The role of intercellular adhesion molecule-1 in chronic airway inflammation.
We have examined the role of intercellular adhesion molecule-1 (ICAM-1) in chronic airway inflammation and airway hyperresponsiveness in a primate model of asthma. Airway cellular composition was assessed by bronchoalveolar lavage (BAL) and airway responsiveness was measured as the bronchoconstrictor response to inhaled methacholine. In animals with chronic airway inflammation (increased BAL eosinophils) and sustained airway hyperresponsiveness, a 7 day dosing scheme with a murine anti-human ICAM-1 monoclonal antibody (R6.5, 2 mg/kg/day; i.v.) did not reduce the existing airway inflammation or airway hyperresponsiveness. In contrast, a similar dosing scheme with dexamethasone (0.2 mg/kg/day, i.m.) was found to significantly reduce both the airway eosinophilia and hyperresponsiveness. However, one week after cessation of dexamethasone treatment, the airway inflammation and hyperresponsiveness returned to pre-treatment levels. In further experiments where animals were first treated with dexamethasone (7 days) followed by a 7 day treatment with R6.5, the reoccurrence of airway inflammation and subsequent increase in airway responsiveness was prevented. We conclude that the efficacy of ICAM-1 is primarily associated with inhibition of the influx of inflammatory cells into the airways and subsequent reduction in airway responsiveness. These data suggest that in lungs with pre-existing inflammation the modulation of ICAM-1 following treatment with glucocorticoids may be a novel and more selective long-term treatment for control of the chronic airway inflammation and hyperresponsiveness associated with bronchial asthma.
Department of Pharmacology, Boehringer Ingelheim Pharmaceuticals, Ridgefield, Connecticut 06877.
R H
RH
Gundel
C D
CD
Wegner
C A
CA
Torcellini
L G
LG
Letts
D000403:Airway Resistance / Q000502:physiology; D000818:Animals; D000911:Antibodies, Monoclonal / Q000008:administration & dosage; D001249:Asthma / Q000209:etiology* / Q000503:physiopathology / Q000628:therapy; D001992:Bronchoalveolar Lavage Fluid / Q000473:pathology; D016084:Bronchoconstriction / Q000502:physiology; D015815:Cell Adhesion Molecules / Q000276:immunology / Q000502:physiology*; D004195:Disease Models, Animal; D004804:Eosinophils / Q000473:pathology; D005938:Glucocorticoids / Q000008:administration & dosage; D007249:Inflammation / Q000209:etiology / Q000628:therapy; D018799:Intercellular Adhesion Molecule-1; D008252:Macaca fascicularis; D008297:Male
D000911:Antibodies, Monoclonal; D015815:Cell Adhesion Molecules; D005938:Glucocorticoids; D018799:Intercellular Adhesion Molecule-1