DS-70, a novel and potent α4 integrin antagonist, is an effective treatment for experimental allergic conjunctivitis in guinea pigs
| Autor: | Dattoli, Samantha Deianira, Baiula, Monica, De Marco, Rossella, Bedini, Andrea, Anselmi, Michele, Gentilucci, Luca, Spampinato, Santi |
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| Přispěvatelé: | Dattoli, Samantha Deianira, Baiula, Monica, De Marco, Rossella, Bedini, Andrea, Anselmi, Michele, Gentilucci, Luca, Spampinato, Santi |
| Jazyk: | angličtina |
| Rok vydání: | 2018 |
| Předmět: |
Male
Mitogen-Activated Protein Kinase 1 Pharmacology Mitogen-Activated Protein Kinase 3 Guinea Pigs Vascular Cell Adhesion Molecule-1 Integrin alpha4beta1 Research Papers Cell Line Disease Models Animal Anti-Allergic Agents Cell Adhesion Animals Humans Peptidomimetics Conjunctiva Conjunctivitis Allergic |
| Popis: | 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 α(4)β(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 α/β‐peptidomimetic α(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 α(4)β(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 α(4)β(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 α(4)β(1) with nanomolar affinity, prevented the adhesion of α(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 8 h incubation with serum. DS‐70 dose‐dependently reduced the clinical symptoms of allergic conjunctivitis, conjunctival α(4) integrin expression and conjunctival levels of chemokines and cytokines in ovalbumin‐sensitized guinea pigs. CONCLUSIONS AND IMPLICATIONS: These findings highlight the role of α(4) integrin in allergic conjunctivitis and suggest that DS‐70 is a potential treatment for this condition. |
| Databáze: | OpenAIRE |
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