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Paul S Frenette - One of the best experts on this subject based on the ideXlab platform.
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A Novel Selectin Antagonist, GMI-1070, Prevents Vaso-Occlusion in Sickle Cell Mice by Inhibiting Leukocyte Adhesion and Activation.
Blood, 2007Co-Authors: Jungshan Chang, Arun K Sarkar, John L Magnani, John T. Patton, Paul S FrenetteAbstract:Previous studies using intravital microscopy in a sickle cell disease (SCD) mouse model (Berkeley) suggest that adherent leukocytes (WBCs) play a key role in vaso-occlusion by capturing circulating erythrocytes (RBCs) in venules. In addition, mice deficient in both P-and E-Selectins are protected from vaso-occlusion (VOC) induced by surgical trauma and TNF-α stimulation, suggesting that targeting selectins or their ligands represents a potentially useful strategy. Selectins bind to specific sialylated and fucosylated carbohydrate structures presented by glycoprotein or glycolipid ligands. Here, we tested the effect of novel small glycomimetic selectin inhibitors, GMI-1070 and GMI-1077, on leukocyte behavior and sickle cell VOC. Berkeley SCD mouse bone marrow was transplantated into lethally irradiated C57BL/6 animals to generate age- and gender-matched genetically identical cohorts of SCD mice. Fully engrafted male SCD mice were treated with TNF-α and prepared for intravital microscopy examination of the cremaster muscle 90 min later. GMI-1070, GMI-1077 (both 20 mg/kg) or vehicle (PBS) were administered immediately prior to cytokine stimulation (t=0 min), and an additional dose was given at t=70min. Another group of mice was injected with antibodies against P-and E-Selectins (PES, 1 mg/kg) as positive control. Several post-capillary and collecting venules were examined between t= 90min and t= 150min. Antibody blockade of endothelial selectins completely ablated leukocyte rolling, whereas GMI-1070 and GMI-1077 significantly increased the rolling flux fractions (PBS: 5.0±1.2 GMI-1070: 10.6±1.3%%; GMI-1077: 9.9±1.0%; p P-selectin. Since the hallmark of E-Selectin-mediated adhesion is the slow leukocyte rolling, we analyzed leukocyte rolling velocities in the various group and indeed found a 2-fold increase in rolling velocities in sickle mice treated with GMI-1070 compared to PBS control (PBS: 21±1 μm/s, GMI-1070: 38±1 μm/s, p
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a novel selectin antagonist gmi 1070 prevents vaso occlusion in sickle cell mice by inhibiting leukocyte adhesion and activation
Blood, 2007Co-Authors: Jungshan Chang, Arun K Sarkar, John L Magnani, John T. Patton, Paul S FrenetteAbstract:Previous studies using intravital microscopy in a sickle cell disease (SCD) mouse model (Berkeley) suggest that adherent leukocytes (WBCs) play a key role in vaso-occlusion by capturing circulating erythrocytes (RBCs) in venules. In addition, mice deficient in both P-and E-Selectins are protected from vaso-occlusion (VOC) induced by surgical trauma and TNF-α stimulation, suggesting that targeting selectins or their ligands represents a potentially useful strategy. Selectins bind to specific sialylated and fucosylated carbohydrate structures presented by glycoprotein or glycolipid ligands. Here, we tested the effect of novel small glycomimetic selectin inhibitors, GMI-1070 and GMI-1077, on leukocyte behavior and sickle cell VOC. Berkeley SCD mouse bone marrow was transplantated into lethally irradiated C57BL/6 animals to generate age- and gender-matched genetically identical cohorts of SCD mice. Fully engrafted male SCD mice were treated with TNF-α and prepared for intravital microscopy examination of the cremaster muscle 90 min later. GMI-1070, GMI-1077 (both 20 mg/kg) or vehicle (PBS) were administered immediately prior to cytokine stimulation (t=0 min), and an additional dose was given at t=70min. Another group of mice was injected with antibodies against P-and E-Selectins (PES, 1 mg/kg) as positive control. Several post-capillary and collecting venules were examined between t= 90min and t= 150min. Antibody blockade of endothelial selectins completely ablated