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PubMed1996

Alterations in circulating intercellular adhesion molecule-1 and L-selectin: further evidence for chronic inflammation in ischemic heart disease.

Atherosclerosis is increasingly thought to be a chronic inflammatory disease. Inflammation requires transmigration of leukocytes from the circulation to the tissues. Adhesion of leukocytes to endothelial calls is the initial event in an inflammatory response and is mediated by expression of several adhesion molecules. In this study we characterize the contribution of intercellular adhesion molecules (ICAM-1) and L-selectin in patients with different coronary artery disease syndromes. Serum concentrations of cICAM-1 and sL-selectin were measured by enzyme-linked immunosorbent assay in 31 patients with stable angina, 30 patients with unstable angina, 18 patients with acute myocardial infarction and 20 healthy subjects in a control group. All patients underwent coronary angiography. Mean (+/-SE) cICAM-1 levels were higher (p < 0.05) in patients with stable angina (249 +/- 6 ng/ml), unstable angina (260 +/- 16 ng/ml), or acute myocardial infarction (261 +/- 24 ng/ml) compared with those in subjects in the control group (171 +/- 11 ng/ml). In contrast, levels of sL-selectin were lower (p < 0.01) in patients with stable angina (1.2 +/- 0.1 microg/ml), unstable angina (1.1 +/- 0.6 microg/ml), or acute myocardial infarction (1.1 +/- 0.1 microg/ml) compared with those in subjects in the control group (1.8 +/- 0.1 microg/ml). No difference was found in cICAM-1 or sL-selectin levels among patients with stable angina, unstable angina, or acute myocardial infarction. No correlation was seen between cICAM-1 or sL-selectin levels and extent (or severity) of coronary artery disease or leukocyte count. L-selectin expression was observed to be depressed in patients with severe angina compared with that in members of the control group. To examine the mechanism of reduction in sL-selectin levels and L-selectin expression on leukocytes, leukocytes from the control group were stimulated in vitro. Stimulation of leukocytes resulted in a rapid downregulation of surface L-selectin expression, measured by flowcytometry, similar to the suppressed expression of L-selectin found on leukocytes from patients with coronary artery disease. In conclusion, altered cICAM-1 and sL-selectin levels in patients with coronary artery disease reflect the presence of a chronic inflammatory process. This inflammatory process results in downregulation of leukocyte expression of L-selectin and thus lower circulating sL-selectin levels.

Angina Pectoris↗
PubMed2003

P-selectin as a candidate target in atherosclerosis.

P-selectin is of critical importance in early atherogenesis by initiating leukocyte rolling at the site of endothelial injury. In order to validate P-selectin as a candidate target for the development of anti-atherogenic strategies, we wanted to obtain quantitative information on P-selectin expression, and identify novel peptide-based lead structures that interact with P-selectin. P-selectin mRNA expression in the aortic arch and in other tissues of apoE-deficient (apoE-/-) mice was determined by real-time PCR technology. P-selectin mRNA expression of apoE-/- mice increased steadily with age to levels 14-fold higher than that of control animals. The onset and level of P-selectin expression correlated well with the extent of lesion development, and was more specific for atherosclerotic tissue as compared with other adhesion molecules. Phage display technology was used to obtain novel P-selectin antagonists. Phage display selections resulted in the isolation of a highly P-selectin-specific phage clone. Synthetic peptide-equivalents of this clone displaced the binding of the parent phage and antagonized the binding of a sialyl Lewis(x) analogue to P-selectin. In conclusion, P-selectin expression correlates with early and advanced atherosclerotic lesion development. P-selectin ligands, like the lead structure we have developed here, can therefore be considered as promising tools to identify, target or antagonize P-selectin function within the chronically inflamed arterial wall.

Animals↗
PubMed2003

Characterization of platelet and soluble-porcine P-selectin (CD62P).

