Substance P Drives Abnormal Lymphatic Vessel Growth in Dry Eye Disease | Research

The takeaway

The substance P/NK1R system promotes pathologic corneal lymphangiogenesis in dry eye disease by upregulating VEGFR3 on lymphatic cells — identifying NK1R antagonists as potential treatments for dry eye-related lymphatic vessel invasion.

NK1R drives lymphatic invasion
Substance P promotes abnormal lymphatic vessel growth in the cornea that perpetuates dry eye inflammation — a new mechanism explaining chronic disease and a druggable target

What the researchers found

SP/NK1R system promotes corneal lymphangiogenesis in DED by upregulating VEGFR3 expression on HDLECs. DED mouse model confirmed NK1R-dependent lymphatic vessel invasion. NK1R antagonism could inhibit pathologic lymphangiogenesis.

Why it matters

Dry eye affects hundreds of millions worldwide. Current treatments manage symptoms but don't address the underlying lymphatic vessel invasion that perpetuates inflammation. Blocking SP/NK1R could break this cycle.

The numbers in context

NK1R antagonist suppressed VEGF-C, VEGF-D, VEGFR3; improved fluorescein staining and tear production in DED mice

How the study worked

In vitro + animal study. Human dermal lymphatic endothelial cells (HDLECs): immunocytochemistry, angiogenesis assay, Western blot for SP/NK1R effects on VEGFR3. DED induced in wild-type C57BL/6 mice. Corneal lymphangiogenesis assessment.

Who was studied

C57BL/6J mice with induced dry eye; human dermal lymphatic endothelial cells

What this study cannot tell us

Mouse DED model may not replicate all aspects of human dry eye. Human cell data is in vitro. NK1R antagonist treatment not tested in the DED model. Clinical translation needs confirmation.

How to read the evidence

Moderate evidence: combined human cell and animal model data with clear mechanistic pathway. Treatment efficacy not yet tested.

When this study was published

Published 2021. NK1R as a target for ocular surface disease continues to be explored.

The bigger picture

Substance P's role in dry eye extends beyond pain — it drives the structural vascular changes that make the disease chronic. This connects neuropeptide biology to the ophthalmology field's search for disease-modifying dry eye treatments.

Questions still open

Would NK1R antagonist eye drops prevent lymphatic invasion in dry eye patients?
Does blocking SP/NK1R reduce dry eye inflammation or just lymphatic growth?
Could this pathway explain why some dry eye patients progress while others stabilize?

Common questions

Why do new blood/lymphatic vessels grow in dry eye?

Chronic inflammation from dry eye triggers substance P release, which activates NK1R receptors on lymphatic cells and increases VEGFR3 expression. This drives abnormal lymphatic vessel growth into the normally vessel-free cornea, creating a cycle of worsening inflammation.

Could blocking substance P treat dry eye?

This study suggests yes — blocking the substance P/NK1R system could prevent the abnormal lymphatic vessel growth that perpetuates dry eye inflammation. NK1R blocking drugs already exist and could potentially be formulated as eye drops.

Read the original research

Corneal lymphangiogenesis in dry eye disease is regulated by substance P/neurokinin-1 receptor system through controlling expression of vascular endothelial growth factor receptor 3.

The ocular surface, 22, 72-79

View on PubMed ↗Publisher’s paper ↗

Citation

Lee, Seok Jae; Im, Sang-Taek; Wu, Jun; Cho, Chang Sik; Jo, Dong Hyun; Chen, Yihe; Dana, Reza; Kim, Jeong Hun; Lee, Sang-Mok. (2021). Corneal lymphangiogenesis in dry eye disease is regulated by substance P/neurokinin-1 receptor system through controlling expression of vascular endothelial growth factor receptor 3.. The ocular surface, 22, 72-79. https://doi.org/10.1016/j.jtos.2021.07.003