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)

Organs used for transplantation undergo varying degrees of cold ischemia and reperfusion injury after transplantation. In renal transplantation, prolonged cold ischemia is strongly associated with delayed graft function, an event that contributes to inferior graft survival. At present, the pathophysiological changes associated with ischemia/reperfusion injury in clinical renal transplantation are poorly understood. We have performed an immunohistochemical analysis of pre- and postreperfusion biopsies obtained from cadaver (n = 55) and living/related donor (LRD) (n = 11) renal allografts using antibodies to adhesion molecules and leukocyte markers to investigate the intragraft changes after cold preservation and reperfusion. Neutrophil infiltration and P-selectin expression were detected after reperfusion in 29 of 55 (53%) and 24 of 55 (44%) cadaver renal allografts, respectively. In marked contrast, neutrophil infiltration was not observed in LRD allografts, and only 1 of 11 (9%) had an increased level of P-selectin after reperfusion. Immunofluorescent double-staining demonstrated that P-selectin expression resulted from platelet deposition and not from endothelial activation. No statistically significant association was observed between neutrophil infiltration and P-selectin expression in the glomeruli or intertubular capillaries despite the large number of cadaver renal allografts with postreperfusion changes. Neutrophil infiltration into the glomeruli was significantly associated with long cold ischemia times and delayed graft function. Elevated serum creatinine levels at 3 and 6 months after transplantation were also associated with the presence of neutrophils and platelets after reperfusion. Our results suggest that graft function may be influenced by early inflammatory events after reperfusion, which can be targeted for future therapeutic intervention.
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PMID:Ischemia/reperfusion injury in human kidney transplantation: an immunohistochemical analysis of changes after reperfusion. 970 15

Focal cerebral ischemia elicits a strong inflammatory response involving early recruitment of granulocytes and delayed infiltration of ischemic areas and the boundary zones by T cells and macrophages. Infiltration of hematogenous leukocytes is facilitated by an upregulation of the cellular adhesion molecules P-selectin, intercellular adhesion molecule-1 and vascular adhesion molecule-1 on endothelial cells. Blocking of the leukocyte/endothelial cell adhesion process significantly reduces stroke volume after transient, but not permanent middle cerebral artery occlusion. In the infarct region microglia are activated within hours and within days transform into phagocytes. Astrocytes upregulate intermediate filaments, synthesize neurotrophins and form glial scars. Local microglia and infiltrating macrophages demarcate infarcts and rapidly remove debris. Remote from the lesion no cellular infiltration occurs, but astroglia and microglia are transiently activated. Astrocytic activation is induced by spreading depression. In focal ischemia neurons die acutely by necrosis and in a delayed fashion by programmed cell death, apoptosis. Proinflammatory cytokines such as tumor necrosis factor-alpha and interleukin-1 beta are upregulated within hours in ischemic brain lesions. Either directly or via induction of neurotoxic mediators such as nitric oxide, cytokines may contribute to infarct progression in the post-ischemic period. On the other hand, inflammation is tightly linked with rapid removal of debris and repair processes. At present it is unclear whether detrimental effects of inflammation outweigh neuroprotective mechanisms or vice versa. In global ischemia inflammatory responses are limited, but micro- and astroglia are also strongly activated. Glial responses significantly differ between brain regions with selective neuronal death and neighbouring areas that are more resistent to ischemic damage.
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PMID:Inflammation and glial responses in ischemic brain lesions. 976 Jun 99

Leukocyte-endothelial adhesion molecules, critical to the development of acute inflammation, are expressed in brain as part of the acute inflammatory response to traumatic brain injury (TBI). We measured the concentrations of the adhesion molecules P-selectin, ICAM-1, E-selectin, L-selectin, and VCAM-1 in ventricular cerebrospinal fluid (CSF) from children with severe TBI (Glasgow coma score < 8) and compared these findings with those from children with bacterial meningitis. P-selectin, an adhesion molecule associated with ischemia/reperfusion, was increased in children with TBI versus meningitis and control. Univariate and multivariate regression analyses demonstrated associations between CSF P-selectin and child abuse and age of < 4 years, and a significant, independent association between CSF intercellular adhesion molecule-1 (ICAM-1) and child abuse. These results are consistent with a specific acute inflammatory component to TBI in children. Future studies of secondary injury mechanisms and therapy after TBI should assess on the roles of P-selectin and ICAM-1 in injury and repair processes in brain after TBI.
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PMID:Soluble adhesion molecules in CSF are increased in children with severe head injury. 981 34