P-selectin (CD62P), an adhesion molecule expressed on activated endothelial cells and platelets, mediates the initial attachment of leukocytes to the stimulated endothelium upon inflammation and the interaction between leukocytes and platelets. A soluble form of P-selectin is present in the serum of healthy individuals as a circulating protein and high levels have been described in various pathological situations. The aim of this study was to characterize P-selectin on porcine platelets and investigate the soluble form of this protein, which are uncharacterized in several animal species including pigs. A new monoclonal antibody (mAb) (SwPsel.1.9) against porcine P-selectin was produced using a mouse cell line transfected with pig P-selectin cDNA. This mAb together with a previously described mAb (P-sel.KO.2.5), produced in our laboratory, was used to develop an ELISA to quantify porcine P-selectin. No significant levels of soluble-porcine P-selectin were observed in healthy animals. However, the total amount of P-selectin measured in porcine platelets was similar to that found in humans. Increased levels of this circulating protein were detected in the plasma from pigs after allograft implantation. In vitro, P-selectin expression on platelet membrane was rapidly induced by PMA and thrombin, as assessed by flow cytometry. However, these activators did not stimulate the release of soluble P-selectin. Analysis of the proteolytic cleavage of this protein from COS-transfected cells revealed that PMA treatment failed to cause the shedding of membrane-bound P-selectin. These data suggest that porcine P-selectin is a suitable marker for inflammation and that the mechanism involved in the generation of circulating P-selectin is not proteolytic release.

Animals↗
PubMed2003

Low L-selectin (CD62L) expression in acute myeloid leukemia correlates with a bad cytogenetic risk.

OBJECTIVES: Interactions between hemopoietic cells and the stromal microenvironment or immunoreactive cells are mediated by specific cell surface receptors. The expression of those molecules may alter the adhesive qualities (mobility and homing) as well as immune response behavior of leukemic blasts. L-Selectin (CD62L) is suggested to play a role in the redistribution and homing of hemopoietic progenitor cells to the bone marrow (BM). Down-regulation of L-selectin is responsible for mobilization of blasts from the BM into the circulation and ligation of L-selectin stimulates proliferation of progenitor cells. This could have an influence on the process of leukemia. METHOD: We have studied the expression of L-selectin on mononuclear BM cells of 36 acute myeloid leukemia (AML) patients at first diagnosis by FACS analysis using a directly fluorescein isothiocyanate conjugated antibody (clone DRE G56). RESULTS: On average the patients presented with 88% blasts in the BM. The expression tended to be higher in primary (p) AML compared with secondary (s) AML. L-Selectin was very heterogenously expressed in all FAB groups. Highest expression was found in cases with AML-M4 with four of nine cases presenting with an inv(16) karyotype. Separating our patient cohort in cytogenetic risk groups we could detect a significantly higher expression of L-selectin in cases with a 'good risk' karyotype and a very low expression in cases with a 'bad risk' karyotype (P = 0.037). Comparing patients who achieved remission after double induction therapy (responders) with patients who showed persisting disease (non-responders) we found a higher percentage of L-selectin+ cases or cells in the responder group than in the non-responder group, although the differences were not significant because of only five cases in the 'non-responder' group. Evaluating cut-off points greatest differences in relapse-free survival probabilities were found in patients who presented with > or = 30% L-selectin+ BM cells compared with cases with < 30%: 86% of cases with > or = 30% L-selectin+ cells were still in remission after a mean follow up time of only 8 months compared with only 46% in the group with < 30% L-selectin+ cells. CONCLUSIONS: We can conclude that (i) expression of L-selectin on AML blasts is variable. This reveals the great diversitiy of immunophenotypes in AML and might contribute to identify individual blast phenotypes in order to detect minimal residual disease in remission. (ii) Low L-selectin expression correlates with a bad cytogenetic risk, with a lower probability to achieve remission and with a shorter relapse-free survival time. This might reflect a decreased homing of the blasts to the BM as well as an impaired cytotoxic T-cell reaction against leukemic cells. The expression of L-selectin on leukemic blasts might be influenced by different cytokine therapies (e.g. with interferon alpha) and this might result in an altered hematologic reconstitution after cytotoxic therapies as well as in an altered immunologic recognition of blasts.