leukocyte rolling, whereas GMI-1070 and GMI-1077 significantly increased the rolling flux fractions (PBS: 5.0±1.2 GMI-1070: 10.6±1.3%%; GMI-1077: 9.9±1.0%; p P-selectin. Since the hallmark of E-Selectin-mediated adhesion is the slow leukocyte rolling, we analyzed leukocyte rolling velocities in the various group and indeed found a 2-fold increase in rolling velocities in sickle mice treated with GMI-1070 compared to PBS control (PBS: 21±1 μm/s, GMI-1070: 38±1 μm/s, p<0.001). Consistent with these results, other studies using a parallel plate flow chamber (0.9 dynes/cm2) revealed that GMI-1070 was much more potent (1000-fold difference) in inhibiting the binding of human PMNs to TNF-α-stimulated (to induce E-Selectin) endothelial cells (HUVEC) than with IL-4 and histamine stimulated HUVECs (to induce P-selectin). Further, competitive inhibition assays revealed that the IC50 of GMI-1070, relative to the standard glycyrrhizin, was much lower for E-Selectin than P-selectin. These studies suggest that E-Selectin-mediated adhesion/signaling may play a more important role than previously appreciated in the pathophysiology of SCD, and suggest that GMI-1070 may be beneficial for the treatment of sickle cell vaso-occlusion.
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hematopoietic progenitor cell rolling in bone marrow microvessels parallel contributions by endothelial selectins and vascular cell adhesion molecule 1
Journal of Experimental Medicine, 1998Co-Authors: Irina Mazo, Denisa D. Wagner, Paul S Frenette, Richard O Hynes, Jose C Gutierrezramos, Ulrich H Von AndrianAbstract:We have used intravital microscopy to study physiologically perfused microvessels in murine bone marrow (BM). BM sinusoids and venules, but not adjacent bone vessels, supported rolling interactions of hematopoietic progenitor cells. Rolling did not involve L-selectin, but was partially reduced in wild-type mice treated with antibodies to P- or E-Selectin and in mice that were deficient in these two selectins. Selectin-independent rolling was mediated by α4 integrins, which interacted with endothelial vascular cell adhesion molecule (VCAM)-1. Parallel contribution of the endothelial selectins and VCAM-1 is not known to direct blood cell trafficking to other noninflamed tissues. This combination of constitutively expressed adhesion molecules may thus constitute a BM-specific recruitment pathway for progenitor cells analogous to the vascular addressins that direct selective lymphocyte homing to lymphoid organs.
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p and e selectins are required for the leukocyte recruitment but not the tissue swelling associated with ige and mast cell dependent inflammation in mouse skin
Laboratory Investigation, 1998Co-Authors: F De Mora, Denisa D. Wagner, Paul S Frenette, C M M Williams, Richard O Hynes, Stephen J GalliAbstract:Many studies, in both experimental animal and human systems, have indicated that P- and/or E-Selectins may contribute importantly to the leukocyte recruitment that occurs in association with mast cell-dependent inflammatory responses. We used mice that genetically lack P-selectin (P -/-), E-Selectin (E -/-), or both selectins (P/E -/-) to investigate the possible roles of these selectins in the IgE- and mast cell-dependent recruitment of neutrophils to the skin of mice. We found that a lack of either or both selectins had little or no effect on the extent of mast cell degranulation or the tissue swelling associated with these reactions. Moreover, a lack of either P- or E-Selectin alone did not reduce the neutrophil infiltration at the reaction sites. However, mice lacking both P- and E-Selectins exhibited an almost complete ablation of IgE- and mast cell-dependent neutrophil recruitment. These findings show that P- and E-Selectins can express overlapping functions in leukocyte recruitment associated with IgE- and mast cell-dependent cutaneous late-phase reactions in mouse skin, and that a lack of both selectins results in a virtual elimination of IgE-dependent leukocyte recruitment.
John L Magnani - One of the best experts on this subject based on the ideXlab platform.
