Adhesion molecules in the pathogenesis of asthma.
Using a primate antigen inhalation model the mechanisms involved in the induction of airway hyperresponsiveness were studied. Antigen inhalation induced a prolonged airway eosinophilia. Chronic airway eosinophilia, intratracheal instillation of eosinophil major basic protein, repeated antigen inhalation, and airway epithelial desquamation induced, or were associated with, an increase in airway responsiveness. Using monoclonal antibodies to intercellular adhesion molecule-1 (ICAM-1) and endothelial-leukocyte adhesion molecule-1 (ELAM-1), the contributions of these cell adhesion molecules to antigen-induced airway hyperresponsiveness were studied. ICAM-1 partially mediated eosinophil adhesion to endothelium in vitro, was upregulated on inflamed endothelium and epithelium in vitro and in vivo, and contributed to repeated antigen-induced airway eosinophilia and hyperresponsiveness. ELAM-1 was upregulated on inflamed endothelium (but not epithelium) in vitro and in vivo, but did not contribute to the repeated antigen-induced airway eosinophilia and hyperresponsiveness. These results indicate that antagonism of ICAM-1, but not ELAM-1, may provide a novel therapeutic approach to reducing the airway inflammation and hyperresponsiveness commonly found in asthmatics.
Wegner
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CD
Boehringer Ingelheim Pharmaceuticals, Inc., Ridgefield, CT 06877.
Rothlein
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R
Gundel
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RH
D000280:Administration, Inhalation; D000818:Animals; D000911:Antibodies, Monoclonal; D000941:Antigens / Q000276:immunology; D001249:Asthma / Q000209:etiology*; D001992:Bronchoalveolar Lavage Fluid / Q000166:cytology; D015815:Cell Adhesion Molecules / Q000502:physiology*; D019040:E-Selectin; D004804:Eosinophils / Q000502:physiology; D007150:Immunohistochemistry; D018799:Intercellular Adhesion Molecule-1; D008252:Macaca fascicularis; D008297:Male; D012130:Respiratory Hypersensitivity / Q000276:immunology
D000911:Antibodies, Monoclonal; D000941:Antigens; D015815:Cell Adhesion Molecules; D019040:E-Selectin; D018799:Intercellular Adhesion Molecule-1