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)

The intercellular adhesion molecule (ICAM) 1 is an Ig-like cell adhesion molecule expressed by several cell types, including leukocytes and endothelial cells. It can be induced in a cell-specific manner by several cytokines, for example, tumor necrosis factor-alpha, interleukin-1, and interferon-gamma, and inhibited by glucocorticoids. Its ligands are the membrane-bound integrin receptors LFA-1 and Mac-1 on leukocytes, CD43, the soluble molecule fibrinogen, the matrix factor hyaluronan, rhinoviruses, and Plasmodium falciparum malaria-infected erythrocytes. ICAM-1 expression is predominantly transcriptionally regulated. The ICAM-1 promoter contains several enhancer elements, among them a novel kappa B element which mediates effects of 12-O-tetradecanoylphorbol-13-acetate, interleukin-1, lipopolysaccharide, tumor necrosis factor-alpha, and glucocorticoids. Expression regulation is cell specific and depends on the availability of cytokine/hormone receptors, signal transduction pathways, transcription factors, and posttranscriptional modification. ICAM-1 plays a role in inflammatory processes and in the T-cell mediated host defense system. It functions as a costimulatory molecule on antigen-presenting cells to activate MHC class II restricted T-cells, and on other cell types in association with MHC class I to activate cytotoxic T-cells. ICAM-1 on endothelium plays an important role in migration of (activated) leukocytes to sites of inflammation. ICAM-1 is shed by the cell and detected in plasma as sICAM-1. Regulation and significance of sICAM-1 are as yet unclear, but sICAM-1 is increased in many pathological conditions. ICAM-1 may play a pathogenetic role in rhinovirus infections. Derangement of ICAM-1 expression probably contributes to the clinical manifestations of a variety of diseases, predominantly by interfering with normal immune function. Among these are malignancies (e.g., melanoma and lymphomas), many inflammatory disorders (e.g., asthma and autoimmune disorders), atherosclerosis, ischemia, certain neurological disorders, and allogeneic organ transplantation. Interference with ICAM-1 leukocyte interaction using mAbs, soluble ICAM-1, antisense ICAM-1 RNA, and in the case of melanoma mAb-coupled immunotoxin, may offer therapeutic possibilities in the future. Integration of knowledge concerning membrane-bound and soluble ICAM-1 into a single functional system is likely to contribute to elucidating the immunoregulatory function of ICAM-1 and its pathophysiological significance in various disease entities.
 ...
PMID:Intercellular adhesion molecule-1. 883 67

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.
 ...
PMID:Impact of adhesion molecules of the selectin family on liver microcirculation at reperfusion following cold ischemia. 887 87

Defibrotide (a polydeoxyribonucleotide) and oligotide (an oligodeoxyribonucleotide) obtained from mammalian single-stranded DNA, have been demonstrated to have anti-ischemic activity in some experimental models of ischemia/reperfusion of kidney in rats. We hypothesized that their anti-ischemic activity could be related to an inhibition of leukocyte-endothelial cell adhesion and also the consequent generation of oxygen free radicals by leukocytes. We studied the in vitro adhesion of neutrophils to human umbilical vein endothelial cells under basal conditions and following neutrophil or endothelial cell activation (using 10(-7) fMLP and 500 U/ml TNF-alpha, respectively). Defibrotide and oligotide significantly inhibited neutrophil adhesion to endothelial cells (after only 1 min of drug treatment). When the anti-LFA-1 70H12 F(ab)2 monoclonal antibody was used, the drugs exerted only slight additional inhibition of the adhesion of fMLP-activated neutrophils to endothelium. These results, confirmed in NIH/3T3-ICAM-1-transfected cells, demonstrate that defibrotide and oligotide interfere with leukocyte adhesion to endothelial cells by an LFA-1-dependent mechanism.
 ...
PMID:The anti-ischemic drugs defibrotide and oligotide analogously inhibit leukocyte-endothelial cell adhesion in vitro. 895 77

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.
 ...
PMID:Expression of adhesion molecules and leukocyte recruitment into gastric mucosa following ischemia-reperfusion. 905 14

