alpha-Neup5Ac-(2--3)-beta-D-Galp-(1--4)-[alpha-L-Fucp-(1--3)]-D-GlcpNAc and Asthma

Asthma and COPD are chronic inflammatory conditions that affect hundreds of millions of patients worldwide. New therapeutics are desperately needed, especially those that target the underlying causes and prevent disease progression. Although asthma and COPD have distinct etiologies, both are associated with reduced airflow caused by excess infiltration of inflammatory cells into healthy lung tissues. As selectin-mediated adhesion of leukocytes to the vascular endothelium is a key early event in the initiation of the inflammatory response, selectin inhibition is thought to be a good target for therapeutic intervention. Three known selectins are expressed in distinct subsets of cells: P-selectin is presented on the surface of activated platelets and endothelial cells, L-selectin is constitutively expressed on leukocytes, and E-selectin synthesis is upregulated in activated endothelial cells. They mediate cell-cell adhesion in the shear flow of the bloodstream via specialized interactions with clusters of oligosaccharides presented on cell surface glycopeptide ligands. The role of selectin-ligand interactions in the inflammatory response has been demonstrated in various animal models, prompting considerable attention from the pharmaceutical industry.Drug discovery efforts have yielded many different classes of selectin inhibitors, including soluble protein ligands, antibodies, oligosaccharides and small molecules. Although many selectin inhibitors have shown activity in preclinical models, clinical progress of selectin-directed therapies has been slow. Early approaches employed carbohydrate-based inhibitors to mimic the natural ligand sialyl Lewis X; however, these compounds proved challenging to develop. Cytel's CY 1503, a complex oligosaccharide, progressed to phase II/III trials for reperfusion injury, but further development was halted when it failed to demonstrate clinical efficacy. Two protein-based selectin inhibitors have reached phase II development. These included Wyeth's recombinant soluble P-selectin ligand, TSI (PSGL-1), which was discontinued after disappointing results in myocardial infarction trials and Protein Design Labs' humanized anti-L-selectin monoclonal antibody, which is currently in development for trauma. Bimosiamose, discovered by Encysive Pharmaceutical and presently being developed by Revotar Biopharmaceuticals, is an 863 g/mol molecular weight dimer with minimal carbohydrate content and is, to date, the leading selectin inhibito

Topics: Animals; Asthma; Hexanes; Humans; Inflammation; Lewis X Antigen; Mannose; Oligosaccharides; P-Selectin; Pulmonary Disease, Chronic Obstructive; Selectins; Sialyl Lewis X Antigen

Inhibition of selectin function is expected to aid in the management of diseases characterized by aberrant or chronic inflammation, as in asthma and chronic obstructive pulmonary disease (COPD). Selectin-mediated adhesion of leukocytes to the vascular endothelium is a critical early event in the initiation of the inflammatory response, making it a good target for therapeutic intervention. Many approaches to modulating selectin function have been explored, including competitive inhibition, altering cell-surface expression and inducing shedding/cleavage from the cell surface; however, clinical success has been elusive.

Topics: Animals; Anti-Asthmatic Agents; Asthma; Biphenyl Compounds; Cell Adhesion; Chemotaxis, Leukocyte; Clinical Trials as Topic; Endothelium, Vascular; Humans; Inflammation; Leukocytes; Ligands; Lung; Mannose; Mannosides; Membrane Glycoproteins; Oligosaccharides; Pulmonary Disease, Chronic Obstructive; Selectins; Sialyl Lewis X Antigen

Asthma is an allergic disease that causes severe infiltration of leukocytes into the lungs. Leukocyte infiltration is mediated by the binding of sialyl Lewis X (sLe

Topics: Animals; Antibodies, Monoclonal; Asthma; Bone Marrow; Cell Differentiation; Disease Models, Animal; Eosinophils; Female; Hypersensitivity; Immunity; Lung; Mice, Inbred C57BL; Models, Biological; P-Selectin; Protein Binding; Sialyl Lewis X Antigen

Atopic dermatitis (AD) is a chronic, or chronically relapsing, inflammatory skin disease associated with asthma and allergic rhinitis, and is dominated by Th2 cells. The co-stimulatory T-cell receptor OX40 and its ligand, OX40L, play a central role in the pathogenesis of AD, as their interactions are crucial for the generation of TH2 memory cells. Using enzyme-linked immunoassay (ELISA) and flow cytometry on blood samples from patients with AD and healthy volunteers, this study shows that the serum level of soluble (s) OX40 is decreased in patients with AD, and the expression of OX40 by activated skin-homing CD4+ T cells is increased. This study further shows, using immunofluorescence on skin biopsies, that OX40+ and OX40L+ cells are co-located within the dermis, indicating local activity of OX40/OX40L. Serum levels of sOX40 were associated with atopic diseases and, together, these results support that the OX40 system is important for chronic inflammation in AD skin.

