Neuroprotectin D1 reduces the severity of herpes simplex virus-induced corneal immunopathology.

Abstract

PURPOSE:

Neuroprotectin D1 (NPD1) is an anti-inflammatory and proresolving lipid mediator biosynthesized from the omega-3-polyunsaturated fatty acid docosahexaenoic acid (DHA). The purpose of this study is to test the therapeutic potential of NPD1 for the treatment of herpes simplex virus (HSV)-induced stromal keratitis (SK) using a mouse model.

METHODS:

C57BL/6 mice were infected ocularly with HSV-1 strain RE. Infected animals were treated topically with methyl ester prodrug NPD1 (300 ng/eye, 5-μL drop). Development of SK lesions, infiltration of inflammatory cells into the cornea, and production of proinflammatory cytokines, chemokines, and angiogenic factors were compared to untreated animals using slit-lamp biomicroscopy, flow cytometry, ELISA, and quantitative PCR (qPCR).

RESULTS:

Topical administration of NPD1 resulted in a significant reduction in the severity and incidence of SK, as well as the extent of corneal neovascularization in the NPD1-treated animals compared to their untreated counterparts. Infiltration of fewer neutrophils and pathogenic CD4⁺ T cells into the cornea, along with a lower number of cells that could be induced ex vivo to produce IFN-γ and IL-17, occurred with NPD1 treatment. Additionally, treatment with NPD1 diminished the production of proinflammatory cytokines, chemokines, and angiogenic factors, such as IL-6, CXCL1, CXCL-10, CCL-20, VEGF-A, MMP-2, and MMP-9 in the corneas of infected animals. Importantly, treatment with NPD1 increased the production of the anti-inflammatory cytokine, IL-10.

CONCLUSIONS:

Our novel findings demonstrate that NPD1 treatment could represent a valuable therapeutic approach to control SK lesions.

• Authors: Naveen K Rajasagi, Pradeep B J Reddy, Sachin Mulik, Per Gjorstrup, Barry T Rouse
• Journal: Investigative ophthalmology & visual science (Invest Ophthalmol Vis Sci) Vol. 54 Issue 9 Pg. 6269-79 (Sep 17 2013) ISSN: 1552-5783 [Electronic] United States
• PMID: 23942967 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)

Chemical References

• Anti-Inflammatory Agents
• Biomarkers
• Chemokines
• Cytokines
• protectin D1
• Docosahexaenoic Acids

Topics

• Administration, Topical
• Animals
• Anti-Inflammatory Agents (therapeutic use)
• Biomarkers (metabolism)
• CD4-Positive T-Lymphocytes (metabolism)
• Chemokines (metabolism)
• Corneal Neovascularization (drug therapy)
• Cytokines (metabolism)
• Disease Models, Animal
• Docosahexaenoic Acids (therapeutic use)
• Enzyme-Linked Immunosorbent Assay
• Female
• Flow Cytometry
• Immunohistochemistry
• Keratitis, Herpetic (drug therapy, immunology)
• Mice
• Mice, Inbred C57BL
• Neutrophils (metabolism)