Acute Disease↗
PubMed1996

Absence of trauma-induced leukocyte rolling in mice deficient in both P-selectin and intercellular adhesion molecule 1.

Leukocyte recruitment during inflammation is achieved through a multistep paradigm that includes margination, selectin-mediated rolling, beta 2 integrin-mediated firm adhesion, emigration, and migration into the site of inflammation. We have used the mouse cremaster muscle as a model of trauma- and cytokine-induced inflammation to study the possible role of intercellular adhesion molecule (ICAM) 1 in leukocyte rolling using gene-targeted mice deficient in ICAM-1, P-selectin, and a combination of P-selectin and ICAM-1. Rolling flux and average leukocyte rolling velocity in ICAM-1-deficient mice was not different from wild-type mice, but P-selectin/ICAM-1-deficient mice showed a total absence of rolling for at least 2 h after surgical trauma. Rolling in both wild-type and ICAM-1-deficient mice 60-120 min after trauma was significantly inhibited by a P-selectin monoclonal antibody (mAb) (RB40.34). In contrast, an mAb (KAT-1) blocking ICAM-1 binding to leukocyte function-associated antigen 1 did not block residual rolling in P-selectin-deficient mice. TNF-alpha induced leukocyte rolling in P-selectin/ICAM-1-deficient mice, but the rolling flux fraction was significantly lower than in TNF-alpha-treated ICAM-1-deficient mice. Leukocyte rolling in P-selectin/ICAM-1-deficient mice treated with TNF-alpha for 3 h was completely blocked by an E-selectin mAb (9A9E3), and partially by an L-selectin mAb (MEL-14). This clearly demonstrates E-selectin-dependent rolling in vivo. Leukocyte rolling velocities were significantly reduced after TNF-alpha treatment and were similar in wild-type and gene-targeted strains. We conclude that the residual trauma-induced leukocyte rolling seen in P-selectin-deficient mice is completely abolished by concomitant ICAM-1 deficiency. This severe defect in leukocyte rolling may explain the absence of leukocyte recruitment into the inflamed peritoneal cavity of P-selectin/ICAM-1-deficient mice at early time points (< or = 4 h).

Animals↗
PubMed1997

Generation and characterization of a novel adhesion function blocking monoclonal antibody recognizing both rat and mouse E-selectin.

The prerequisite for the recruitment of circulating leukocytes to sites of inflammation is adhesion to vascular endothelial cells. Selectins play a significant role in the initiation of this multistep process by mediating "rolling" of the leukocytes on the endothelium. Investigation of selectin-dependent cell interactions using function blocking monoclonal antibodies (MAb) provides insights into the mechanisms involved in leukocyte migration into inflammation. Until now most studies in inflammation models in rats have relied on cross-reactive or polyclonal antibodies against rat E-selectin. In an E-selectin knockout mouse, we aimed to generate an adhesion function blocking MAb to rat E-selectin by immunization with rat E-selectin transfected Chinese hamster ovary cells (RESEC). An IgG1 kappa MAb was identified that reacts with RESEC but not with untransfected Chinese hamster ovary cells, as well as with recombinant mouse E-selectin protein as assessed by ELISA. This MAb is designated RME-1. It does not cross-react with rat L-selectin or rat P-selectin or E-selectin expressed on human umbilical vein endothelium. Adhesion of the HL-60 myeloid cells to immobilized mouse E-selectin was completely inhibited by MAb RME-1 under static conditions and adhesion of rat polymorphonuclear leukocytes to recombinant mouse E-selectin was blocked under rotation condition. This novel antibody thus recognizes a function-related epitope on rodent E-selectin.

Animals↗
PubMed1992

Further characterization of the interaction between L-selectin and its endothelial ligands.

