Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0022116 (ischemia)
 91,303 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

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.
 ...
PMID:Blocking L-selectin function attenuates reperfusion injury following hemorrhagic shock in rabbits. 894 3

Antibodies against cellular adhesion molecules protect against neutrophil-induced hepatic injury during ischemia-reperfusion and endotoxemia. To test if beta 2 integrins on neutrophils and intercellular adhesion molecule-1 (ICAM-1) on endothelial cells are involved in neutrophil sequestration in the hepatic vasculature, neutrophil accumulation in the liver was characterized during the early phase of endotoxemia. Intravenous injection of Salmonella enteritidis endotoxin induced a dose-dependent activation of complement, tumor necrosis factor-alpha (TNF-alpha) formation, and an increase of hepatic neutrophils with maximal numbers at 5 mg/kg (90 min: 339 +/- 14 cells/50 high power fields; controls: 18 +/- 2). Administration of 15 micrograms/kg TNF-alpha and intravascular complement activation with cobra venom factor (75 micrograms/kg) had additive effects on hepatic neutrophil accumulation compared with each mediator alone. Monoclonal antibodies (2 mg/kg) to ICAM-1 and the alpha-chain (CD11a, CD11b) or the beta-chain (CD18) of beta 2 integrins had no significant effect on hepatic neutrophil count after endotoxin. In contrast, these antibodies inhibited peritoneal neutrophil infiltration in response to glycogen administration by 28% (CD11b), 60% (CD11a, ICAM-1), and 92% (CD18). Our data suggest that TNF-alpha and complement factors contribute to hepatic neutrophil sequestration during the early phase of endotoxemia. Despite the fact that these inflammatory mediators can up-regulate integrins and ICAM-1, these adhesion molecules are not necessary for neutrophil accumulation in hepatic sinusoids. The protective effect of these antibodies against neutrophil-induced liver injury appears to be due to inhibition of transendothelial migration and adherence to parenchymal cells.
 ...
PMID:Sequestration of neutrophils in the hepatic vasculature during endotoxemia is independent of beta 2 integrins and intercellular adhesion molecule-1. 894 51

We tested the hypothesis that treatment of transient focal cerebral ischemia in rat with antibodies directed against adhesion molecules reduces apoptosis. Rats (n = 31) were subjected to 2 h of middle cerebral artery (MCA) occlusion induced by intraluminal insertion of a nylon monofilament into the internal carotid artery. Upon reperfusion, animals were treated with monoclonal antibodies directed against intercellular adhesion molecule (ICAM)-1) (n = 8) or integrin CD11b/CD18 (n = 10), or administered IgG1 as a control (n = 13). At 48 h after ischemia, animals were killed and the brains analyzed for ischemic cell damage, using hematoxylin and eosin (H/E); apoptosis, using the terminal deoxynucleotidyl transferase (TdT)-mediated dUTP-biotin nick end labeling (TUNEL) method; and inflammatory cells, using immunohistochemistry with an anti-myeloperoxidase (MPO) antibody. Data revealed a significant reduction in the volume of infarction (p < 0.01) and a decline in the absolute (p < 0.001), and normalized (to the ischemic areas, p < 0.05) numbers of apoptotic cells in both animals treated with anti-ICAM-1 and anti-CD11b antibodies compared to control animals. The numbers of immunoreactive MPO cells were also reduced in the treatment groups compared to those in the control group (p < 0.05). These data suggest that treatment with anti-adhesion molecule antibodies selectively reduce apoptosis, and that a contributing factor to the beneficial effect of antibody treatment for reducing ischemic cell damage may be a reduction in numbers of apoptotic cells.
 ...
PMID:Antibodies against adhesion molecules reduce apoptosis after transient middle cerebral artery occlusion in rat brain. 896 96