Topics: Adolescent; Adult; Asthma; Case-Control Studies; CD4-Positive T-Lymphocytes; Child; Child, Preschool; Dermatitis, Atopic; Humans; Immunoglobulin E; Mast Cells; Middle Aged; Oligosaccharides; OX40 Ligand; Receptors, OX40; Severity of Illness Index; Sialyl Lewis X Antigen; Skin; Young Adult

L-selectins on leukocytes and their counter-receptors on endothelial cells have been shown to be involved in leukocyte recruitment in chronic rhinosinusitis without nasal polyps (NP).. The purpose of this study was to evaluate the expression level of functionally active endothelial L-selectin ligands in NP obtained from patients with NP of different etiology [simple NP, antro-choanal polyps (ACP) and cystic fibrosis (CF) NP] and inferior turbinate specimens of healthy controls and to compare these levels to the presence of various leukocyte subsets.. Nasal polyp specimens and healthy nasal mucosa specimens were obtained from patients undergoing surgery and were immunohistochemically stained with monoclonal antibodies detecting CD34, sialyl Lewis x (sLe(x)) of sulfated extended core 1 lactosamines and various leukocyte subsets.. All NP are characterized by a decrease in the number of CD34+ vessels. The number of eosinophils and the percentage of vessels expressing endothelial sulfated sLe(x) epitopes is upregulated in all groups of simple NP. Tissue eosinophilia is increased in those patients with increased disease severity (acetyl salicylic acid intolerance), but the percentage of endothelial sulfated sLe(x) epitopes is not. Results on CF NP are similar to those observed for simple NP. Antro-choanal polyps, on the contrary, are characterized by low numbers of tissue eosinophils and relatively few vessels expressing endothelial sulfated sLe(x) epitopes.. Our results suggest that functionally active L-selectin ligands might play a role in guiding leukocyte traffic into NP in patients with simple NP and CF NP but not ACP.

Topics: Adolescent; Adult; Aged; Antigens, CD34; Asthma; Basophils; Chemotaxis, Leukocyte; Endothelial Cells; Female; Humans; Immunohistochemistry; L-Selectin; Leukocytes; Ligands; Macrophages; Male; Mast Cells; Middle Aged; Nasal Mucosa; Nasal Polyps; Oligosaccharides; Sialyl Lewis X Antigen

Lymphocyte infiltrate is a hallmark of inflammatory responses. We have previously shown that de novo-induced endothelial sialyl Lewis x (sLex) expression guides lymphocytes in an L-selectin-dependent manner to sites of acute organ transplant rejections. In this research, we have analyzed five groups of chronic lung inflammations to determine the presence of properly glycosylated, i.e., sulfated, sLex-decorated, L-selectin ligands. Two anti-sLex (2F3 and HECA-452) and one anti-6- and/or 6'-sulfated and/or 6,6'-bisulfated (MECA-79) monoclonal antibodies (mAbs) were used. The control lung specimens did not express L-selectin ligands on endothelium. In contrast, the endothelial staining intensity and the number of positive peribronchial venules and capillaries with mAbs 2F3, HECA-452, and MECA-79 were significantly greater in bronchial biopsies from patients with asthma compared with normal specimens (P<0.003). However, no significant increase of peribronchial endothelial reactivity with these antibodies was observed in adult respiratory distress syndrome, chronic bronchitis, fibrosing alveolitis, and granulomatous inflammation compared with controls. These data suggest that sulfated sLex glycans, acting putatively as ligands for L-selectin, could be instrumental in lymphocyte extravasation into human peribronchial lung tissue during asthma, but not so important in several other inflammatory lung diseases.

Topics: Adult; Asthma; Carbohydrate Sequence; Chronic Disease; Female; Humans; Immunohistochemistry; L-Selectin; Ligands; Male; Oligosaccharides; Pneumonia; Polysaccharides; Sialyl Lewis X Antigen; Sulfates

Preferential eosinophil accumulation is characteristic of airway inflammation in asthma. Although little is known about its mechanism, the effect of a sialyl Lewis X analog on airway eosinophilia was examined in a guinea-pig model of asthma. Guinea-pigs were sensitized by repeated inhalation of ovalbumin. After a single inhalation challenge, the animals showed striking airway eosinophilia and a late asthmatic response. In contrast, when guinea-pigs were pretreated intravenously with sialyl Lewis X analog (LX 0104) 1 h before antigen challenge, both eosinophil infiltration in the tracheal wall and the late asthmatic response were significantly inhibited in a dose-dependent manner. In a further in vitro study, LX 0104 significantly suppressed the adhesion of human and guinea-pig eosinophils to human umbilical vein endothelial cells activated with interleukin-1 beta. These results suggest that LX 0104 plays a critical role in antigen-induced airway eosinophilia and the late asthmatic response.

Topics: Animals; Anti-Inflammatory Agents; Asthma; Cell Adhesion; Cells, Cultured; Chemotaxis, Leukocyte; Cross Reactions; Endothelium, Vascular; Eosinophils; Guinea Pigs; Humans; Male; Oligosaccharides; Sialyl Lewis X Antigen; Time Factors