L-Selectin is a lectin-like receptor on lymphocytes which mediates their attachment to high endothelial venules (HEV) within lymph nodes. Previous work has identified HEV-associated endothelial ligands for L-selectin as sialylated, fucosylated and sulphated glycoproteins of approximately 50 kDa and approximately 90 kDa (Sgp50 and Sgp90). The interaction of L-selectin with these ligands is carbohydrate directed, reflecting the involvement of its amino-terminal, calcium-type lectin domain. It has been reported, and we have confirmed, that anti-Ly22 blocks the adhesive function of L-selectin without reducing its binding to a carbohydrate- based ligand PPME (phosphomannan monoester core from Hansenula hostii). The epitope for this monoclonal antibody depends on the epidermal growth factor (EGF) domain of L-selectin. We demonstrate that anti-Ly22 inhibits the interaction of L-selectin with both of the Sgps, thus establishing that the interaction of L-selectin with HEV can be accounted for by the Sgps. Furthermore, the interaction of trypsin fragments of Sgp50 with L-selectin is inhibitable both by an antibody that maps to the lectin domain and by anti-Ly22. These findings raise the possibility that anti-Ly22 is affecting the function of the lectin domain of L-selectin rather than directly antagonizing the EGF domain. Toward a further characterization of L-selectin's carbohydrate specificity, we show that Sgp50 is partially inactivated by the linkage-specific Newcastle Disease virus sialidase (alpha 2,3 linkage). We additionally demonstrate that a sialyl Lewis x-related tetrasaccharide can interact with L-selectin, as has also been demonstrated for E-selectin and P-selectin.

Animals↗
PubMed1998

Circulating L-selectin levels and endothelial CD34 expression in inflammatory bowel disease.

OBJECTIVE: Soluble L-selectin (sL-selectin) concentrations are positively correlated with disease activity in ulcerative colitis (UC) but not in Crohn's disease (CD). This difference in sL-selectin regulation could be due to a disease specific regulation of L-selectin ligands. The aim of this study was to compare levels of circulating sL-selectin, expression of the L-selectin ligand CD34 in the affected colon, and inflammatory bowel disease activity. METHODS: Twenty-three patients with UC, 16 patients with CD, and 18 control subjects were included in the study. In blood samples concentrations of serum sL-selectin were determined by an ELISA technique. In colonoscopically obtained biopsies, CD34 expression was evaluated by immunohistochemical methods using monoclonal CD34 antibodies. Disease activity was determined by a clinical semiquantitative scale. RESULTS: sL-selectin levels were found to be significantly increased along with increasing disease activity in UC (p < 0.001) but not in CD (p > 0.05) patients. UC patients with quiescent and severe disease activity had significantly lower (p < 0.005) and higher (p < 0.002) sL-selectin concentrations than controls, respectively. CD34 expression was found to be increased in both disease groups as compared with controls (p < 0.05). CONCLUSION: A disease-specific regulation of CD34 was not found as an explanation for the distinction in sL-selectin regulation. In the light of recent reports on low sL-selectin in other diseases, it is suggested instead that ongoing neutrophil activation may be the reason for low sL-selectin concentrations during quiescent disease stages, whereas chemokine secretion could explain the increased levels of sL-selectin associated with severe disease activity.

Adult↗
PubMed1993

Correlation between serum level of soluble L-selectin and leukocyte count in chronic myeloid and lymphocytic leukemia and during bone marrow transplantation.

