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Factor Xa and thrombin stimulate proinflammatory and profibrotic mediator production by retinal pigment epithelial cells: a role in vitreoretinal disorders?

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Abstract

Background

Vitreoretinal disorders, including proliferative vitreoretinopathy (PVR), proliferative diabetic retinopathy (PDR) and exudative age-related macular degeneration (AMD), are a major cause of visual impairment worldwide and can lead to blindness when untreated. Loss of blood-retinal barrier (BRB) integrity associated with vitreoretinal fibrin deposition, inflammation, fibrosis and neovascularization contribute to the pathophysiological processes in these disorders. Retinal pigment epithelial (RPE) cells are well recognized to contribute to vitreoretinal inflammation/fibrosis and are likely to encounter contact with coagulation factor upon loss of BRB integrity.

Methods

An extensive study was performed in which we examined the effect of factor Xa and thrombin on the production of a broad panel of cytokines/chemokines and growth factors by RPE cells. For this purpose we used the ARPE-19 cell line as well as primary RPE cells, a glass slide based array that allows simultaneous detection of 120 cytokines/chemokines and growth factors, ELISA and real-time-quantitative PCR. The involved signaling cascade was examined using specific inhibitors for protease activated receptor (PAR)1, PAR2 and nuclear factor kappa-B (NF-κB).

Results

Factor Xa and thrombin regulated the production of cytokines and growth factors (including GM-CSF, IL-6, IL-8, MCP-3, PDGF-AA, PDGF-BB, TIMP-1 and TGF-α) that fit well in the pathobiology of vitreoretinal disease. Blocking studies revealed that the effects were mediated via PAR1 induced NF-κB activation.

Conclusions

Our findings suggest that factor Xa and thrombin can drive vitreoretinal inflammation and fibrosis and should be considered as treatment targets in vitreoretinal disorders such as PVR, PDR and AMD.

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Acknowledgments

The authors thank Sandra de Bruin – Versteeg for her help with the illustrations.

Conflict of interest disclosure

The authors declare that there are no conflicts of interest.

Author information

Authors and Affiliations

  1. The Rotterdam Eye Hospital, Rotterdam, The Netherlands

    Jeroen Bastiaans & Jan C. van Meurs

  2. Department of Immunology, Erasmus MC, Dr. Molewaterplein 50, 3015 GE, Rotterdam, The Netherlands

    Jeroen Bastiaans, Conny van Holten-Neelen, Marja Smits-te Nijenhuis, Marion J. Kolijn-Couwenberg, P. Martin van Hagen, Herbert Hooijkaas & Willem A. Dik

  3. Department of Internal Medicine, Erasmus MC, Rotterdam, The Netherlands

    P. Martin van Hagen

  4. Department of Ophthalmology, Erasmus MC, Rotterdam, The Netherlands

    Jan C. van Meurs & Robert W. A. M. Kuijpers

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  1. Jeroen Bastiaans
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Correspondence to Jeroen Bastiaans.

Additional information

This study is financially supported by: Combined Ophthalmic Research Rotterdam (CORR- Project code: 3.1.0)

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Bastiaans, J., van Meurs, J.C., van Holten-Neelen, C. et al. Factor Xa and thrombin stimulate proinflammatory and profibrotic mediator production by retinal pigment epithelial cells: a role in vitreoretinal disorders?. Graefes Arch Clin Exp Ophthalmol 251, 1723–1733 (2013). https://doi.org/10.1007/s00417-013-2335-2

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