Journal
BRITISH JOURNAL OF PHARMACOLOGY
Volume 175, Issue 20, Pages 3891-3910Publisher
WILEY
DOI: 10.1111/bph.14458
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Funding
- University of Bologna FARB [FFBO 125290]
- MIUR (PRIN 2010)
- Chiesi Foundation Onlus (Parma, Italy)
- RFO 2014
- RFO 2015
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BACKGROUND AND PURPOSE Allergic conjunctivitis is an eye inflammation that involves the infiltration of immune cells into the conjunctiva via cell surface-adhesion receptors, such as integrin alpha(4)beta(1). These receptors interact with adhesion molecules expressed on the conjunctival endothelium and may be a target to treat this disease. We synthesized DS-70, a novel alpha/beta-peptidomimetic alpha(4) integrin antagonist, to prevent the conjunctival infiltration of immune cells and clinical symptoms in a model of allergic conjunctivitis. EXPERIMENTAL APPROACH In vitro, DS-70 was pharmacologically characterized using a scintillation proximity procedure to measure its affinity for alpha(4)beta(1) integrin, and its effect on cell adhesion mediated by different integrins was also evaluated. The effects of DS-70 on vascular cell adhesion molecule-1 (VCAM-1)-mediated degranulation of a human mast cell line and an eosinophilic cell line, which both express alpha(4)beta(1), and on VCAM-1-mediated phosphorylation of ERK 1/2 in Jurkat E6.1 cells were investigated. Effects of DS-70 administered in the conjunctival fornix of ovalbumin-sensitized guinea pigs were evaluated. KEY RESULTS DS-70 bound to integrin alpha(4)beta(1) with nanomolar affinity, prevented the adhesion of alpha(4) integrin-expressing cells, antagonized VCAM-1-mediated degranulation of mast cells and eosinophils and ERK 1/2 phosphorylation. Only 20% was degraded after an 8h incubation with serum. DS-70 dose-dependently reduced the clinical symptoms of allergic conjunctivitis, conjunctival alpha(4) integrin expression and conjunctival levels of chemokines and cytokines in ovalbumin-sensitized guinea pigs. CONCLUSIONS AND IMPLICATIONS These findings highlight the role of alpha(4) integrin in allergic conjunctivitis and suggest that DS-70 is a potential treatment for this condition.
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