L-selectin is a glycoprotein which is one of three members in a family of cell adhesion molecules called selectins. L-selectin is present in distinct forms on both neutrophil granulocytes and lymphocytes, and it appears to play an important role in the early stages of leukocyte-endothelial cell interaction. Activation of leukocytes leads to shedding of the extracellular part of L-selectin which thus forms a soluble adhesion molecule, sL-selectin, which retains functional capacity and can be detected in serum. In the present study we have developed a specific, sensitive sandwich ELISA to measure the serum level of sL-selectin in patients with hematological and infectious disorders. Three patients with acute myeloid leukemia in remission and 1 patient with chronic myeloid leukemia in chronic phase were followed during bone marrow transplantation and the level of sL-selectin was found to correlate closely to the leukocyte counts with no detectable sL-selectin during periods of severe leukopenia. In 11 patients with chronic phase chronic myeloid leukemia and 13 patients with chronic lymphocytic leukemia the sL-selectin level was also found to correlate closely to the leukocyte count (R = 0.98; p = 0.001 and R = 0.83; p = 0.004 respectively). One CML patient with a leukocytosis of 385 x 10(9)/l was found to have an sL-selectin concentration 625 times above normal. Ten patients with acute pneumonia were evaluated at diagnosis and at the time of follow-up 4-8 weeks later. In all patients the initial sL-selectin level was higher than at follow-up. However, no close correlation between sL-selectin and leukocyte count or CRP (C-reactive protein) at the time of diagnosis was found. In summary, we have found that the sL-selectin level in human serum closely correlates to the leukocyte count in both CML and CLL and during bone marrow transplantation.

Acute Disease↗
PubMed1999

Mechanisms that regulate the function of the selectins and their ligands.

Selectins are a family of three cell adhesion molecules (L-, E-, and P-selectin) specialized in capturing leukocytes from the bloodstream to the blood vessel wall. This initial cell contact is followed by the selectin-mediated rolling of leukocytes on the endothelial cell surface. This represents the first step in a cascade of molecular interactions that lead to leukocyte extravasation, enabling the processes of lymphocyte recirculation and leukocyte migration into inflamed tissue. The central importance of the selectins in these processes has been well documented in vivo by the use of adhesion-blocking antibodies as well as by studies on selectin gene-deficient mice. This review focuses on the molecular mechanisms that regulate expression and function(s) of the selectins and their ligands. Cell-surface expression of the selectins is regulated by a variety of different mechanisms. The selectins bind to carbohydrate structures on glycoproteins, glycolipids, and proteoglycans. Glycoproteins are the most likely candidates for physiologically relevant ligands. Only a few glycoproteins are appropriately glycosylated to allow strong binding to the selectins. Recently, more knowledge about the structure and the regulated expression of some of the carbohydrates on these ligands necessary for selectin binding has been accumulated. For at least one of these ligands, the physiological function is now well established. A novel and exciting aspect is the signaling function of the selectins and their ligands. Especially in the last two years, convincing data have been published supporting the idea that selectins and glycoprotein ligands of the selectins participate in the activation of leukocyte integrins.

Animals↗
PubMed1996

E-selectin appears in nonischemic tissue during experimental focal cerebral ischemia.

BACKGROUND AND PURPOSE: E-selectin participates in leukocyte-endothelial adhesion and the inflammatory processes that follow focal cerebral ischemia and reperfusion. The temporal and topographical patterns of microvascular E-selectin presentation after experimental focal cerebral ischemia are relevant to microvascular reactivity to ischemia. METHODS: The upregulation and fate of E-selectin antigen during 2 hours of middle cerebral artery occlusion (n = 4) and 3 hours of occlusion with reperfusion (1 hour, n = 4; 4 hours, n = 6; 24 hours, n = 6) were evaluated in the nonhuman primate. E-selectin and E:P-selectin immunoreactivities were semiquantitated with the use of computerized light microscopy video imaging and laser confocal microscopy. RESULTS: Three patterns of microvascular E-selectin expression, defined by the antibody E-1E4, were confirmed by complete elimination of E-1E4 binding after incubation with soluble recombinant human E-selectin: (1) Low immunoperoxidase intensity was observed in ischemic microvessels at 2 hours of occlusion extending to 4 hours of reperfusion (E-selectin/laminin = 0.32 +/- 0.10). (2) A significant fraction of ischemic microvessels displayed high-intensity E-selectin signal by 24 hours of reperfusion (0.61 +/- 0.17) compared with control and nonischemic tissues (2P < .003). (3) In the contralateral nonischemic basal ganglia and other nonischemic tissues, low but significant E-selectin levels appeared by 24 hours of reperfusion (2P = .0005). The latter were further confirmed by an E:P-selectin immunoprobe. CONCLUSIONS: E-selectin antigen is distinctively and significantly upregulated in nonhuman primate brain after focal ischemia and reperfusion. The late appearance of E-selectin in nonischemic cerebral tissues suggests stimulation by transferable factors generated during brain injury.

