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)

Recently, the selectin family of glycoprotein adhesion molecules (P-selectin, E-selectin, and L-selectin) has been implicated in the pathogenesis of a number of inflammatory disease states. The selectins modulate the early adhesive interactions between circulating neutrophils and the endothelium. Both P-selectin and E-selectin can be expressed on the surface of endothelial cells following stimulation by a number of inflammatory mediators. In contrast, L-selectin is constitutively expressed on the surface of neutrophils at very high levels. In addition, neutrophils also express ligands for the endothelial selectins, including the carbohydrate sialyl Lewis(x) and the high-affinity ligand P-selectin glycoprotein ligand 1, which facilitate neutrophil-endothelial interactions. Selectins have been extensively investigated in ischemia/reperfusion injury states. The study of selectin involvement in ischemia/reperfusion injury has been facilitated by the development of highly specific selectin antagonists, including monoclonal antibodies, carbohydrates, small molecule inhibitors, and soluble forms of P-selectin glycoprotein ligand 1. This article reviews the results of current studies of selectin antagonists in experimental models of ischemia/reperfusion injury.
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PMID:Pharmacology of selectin inhibitors in ischemia/reperfusion states. 1083 37

Monolayers of cultured endothelial cells exposed to hypoxia-reoxygenation exhibit a transcription-dependent increase in E-selectin expression and E-selectin-dependent neutrophil-endothelial cell adhesion. The overall objectives of this study were 1) to determine whether ischemia-reperfusion (I/R) promotes upregulation of E-selectin in vivo; 2) if so, to define the mediators of this response; and 3) to assess the contribution of E-selectin to I/R-induced neutrophil recruitment. The dual-radiolabeled monoclonal antibody (MAb) technique was used to measure E-selectin expression in the intestinal vasculature. Ischemia was induced by complete occlusion (30-60 min) of the superior mesenteric artery followed by 3-24 h of reperfusion. Increasing durations of ischemia elicited progressively increasing (2- to 5-fold) levels of E-selectin expression, with the peak response noted after 45 min of ischemia and 5 h of reperfusion. Subsequent experiments revealed that I/R-induced increase in E-selectin expression (at 5 h) is significantly blunted in transgenic mice that overexpress Cu,Zn-superoxide dismutase or by treatment of wild-type mice with either a blocking antibody against tumor necrosis factor (TNF)-alpha or an inhibitor of nuclear factor-kappaB (NF-kappaB) activation (PS341). Administration of an E-selectin-specific MAb dramatically reduced I/R-induced recruitment of neutrophils in the intestine. These findings suggest that superoxide and TNF-alpha mediate gut I/R-induced E-selectin expression via an NF-kappaB-dependent mechanism; this upregulation of E-selectin contributes significantly to I/R-induced neutrophil recruitment.
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PMID:Regulation of E-selectin expression in postischemic intestinal microvasculature. 1085 17

Preclinical studies in animal models and early results of clinical trials in patients suggest that intramuscular injection of naked plasmid DNA encoding vascular endothelial growth factor (VEGF) can promote neovascularization of ischemic tissues. Such neovascularization has been attributed exclusively to sprout formation of endothelial cells derived from preexisting vessels. We investigated the hypothesis that VEGF gene transfer may also augment the population of circulating endothelial progenitor cells (EPCs). In patients with critical limb ischemia receiving VEGF gene transfer, gene expression was documented by a transient increase in plasma levels of VEGF. A culture assay documented a significant increase in EPCs (219%, P<0.001), whereas patients who received an empty vector had no change in circulating EPCs, as was the case for volunteers who received saline injections (VEGF versus empty vector, P<0.001; VEGF versus saline, P<0.005). Fluorescence-activated cell sorter analysis disclosed an overall increase of up to 30-fold in endothelial lineage markers KDR (VEGF receptor-2), VE-cadherin, CD34, alpha(v)beta(3), and E-selectin after VEGF gene transfer. Constitutive overexpression of VEGF in patients with limb ischemia augments the population of circulating EPCs. These findings support the notion that neovascularization of human ischemic tissues after angiogenic growth factor therapy is not limited to angiogenesis but involves circulating endothelial precursors that may home to ischemic foci and differentiate in situ through a process of vasculogenesis.
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PMID:Vascular endothelial growth factor(165) gene transfer augments circulating endothelial progenitor cells in human subjects. 1086 8