This article reviews the molecular basis of cell adhesion and its possible implications in surgery. Adhesion of circulating cells to endothelial cells is mediated by a variety of celladhesion molecules. The first steps in the cell adhesion cascade (rolling, tethering) are regulated by selectins (P, E, L selectin). Stable adhesion and transmural migration predominantly involve integrins (LFA-1, etc.) and members of the immunoglobulin supergene family (ICAM-1, etc). The mechanisms of leucocyte-endothelial interaction are markedly similar in various organs under both physiological and pathophysiological conditions. However, it is likely that cell trafficking to specific tissues/organs (e.g., homing) is regulated by additional organ-specific, topical adhesion molecules (e.g., MAdCAM-1). In surgery, cell adhesion molecules are involved in organ-transplantation pathology (ischemia/reperfusion injury, rejection), inflammation (e.g., chronic inflammatory bowel diseases), tumor metastasis. Animal experiments with anti-adhesive substances show that blocking the leukocyte-endothelial interaction reduces the cellular inflammatory infiltrate and organ rejection. The transfer of experimental data into clinical practice requires further understanding of the regulators of cell adhesion (cytokines, chemoattractant substances, etc.) and the specificity of the process. Current experimental data suggest that early intervention in cell-adhesion mechanisms may offer innovative therapeutic strategies.
 ...
PMID:[Cell adhesion. Molecular principles and initial implications for surgery]. 930 36

Sulfatide binds to P- and L-selectin, which play important roles in the initiation of neutrophil-endothelial interactions. Sulfatide protects skin flaps from ischemia-reperfusion injury. The purpose of this study was to evaluate the augmented protection when anti-rat ICAM-1 and anti-rat LFA-1 antibodies are combined with sulfatide in the ischemia-reperfusion model of rat skin flaps. Sulfatide was administered intravenously just before elevation of the right abdominal epigastric flap, and monoclonal antibodies were injected 30 min before clamp release. The femoral artery and vein were clamped above and below the epigastric vessels for 11 h and then the clamp was released. The administration of both sulfatide and monoclonal antibodies significantly increased the flap surviving area (6.58 +/- 0.61 cm(2) versus the group with monoclonal antibodies alone, 4.43 +/- 0.32 cm(2), P = 0.01). In the untreated rats the area was 1.86 +/- 0.36 cm(2). Histological examination 24 h after reperfusion in the group treated with sulfatide and monoclonal antibodies showed only slight leukocyte invasion into the flap, and myeloperoxidase activity 24 h after reperfusion was significantly reduced. This study indicates that both sulfatide and monoclonal antibodies protect rat skin flaps from ischemia-reperfusion injury.
 ...
PMID:Sulfatide and monoclonal antibodies prevent reperfusion injury in skin flaps. 1064 77

The systemic inflammatory response (SIRS) results from various types of injuries such as severe infection, trauma, ischemia-reperfusion and major surgery including cardiac surgery with cardio-pulmonary bypass. This response involves immune cell activation and a complex network of proinflammatory cytokines, which may induce multiple organ failure when uncontrolled. The monocyte plays a central role in the response to infection with the release of TNF, IL-1, and IL-12. In addition, monocytes present antigens to T lymphocytes. An optimal antigen presentation requires the expression of MHC class II HLA-DR on monocytes surface and of co-stimulatory molecules such as CD54 on monocytes and LFA-1 on lymphocytes. It has become increasingly apparent that the pro-inflammatory response is balanced by concomitant anti-inflammatory mechanisms that results in monocyte deactivation, characterized by a decrease in HLA-DR expression and the release of anti-inflammatory cytokines such as IL-10. This counterregulatory response, if prolonged or predominant, may predispose the patient to a higher risk of infection. Further studies need to be conducted to precise: 1) the intensity of depression of the surface molecule expression assessing monocyte function, such as HLA DR and CD54; 2) the level of IL-10 and IL-12 release in patients with severe sepsis; 3) the immunomodulating effects of frequently used treatments in these patients with severe sepsis and in surgical patients; 4) the time course of recovery; 5) if the monitoring of HLA-DR, CD54, IL-10 and IL-12 will better predict the clinical outcome than clinical parameters.
 ...
PMID:Assessment of immunological status in the critically ill. 1096 15

Intercellular adhesion molecule (ICAM)-5 (telencephalin) is unique among the ICAMs, because it is only expressed in somatodendritic membranes of telencephalic neurons. To investigate the fate of ICAM-5 during focal brain injury, we induced hypoxia-ischemia (HI) damage in adult mice by right common carotid artery ligation followed by hypoxia. ICAM-5 was detectable in serum within a 48-hour window after HI injury. In HI brain, dendritic ICAM-5 immunore-activity was abolished, but it was present in the neuropil and soma of hippocampal pyramidal, dentate granule, and some cortical and striatal neurons. After HI injury, levels of ICAM-5 protein and messenger RNA initially increased, and ICAM-5 messenger RNA expression then decreased, although protein levels continued to increase. Because HI injury induces microglial activation with increases in CD11a/CD18 (lymphocyte function antigen [LFA]-1) counterreceptors to ICAM-5, we investigated whether modulation of interactions between LFA-1 receptors and brain ICAM-5 during HI injury are associated with changes in levels of serum ICAM-5. Intracerebroventricular administration of lipopolysaccharide to activate microglia before HI injury resulted in elevated serum ICAM-5 levels compared with those in mice with only HI injury. Pretreatment with anti-LFA-1 antibodies before HI injury or LFA-1 receptor knockout mice with HI injury had markedly reduced levels of serum ICAM-5. Lipopolysaccharide levels increased, whereas LFA-1 receptor blockade or LFA-1 knockout decreased HI injury in the first 12 hours. These data suggest that during the necrotic phase of HI injury, serum ICAM-5 may be a potential marker for somatodendritic neuronal damage.
 ...
PMID:Release of the neuronal glycoprotein ICAM-5 in serum after hypoxic-ischemic injury. 1102 42

