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Yi Wei, Pengcheng Li, Jun Zou, Seth Epstein, Neha Gadaria-Rathod, Penny Asbell; Secretory Group Two A Phospholipase (sPLA2) Inhibition Decreases Corneal Superficial Punctate Keratitis (SPK) in Dry Eye Mice. Invest. Ophthalmol. Vis. Sci. 2013;54(15):4326.
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sPLA2-IIa is an enzyme found in high concentration in healthy tears. The concentration is further increased in tears of patients with dry eye disease (DED), associated with inflammation of the ocular surface. We have shown previously that sPLA2-IIa and its isoforms play an important role in pathogenesis of experimentally induced DED in mice by amplification of the ocular surface inflammation. We’ve further demonstrated in vitro that an sPLA2-IIa-specific inhibitor significantly decreases PGE2 concentration upon sPLA2 stimulation. This study determined the role of topical sPLA2 inhibition on the signs of DED and inflammation in BALB/c DE mice
DE was induced by scopolamine-air ventilation as previously published. BALB/c mice were divided into groups: (1) normal control, no treatment; (2) DE control, no eye drops; (3) DE + one of the inhibitors, S3319 or Varespladib; (4) DE + dimethylsulfoxide, the solvent for inhibitors; (5) DE + one of the sPLA2 antibodies against sPLA2-IIa, V or X; (6) PBS + 0.1% BSA buffer as antibody controls. Groups 1-4 had 5-6 mice each; groups 5-6 had 3 mice each. Eye drops (5 μL per eye) containing inhibitors, solvent or antibodies were applied, starting at Day 1, to both eyes of the mice in groups 3-6, twice per day. Pheno-Red Thread was run for tear volume and biomicroscopic examination was performed for SPK by masked ophthalmologists on Days 0, 4 and 7. Biopsies of mouse corneal, conjunctival and lacrimal gland were analyzed by Immunofluorescence staining (IFA) at the termination of the study (Day 8).
As compared to DE- or solvent-controls, all the tested inhibitors reduced SPK scores on Days 4 and 7. None showed any effect on tear secretion. All the tested antibodies also reduced SPK scores. The antibody against sPLA2-IIa showed a peak of SPK-reduction on Day 4 while that against sPLA2-V appeared on Day 7. Antibody against sPLA2-X had constant SPK-reducing effect on both Days 4 and 7. Furthermore, the reduction in SPK scores in inhibitor-treated mice was corroborated by a concomitant decrease in sPLA2-IIa and CD45 staining by IFA.
The results demonstrate that topical sPLA2-specific inhibition may have a protective role for ocular surface disease associated with DED. This inhibition may provide new strategies for treatment of ocular surface inflammation associated with DED and/or other inflammatory conditions.
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