Improvement of Outcome Measures of Dry Eye by a Novel Integrin Antagonist in the Murine Desiccating Stress Model.
OBJECTIVE
We investigated the effects of GW559090, a novel, competitive, and high-affinity α4 integrin antagonist, in a murine model of dry eye. Through interaction with vascular cell adhesion molecule 1 (VCAM-1) and fibronectin α4β1 integrin is involved in leukocyte trafficking and activation.


METHODS
Female C57BL/6 mice, aged 6 to 8 weeks, were subjected to desiccating stress (DS). Bilateral topical twice daily treatment with GW559090 was compared to vehicle-treated controls. Treatment was initiated at the time of DS induction. Treatment effects were assessed on corneal staining with Oregon Green Dextran (OGD) and expression of inflammatory markers in ocular surface tissues by real time PCR. Dendritic cell activation was measured in draining cervical lymph nodes (CLN) by flow cytometry. Separate groups of mice received GW559090 subcutaneously to evaluate the effects of systemic administration on corneal staining and cells in CLN.


RESULTS
Topical GW559090 significantly reduced corneal uptake of OGD compared to vehicle-treated disease controls in a dose-dependent manner (1, 3, 10, and 30 mg/mL) with 30 mg/mL showing the greatest reduction in OGD staining. When administered topically, corneal expression of IL-1α, matrix metalloproteinase (MMP)-9, chemokine ligand 9 (CXCL9), and TGF-β1 was reduced in GW559090-treated eyes. Topical treatment with GW559090 decreased dendritic cell activation in lymph nodes. The effects on corneal staining and cellular composition in CLN were not reproduced by systemic administration of GW559090, suggestive of a local role for integrin antagonism in the treatment of dry eye.


CONCLUSIONS
The novel α4 integrin antagonist, GW559090, improved outcome measures of corneal staining and ocular surface inflammation in this murine model of dry eye. These results indicate the potential of this novel agent for the treatment of dry eye disease.
GSK Ophthalmology King of Prussia, Pennsylvania, United States.
Achim H
AH
Krauss
Ocular Surface Center, Cullen Eye Institute, Deptartment of Ophthalmology, Baylor College of Medicine, Houston, Texas, United States.
Rosa M
RM
Corrales
Ocular Surface Center, Cullen Eye Institute, Deptartment of Ophthalmology, Baylor College of Medicine, Houston, Texas, United States.
Flavia S A
FS
Pelegrino
Ocular Surface Center, Cullen Eye Institute, Deptartment of Ophthalmology, Baylor College of Medicine, Houston, Texas, United States.
Johanna
J
Tukler-Henriksson
Ocular Surface Center, Cullen Eye Institute, Deptartment of Ophthalmology, Baylor College of Medicine, Houston, Texas, United States.
Stephen C
SC
Pflugfelder
Ocular Surface Center, Cullen Eye Institute, Deptartment of Ophthalmology, Baylor College of Medicine, Houston, Texas, United States.
Cintia S
CS
de Paiva
D000287:Administration, Topical; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000627:therapeutic use*; D015415:Biomarkers / Q000378:metabolism; D002448:Cell Adhesion / Q000187:drug effects; D002478:Cells, Cultured; D003315:Cornea / Q000378:metabolism; D003713:Dendritic Cells / Q000187:drug effects; D004195:Disease Models, Animal; D015352:Dry Eye Syndromes / Q000188:drug therapy* / Q000378:metabolism; D005260:Female; D005434:Flow Cytometry; D039001:Integrin alpha Chains / Q000037:antagonists & inhibitors*; D039441:Integrin alpha4; D039041:Integrin alpha4beta1 / Q000502:physiology; D007962:Leukocytes; D051379:Mice; D008810:Mice, Inbred C57BL; D009930:Organic Chemicals / Q000378:metabolism; D010649:Phenylalanine / Q000031:analogs & derivatives* / Q000627:therapeutic use; D010880:Piperidines / Q000627:therapeutic use*; D019010:Vascular Cell Adhesion Molecule-1 / Q000502:physiology
D000893:Anti-Inflammatory Agents; D015415:Biomarkers; C000602898:GW559090; D039001:Integrin alpha Chains; D039041:Integrin alpha4beta1; C403124:Oregon Green BAPTA-dextran; D009930:Organic Chemicals; D010880:Piperidines; D019010:Vascular Cell Adhesion Molecule-1; D039441:Integrin alpha4; D010649:Phenylalanine