The systemic inflammatory response (SIRS) results from various types of injuries such as severe infection, trauma, ischemia-reperfusion and major surgery including cardiac surgery with cardio-pulmonary bypass. This response involves immune cell activation and a complex network of proinflammatory cytokines, which may induce multiple organ failure when uncontrolled. The monocyte plsys a central role in the response to infection with the release of TNF-alpha, IL-1 beta, and IL-12. In addition, monocytes present antigens to T lymphocytes. An optimal antigen presentation requires the expression of MHC class II HLA-DR on monocytes surface and of costimulatory molecules such as CD54 on monocytes and LFA-1 on lymphocytes. It has become increasingly apparent that the proinflammatory response is balanced by concomitant anti-inflammatory mechanisms that results in monocyte deactivation, characterized by a decrease in HLA-DR expression and the release of anti-inflammatory cytokines such as IL-10. This counterregulatory response, if prolonged or predominant, may predispose the patient to a higher risk of infection. Further studies need to be conducted to precise: i) the intensity of depression of the surface molocule expression assessing monocyte function, such as HLA DR and CD54; ii) the level of IL-10 and IL-12 release in patients with severe sepsis; iii) the immuno-modulating effects of frequently used treatments in these patients with severe sepsis and in surgical patients; iv) the time course of recovery; v) if the monitoring of HLA-DR, CD54, IL-10 and IL-12 will better predict the clinical outcome than clinical parameters.
 ...
PMID:Assessment of immunological status in the critically ill. 1119 84

Leukocyte adherence mediated by intercellular adhesion molecule-1 (ICAM-1) binding to leukocyte function-associated antigen (LFA-1) is required for proper inflammatory and immune function. Inhibition of ICAM-1\LFA-1 binding using monoclonal antibodies (mAb) has been shown to be efficacious at inhibiting lymphoma metastasis as well as leukocyte emigration into tissue in a number of inflammatory diseases such as ischemia-reperfusion injury, septic shock and rheumatoid arthritis. In this report, we describe the development and characterization of a small peptide antagonist of ICAM-1-dependent cell aggregation. By using repeated selection of a cyclic nonapeptide phage display library on purified ICAM-1, we identified phage that were competitively eluted with anti-ICAM-1 mAb. The peptide sequences were determined by nucleotide sequencing, and the peptide sequence (C*LLRMRSIC*) (IP01) that occurred most frequently was chosen for further study. Phage expressing this peptide sequence specifically bound ICAM-1 over a range of 5 x 10(6) to 1 x 10(8) phage/microL. A cyclic IP01 peptide, linear IP01 peptide, a cyclic nonapeptide with a scrambled IP01 sequence, and a random, cyclic nonapeptide were synthesized. The cyclic and linear IP01 peptides were able to inhibit ICAM-1-mediated cell aggregation at a concentration of 1 mM, whereas the random and scrambled peptide sequences did not alter aggregation. Cyclic IP01 had a half-maximal inhibitory concentration of approximately 970 microM. Cyclic IP01 did not inhibit cellular aggregation that was dependent on ICAM-2 or ICAM-3. Alanine substitutions in the cyclic IP01 identified at least four amino acids necessary for inhibition of ICAM-1 dependent cell aggregation; leucine 2, leucine 3, methionine 5, and arginine 6. Finally, we showed that cyclic IP01 can inhibit firm adhesion of neutrophils to endothelium, a critical event in inflammatory diseases, in an assay that recapitulates physiologic flow conditions. Homology of IP01 with the primary amino acid sequences of the alpha or beta subunit of LFA-1 was not identified. Thus, we identified a unique molecule that inhibits ICAM-1 dependent cell adhesion, but is not related to the primary sequence of the ICAM-1 ligand LFA-1. Due to the small size and ability to block cell-cell adhesion, IP01 may serve as a useful tool for study of ICAM-1 and LFA-1 biology as well as for the development of small molecule therapeutics.
 ...
PMID:Novel cyclic peptide inhibits intercellular adhesion molecule-1-mediated cell aggregation. 1153 73


<< Previous 1 2 3 4 Next >>