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Improvement of Outcome Measures of Dry Eye by a Novel Integrin Antagonist in the Murine Desiccating Stress Model
- Source :
- Investigative Opthalmology & Visual Science. 56:5888
- Publication Year :
- 2015
- Publisher :
- Association for Research in Vision and Ophthalmology (ARVO), 2015.
-
Abstract
- Dry eye disease (DED) is one of the most common and discomforting eye disorders. It has been defined as a multifactorial ocular surface disease more prevalent in women and the elderly. Dry eye disease is associated with symptoms of discomfort, visual disturbance, tear film instability, and inflammation of the ocular surface leading to potential damage to the ocular surface tissues.1 The proinflammatory milieu is characterized by increased levels of cytokines and chemokines in the tear film, cornea, and conjunctiva, and increased autoreactive T-cell infiltration of the conjunctival epithelium and sometimes lacrimal gland2–4; reviewed by Stern et al.5,6 Alteration of the tear film composition (mucins, lipids, proteins) and decreased volume lead to tear film abnormalities that contribute to the disease cycle. Subjecting mice to a controlled environment of desiccating stress results in ocular surface pathology reminiscent of human DED in patients in many respects.3,7–9 As of today, this model represents the best characterized animal model to study DED. Integrins are heterodimeric glycoproteins consisting of one α- and one β-subunit. Expressed on the cell surface of leukocytes, integrins have a role in their recruitment to sites of inflammation. The association of a specific α- and β-subunit determines the ligand specificity of the integrin. The α4 integrin subunit (CD49d) is a constituent of Very Late Antigen-4 (VLA-4, integrin a4b1, CD49d/CD29), and α4β7 (CD49d/CD103). In the case of integrin α4β1 the corresponding ligands are the immunoglobulin superfamily adhesion molecule vascular cell adhesion molecule 1 (VCAM-1) on vascular endothelial cells and the extracellular matrix glycoprotein fibronectin, which are responsible for the homing, trafficking, differentiation, priming, activation, and survival of integrin α4β1 expressing cells. Integrin α4β1 is expressed on lymphocytes, monocytes, macrophages, NK cells, and eosinophils. Integrin α4β7 and its corresponding ligand Mucosal Addressin Cell Adhesion Molecule-1 (MAdCAM) selectively regulate leukocyte trafficking to the gut and consequently are unlikely to be involved in the effects described herein. Natalizumab, an antibody directed against the α4 integrin subunit, has been shown to profoundly inhibit inflammation and improve clinical outcomes in multiple sclerosis10 and Crohn's disease,11 which also are T-cell–mediated diseases. Lifitegrast, a small molecule antagonist, directed against a different adhesion molecule (LFA-1, integrin αLβ2), has been shown to reduce corneal staining and improve symptoms when delivered topically to dry eye patients.12 Furthermore, a specific antagonist to integrin α4β1, BIO-8809, had been shown to decrease corneal fluorescein staining, conjunctival T-cell infiltrates, and TNFα expression in cornea and conjunctiva in a murine dry eye model.13 Taken together these considerations provided a rationale for further exploring the blockade of integrin α4 in an animal model of DED. In the current study, we tested the hypothesis using {"type":"entrez-nucleotide","attrs":{"text":"GW559090","term_id":"289141609","term_text":"GW559090"}}GW559090, a potent integrin α4 antagonist that previously had been clinically investigated in asthma patients by the oral inhalation route.14
- Subjects :
- Administration, Topical
Integrin alpha4
Phenylalanine
Integrin
Anti-Inflammatory Agents
Vascular Cell Adhesion Molecule-1
Integrin alpha4beta1
CD49d
Collagen receptor
Cornea
Mice
Piperidines
Cell Adhesion
Leukocytes
Animals
Organic Chemicals
Cells, Cultured
Integrin alpha Chains
biology
Cell adhesion molecule
CD29
Dendritic Cells
Flow Cytometry
eye diseases
Mice, Inbred C57BL
Disease Models, Animal
Integrin alpha M
Immunology
biology.protein
Eye disorder
Dry Eye Syndromes
Female
Biomarkers
Subjects
Details
- ISSN :
- 15525783
- Volume :
- 56
- Database :
- OpenAIRE
- Journal :
- Investigative Opthalmology & Visual Science
- Accession number :
- edsair.doi.dedup.....bfd40473c8b96d76e1519c6a19bcabec