In sickle cell anemia, the initiation, progression, and resolution of a vasoocclusive episode may present features of ischemia-reperfusion injury, with recurrent episodes of ischemia/hypoxia and reoxygenation promoting inflammation. Here, we have tested the hypothesis that hypoxia/reoxygenation triggers inflammation in the transgenic sickle mouse. In these mice, even at ambient air, peripheral leukocyte counts are elevated by 1.7-fold and neutrophil counts by almost 3-fold. Two hours of hypoxia, followed by reoxygenation, induced a greater than normal rolling flux and adhesion of leukocytes in these mice, but no leukocyte extravasation. When 3 hours of hypoxia was followed by reoxygenation, sickle mice, but not normal mice, showed a distinct inflammatory response characterized by an increased number of adherent and emigrated leukocytes. Because these events, which are exaggerated in sickle mice, are not seen in response to hypoxia alone, we conclude that they represent a form of reperfusion injury. Studies using an H(2)O(2)-sensitive probe revealed clear evidence of oxidant production in vascular endothelial cells after hypoxia/reoxygenation in sickle mice. Infusion of an anti-P-selectin antibody, but not an anti-E-selectin antibody, completely inhibited this inflammatory response and significantly increased wall shear rates. These findings suggest that leukocyte-endothelium interaction contribute to vasoocclusive events in the sickle mice and perhaps in human sickle disease.
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PMID:Hypoxia/reoxygenation causes inflammatory response in transgenic sickle mice but not in normal mice. 1093 Apr 36

Although acute myocardial infarction (AMI) may involve both plaque rupture and ischemia-reperfusion injury, the pathogenesis of these phenomena is unclear. To elucidate the pathogenesis of AMI, serial measurements of platelet activating factor (PAF), interleukin-6 and cell adhesion molecules were made in patients with AMI. The PAF levels were measured upon hospital admission and at 24 and 72h in 8 patients with AMI. Serum levels of interleukin-6, soluble E-selectin (sE-selectin), soluble intercellular adhesion molecule-1 and soluble vascular cell adhesion molecule- 1 (sVCAM- 1) were measured upon admission and at 24 h and 4 weeks in 30 patients with AMI and 15 patients with stable effort angina. PAF levels were higher in patients with AMI than in normal volunteers; the increased levels lasting at least 72h. In contrast, interleukin-6 increased at 24h. sE-selectin was elevated at admission and sVCAM-1 increased later. sE-selectin levels upon admission in patients with additional ST-segment elevation after reperfusion were significantly higher than those in patients without ST-elevation. In patients with AMI, the time-course of changes in blood levels of cytokines varied according to the individual substances. Although it is unclear what is the precise role of each of the cytokines in the pathophysiology of AMI, sE-selectin may be possibly related to the reperfusion injury in the infarcted myocardium.
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PMID:Role of cytokines and adhesion molecules in ischemia and reperfusion in patients with acute myocardial infarction. 1094 15

