Wm. Abraham et al., BLOCKADE OF LATE-PHASE AIRWAY RESPONSES AND AIRWAY HYPERRESPONSIVENESS IN ALLERGIC SHEEP WITH A SMALL-MOLECULE PEPTIDE INHIBITOR OF VLA-4, American journal of respiratory and critical care medicine, 156(3), 1997, pp. 696-703
Citations number
28
Categorie Soggetti
Emergency Medicine & Critical Care","Respiratory System
The leukocyte integrin very late antigen-4 (VLA-4) (alpha(4) beta(1) C
D49d/CD29) is an adhesion receptor predominantly expressed on lymphocy
tes, monocytes, and eosinophils, but not on neutrophils. Recent studie
s with monoclonal antibodies against VLA-4 suggest that antigen-induce
d late responses and airway hyperresponsiveness (AHR) may depend on th
e recruitment and/or activation of VLA-4-expressing leukocytes. To fur
ther test this hypothesis, we administered by aerosol either a potent
small-molecule inhibitor of VLA-4, which prevents VLA-4-mediated bindi
ng to fibronectin (CS-1 ligand mimic), or an inactive control (30 mg t
wice daily for 3 d, and on the fourth day 0.5 h before and 4 h after a
ntigen challenge) to six sheep with airway hypersensitivity to Ascaris
suum antigen. Treatment with the small-molecule VLA-4 inhibitor resul
ted in a significant decrease in the early antigen-induced bronchial r
esponse (40%, p < 0.05), and almost complete blockade of the late-phas
e airway response (88%, p < 0.05). Moreover, at 24 h after antigen cha
llenge, AHR to inhaled carbachol was not observed when the animals wer
e dosed with the small-molecule VLA-4 inhibitor. In accord with protec
tion against the functional abnormalities associated with antigen chal
lenge, analysis of biopsy specimens taken 24 h after challenge indicat
ed that the total numbers of VLA-4-positive cells (lymphocytes, eosino
phils, and metachromatic-staining cells) in the group treated with the
VLA-4 inhibitor did not increase, whereas these cells increased in th
e control group. The active agent, but not the inactive control, signi
ficantly blocked macrophage adherence to fibronectin (FN), indicating
that the CS-1 ligand interfered with VLA-4-mediated adhesion in sheep
cells. These results support our previous findings with a monoclonal a
ntibody to VLA-4, and demonstrate that a small-molecule VLA-4 inhibito
r, when given by aerosol, has a protective effect against antigen-indu
ced late responses and AHR in allergic sheep.