Dataset Information

DS-70, a novel and potent ?₄ integrin antagonist, is an effective treatment for experimental allergic conjunctivitis in guinea pigs.

ABSTRACT:

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 ?₄ ?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 ?/?-peptidomimetic ?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 ?₄ ?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 ?₄ ?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 ?₄ ?₁ with nanomolar affinity, prevented the adhesion of ?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 ?₄ integrin expression and conjunctival levels of chemokines and cytokines in ovalbumin-sensitized guinea pigs.

Conclusions and implications

These findings highlight the role of ?₄ integrin in allergic conjunctivitis and suggest that DS-70 is a potential treatment for this condition.

SUBMITTER: Dattoli SD

PROVIDER: S-EPMC6151342 | biostudies-literature | 2018 Oct

REPOSITORIES: biostudies-literature

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Publications

DS-70, a novel and potent α<sub>4</sub> integrin antagonist, is an effective treatment for experimental allergic conjunctivitis in guinea pigs.

Dattoli Samantha Deianira SD Baiula Monica M De Marco Rossella R Bedini Andrea A Anselmi Michele M Gentilucci Luca L Spampinato Santi S

British journal of pharmacology 20180917 20

<h4>Background and purpose</h4>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<sub>4</sub> β<sub>1</sub> . 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<sub>4</sub> integrin antagonist, to prevent the conjunctival infiltration of immune c ...[more]

PMID: 30051467

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Project description:Asthma is a chronic inflammatory disease of the airways characterized by immune cell infiltrates, bronchial hyperresponsiveness, and declining lung function. Thus, the possible effects of virgin coconut oil on a chronic allergic lung inflammation model were evaluated. Morphology of lung and airway tissue exhibited peribronchial inflammatory infiltrate, epithelial hyperplasia, and smooth muscle thickening in guinea pigs submitted to ovalbumin sensitization, which were prevented by virgin coconut oil supplementation. Additionally, in animals with lung inflammation, trachea contracted in response to ovalbumin administration, showed a greater contractile response to carbachol (CCh) and histamine, and these responses were prevented by the virgin coconut oil supplementation. Apocynin, a NADPH oxidase inhibitor, did not reduce the potency of CCh, whereas tempol, a superoxide dismutase mimetic, reduced potency only in nonsensitized animals. Catalase reduced the CCh potency in nonsensitized animals and animals sensitized and treated with coconut oil, indicating the participation of superoxide anion and hydrogen peroxide in the hypercontractility, which was prevented by virgin coconut oil. In the presence of L-NAME, a nitric oxide synthase (NOS) inhibitor, the CCh curve remained unchanged in nonsensitized animals but had increased efficacy and potency in sensitized animals, indicating an inhibition of endothelial NOS but ineffective in inhibiting inducible NOS. In animals sensitized and treated with coconut oil, the CCh curve was not altered, indicating a reduction in the release of NO by inducible NOS. These data were confirmed by peribronchiolar expression analysis of iNOS. The antioxidant capacity was reduced in the lungs of animals with chronic allergic lung inflammation, which was reversed by the coconut oil, and confirmed by analysis of peribronchiolar 8-iso-PGF2α content. Therefore, the virgin coconut oil supplementation reverses peribronchial inflammatory infiltrate, epithelial hyperplasia, smooth muscle thickening, and hypercontractility through oxidative stress and its interactions with the NO pathway.

Dataset Information

DS-70, a novel and potent ?₄ integrin antagonist, is an effective treatment for experimental allergic conjunctivitis in guinea pigs.

Background and purpose

Experimental approach

Key results

Conclusions and implications

Publications

DS-70, a novel and potent α<sub>4</sub> integrin antagonist, is an effective treatment for experimental allergic conjunctivitis in guinea pigs.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets

Dataset Information

DS-70, a novel and potent ?4 integrin antagonist, is an effective treatment for experimental allergic conjunctivitis in guinea pigs.

Background and purpose

Experimental approach

Key results

Conclusions and implications

Publications

DS-70, a novel and potent α<sub>4</sub> integrin antagonist, is an effective treatment for experimental allergic conjunctivitis in guinea pigs.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets

DS-70, a novel and potent ?₄ integrin antagonist, is an effective treatment for experimental allergic conjunctivitis in guinea pigs.