title: Blockade of late-phase airway responses and airway hyperresponsiveness in allergic sheep with a small-molecule peptide inhibitor of VLA-4.
abstract: The leukocyte integrin very late antigen-4 (VLA-4) (alpha 4 beta 1, CD49d/CD29) is an adhesion receptor predominantly expressed on lymphocytes, monocytes, and eosinophils, but not on neutrophils. Recent studies with monoclonal antibodies against VLA-4 suggest that antigen-induced late responses and airway hyperresponsiveness (AHR) may depend on the recruitment and/or activation of VLA-4-expressing leukocytes. To further test this hypothesis, we administered by aerosol either a potent small-molecule inhibitor of VLA-4, which prevents VLA-4-mediated binding to fibronectin (CS-1 ligand mimic), or an inactive control (30 mg twice daily for 3 d, and on the fourth day 0.5 h before and 4 h after antigen challenge) to six sheep with airway hypersensitivity to Ascaris suum antigen. Treatment with the small-molecule VLA-4 inhibitor resulted in a significant decrease in the early antigen-induced bronchial response (40%, p < 0.05), and almost complete blockade of the late-phase airway response (88%, p < 0.05). Moreover, at 24 h after antigen challenge, AHR to inhaled carbachol was not observed when the animals were dosed with the small-molecule VLA-4 inhibitor. In accord with protection against the functional abnormalities associated with antigen challenge, analysis of biopsy specimens taken 24 h after challenge indicated that the total numbers of VLA-4-positive cells (lymphocytes, eosinophils, and metachromatic-staining cells) in the group treated with the VLA-4 inhibitor did not increase, whereas these cells increased in the control group. The active agent, but not the inactive control, significantly blocked macrophage adherence to fibronectin (FN), indicating that the CS-1 ligand interfered with VLA-4-mediated adhesion in sheep cells. These results support our previous findings with a monoclonal antibody to VLA-4, and demonstrate that a small-molecule VLA-4 inhibitor, when given by aerosol, has a protective effect against antigen-induced late responses and AHR in allergic sheep.
authors.affiliation: Division of Pulmonary Disease, Mount Sinai Medical Center, Miami Beach, Florida 33140, USA.
authors.forename: W M
authors.initials: WM
authors.lastname: Abraham
authors.forename: A
authors.initials: A
authors.lastname: Ahmed
authors.forename: M W
authors.initials: MW
authors.lastname: Sielczak
authors.forename: M
authors.initials: M
authors.lastname: Narita
authors.forename: T
authors.initials: T
authors.lastname: Arrhenius
authors.forename: M J
authors.initials: MJ
authors.lastname: Elices
mesh_terms: D000818:Animals; D018926:Anti-Allergic Agents / Q000037:antagonists & inhibitors* / Q000276:immunology*; D001706:Biopsy; D016535:Bronchial Hyperreactivity / Q000188:drug therapy* / Q000276:immunology*; D001985:Bronchial Provocation Tests; D002352:Carrier Proteins / Q000187:drug effects*; D004195:Disease Models, Animal; D004353:Drug Evaluation, Preclinical; D006967:Hypersensitivity / Q000150:complications*; D039041:Integrin alpha4beta1; D016023:Integrins / Q000037:antagonists & inhibitors* / Q000276:immunology*; D008262:Macrophage Activation / Q000187:drug effects; D016676:Macrophages, Alveolar / Q000187:drug effects; D009842:Oligopeptides / Q000187:drug effects* / Q000494:pharmacology*; D016201:Receptors, Lymphocyte Homing / Q000037:antagonists & inhibitors* / Q000276:immunology*; D012756:Sheep
chemical_list: D018926:Anti-Allergic Agents; D002352:Carrier Proteins; D039041:Integrin alpha4beta1; D016023:Integrins; D009842:Oligopeptides; D016201:Receptors, Lymphocyte Homing; C094697:glutamyl-isoleucyl-leucyl-aspartyl-valine; C108486:phenylacetyl-leucyl-aspartyl-phenylalanyl-prolineamide