The surface expression of beta2-integrins was investigated in leukocytes from patients undergoing ischemia induced by tourniquet application for elective hand surgery. Blood samples were obtained before initiation, at the end of ischemia, and after 15 minutes of reperfusion from ischemic and contralateral arms of five patients. Comparable expression of CD18, CD11a, CD11b, and CD11c could be detected by immunofluorescence in leukocytes from samples drawn from either arm before tourniquet application. In contrast, a significant increase in the expression of CD18 was detectable in monocytes, granulocytes, and lymphocytes from the ischemic arm compared with that in the nonischemic contralateral control, at the end of the ischemia time (80 +/- 16 minutes). A significantly increased expression of CD11b, but not CD11a or CD11c, determinants was also observed in granulocytes and monocytes. Concomitantly, a significant reduction in the percentages of granulocytes in samples from ischemic areas was detectable. After 15 minutes of reperfusion, differences in the expression of these adhesion molecules were no longer significant. The expression of the genes encoding interleukins IL-1alpha, IL-1beta, and IL-6 and tumor necrosis factor alpha (TNFalpha) proinflammatory cytokines was also studied by reverse polymerase chain reaction (rPCR) in peripheral blood mononuclear cells (PBMCs) obtained from the same samples in three patients. IL-1beta or IL-6 gene expression was never observed. Expression of IL-1alpha and TNFalpha genes, as detected in two patients, was not related with induction of ischemia. However, in these patients expression of one or both these genes was observed in samples derived from the ischemic but not the control arm after 15 minutes of reperfusion. These data document that overexpression of adhesion molecules and sequestration of leukocytes take place following short ischemia times, as routinely applied clinically for minor surgical procedures.
 ...
PMID:Increased surface expression of CD18 and CD11b in leukocytes after tourniquet ischemia during elective hand surgery. 899 75

The concept that leukocyte-endothelial cell adhesion (LECA) is a major determinant of the tissue injury elicited by ischemia/reperfusion (I/R) is largely based on studies employing adhesion molecule-specific monoclonal antibodies. The objective of this study was to assess the contribution of LECA to I/R injury using mutant mice (all on a C57B1 background) that are deficient in either intracellular adhesion molecule-1, P-selectin, or CD11/CD18. The accumulation of fluorescently labeled leukocytes and the number of nonperfused sinusoids in livers of control and adhesion molecule-deficient mice were monitored by intravital microscopy for 1 h after release of the occluded (for 15 min) superior mesenteric artery. Autofluorescence of pyridine nucleotide (NADH) was measured as an indicator of mitochondrial O2 consumption and redox status. The number of stationary leukocytes in the liver after gut I/R was significantly elevated compared with baseline values in C57B1 (control) mice. Autofluorescence of NADH was also significantly increased (indicating hypoxia) after I/R in these mice, especially in the pericentral region. Intercellular adhesion molecule-1-, CD11/CD18-, and P-selectin-deficient mice all exhibited a blunted leukosequestration response to I/R and smaller increments in nonperfused sinusoids, relative to C57B1 mice. All adhesion molecule-deficient mice also exhibited an attenuated increment in NADH autofluorescence in the pericentral region, relative to control mice. These results from adhesion molecule-deficient mice provide additional support for the view that LECA is an important determinant of the liver dysfunction induced by gut I/R.
 ...
PMID:Hepatic leukostasis and hypoxic stress in adhesion molecule-deficient mice after gut ischemia/reperfusion. 904 83

Effects of microspheres (5 microns or 10 microns diameter) and polymorphonuclear leucocytes (PMN) on coronary resistance were compared in beating, non-working isolated guinea-pig hearts (Langendorff preparation). The hearts were buffer perfused (5 ml/min, constant flow) and particles or cells were infused into the coronary system as a bolus (1 ml, 1 min). Coronary perfusion pressure, coronary flow and formation of epicardial transudate were measured before and after bolus administration. Coronary resistance was estimated from these parameters. Retention of particles or cells was monitored by quantifying the numbers emerging in the coronary effluent in relation to the number administered. The effects of PMN were also studied after 15 min of global ischemia. Coronary resistance correlated with the number of 10-micron particles infused, which were almost quantitatively retained. In contrast, 5-micron beads had no such effect and were not retained in the coronary system. Though considerable numbers of PMN were retained in the hearts (about 21% under control conditions and 35% after ischaemia), coronary resistance was not increased in either case. Blockage of the CD18 adhesion complex by monoclonal antibodies lowered basal retention to 11% and completely prevented the elevation of retention by ischaemia. We conclude that, in this experimental model, PMN, permanently retained in the hearts under normal flow conditions and especially after brief ischaemia, do not cause acute, haemodynamically relevant capillary plugging, but adhere to postcapillary venules via CD18.
 ...
PMID:Retention of leucocytes in reperfused, isolated hearts does not cause haemodynamically relevant permanent capillary plugging. 904 61