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Probing the Carbohydrate Recognition Domain of E-Selectin : The Importance of the Acid Orientation in sLex Mimetics
Bioorganic & Medicinal Chemistry, 2009Co-Authors: Alexander Titz, Oliver Schwardt, Zorana Radic, Martin Smiesko, John L Magnani, John T. Patton, Beat ErnstAbstract:Abstract The selectin–leukocyte interaction is the initial event in the early inflammatory cascade. This interplay proceeds via the terminal tetrasaccharide sialyl Lewis x (sLe x ), present on physiological selectin ligands and E- and P-selectins located on the endothelial surface. Blocking this process is regarded as a promising therapeutic approach for inflammatory diseases where excessive leukocyte efflux is responsible for tissue damage. Selectin antagonists are generally based on sLe x as lead structure, containing the essential pharmacophores pre-oriented in the bioactive conformation. In this work, we describe a set of competitive sLe x mimetics possessing the carboxylic acid pharmacophore equipped with additional hydrophobic substituents as neuraminic acid (Neu5Ac) replacements. This small library of antagonists derived from Huisgen-1,3-dipolar cycloadditions allows to further probe the carbohydrate recognition domain of E-Selectin.
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A Novel Selectin Antagonist, GMI-1070, Prevents Vaso-Occlusion in Sickle Cell Mice by Inhibiting Leukocyte Adhesion and Activation.
Blood, 2007Co-Authors: Jungshan Chang, Arun K Sarkar, John L Magnani, John T. Patton, Paul S FrenetteAbstract:Previous studies using intravital microscopy in a sickle cell disease (SCD) mouse model (Berkeley) suggest that adherent leukocytes (WBCs) play a key role in vaso-occlusion by capturing circulating erythrocytes (RBCs) in venules. In addition, mice deficient in both P-and E-Selectins are protected from vaso-occlusion (VOC) induced by surgical trauma and TNF-α stimulation, suggesting that targeting selectins or their ligands represents a potentially useful strategy. Selectins bind to specific sialylated and fucosylated carbohydrate structures presented by glycoprotein or glycolipid ligands. Here, we tested the effect of novel small glycomimetic selectin inhibitors, GMI-1070 and GMI-1077, on leukocyte behavior and sickle cell VOC. Berkeley SCD mouse bone marrow was transplantated into lethally irradiated C57BL/6 animals to generate age- and gender-matched genetically identical cohorts of SCD mice. Fully engrafted male SCD mice were treated with TNF-α and prepared for intravital microscopy examination of the cremaster muscle 90 min later. GMI-1070, GMI-1077 (both 20 mg/kg) or vehicle (PBS) were administered immediately prior to cytokine stimulation (t=0 min), and an additional dose was given at t=70min. Another group of mice was injected with antibodies against P-and E-Selectins (PES, 1 mg/kg) as positive control. Several post-capillary and collecting venules were examined between t= 90min and t= 150min. Antibody blockade of endothelial selectins completely ablated leukocyte rolling, whereas GMI-1070 and GMI-1077 significantly increased the rolling flux fractions (PBS: 5.0±1.2 GMI-1070: 10.6±1.3%%; GMI-1077: 9.9±1.0%; p P-selectin. Since the hallmark of E-Selectin-mediated adhesion is the slow leukocyte rolling, we analyzed leukocyte rolling velocities in the various group and indeed found a 2-fold increase in rolling velocities in sickle mice treated with GMI-1070 compared to PBS control (PBS: 21±1 μm/s, GMI-1070: 38±1 μm/s, p
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a novel selectin antagonist gmi 1070 prevents vaso occlusion in sickle cell mice by inhibiting leukocyte adhesion and activation
