Selectin blockade prevents antigen-induced late bronchial responses and airway hyperresponsiveness in allergic sheep.

Antigen challenge can elicit an allergic inflammatory response in the airways that involves eosinophils, basophils, and neutrophils and that is expressed physiologically as a late airway response (LAR) and airway hyperresponsiveness (AHR). Although previous studies have suggested that E-selectin participates in these allergic airway responses, there is little information concerning the role of L-selectin. To address this question, we examined the effects of administering an L-selectin-specific monoclonal antibody, DU1-29, as well as three small molecule selectin binding inhibitors, on the development of early airway responses (EAR), LAR and AHR in allergic sheep undergoing airway challenge with Ascaris suum antigen.

A tissue plasminogen activator/P-selectin fusion protein is an effective thrombolytic agent.

Background: P-selectin is expressed on the surface of activated endothelial cells and platelets. We hypothesized that a tissue plasminogen activator (TPA)/P-selectin fusion protein would have not only thrombolytic activity but also might target TPA to the thrombi. In addition, it seemed possible that this chimeric protein would competitively inhibit the binding of native P-selectin on endothelial cells and platelets to leukocytes and thus further promote thrombolysis.

Single amino acid residues in the E- and P-selectin epidermal growth factor domains can determine carbohydrate binding specificity.

E-selectin and P-selectin are two closely related vascular cell adhesion proteins. Each selectin has an amino-terminal C-type lectin domain that is thought to possess the carbohydrate binding site that binds the sialylated Lewisx antigen (sLex or CD15s) (Neu5Acalpha2-3Galbeta1-4(Fucalpha1-3)GlcNAc). In addition to the sLex carbohydrate, P-selectin binds sulfated proteoglycan, 3-sulfated galactosyl ceramide (sulfatide), and heparin.

Structure-function analysis of P-selectin-sialyl LewisX binding interactions. Mutagenic alteration of ligand binding specificity.

P-selectin is a vascular cell adhesion molecule that is expressed on the surface of platelets and endothelial cells in response to inflammatory stimuli. It is believed to aid in the binding and recruitment of leukocytes to inflamed tissue. P-selectin adhesion to leukocytes is mediated by the amino-terminal lectin domain that binds the sialyl LewisX (sLeX) carbohydrate (Neu5Acalpha2-3Galbeta1-4(Fucalpha1-3)GlcNAc).

Rational design and synthesis of small molecule, non-oligosaccharide selectin inhibitors: (alpha-D-mannopyranosyloxy)biphenyl-substituted carboxylic acids.

The calcium dependent E-selectin/sialyl Lewisx (sLex) interaction plays a key role in inflammation where it mediates the rolling of leukocytes prior to firm adhesion and extravasation from the vasculature. A model of E-selectin/sLex binding, along with previously reported structure-activity relationships of sLex-related oligosaccharide, was used in the rational design of non-oligosaccharide inhibitors of this pivotal interaction. A palladium-mediated biaryl-coupling (Suzuki) reaction was used as the key step to prepare a number of substituted biphenyls which were assayed for their ability to inhibit the binding of E-, P-, and L-selectin-IgG fusion proteins to sLex expressed on the surface of HL60 cells.

A single amino acid residue can determine the ligand specificity of E-selectin.

E-selectin (ELAM-1) is a member of the selectin family of cellular adhesion molecules. This family of proteins possesses an amino-terminal Ca(2+)-dependent lectin or carbohydrate recognition domain that is essential for ligand binding. A known E-selectin ligand is the carbohydrate antigen, sialyl Lewis(x) (sLe(x) (Neu5Ac alpha 2-3Gal beta 1-4(Fuc alpha 1-3)GlcNAc).