Expression of endothelial and leukocyte cell adhesion molecules is a principal determinant of polymorphonuclear neutrophil (PMN) recruitment during inflammation. It has been demonstrated that pharmacological inhibition of these molecules can attenuate PMN influx and subsequent tissue injury. We determined the temporal expression of alpha-granule membrane protein-40 (P-selectin), endothelial leukocyte adhesion molecule 1 (E-selectin), and intercellular cell adhesion molecule 1 (ICAM-1) after coronary artery occlusion and up to 3 days of reperfusion. The expression of all of these cell adhesion molecules peaked around 24 h of reperfusion. We determined the extent to which these molecules contribute to PMN infiltration by utilizing mice deficient (-/-) in P-selectin, E-selectin, ICAM-1, and CD18. Each group underwent 30 min of in vivo, regional, left anterior descending (LAD) coronary artery ischemia and 24 h of reperfusion. PMN accumulation in the ischemic-reperfused (I/R) zone was assessed using histological techniques. Deficiencies of P-selectin, E-selectin, ICAM-1, or CD18 resulted in significant (P < 0.05) attenuation of PMN infiltration into the I/R myocardium (MI/R). In addition, P-selectin, E-selectin, ICAM-1, and CD18 -/- mice exhibited significantly (P < 0.05) smaller areas of necrosis after MI/R compared with wild-type mice. These data demonstrate that MI/R induces coronary vascular expression of P-selectin, E-selectin, and ICAM-1 in mice. Furthermore, genetic deficiency of P-selectin, E-selectin, ICAM-1, or CD18 attenuates PMN sequestration and myocardial injury after in vivo MI/R. We conclude that P-selectin, E-selectin, ICAM-1, and CD18 are involved in the pathogenesis of MI/R injury in mice.
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PMID:Leukocyte and endothelial cell adhesion molecules in a chronic murine model of myocardial reperfusion injury. 1104 53

Neutrophils can cause parenchymal cell injury in the liver during ischemia-reperfusion and endotoxemia. Neutrophils relevant for the injury accumulate in sinusoids, transmigrate, and adhere to hepatocytes. To investigate the role of E- and L-selectin in this process, C3Heb/FeJ mice were treated with 700 mg/kg galactosamine and 100 microgram/kg endotoxin (Gal/ET). Immunogold labeling verified the expression of E-selectin on sinusoidal endothelial cells 4 hours after Gal/ET injection. In addition, Gal/ET caused up-regulation of Mac-1 (CD11b/CD18) and shedding of L-selectin from circulating neutrophils. Gal/ET induced hepatic neutrophil accumulation (422 +/- 32 polymorphonuclear leukocytes [PMN]/50 high power fields [HPF]) and severe liver injury (plasma alanine transaminase [ALT] activities: 4,120 +/- 960 U/L; necrosis: 44 +/- 3%) at 7 hours. Treatment with an anti-E-selectin antibody (3 mg/kg, intravenously) at the time of Gal/ET administration did not significantly affect hepatic neutrophil accumulation and localization. However, the anti-E-selectin antibody significantly attenuated liver injury as indicated by reduced ALT levels (-84%) and 43% less necrotic hepatocytes. In contrast, animals treated with an anti-L-selectin antibody or L-selectin gene knock out mice were not protected against Gal/ET-induced liver injury. However, E-, L-, and P-selectin triple knock out mice showed significantly reduced liver injury after Gal/ET treatment as indicated by lower ALT levels (-65%) and reduced necrosis (-68%). Previous studies showed that circulating neutrophils of E-selectin-overexpressing mice are primed and activated similar to neutrophils adhering to E-selectin in vitro. Therefore, we conclude that blocking E-selectin or eliminating this gene may have protected against Gal/ET-induced liver injury in vivo by inhibiting the full activation of neutrophils during the transmigration process.
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PMID:Pathophysiologic importance of E- and L-selectin for neutrophil-induced liver injury during endotoxemia in mice. 1105 49