Splanchnic artery occlusion and reperfusion (SAO/R) results in a severe form of circulatory shock that has a high mortality rate. To examine the time course of the early events involved in SAO/R, occlusion of the superior mesenteric artery (SMA) and the celiac artery (120 min) were followed by reperfusion periods of 0, 2.5, 5, 20, 30, 60, or 120 min. Relaxation of isolated SMA vascular rings to the endothelium-dependent vasodilator ACh was unimpaired following 120 min of ischemia (86 +/- 5%); however, significant (P < 0.01) reductions in endothelium-dependent vasorelaxation were observed following 2.5 min (53 +/- 6%) of reperfusion with severe dysfunction (P < 0.001) observed at 20 min (29 +/- 4%). Neutrophil adherence to the endothelium increased as a function of reperfusion time with a 2.3-fold increase observed at 20 min (P < 0.01) and a 3.4-fold increase observed at 120 min (P < 0.001). Intestinal myeloperoxidase activity was significantly increased 30 min after reperfusion (P < 0.05), whereas surface expression of P-selectin progressively increased at 5 (P < 0.05) and 30 min (P < 0.001) postreperfusion. These findings demonstrate that endothelial dysfunction is a very early event in the pathophysiology of SAO/R, subsequently resulting in increased surface expression of P-selectin and the adherence of neutrophils to the endothelium that leads to neutrophil accumulation in the splanchnic viscera.
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PMID:Time course of endothelial-neutrophil interaction in splanchnic artery ischemia-reperfusion. 984 7

The anti-inflammatory role of nitric oxide (NO) was studied in a model of hepatic ischemia-reperfusion (I/R) in rats. Male Fischer rats were subjected to 30 min of no-flow ischemia of the left and median lobes of the liver, and animals were examined for a 4-h period of reperfusion. The animals were divided into the following groups: control-vehicle; I/R-vehicle; I/R-Nomega-nitro-L-arginine methyl ester (L-NAME, 10 mg/kg iv, 10 min before reperfusion); sham control-L-NAME, and I/R-S-nitroso-N-acetyl-penicillamine (SNAP, 25 micromol/kg iv, 10 min before reperfusion, followed by 20 micromol. kg-1. h-1 in 1.0 ml saline infused for 4 h). Results showed that mean arterial blood pressure was significantly increased in the sham control-L-NAME or I/R-L-NAME groups compared with either the I/R-vehicle or I/R-SNAP groups. However, cardiac index (CI) and stroke volume index (SVI) were markedly decreased, and systemic vascular resistance index (SVRI) was dramatically increased. Interestingly, the CI and SVI in rats treated with SNAP were markedly improved over that of the I/R group. Plasma nitrate and nitrite levels were significantly decreased in the I/R-L-NAME group; however, superoxide generation in the ischemic lobes and plasma alanine aminotransferase activity were higher compared with I/R-SNAP rats. The L-NAME-induced enhancement of hepatic injury in rats with I/R may be due in part to neutrophil infiltration, which was significantly increased compared with animals subjected to I/R or I/R-SNAP. The mechanism of L-NAME-enhanced neutrophil infiltration may be due to the fact that the ratios of P-selectin and intercellular adhesion molecule 1 (ICAM-1) mRNA to glyceraldehyde-3-phosphate dehydrogenase mRNA extracted from the ischemic lobes of I/R-L-NAME rats were significantly increased when compared with the I/R-SNAP group. These results suggest that 1) endogenous NO reduces the SVRI and permits an increased CI and SVI; 2) exogenous NO further improves CI and SVI; and 3) endogenous, but not exogenous, NO decreases P-selectin and ICAM-1 mRNA expression, thereby reducing polymorphonuclear neutrophil-dependent reperfusion tissue injury.
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PMID:NO modulates P-selectin and ICAM-1 mRNA expression and hemodynamic alterations in hepatic I/R. 984 19