Blood, 2007Co-Authors: Jungshan Chang, Arun K Sarkar, John L Magnani, John T. Patton, Paul S FrenetteAbstract:Previous studies using intravital microscopy in a sickle cell disease (SCD) mouse model (Berkeley) suggest that adherent leukocytes (WBCs) play a key role in vaso-occlusion by capturing circulating erythrocytes (RBCs) in venules. In addition, mice deficient in both P-and E-Selectins are protected from vaso-occlusion (VOC) induced by surgical trauma and TNF-α stimulation, suggesting that targeting selectins or their ligands represents a potentially useful strategy. Selectins bind to specific sialylated and fucosylated carbohydrate structures presented by glycoprotein or glycolipid ligands. Here, we tested the effect of novel small glycomimetic selectin inhibitors, GMI-1070 and GMI-1077, on leukocyte behavior and sickle cell VOC. Berkeley SCD mouse bone marrow was transplantated into lethally irradiated C57BL/6 animals to generate age- and gender-matched genetically identical cohorts of SCD mice. Fully engrafted male SCD mice were treated with TNF-α and prepared for intravital microscopy examination of the cremaster muscle 90 min later. GMI-1070, GMI-1077 (both 20 mg/kg) or vehicle (PBS) were administered immediately prior to cytokine stimulation (t=0 min), and an additional dose was given at t=70min. Another group of mice was injected with antibodies against P-and E-Selectins (PES, 1 mg/kg) as positive control. Several post-capillary and collecting venules were examined between t= 90min and t= 150min. Antibody blockade of endothelial selectins completely ablated leukocyte rolling, whereas GMI-1070 and GMI-1077 significantly increased the rolling flux fractions (PBS: 5.0±1.2 GMI-1070: 10.6±1.3%%; GMI-1077: 9.9±1.0%; p P-selectin. Since the hallmark of E-Selectin-mediated adhesion is the slow leukocyte rolling, we analyzed leukocyte rolling velocities in the various group and indeed found a 2-fold increase in rolling velocities in sickle mice treated with GMI-1070 compared to PBS control (PBS: 21±1 μm/s, GMI-1070: 38±1 μm/s, p<0.001). Consistent with these results, other studies using a parallel plate flow chamber (0.9 dynes/cm2) revealed that GMI-1070 was much more potent (1000-fold difference) in inhibiting the binding of human PMNs to TNF-α-stimulated (to induce E-Selectin) endothelial cells (HUVEC) than with IL-4 and histamine stimulated HUVECs (to induce P-selectin). Further, competitive inhibition assays revealed that the IC50 of GMI-1070, relative to the standard glycyrrhizin, was much lower for E-Selectin than P-selectin. These studies suggest that E-Selectin-mediated adhesion/signaling may play a more important role than previously appreciated in the pathophysiology of SCD, and suggest that GMI-1070 may be beneficial for the treatment of sickle cell vaso-occlusion.
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comparison of l selectin and e selectin ligand specificities the l selectin can bind the e selectin ligands sialyl lex and sialyl lea
Biochemical and Biophysical Research Communications, 1992Co-Authors: Aaron R Warnock, Martyn Kim Robinson, John L Magnani, Ellen L Berg, Eugene C ButcherAbstract:Abstract The L- and E-Selectins are leukocyte and endothelial cell surface molecules which mediate leukocyte-endothelial cell adhesion by interacting with carbohydrate ligands. In the present study we find that L-selectin, like E-Selectin, can interact with synthetic neoglycoproteins containing Sialyl Le x (Neu5Acα2-3Galβ1-4[Fucα1-3]GlcNAcβ-R), or Sialyl Le a (Neu5Ac-α2-3Galβ1-3[Fucα1-4]GlcNAcβ-R). Additionally, both the E-Selectin and L-selectin can bind the peripheral lymph node addressin, a high endothelial venule ligand for L-selectin. Despite overlapping interactions, the L- and E-Selectins discriminate between their native ligands. The peripheral lymph node addressin is a preferential ligand for L-selectin; and furthermore, L-selectin expressing cells do not interact detectably with the cutaneous lymphocyte antigen, a native glycoprotein ligand for E-Selectin found on a subset of lymphocytes associated with the skin.
Tal Pupko - One of the best experts on this subject based on the ideXlab platform.
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Selecton 2007: advanced models for detecting positive and purifying selection using a Bayesian inference approach.