Animals↗
PubMed1998

P-selectin expression in canine cutaneous inflammatory diseases and mast cell tumors.

P-selectin, a member of the selectin family of adhesion molecules, mediates the initial adhesion of leukocytes to the blood vessel wall during their emigration from the circulation. Adhesion molecules play an important role in the pathogenesis of several diseases, including various skin conditions. The objectives of the present study were to characterize the expression of vascular P-selectin in the skin of dogs suffering from inflammatory diseases or from common cutaneous neoplasms, and to determine if a correlation exists between P-selectin expression and inflammatory cell infiltration in these conditions. Immunohistochemistry was performed on formalin-fixed canine skin using a specific anti-canine P-selectin monoclonal antibody (MD3). Results showed that P-selectin was minimally expressed in normal canine skin. However, the number of P-selectin-expressing blood vessels was significantly increased (P < 0.05) in cases of allergic dermatitis, autoimmune dermatitis, pyogranulomatous dermatitis, dermatophytosis, and panniculitis. Highest P-selectin expression (percentage of MD3-positive vessels and intensity of the reaction) was observed in cases of autoimmune and pyogranulomatous dermatitis (55.3+/-7.4 and 44.0+/-9.9% P-selectin-positive vessels, respectively). In all conditions studied, a positive correlation existed between the number of P-selectin-positive blood vessels and the number of infiltrating leukocytes (r=0.556, P < 0.01). A significant number of blood vessels in mast cell tumors also expressed P-selectin, whereas no staining was observed in any of the histiocytomas examined. These results reveal that P-selectin expression is increased in different types of canine inflammatory skin diseases and suggest that P-selectin could participate in the local recruitment of leukocytes in canine cutaneous diseases.

Animals↗
PubMed2002

Specific inhibition of P-selectin-mediated cell adhesion by phage display-derived peptide antagonists.

P-selectin is a leukocyte adhesion receptor expressed on activated vascular endothelium and platelets that mediates leukocyte rolling and attachment. Because P-selectin is critically involved in inflammation, we used phage display libraries to identify P-selectin-specific peptides that might interfere with its proinflammatory function. Isolated phage contained a highly conserved amino acid motif. Synthetic peptides showed calcium-dependent binding to P-selectin, with high selectivity over E-selectin and L-selectin. The peptides completely antagonized adhesion of monocyte-derived HL60 cells to P-selectin and increased their rolling velocities in flow chamber experiments. Peptide truncation and alanine-scanning studies indicated that an EWVDV (single-letter amino acid codes) consensus motif sufficed for effective inhibition. Intriguingly, the apparent avidity of the peptides was increased 200-fold when presented in a tetrameric form (2 microM versus 10 nM), which is consistent with the proposed divalent interaction of P-selectin glycoprotein ligand 1 (PSGL-1) with P-selectin. As the EWVDV peptides inhibit the binding of an established glycoside ligand for P-selectin (sulfated Lewis A), it is conceivable that EWVDV interacts with or in close proximity to the actual carbohydrate recognition domain of P-selectin, without being a direct structural mimic of sialyl Lewis(x). These ligands are among the most potent antagonists of P-selectin yet designed. Their high affinity, selectivity, and accessible synthesis provide a promising entry to the development of new anti-inflammatory therapeutics and might be a powerful tool to provide important information on the binding site of P-selectin.

Amino Acid Sequence↗
PubMed2004

A down-regulatable E-selectin ligand is functionally important for PSGL-1-independent leukocyte-endothelial cell interactions.

