Endothelial leukocyte adhesion molecule-1 mediates antigen-induced acute airway inflammation and late-phase airway obstruction in monkeys.

Abstract

This study examines the role of endothelial leukocyte adhesion molecule-i in the development of the acute airway inflammation (cell influx) and late-phase airway obstruction in a primate model of extrinsic asthma. In animals sensitive to antigen, a single inhalation exposure induced the rapid expression of ELAM-1 (6 h) exclusively on vascular endothelium that correlated with the influx of neutrophils into the lungs and the onset of late-phase airway obstruction. In contrast, basal levels of ICAM-1 was constitutively expressed on vascular endothelium and airway epithelium before antigen challenge. After the single antigen exposure, changes in ICAM-1 expression did not correlate with neutrophil influx or the change in airway caliber. This was confirmed by showing that pretreatment with a monoclonal antibody to ICAM-1 did not inhibit the acute influx of neutrophils associated with late-phase airway obstruction, whereas a monoclonal antibody to ELAM-1 blocked both the influx of neutrophils and the late-phase airway obstruction. This study demonstrates a functional role for ELAM-1 in the development of acute airway inflammation in vivo. We conclude that, in primates, the late-phase response is the result of an ELAM-1 dependent influx of neutrophils. Therefore, the regulation of ELAM-1 expression may provide a novel approach to controlling the acute inflammatory response, and thereby, affecting airway function associated with inflammatory disorders, including asthma. (J. Clin. Invest.

Recruitment of lymphocytes during cutaneous delayed hypersensitivity in nonhuman primates is dependent on E-selectin and vascular cell adhesion molecule 1.

“…First, this edema is not likely secondary to endothelial injury mediated by antibody-dependent cell-mediated cytotoxicity mechanisms in that F(ab')2 fragments of murine antibodies were used for all in vivo infusions. Secondly, in other animal studies using murine antibodies to E-selectin, similar observations were not described (25,56,57). Thirdly, we cannot be certain that increased vascular permeability occurred in animals treated with murine antibodies since precise kinetic and quantitative assessments of vascular leakage were not performed.…”

Alpha 4-integrins mediate antigen-induced late bronchial responses and prolonged airway hyperresponsiveness in sheep.

“…In an acute challenge model, an anti-human E-selectin mAb (CL2, 2 mg/kg, i.v.) was found to block the late bronchial response (56). This protection was associated with a reduction in leukocyte, specifically in neutrophil, infiltration into the lung.…”

E- and P-Selectins Are Essential for the Development of Cockroach Allergen-Induced Airway Responses

“…In previous studies of allergic inflammation in the mouse, ICAM1/LFA-1, very late Ag-4/VCAM1, and P-selectin have been implicated in the development of both peribronchial inflammation and airway hyperreactivity (9 -13). Additionally, early primate studies showed that blockade of E-selectin also reduced allergic pulmonary inflammation (8). Finally, increased expression of the E-and P-selectins has been observed in asthmatic patients (14 -17), suggesting that these molecules are up-regulated in human disease and may contribute to the alteration of pathophysiology.…”

“…Chemokines produced locally then promote the arrest of leukocytes on the lumenal surface and their migration into surrounding tissues. Both adhesion receptor-dependent and independent recruitment pathways have been identified in lung inflammation (5)(6)(7)(8). In previous studies of allergic inflammation in the mouse, ICAM1/LFA-1, very late Ag-4/VCAM1, and P-selectin have been implicated in the development of both peribronchial inflammation and airway hyperreactivity (9 -13).…”