Nucleic acids research, 2007Co-Authors: Adi Stern, Adi Doron-faigenboim, Elana Erez, Eric Martz, Eran Bacharach, Tal PupkoAbstract:Biologically significant sites in a protein may be identified by contrasting the rates of synonymous (K(s)) and non-synonymous (K(a)) substitutions. This enables the inference of site-specific positive Darwinian selection and purifying selection. We present here Selecton version 2.2 (http://selecton.bioinfo.tau.ac.il), a web server which automatically calculates the ratio between K(a) and K(s) (omega) at each site of the protein. This ratio is graphically displayed on each site using a color-coding scheme, indicating either positive selection, purifying selection or lack of selection. Selecton implements an assembly of different evolutionary models, which allow for statistical testing of the hypothesis that a protein has undergone positive selection. Specifically, the recently developed mechanistic-empirical model is introduced, which takes into account the physicochemical properties of amino acids. Advanced options were introduced to allow maximal fine tuning of the server to the user's specific needs, including calculation of statistical support of the omega values, an advanced graphic display of the protein's 3-dimensional structure, use of different genetic codes and inputting of a pre-built phylogenetic tree. Selecton version 2.2 is an effective, user-friendly and freely available web server which implements up-to-date methods for computing site-specific selection forces, and the visualization of these forces on the protein's sequence and structure.
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Selecton 2007: advanced models for detecting positive and purifying selection using a Bayesian inference approach
Nucleic Acids Research, 2007Co-Authors: Adi Stern, Adi Doron-faigenboim, Elana Erez, Eric Martz, Eran Bacharach, Tal PupkoAbstract:Biologically significant sites in a protein may be identified by contrasting the rates of synonymous (Ks) and non-synonymous (Ka) substitutions. This enables the inference of site-specific positive Darwinian selection and purifying selection. We present here Selecton version 2.2 (http://selecton. bioinfo.tau.ac.il), a web server which automatically calculates the ratio between Ka and Ks (u) at each site of the protein. This ratio is graphically displayed on each site using a color-coding scheme, indicating either positive selection, purifying selection or lack of selection. Selecton implements an assembly of different evolutionary models, which allow for statistical testing of the hypothesis that a protein has undergone positive selection. Specifically, the recently developed mechanisticempirical model is introduced, which takes into account the physicochemical properties of amino acids. Advanced options were introduced to allow maximal fine tuning of the server to the user’s specific needs, including calculation of statistical support of the u values, an advanced graphic display of the protein’s 3-dimensional structure, use of different genetic codes and inputting of a pre-built phylogenetic tree. Selecton version 2.2 is an effective, user-friendly and freely available web server which implements up-to-date methods for computing site-specific selection forces, and the visualization of these forces on the protein’s sequence and structure.
John T. Patton - One of the best experts on this subject based on the ideXlab platform.
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Probing the Carbohydrate Recognition Domain of E-Selectin : The Importance of the Acid Orientation in sLex Mimetics
Bioorganic & Medicinal Chemistry, 2009Co-Authors: Alexander Titz, Oliver Schwardt, Zorana Radic, Martin Smiesko, John L Magnani, John T. Patton, Beat ErnstAbstract:Abstract The selectin–leukocyte interaction is the initial event in the early inflammatory cascade. This interplay proceeds via the terminal tetrasaccharide sialyl Lewis x (sLe x ), present on physiological selectin ligands and E- and P-selectins located on the endothelial surface. Blocking this process is regarded as a promising therapeutic approach for inflammatory diseases where excessive leukocyte efflux is responsible for tissue damage. Selectin antagonists are generally based on sLe x as lead structure, containing the essential pharmacophores pre-oriented in the bioactive conformation. In this work, we describe a set of competitive sLe x mimetics possessing the carboxylic acid pharmacophore equipped with additional hydrophobic substituents as neuraminic acid (Neu5Ac) replacements. This small library of antagonists derived from Huisgen-1,3-dipolar cycloadditions allows to further probe the carbohydrate recognition domain of E-Selectin.
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A Novel Selectin Antagonist, GMI-1070, Prevents Vaso-Occlusion in Sickle Cell Mice by Inhibiting Leukocyte Adhesion and Activation.