This study investigates the role of neutrophils in ischemia-induced aspermatogenesis in the mouse. Previous studies in the rat have demonstrated that ischemia-inducing testicular torsion followed by torsion repair and reperfusion resulted in germ cell-specific apoptosis. This was correlated with an increase in neutrophil adhesion to subtunical venules, an increase in reactive oxygen species, and increased expression of several apoptosis-associated molecules. In the present investigation, wild-type C57BL/6 mice were subjected to various degrees and duration of testicular torsion. A torsion of 720 degrees for 2 h caused disruption of the seminiferous epithelium and significantly reduced testis weight and daily sperm production. An immunohistochemical method specific for apoptotic nuclei indicated that these effects were due to germ cell-specific apoptosis. An increase in myeloperoxidase (MPO) activity and an increase in the number of neutrophils adhering to testicular subtunical venules after torsion repair/reperfusion demonstrated an increase in neutrophil recruitment to the testis. In contrast, E-selectin knockout mice and wild-type mice rendered neutropenic showed a significant decrease in neutrophil recruitment as evidenced by MPO activity and microscopic examination of subtunical venules. Importantly, germ cell-specific apoptosis was also reduced. Thus, germ cell-specific apoptosis is observed after ischemia/reperfusion of the murine testis, and this apoptosis is directly linked to the recruitment of neutrophils to subtunical venules. Endothelial cell adhesion molecules, particularly E-selectin, play an important role in mediating this pathology.
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PMID:Essential role of neutrophils in germ cell-specific apoptosis following ischemia/reperfusion injury of the mouse testis. 1151 33

Genetic variants are risk factors for coronary disease, but their role in recurrent events and in response to treatment is less clear. We genotyped genetic variants implicated in primary coronary disease in 924 Caucasians with acute coronary syndromes participating in the OPUS-TIMI16 trial of the GPIIb/IIIa antagonist orbofiban. These were the platelet glycoprotein (GP) receptors GPIIIa, GPIa, GPIbalpha; platelet ligands beta-fibrinogen and von Willebrand Factor (vWF); interleukins (IL) IL-1RN, and IL-6; adhesion proteins E-selectin and P-selectin; and metalloproteinase MMP-9. Cox modelling of all genetic variants demonstrated no significant impact on the composite endpoint (P = 0.88), which included myocardial infarction (MI), death, recurrent ischemia, urgent revascularisation and stroke, but a significant impact on recurrent myocardial infarction alone (chi(2) = 20.4, 10 df, P = 0.04). There was a significant interaction of the polymorphisms with orbofiban treatment influencing bleeding outcomes (P = 0.004). Thus, genetic polymorphisms may be associated with subsequent myocardial infarction, and may also be associated with treatment-associated bleeding among coronary patients.
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PMID:The contribution of genetic factors to thrombotic and bleeding outcomes in coronary patients randomised to IIb/IIIa antagonists. 1208 90

Lack of enteral feeding increases P- and E-selectin and ICAM-1 expression on endothelial cells in organs, such as the small intestine and lung, and increases neutrophils in the intestine. These changes are associated with increased mortality after gut ischemia. We hypothesize that nutritional regimen affects endothelial ICAM-1 levels and leukocyte beta2 integrins after gut ischemia. Mice received chow, intravenous (IV) TPN, or intragastric (IG) TPN. In experiment 1, after 5 days of diet, 28 mice underwent 15 min of superior mesenteric artery (SMA) occlusion (I/R) for quantification of ICAM-1 expression in organs 3 h later. In experiment 2, after the same nutrient pretreatments of 38 mice, peripheral blood was obtained with or without gut I/R to measure CD11a and CD11b expression on myeloid cells. CD18 immunofluorescence staining was studied in the lung. Expression of ICAM-1 in the liver, kidney, and small intestine was significantly higher after IV-TPN than chow. IG-TPN reduced liver and kidney ICAM-1 levels midway between the chow and IV-TPN groups, but not intestinal expression. Expression of CD11b on the myeloid cell population in each group was similar before I/R, but CD11b levels increased after IV-TPN on circulating cells after I/R compared with all uninjured animals or injured chow or IG-TPN mice. Only IV-TPN mice had lung CD18-positive leukocytes after I/R. After I/R, lack of enteral feeding increases organ expression of ICAM-1, CD11b levels on myeloid cells, and lung of CD18 positive leukocytes. Through these changes, lack of enteral feeding may increase organ damage after gut ischemia.
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PMID:Increased ICAM-1 and beta2 integrin expression in parenterally fed mice after a gut ischemic insult. 1216 73


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