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1 Department of Biochemistry and Molecular Biology, Mayo Clinic Scottsdale, Scottsdale, Arizona 85259; and 2 Genetics Institute, Incorporated, Cambridge, Massachusetts 02140
Lymphocyte and/or eosinophil
recruitment is dependent on the sequential interactions between
adhesion molecules expressed on activated endothelial cells and both
leukocyte subtypes. Endothelial P- and E-selectins mediate tethering
and rolling of leukocytes through interactions with P-selectin
glycoprotein ligand-1 (PSGL-1), and diapedesis subsequently occurs by
engagement of endothelial vascular cell adhesion molecule-1 and CD49d
(
4-integrins). The anti-inflammatory potential of
interfering with these adhesive interactions was assessed with an
ovalbumin challenge mouse model of asthma. Administration of a soluble
form of PSGL-1 reduced eosinophils (80%) and lymphocytes (50%) in
bronchoalveolar lavage fluid without affecting epithelial changes or
airway hyperreactivity (AHR). In contrast, although administration of
anti-CD49d monoclonal antibodies (PS/2) resulted in similar reductions
in eosinophils (75%) and lymphocytes (50%), PS/2 reduced and
abolished mucous cell metaplasia and AHR, respectively.
Administration of both PSGL-1 and PS/2 had the additive effect of
eliminating eosinophils from the airways (96% decrease), with few or
no additional reductions (relative to PS/2 administration alone) in
lymphocyte recruitment, mucous cell metaplasia, or AHR. These data show
that eosinophils and lymphocytes differentially utilize adhesive
interactions during recruitment and that the inhibition of AHR is
independent of this recruitment.
airway hyperreactivity; 4-integrin; P-selectin
glycoprotein ligand-1
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