This study was designed to test the effects of polymorphonuclear leukocytes (PMNs) in the presence and absence of a P-selectin blocker, mocarhagin, in provoking cardiac dysfunction in isolated perfused rat hearts following ischemia and reperfusion. Control rat hearts not subjected to ischemia were perfused without blood cells for 80 min. Additional control rat hearts were perfused with 100 x 10(6) PMNs in the presence and absence of 0.2 microgram/ml mocarhagin over a 5-min perfusion followed by a 45-min observation period. No significant reduction in coronary flow (CF), left ventricular developed pressure (LVDP), or the first derivative of LVDP (dP/dt max) was observed at the end of the observation period in any non-ischemic group. Similarly, global ischemia (I) for 20 min followed by 45 min of reperfusion (R) produced no sustained effects on the final recovery of any of these parameters in any group of hearts perfused in the absence of PMNs. I/R hearts perfused with PMNs exhibited decreases of 50-60% in all measurements of cardiac function (P < 0.001). These PMN perfused I/R hearts also exhibited marked increases in cardiac myeloperoxidase (MPO) activity indicating a significant PMN infiltration, and enhanced P-selection expression on the coronary microvascular endothelium. All cardiodynamic effects as well as MPO accumulation and PMN infiltration were attenuated markedly by the metalloproteinase, mocarhagin, which inhibits P-selectin-mediated cell adhesion by cleaving its high-affinity receptor, PSGL-1, present on neutrophils. These results provide evidence that neutrophils provoke post-reperfusion cardiac dysfunction, and that this may be largely due to P-selectin-induced adherence of neutrophils to the endothelium.
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PMID:Effects of a metalloproteinase that truncates P-selectin glycoprotein ligand on neutrophil-induced cardiac dysfunction in ischemia/reperfusion. 999 May 28

Resuscitation from hemorrhage induces profound pathophysiologic alterations and activates inflammatory cascades able to initiate neutrophil accumulation in a variety of tissues. This process is accompanied by acute organ damage (e.g., lungs and liver). We have previously demonstrated that significant leukocyte-endothelium interactions occur very early in other forms of ischemia/reperfusion (i.e., splanchnic ischemia/reperfusion and traumatic shock) which are largely mediated by increased expression of the adhesion molecule, P-selectin, on the vascular endothelium. Here we postulated that increased endothelial expression of P-selectin in the microvasculature would play an essential role in initiating the inflammatory signaling of hemorrhagic shock. Using intravital microscopy, we found that hemorrhagic shock significantly increased the number of rolling and adherent leukocytes in the mouse splanchnic microcirculation. In contrast, mice genetically deficient in P-selectin, or wild-type mice given either an anti-P-selectin monoclonal antibody or a recombinant soluble P-selectin glycoprotein ligand (PSGL)-1 immunoglobulin, exhibited markedly attenuated leukocyte-endothelium interaction after hemorrhagic shock. Thus, activation of P-selectin protein on the microvascular endothelium is essential for the initial upregulation of the inflammatory response occurring in hemorrhagic shock. Moreover, endogenous levels of PSGL-1 mRNA were significantly increased in the lung, liver, and small intestine of wild-type mice subjected to hemorrhagic shock. Since PSGL-1 promotes adhesive interactions largely through P-selectin expressed on the vascular endothelium, this result further supports the crucial role played by P-selectin in the recruitment of leukocytes during hemorrhagic shock.
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PMID:Essential role of P-selectin in the initiation of the inflammatory response induced by hemorrhage and reinfusion. 1007 76