P-selectin glycoprotein-1 (PSGL-1) supports P-selectin-dependent rolling in vivo and in vitro. However, controversy exists regarding the importance of PSGL-1-dependent and -independent E-selectin rolling. Using antibodies against PSGL-1 and PSGL-1(-/-) mice, we demonstrated abolition of P-selectin-dependent rolling but only partial inhibition of E-selectin-mediated rolling in the cremaster microcirculation following local administration of tumor necrosis factor alpha (TNF-alpha). In vitro studies demonstrated that binding of recombinant mouse E-selectin chimera to PSGL-1(-/-) neutrophils was dramatically decreased in mice treated systemically but not locally with TNF-alpha. Further, PSGL-1 blockade abolished E-selectin-dependent rolling in wild-type mice following systemic TNF-alpha administration but not local TNF-alpha administration. Together, these data support an E-selectin ligand present on PSGL-1(-/-) neutrophils that is down-regulatable upon systemic but not local activation. To determine whether the PSGL-1-independent E-selectin ligand was physiologically important, we used a P- and E-selectin-dependent cutaneous contact hypersensitivity model. Binding studies showed no E-selectin ligand down-regulation in this model. The few cells that rolled on E-selectin ligand following PSGL-1 antibody administration or in PSGL-1 deficiency were sufficient to induce profound contact hypersensitivity. In conclusion, E-selectin mediates PSGL-1-dependent and independent rolling and the latter can be down-regulated by systemic activation and can replace PSGL-1 to support the development of inflammation.

Animals↗
PubMed1999

Soluble L-selectin level is a marker for coronary artery disease in type 2 diabetic patients.

OBJECTIVE: To investigate whether the fall in soluble L-selectin (sL-selectin) level constitutes a marker for myocardial ischemia. RESEARCH DESIGN AND METHODS: The levels of soluble forms of adhesion molecules, i.e., intercellular adhesion molecule-1 (sICAM-1), vascular cell adhesion molecule-1 (sVCAM-1), E-selectin (sE-selectin), P-selectin (sP-selectin), and L-selectin (sL-selectin), were compared in type 2 diabetic patients without inflammatory syndrome but with symptomatic coronary artery disease (CAD) (group 1, n = 11), with silent ischemic disorders and proven coronary stenoses (group 2, n = 11), with silent myocardial ischemia (SMI) and normal coronary angiography (group 3, n = 10), and without proven SMI (group 4, n = 13). These levels were compared with those of 22 control subjects. RESULTS: The sL-selectin level was significantly lower in groups 1, 2, or 3 with symptomatic CAD or with SMI as compared with the control group (P = 0.0004). Group 4 without myocardial ischemia did not significantly differ from the control subjects (P = 0.6). In type 2 diabetic patients, after controlling for HbA1c, a partial correlation between sL-selectin and the CAD status was significant (P = 0.001). sICAM-1 and sP- or sE-selectin did not differ significantly between type 2 diabetic patients and control subjects or among the different groups of patients. The sVCAM-1 level in type 2 diabetic patients was significantly higher than in the control subjects (P = 0.001), but there were no significant intergroup differences (P = 0.4). CONCLUSIONS: In type 2 diabetic patients, sVCAM-1 is increased with regard to glycemic control, whatever the CAD status. In type 2 diabetic patients with symptomatic CAD or SMI associated with coronary stenoses, sL-selectin is significantly decreased. A marked fall in sL-selectin might constitute a marker for silent CAD in type 2 diabetic patients.

Aged↗
PubMed1994

Expression of P-selectin on endothelial cells is upregulated by LPS and TNF-alpha in vivo.

