Role of the VLA-4 integrin in leucocyte recruitment and bronchial hyperresponsiveness in the guinea-pig

doi:10.1016/0014-2999(95)00340-Q

European Journal of Pharmacology

Volume 282, Issues 1–3, 25 August 1995, Pages 243-249

https://doi.org/10.1016/0014-2999(95)00340-Q Get rights and content

Abstract

Guinea-pigs sensitized to ovalbumin develop airway eosinophilia and bronchial hyperresponsiveness to acetylcholine 24 h following ovalbumin challenge. We have used an antibody to the very late antigen-4 (VLA-4) integrin (HP $12$ ) to investigate the role of this integrin in the recruitment of leucocytes to the airways and to study the link between eosinophilia and the development of bronchial hyperresponsiveness. In this model, HP $12$ reduced the number of eosinophils recovered from bronchoalveolar lavage fluid, as well as reducing the activity of the enzyme eosinophil peroxidase in both bronchoalveolar lavage fluid and whole lung extracts. However, HP $12$ did not reduce bronchial hyperresponsiveness. The results suggest that after antigen challenge, the VLA-4 integrin is involved in the recruitment of leucocytes to the airways at the level of the vascular endothelium, but increased numbers of eosinophils in lavage fluid or in the lung tissue are not an essential correlate of bronchial hyperresponsiveness in this model.

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A series of prolyl-N-isonicotinoyl-(L)-4-aminophenylalanine derivatives substituted at the proline 4-position with cyclic amines was evaluated as VLA-4 antagonists. The ring size and presence or absence of fluorine affected potency and receptor occupancy. The analog with 3,3-difluoropiperidine at the proline 4-position (13) was the most potent compound and had very good duration of receptor occupancy in vitro. The ethyl ester prodrug of 13 demonstrated excellent receptor occupancy after oral dosing in rats.
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The integrin adhesion molecules are involved in the recruitment and activation of inflammatory cells at sites of inflammation in a variety of diseases. In the present study, we have investigated the effects of blocking monoclonal antibodies (mAbs) directed against CD49d (α₄ integrin), CD18 (β₂ integrin) and the α sub-units of β₂ integrin CD11a (LFA-1 integrin) and CD11b (Mac-1 integrin), on antigen (Ag)-induced acute bronchoconstriction and cellular recruitment in allergic rabbits in vivo. Inhaled Ag (Alternaria tenuis) challenge of neonatally sensitised rabbits caused an acute bronchoconstriction demonstrated by an increase in lung resistance (R_L) and decrease in dynamic compliance (C_dyn) and pulmonary inflammation characterised by an increase in bronchoalveolar lavage (BAL) inflammatory cells, particularly eosinophils, 24 h after challenge.
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Regular paperRole of the VLA-4 integrin in leucocyte recruitment and bronchial hyperresponsiveness in the guinea-pig

Abstract

Lancet i

Cell

J. Biol. Chem.

J. Immunol. Methods

α4-Integrins mediate antigen-induced late bronchial responses and prolonged airway hyperresponsiveness in sheep

J. Clin. Invest.

Adhesion to fibronectin prolongs eosinophil survival

J. Exp. Med.

Expression and modulation of adhesion molecules on human bronchial epithelial cells

Am. J. Respir. Cell Mol. Biol.

The relationship between inflammation and hyperreactivity of the airways in asthma

Clin. Exp. Allergy.

Mechanisms of eosinophil adherence to cultured vascular endothelial cells

Eosinophils bind to the cytokine-induced endothelial ligand vascular cell adhesion molecule-1 via the very late activation antigen-4 integrin receptor

J. Clin. Invest.

Development of a prolonged eosinophil-rich inflammatory leukocyte infiltration in the guinea-pig asthmatic response to ovalbumin inhalation

Am. Rev. Respir. Dis.

The pathology of asthma, with special reference to changes in the bronchial mucosa

J. Clin. Pathol.

Lung myeloperoxidase as a measure of pulmonary leukostasis in rabbits

J. Appl. Physiol.

Regular paper
Role of the VLA-4 integrin in leucocyte recruitment and bronchial hyperresponsiveness in the guinea-pig

α₄-Integrins mediate antigen-induced late bronchial responses and prolonged airway hyperresponsiveness in sheep