Blood, 2007Co-Authors: Jungshan Chang, Arun K Sarkar, John L Magnani, John T. Patton, Paul S FrenetteAbstract:Previous studies using intravital microscopy in a sickle cell disease (SCD) mouse model (Berkeley) suggest that adherent leukocytes (WBCs) play a key role in vaso-occlusion by capturing circulating erythrocytes (RBCs) in venules. In addition, mice deficient in both P-and E-Selectins are protected from vaso-occlusion (VOC) induced by surgical trauma and TNF-α stimulation, suggesting that targeting selectins or their ligands represents a potentially useful strategy. Selectins bind to specific sialylated and fucosylated carbohydrate structures presented by glycoprotein or glycolipid ligands. Here, we tested the effect of novel small glycomimetic selectin inhibitors, GMI-1070 and GMI-1077, on leukocyte behavior and sickle cell VOC. Berkeley SCD mouse bone marrow was transplantated into lethally irradiated C57BL/6 animals to generate age- and gender-matched genetically identical cohorts of SCD mice. Fully engrafted male SCD mice were treated with TNF-α and prepared for intravital microscopy examination of the cremaster muscle 90 min later. GMI-1070, GMI-1077 (both 20 mg/kg) or vehicle (PBS) were administered immediately prior to cytokine stimulation (t=0 min), and an additional dose was given at t=70min. Another group of mice was injected with antibodies against P-and E-Selectins (PES, 1 mg/kg) as positive control. Several post-capillary and collecting venules were examined between t= 90min and t= 150min. Antibody blockade of endothelial selectins completely ablated leukocyte rolling, whereas GMI-1070 and GMI-1077 significantly increased the rolling flux fractions (PBS: 5.0±1.2 GMI-1070: 10.6±1.3%%; GMI-1077: 9.9±1.0%; p P-selectin. Since the hallmark of E-Selectin-mediated adhesion is the slow leukocyte rolling, we analyzed leukocyte rolling velocities in the various group and indeed found a 2-fold increase in rolling velocities in sickle mice treated with GMI-1070 compared to PBS control (PBS: 21±1 μm/s, GMI-1070: 38±1 μm/s, p
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a novel selectin antagonist gmi 1070 prevents vaso occlusion in sickle cell mice by inhibiting leukocyte adhesion and activation
Blood, 2007Co-Authors: Jungshan Chang, Arun K Sarkar, John L Magnani, John T. Patton, Paul S FrenetteAbstract:Previous studies using intravital microscopy in a sickle cell disease (SCD) mouse model (Berkeley) suggest that adherent leukocytes (WBCs) play a key role in vaso-occlusion by capturing circulating erythrocytes (RBCs) in venules. In addition, mice deficient in both P-and E-Selectins are protected from vaso-occlusion (VOC) induced by surgical trauma and TNF-α stimulation, suggesting that targeting selectins or their ligands represents a potentially useful strategy. Selectins bind to specific sialylated and fucosylated carbohydrate structures presented by glycoprotein or glycolipid ligands. Here, we tested the effect of novel small glycomimetic selectin inhibitors, GMI-1070 and GMI-1077, on leukocyte behavior and sickle cell VOC. Berkeley SCD mouse bone marrow was transplantated into lethally irradiated C57BL/6 animals to generate age- and gender-matched genetically identical cohorts of SCD mice. Fully engrafted male SCD mice were treated with TNF-α and prepared for intravital microscopy examination of the cremaster muscle 90 min later. GMI-1070, GMI-1077 (both 20 mg/kg) or vehicle (PBS) were administered immediately prior to cytokine stimulation (t=0 min), and an additional dose was given at t=70min. Another group of mice was injected with antibodies against P-and E-Selectins (PES, 1 mg/kg) as positive control. Several post-capillary and collecting venules were examined between t= 90min and t= 150min. Antibody blockade of endothelial selectins completely ablated leukocyte rolling, whereas GMI-1070 and GMI-1077 significantly increased the rolling flux fractions (PBS: 5.0±1.2 GMI-1070: 10.6±1.3%%; GMI-1077: 9.9±1.0%; p P-selectin. Since the hallmark of E-Selectin-mediated adhesion is the slow leukocyte rolling, we analyzed leukocyte rolling velocities in the various group and indeed found a 2-fold increase in rolling velocities in sickle mice treated with GMI-1070 compared to PBS control (PBS: 21±1 μm/s, GMI-1070: 38±1 μm/s, p<0.001). Consistent with these results, other studies using a parallel plate flow chamber (0.9 dynes/cm2) revealed that GMI-1070 was much more potent (1000-fold difference) in inhibiting the binding of human PMNs to TNF-α-stimulated (to induce E-Selectin) endothelial cells (HUVEC) than with IL-4 and histamine stimulated HUVECs (to induce P-selectin). Further, competitive inhibition assays revealed that the IC50 of GMI-1070, relative to the standard glycyrrhizin, was much lower for E-Selectin than P-selectin. These studies suggest that E-Selectin-mediated adhesion/signaling may play a more important role than previously appreciated in the pathophysiology of SCD, and suggest that GMI-1070 may be beneficial for the treatment of sickle cell vaso-occlusion.
