Basic Science

Graefe's Archive for Clinical and Experimental Ophthalmology

, Volume 251, Issue 7, pp 1723-1733

First online:

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

  • Jeroen BastiaansAffiliated withThe Rotterdam Eye HospitalDepartment of Immunology, Erasmus MC Email author 
  • , Jan C. van MeursAffiliated withThe Rotterdam Eye HospitalDepartment of Ophthalmology, Erasmus MC
  • , Conny van Holten-NeelenAffiliated withDepartment of Immunology, Erasmus MC
  • , Marja Smits-te NijenhuisAffiliated withDepartment of Immunology, Erasmus MC
  • , Marion J. Kolijn-CouwenbergAffiliated withDepartment of Immunology, Erasmus MC
  • , P. Martin van HagenAffiliated withDepartment of Immunology, Erasmus MCDepartment of Internal Medicine, Erasmus MC
  • , Robert W. A. M. KuijpersAffiliated withDepartment of Ophthalmology, Erasmus MC
  • , Herbert HooijkaasAffiliated withDepartment of Immunology, Erasmus MC
  • , Willem A. DikAffiliated withDepartment of Immunology, Erasmus MC

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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.

Keywords

Factor Xa Thrombin Retinal pigment epithelium Vitreoretinal fibrotic disorders Cytokine antibody array Inflammation Fibrosis