Platelets and polymorphonuclear granulocytes (PMN) contribute to post-ischemic myocardial reperfusion damage. However, to elicit any deleterious actions, they first need to become adherent to the vascular endothelium. Numerous studies have documented an A2-receptor mediated platelet-stabilizing action of adenosine and an A2-dependent antiinflammatory effect on PMN themselves. Intriguingly, an A1-receptor mediated chemotactic action of adenosine on isolated PMN has also been reported. A1-receptors are more sensitive towards adenosine than A2-receptors, and interactions between platelets and leukocytes could alter the net-adhesive potential. Furthermore, the endothelial cells also express adenosine A1- and A2-receptors. In the situation of ischemia and reperfusion both, the intracoronary concentration of adenosine and the shear forces, vary with time. We have, therefore, investigated the influence of adenosine on intracoronary adhesion of PMN and platelets, applied to isolated heart preparations (guinea pig), both separately and in combination, and determined the resultant effect on postischemic myocardial pump function. At submicromolar adenosine concentrations, as found after brief ischemia (15 min stopped-flow or 30 min low-flow), adenosine enhanced intracoronary PMN retention by preferentially stimulating endothelial A1-receptors. The effect required the intermediate formation of platelet activating factor (PAF) and occurred via CD11/CD18 adhesion molecules on the PMN. Higher, i.e., micromolar levels of adenosine, in contrast, inhibited PMN adhesion via an A2-receptor dependent mechanism. Thrombin-induced platelet adhesion was inhibited by adenosine at high shear rates by both A1- and A2-receptor dependent mechanisms. However, adenosine was not protective at low shear rates, or at high flow in the presence of PMN. Pertinently, adhesion of either PMN or platelets, alone or in combination, regularly caused deterioration of post-ischemic myocardial function. Thus, depending on its concentration and on the phase of ischemia/reperfusion, adenosine may elicit cardioprotective or detrimental effects in the reperfused myocardium, which makes general prognosis of its role in such situations difficult. However, in the course of every reperfusion, the adenosine levels will inevitably fall into the proadhesive range. Thus, prophylactic inhibition of A1-receptor effects may be beneficial.
 ...
PMID:[Interaction of adenosine with leukocytes and thrombocytes]. 906 61

Ischemia and reperfusion cause coronary vascular and myocardial injury, which may be due to leukocyte-mediated processes. Antileukocyte measures have reduced injury after brief reperfusion periods of 1-3 h, but there has been little information on whether benefits are apparent after longer periods of reperfusion. We examined the effect of pretreatment with a monoclonal antibody (R15.7) to the CD18 family of leukocyte adhesion molecules (beta2-integrins) in dogs exposed to regional coronary ischemia for 1 h of left anterior descending coronary artery ligation and then reperfused for 48 h. Coronary microvascular permeability was assessed in vivo by measurement of protein leak index (PLI), using a double-isotope technique with autologous radiolabeled transferrin and erythrocytes. Vasorelaxation was measured in vitro with preconstricted epicardial coronary artery rings subjected to increasing concentrations of the endothelium-dependent vasodilators bradykinin (BK) and ADP and the endothelium-independent vasodilator nitroprusside. At 48 h of reperfusion in untreated dogs there were substantial increases in PLI in the previously ischemic regions, indicative of increased extravascular transferrin. These abnormalities were decreased, but not abolished, in the dogs treated with R15.7. Relaxation of rings from the ischemic/reperfused artery to BK and ADP were blunted in the untreated dogs. R15.7 resulted in improvement in some, but not all, indexes of relaxation in response to BK and ADP. Relaxation to nitroprusside was normal in ischemic/reperfused coronary rings from both treated and untreated dogs. Therefore, after 1 h of regional coronary ischemia and 48 h of reperfusion, coronary endothelial injury, which was manifested by increased coronary microvascular permeability and abnormalities in coronary endothelium-dependent relaxation, was reduced by pretreatment with the anti-CD18 integrin antibody R15.7.
 ...
PMID:An antibody to leukocyte integrins attenuates coronary vascular injury due to ischemia and reperfusion in dogs. 912 17