Eugene C Butcher - One of the best experts on this subject based on the ideXlab platform.
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e selectin mediates leukocyte rolling in interleukin 1 treated rabbit mesentery venules
Blood, 1994Co-Authors: A M Olofsson, Karl-e. Arfors, L Ramezani, B A Wolitzky, Eugene C Butcher, Ulrich H Von AndrianAbstract:The selectins are lectin-like cell surface glycoproteins that have been implicated in playing a crucial role in the initiation of leukocyte adhesion to endothelial cells (ECs) during inflammation. Binding of selectins under conditions of flow mediates leukocyte rolling, which in vivo is almost exclusively observed in venular microvessels. We have shown in previous experiments that intraperitoneal treatment of rabbits with interleukin-1 beta (IL-1) increases leukocyte rolling in exteriorized mesenteries. In the present study, we used immunohistochemistry of mesenteries and found that IL-1 induced a marked E-Selectin immunoreactivity, preferentially in venules. We therefore hypothesized that the increased rolling in response to IL-1 may be related to the induction of E-Selectin on venular ECs. Intravital microscopy was used to investigate interactions between leukocytes and ECs after intraperitoneal application of IL-1. The rabbit E-Selectin monoclonal antibody (MoAb) 9H9 significantly reduced rolling of leukocytes by approximately 40%. Vehicle alone, class- matched control MoAb or the nonblocking anti-E-Selectin MoAb 14G2 had no effect on rolling. These results indicate that leukocytes roll on inflamed venular ECs partly through interactions with E-Selectin. Furthermore, we propose that the restricted E-Selectin immunoreactivity by venular ECs contributes to the remarkable difference seen between arterioles and venules in exhibiting leukocyte rolling in vivo.
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comparison of l selectin and e selectin ligand specificities the l selectin can bind the e selectin ligands sialyl lex and sialyl lea
Biochemical and Biophysical Research Communications, 1992Co-Authors: Aaron R Warnock, Martyn Kim Robinson, John L Magnani, Ellen L Berg, Eugene C ButcherAbstract:Abstract The L- and E-Selectins are leukocyte and endothelial cell surface molecules which mediate leukocyte-endothelial cell adhesion by interacting with carbohydrate ligands. In the present study we find that L-selectin, like E-Selectin, can interact with synthetic neoglycoproteins containing Sialyl Le x (Neu5Acα2-3Galβ1-4[Fucα1-3]GlcNAcβ-R), or Sialyl Le a (Neu5Ac-α2-3Galβ1-3[Fucα1-4]GlcNAcβ-R). Additionally, both the E-Selectin and L-selectin can bind the peripheral lymph node addressin, a high endothelial venule ligand for L-selectin. Despite overlapping interactions, the L- and E-Selectins discriminate between their native ligands. The peripheral lymph node addressin is a preferential ligand for L-selectin; and furthermore, L-selectin expressing cells do not interact detectably with the cutaneous lymphocyte antigen, a native glycoprotein ligand for E-Selectin found on a subset of lymphocytes associated with the skin.
