June 2015
Volume 56, Issue 7
Free
ARVO Annual Meeting Abstract  |   June 2015
Long-term Use of Diclofenac Exacerbates Immune Driven Dry Eye Disease by Inhibiting Lipoxin A4 formation in Lymph Nodes and Lacrimal Glands
Author Affiliations & Notes
  • Karsten Gronert
    Vision Science, School of Optometry, University of California, Berkeley, Berkeley, CA
  • John Su
    Vision Science, School of Optometry, University of California, Berkeley, Berkeley, CA
  • Xiaoxuan Li
    Vision Science, School of Optometry, University of California, Berkeley, Berkeley, CA
  • Matthew Greenwood
    Vision Science, School of Optometry, University of California, Berkeley, Berkeley, CA
  • Wangqi Chen
    Vision Science, School of Optometry, University of California, Berkeley, Berkeley, CA
  • Yuan Gao
    Vision Science, School of Optometry, University of California, Berkeley, Berkeley, CA
  • Footnotes
    Commercial Relationships Karsten Gronert, None; John Su, None; Xiaoxuan Li, None; Matthew Greenwood, None; Wangqi Chen, None; Yuan Gao, None
  • Footnotes
    Support None
Investigative Ophthalmology & Visual Science June 2015, Vol.56, 289. doi:
  • Views
  • Share
  • Tools
    • Alerts
      ×
      This feature is available to Subscribers Only
      Sign In or Create an Account ×
    • Get Citation

      Karsten Gronert, John Su, Xiaoxuan Li, Matthew Greenwood, Wangqi Chen, Yuan Gao; Long-term Use of Diclofenac Exacerbates Immune Driven Dry Eye Disease by Inhibiting Lipoxin A4 formation in Lymph Nodes and Lacrimal Glands. Invest. Ophthalmol. Vis. Sci. 2015;56(7 ):289.

      Download citation file:


      © ARVO (1962-2015); The Authors (2016-present)

      ×
  • Supplements
Abstract

Purpose: Prostaglandins (PG) are lipid mediators (LM) with key roles in many physiologic and pathophysiologic processes; their roles in the eye are poorly defined. Inhibition of PG formation by the NSAID-diclofenac is an important treatment option for inflammatory diseases of the eye, including forms of Dry Eye Syndrome. Clinical data demonstrates that NSAIDs can reduce ocular discomfort and filamentary keratitis in dry eye patients. We have reported significant formation of PG in the eye and important immune regulatory functions of other LM such as LXA4. Hence, we set out to investigate the role of PG and the impact of long-term diclofenac treatment in immune-driven Dry Eye Disease (DED).

Methods: Mice were treated with diclofenac systemically and topically to globally inhibit PG formation for 10 or 30 days prior to and throughout 10-day desiccating stress. Schirmer’s test, clinical fluorescence scoring and goblet cell density were used to assess dry eye disease severity. CD4+ T cells, as marker of T cell activation, were identified and quantified by fluorescence confocal microscopy and flow cytometry. Lipid mediator formation was quantified by LC/MS/MS-based lipidomics, and gene expression by QPCR.

Results: Diclofenac treatment in all groups significantly increased DED, which directly correlated with duration of NSAID treatment. 40-day diclofenac treatment increased CD4+ T cell by 86% in limbus, 34% in lacrimal glands and 66% in lymph nodes compared to controls and correlated with marked increased ocular surface defect and decreased goblet cell density. As expected, diclofenac treatment abrogated PGE2 formation but unexpectedly also inhibited LXA4 formation in all tissues. Diclofenac-treated mice were treated with LXA4 systemically and topically, after inducing Dry Eye. LXA4 treatment markedly increased tear production, decreased corneal defect and significantly reduced CD4+ T cells.

Conclusions: The findings provide evidence for a key role of PG in controlling immune-driven DED, which is consistent with recent reports that demonstrate PG regulation of B- and T-lymphocytes. In addition, results suggest that PG regulate the protective and immune regulatory LXA4 circuit. NSAIDS are widely used systemically and topically, our findings raise questions about their potential side effects in Dry Eye Disease pathogenesis.

×
×

This PDF is available to Subscribers Only

Sign in or purchase a subscription to access this content. ×

You must be signed into an individual account to use this feature.

×