The purpose of this study was to evaluate if the venular neutrophil-endothelial adhesion associated with ischemia-reperfusion of skeletal muscle is dependent on leukocyte adhesion glycoprotein CD18 function and to determine if this interaction influences the vasoactive response in nearby arterioles. An in vivo microscopy preparation of transilluminated gracilis muscle in 13 male Wistar rats was used for this experiment. Observations of nonischemic muscle (sham) demonstrated this preparation to be stable for 8 hours with negligible change in neutrophil adherence or arteriole diameter. Three groups were evaluated in this study: (1) sham, no ischemia, no treatment (n = 5, 20 arterioles. 20 venules), (2) 4 hours of global ischemia only (n = 4, 19 venules, 22 arterioles), and (3) 4 hours of ischemia plus monoclonal antibody against CD18 (n = 4, 12 venules, 9 arterioles). The murine monoclonal antibody (WT.3, Seikagaku America, Inc.), which binds the rat leukocyte function antigen I CD18 chain, was infused into the contralateral femoral vein 30 minutes prior to reperfusion. The number of leukocytes rolling and adherent to endothelium (15 seconds of observation) was counted in 100-microns venular segments, and arteriole diameters were measured at various times during reperfusion. All counts and measurements were normalized to baseline preischemic readings for each animal. Mean changes from baseline were compared between groups. The increase in ischemia-reperfusion-induced neutrophil-endothelial adherence in venules was blocked by monoclonal antibody, but rolling behavior was not changed. The ischemia-reperfusion-induced progressive vasoconstriction in arterioles was blocked by monoclonal antibody. These results suggest that (1) neutrophil-endothelial adherence function associated with ischemia-reperfusion in this model is CD18-dependent, (2) neutrophil rolling function does not appear to be dependent on CD18, and (3) neutrophil CD18 function is a prerequisite for ischemia-reperfusion-induced arteriolar vasoconstriction. These findings provide important mechanistic information that may help explain the deleterious microcirculatory events associated with ischemia-reperfusion injury skeletal muscle.
 ...
PMID:Ischemia-reperfusion injury in skeletal muscle: CD 18-dependent neutrophil-endothelial adhesion and arteriolar vasoconstriction. 918 Jul 24

Ischemic brain injury is exacerbated by leukocyte infiltration and formation of vasogenic edema. In this study we demonstrate that intercellular adhesion molecule-1 (ICAM-1) is dramatically (3 to 15-fold) up-regulated in human cerebromicrovascular endothelial cells (HCEC) by a 16 h exposure to the cytokine, IL-1 beta (50-200 u/ml), the phorbol ester, TPA (1-100 nM), or by simulated in vitro ischemia/reperfusion. These treatments also significantly increased the adhesion of allogeneic neutrophils to HCEC monolayers. Both IL-1 beta- and TPA-induced expression of ICAM-1 and increased neutrophil adhesion to HCEC were inhibited by the transcriptional inhibitor, actinomycin D (AcD; 1-10 micrograms/ml), and by an anti-ICAM-1 antibody (ICAM-1 Ab). By contrast, ischemia-induced neutrophil adhesion was only slightly affected by AcD and ICAM-1 Ab alone, but it was abolished by the combination of anti-ICAM-1 and anti-CD18 antibodies. The increase in surface expression of ICAM-1 and neutrophil adhesion by IL-1 beta, TPA and ischemia were significantly reduced by the cyclo-oxygenase (COX) inhibitors, indomethacin (100-300 microM) and dexamethasone (10-50 microM). These results indicate that ICAM-1 expression in HCEC can lead to enhanced neutrophil adhesion and that COX activation in HCEC likely plays a role in the processes by which leukocyte adhesion and recruitment take place in the brain during inflammation and ischemia in vivo.
 ...
PMID:The induction of ICAM-1 in human cerebromicrovascular endothelial cells (HCEC) by ischemia-like conditions promotes enhanced neutrophil/HCEC adhesion. 918 51


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>