P-selectin is an endothelial cell adhesion molecule which mediates the binding of neutrophils and monocytes. Its appearance at the cell surface can be induced within minutes by histamine and thrombin which rapidly stimulate the transport of P-selectin from intracellular storage granules to the plasma membrane. We have recently found a second regulation mechanism for P-selectin on mouse endothelioma cells. Like E-selectin, P-selectin is also regulated at the level of transcription. Both selectins are induced by LPS or TNF-alpha with a maximal expression level at the cell surface 3-4 h after stimulation. Here, we report that this up-regulation of the synthesis of P-selectin also occurs in vivo in endothelium of the mouse. Analysing brain tissue, which is devoid of constitutive expression of P-selectin, we found that LPS and also TNF-alpha strongly induce the expression of P-selectin on all venular endothelial cells of the leptomeninges and, at a weaker level, on some blood vessels of the brain parenchyma. Induction of P-selectin expression could also be observed in tissues, such as the tongue, where P-selectin is constitutively expressed on small venules but only rarely on larger venules. Strong staining for P-selectin on endothelium of all large venules was observed in tissues of LPS and TNF-alpha treated animals and staining for this newly synthesized P-selectin was enriched at the luminal surface of these cells.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1998

Kinetics of platelet P-selectin mobilization: concurrent surface expression and release induced by thrombin or PMA, and inhibition by the NO donor SNAP.

Activated platelets and endothelium surface express the cell adhesion molecule P-selectin (CD62P), which plays an important role in mediating interactions with leukocytes. Increased levels of a functional soluble form of P-selectin (sP-selectin) have been reported in several pathological states but it is not clear whether this circulating sP-selectin originates from platelets and/or endothelial cells. Here we describe the concurrent kinetics of intracellular storage, surface expression and release of platelet P-selectin induced by thrombin or the protein kinase C activator PMA. Platelet activation with submaximal concentrations of thrombin (0.1 U/ml) resulted in a rapid decrease of intracellular P-selectin. This decrease of intracellular P-selectin concurred with a gradual increase of surface expression and an initial increase of sP-selectin. Our results indicate that intracellular stores of P-selectin were only partly mobilized upon activation with submaximal concentrations of thrombin. A high concentration of thrombin (1.0 U/ml) induced a rapid and nearly total decrease of intracellular stores and a more pronounced, but transient, increase of surface expression. The release of P-selectin was fast and occurred during the initial activation phase. The NO donor SNAP inhibited both surface expression and release of platelet P-selectin in a similar manner. PMA (0.1-1.0 microM) mediated a more slow, gradual and sustained surface expression and release of P-selectin than thrombin. Thus, surface expression and release of platelet P-selectin show different kinetics depending on the mode of activation.

Blood Platelets↗
PubMed1998

GlyCAM-1 supports leukocyte rolling in flow: evidence for a greater dynamic stability of L-selectin rolling of lymphocytes than of neutrophils.

L-selectin plays a major role in leukocyte traffic through lymph node high endothelial venules (HEV). We have investigated the role of GlyCAM-1, a major L-selectin ligand produced by HEV, in mediating leukocyte rolling under in vitro flow conditions. Purified GlyCAM-1 was found to support tethering and rolling in physiological shear flow of both human and murine L-selectin expressing leukocytes at an efficiency comparable to the HEV-derived L-selectin ligands termed peripheral node addressin (PNAd). Major dynamic differences between L-selectin rolling of peripheral blood T lymphocytes and neutrophils expressing similar L-selectin level were observed on GlyCAM-1. Lymphocytes established slower and more shear resistant rolling than neutrophils and could roll on GlyCAM-1 at shear stresses lower than the threshold values required for L-selectin-mediated neutrophil rolling. Notably, high stability of L-selectin rolling of lymphocytes requires intact cellular energy, although initial lymphocyte tethering to L-selectin ligands is energy-independent. By contrast, L-selectin mediated rolling of neutrophils is insensitive to energy depletion. The distinct dynamic behavior and energy-dependence of L-selectin rolling in different leukocytes suggest that L-selectin adhesiveness in shear flow is regulated in a cell-type specific manner. The greater stability of L-selectin rolling of lymphocytes on surface-adsorbed GlyCAM-1 may contribute to their selective recruitment at peripheral lymph nodes.

Animals↗