The expression of P-selectin on postischemic endothelium after reperfusion has been shown to trigger neutrophil attachment and the subsequent inflammatory responses. Extensive studies have demonstrated that P-selectin is involved in the progression of neutrophil-mediated myocardial infarction and no-reflow phenomenon. In the present study, we examined the effects of selectin inhibitors, sialyl Lewis X-oligosaccharide and anti-P-selectin monoclonal antibody, PB1.3 on neutrophil-dependent left ventricular dysfunction in isolated rat heart. The hearts were subjected to global ischemia for 20 min and then reperfused for 45 min with rat plasma in the presence of human neutrophils during the first 5 min of the reperfusion. Left ventricular developed pressure and other parameters of the left ventricular function deteriorated throughout the reperfusion period in a neutrophil-dependent manner. In contrast, the coronary flow was reduced early on (< 15 min) but recovered to the level in the hearts reperfused with no neutrophils 45 min after the reperfusion. We examined the effects of selectin inhibitors under experimental conditions in which the hearts were perfused with 30 million neutrophils. The treatment with sialyl Lewis X-oligosaccharide at a dose of 0.3 mg/min resulted in amelioration of left ventricular developed pressure to 57.2 +/- 14%, compared to 26.1 +/- 4.3% in the saline-treated group (P < 0.05). Similarly, the treatment with mouse anti-human P-selectin monoclonal antibody (IgG1) PB1.3 at a dose of 0.6 mg/min resulted in the prominent recovery of left ventricular developed pressure after 45 min of reperfusion (59.9 +/- 9.3% vs. 26.1 +/- 4.3% in the saline-treated group, P < 0.05). PB1.3 also attenuated the elevation of left ventricular end-diastolic pressure compared to that of the saline-treated group during the reperfusion period. Moreover, the treatment with PB1.3 ameliorated the recovery of coronary flow until 10 min after the reperfusion and the recovery of coronary flow 10 min after the reperfusion was 55.2 +/- 9.2%, as compared to 28.2 +/- 7.7% in saline-treated hearts (P < 0.05). To our knowledge, this is the first direct demonstration that the specific inhibition of P-selectin results in the inhibition of neutrophil-mediated left ventricular dysfunction or myocardial stunning.
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PMID:Inhibition of P-selectin attenuates neutrophil-mediated myocardial dysfunction in isolated rat heart. 1008 9

Ischemia followed by reperfusion in the presence of polymorphonuclear leukocytes (PMNs) results in cardiac contractile dysfunction as well as myocardial injury. These effects are due in large part to endothelial dysfunction leading to an upregulation of cell adhesion molecules and subsequent neutrophil induced cardiac injury. The proteasome inhibitor, PS-519, has been shown to attenuate leukocyte-endothelial cell interactions. We tested the effects of PS-519 on neutrophil mediated cardiac dysfunction in ischemia/reperfusion. This study examines the effects of PS-519 in a neutrophil dependent isolated perfused rat heart model of ischemia (I) (20 min) and reperfusion (R) (45 min). Administration of PS-519 (0.01, 0.1, 0.3, 1.0 mg/kg) to I/R hearts perfused with PMNs improved coronary flow, and preserved left ventricular developed pressure (LVDP) and + dP/dt max as indices of cardiac contractile function. At 1.0 mg/kg, PS-519 treated hearts exhibited a final LVDP of 98 +/- 3% of initial compared to 52 +/- 8% in I/R hearts receiving only vehicle (P < 0.001). In addition, PS-519 significantly reduced PMN accumulation in the ischemic myocardium from 25.1 +/- 2.1 PMNs/mm2 in untreated hearts to 7.3 PMNs/mm2, and attenuated P-selectin surface expression on coronary vascular endothelium from 7.1 +/- 0.3% to 1.4 +/- 0.2% (P < 0.01). These results provide evidence that PS-519 is a potent and effective cardioprotective agent that inhibits P-selectin leukocyte-endothelial cell interactions and preserves cardiac contractile function and coronary perfusion following myocardial ischemia and reperfusion.
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PMID:Cardioprotective effects of a novel proteasome inhibitor following ischemia and reperfusion in the isolated perfused rat heart. 1009 58

Hepatic damage following ischemia-reperfusion injury involves polymorphonuclear leukocytes (PMN) and platelet sequestration, however the mechanisms of adhesion remain elusive. In this study, using gene-targeted deficient mice, we evaluated P-selectin and its contribution to PMN and platelet adhesion in hepatic damage. In an in vivo warm ischemia model, hepatic injury was assessed by serum transaminase levels, survival, PMN adhesion by histological analysis, and platelet sequestration by immunostaining. Serum transaminase levels were strikingly reduced (by up to threefold) in the P-selectin deficient mice, particularly at 90 minutes of ischemia, when compared with wild-type controls. PMN adhesion and platelet sequestration was also significantly decreased in P-selectin deficient mice following 90 minutes of partial ischemia. Animal survival was significantly improved after 75 minutes of total hepatic ischemia in P-selectin deficient mice when compared with wild-type mice. Survival was also achieved after 90 minutes of ischemia in the mutant mice whereas none of the wild-type animals survived. These data show that P-selectin plays a critical role in PMN and platelet adhesion following ischemia-reperfusion injury to the liver.
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PMID:P-Selectin mediates reperfusion injury through neutrophil and platelet sequestration in the warm ischemic mouse liver. 1021 34


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