Blockade of Prolymphangiogenic Vascular Endothelial Growth Factor C in Dry Eye Disease

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Abstract

Objective

To determine whether blocking prolymphangiogenic factors such as vascular endothelial growth factor C (VEGF-C) would suppress alloimmunity in dry eye disease using a murine model.

Methods

The effects of intraperitoneal injections of 400 μg of anti–VEGF-C antibody (treated group) and intraperitoneal normal saline (untreated group) were studied in murine dry eyes induced by exposing mice to high-flow desiccated air in a controlled-environment chamber. Growth of lymphatic vessels and infiltration of macrophages were evaluated by immunohistochemistry using CD31 (panendothelial marker), lymphatic vessel endothelial receptor 1 (lymphatic endothelial marker), and CD11b (monocyte and macrophage marker). Real-time polymerase chain reaction was performed to quantify expression of different inflammatory cytokine transcripts in the conjunctiva and lymph nodes as well as vascular endothelial growth factors and their receptors (VEGF-A, VEGF-C, VEGF-D, VEGFR-2, and VEGFR-3) in the cornea.

Results

Blocking VEGF-C led to significant reductions in lymphatic caliber (P = .02) and lymphatic area (P = .006) in the corneas of mice with dry eye disease. In addition to significantly decreasing CD11b+ cells (P = .005), anti–VEGF-C treatment significantly decreased transcript levels of VEGF-C (P = .002), VEGF-D (P = .01), and VEGFR-3 (P = .02) in the corneas of the treated group. A significant decrease in expression of inflammatory cytokines in the conjunctiva (interleukin 1α, P = .003; interleukin 1β, P = .02; interleukin 6, P = .005) and lymph nodes (interferon γ, P = .008; interleukin 17, P = .003) was also seen with anti–VEGF-C treatment.

Conclusion

Treatment with anti–VEGF-C led to significant improvement in dry eye disease, reflected by a decrease in inflammation at the clinical, molecular, and cellular levels.

Clinical Relevance

Targeting prolymphangiogenic growth factors or their receptors could inhibit the trafficking of antigen-presenting cells to the draining lymph nodes and hence prove to be a potential therapeutic target for dry eye disease.

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