for a possible benefit of E- and L-selectin blockade in the preceding experimental setting. In experiment 1, full-thickness biopsies were collected sequentially over an 8-hour ischemia and subsequent 6-hour reperfusion period. Immunocytochemistry was performed with monoclonal antibody EL-246, an antibody that crossreacts with both E- and L-selectin. In experiment 2, the binding of EL-246 to L-selectin on circulating porcine neutrophils was determined by flow cytometric analysis. In experiment 3, in situ hybridization was performed using complementary RNA probes for detection of endothelial E-selectin mRNA. In experiment 4, bilateral flaps were elevated in six pigs and subjected to 8 hours of arterial ischemia followed by 20 hours of reperfusion. Flaps on each animal were randomly assigned to receive either treatment with a continuous local intraarterial infusion of EL-246 (1 mg per flap) or solvent vehicle. Muscle and skin survivals were assessed by nitroblue tetrazolium and intravenous fluorescein staining techniques, respectively. Computer digitization permitted quantitation of relative tissue survival. In experiment 1, specific immunostaining of microvascular endothelium was achieved using EL-246. Greater-intensity staining was detected in reperfusion than in baseline or ischemic sections. In experiment 2, flow cytometric analysis indicated specific recognition by EL-246 of isolated peripheral porcine neutrophils (> 45 percent staining) as compared with an isotype-matched control antibody (< 3 percent staining). In experiment 3, in situ hybridization studies demonstrated an early ischemic up-regulation and later reperfusion downregulation of E-selectin mRNA during the reperfusion period. In experiment 4, administration of monoclonal antibody EL-246 afforded a significant augmentation in mean percentage survival of muscle (37.6 versus 18.7 percent, p = 0.015) and skin (48.6 versus 29.3 percent, p = 0.046). In conclusion, it was determined that E-selectin is expressed along the microvascular surface and is upregulated and subsequently downregulated during ischemia-reperfusion conditions. The monoclonal antibody EL-246 appears to recognize porcine L-selectin as well as E-selectin. Blockade of E/L-selectin-mediated leukocyte adhesion significantly reduces musculocutaneous flap reperfusion injury.
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PMID:E- and L-selectin adhesion molecules in musculocutaneous flap reperfusion injury. 918 Jul 25

The clinical concern in using neutrophil adhesion blocking agents is whether or not neutrophil function may be down-regulated, rendering neutrophils incapable of dealing with infections that may threaten the patient. In a sheep model of ischemia and reperfusion, we have investigated the effect of anti-L-selectin (EL-246) on the pulmonary injury as well as on the neutrophil function, assessed by in vitro chemiluminescence (CL) of isolated neutrophils. Infrarenal ischemia (3 h) followed by reperfusion (4 h) resulted in pulmonary capillary leakage as evident by an increased alveolar/plasma protein ratio (.76 vs. .19 in control, p < .01) and also led to a significant pulmonary neutrophil accumulation as assessed by the myeloperoxidase content in homogenized lung tissue (31.7 vs. 6.1 U, p < .01). Anti-L-selectin, infused at a dose of 1 mg/kg at the time of reperfusion, significantly reduced the pulmonary leakage by 59% (.42 vs. .76 U) and neutrophil accumulation by 84% (10.2 vs. 31.7 U). Pulmonary function improved by anti-L-selectin as represented by an increase of the arterio-venous oxygen ratio. CL decreased from 1.85 x 10(5) counts(c)/min to 1.02 x 10(6) c/min at 15 min of reperfusion in the positive control followed by a subsequent return to normal. In contrast to myeloperoxidase, the significant change in CL was not affected by the use of anti-L-selectin. Based on our data, we conclude that anti-L-selectin is able to significantly reduce the pulmonary injury in ischemia-reperfusion but in parallel does not result in neutrophil dysfunction regarding for example, the respiratory burst. Thus, using neutrophil adhesion blocking agents in patients appears to be unlikely to increase the risk of septic complications.
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PMID:The effect of anti-L-selectin (EL-246) on remote lung injury after infrarenal ischemia/reperfusion. 918 46

Injury associated with ischemia and reperfusion is a significant factor in a number of clinical diseases. We have completed a number of preclinical studies investigating the blockade of leukocyte adhesion molecules in ischemia-reperfusion injury. In our work and in the work of other investigators, monoclonal antibodies directed to CD18, P-selectin and L-selectin were effective in reducing ischemia-reperfusion injury to the rabbit ear and in reducing injury following hemorrhagic shock in both rabbits and nonhuman primates. Ischemia-reperfusion injury was also reduced by synthetic oligosaccharide sLe(x). These studies suggest that adhesion blockade might be effective in the clinical setting.
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PMID:Endothelial and leukocyte adhesion molecules in inflammation and disease. 966 66


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