Substance P Neuropeptide Enhances Collagen Production in Corneal Wound Healing via TGF-β Signaling

Substance P had no independent effect on corneal fibroblast collagen synthesis or MMP-1 expression. However, it significantly enhanced TGF-β-induced collagen type I synthesis. This effect was mediated by p38 MAPK activation and was blocked by neurokinin-1 receptor inhibition. SP did not affect IL-1β-stimulated MMP-1 expression.

In vitro study using cultured human corneal fibroblasts. Collagen type I synthesis measured with and without substance P, TGF-β, and IL-1β. p38 MAPK activation assessed by phosphorylation assays. Pharmacological inhibition of p38 MAPK and neurokinin-1 receptor used to confirm signaling pathway.

Neurotrophic keratopathy affects people after eye surgery, herpes infections, or diabetes-related nerve damage. Understanding that substance P amplifies wound healing signals provides a molecular explanation for why denervated corneas heal poorly and points toward potential therapeutic strategies using neuropeptide supplementation.

This study bridges neuroscience and ophthalmology, showing how nerve-derived neuropeptides directly modulate wound healing at the molecular level. It helps explain the clinical observation that denervated corneas develop progressive thinning and melting, and supports the rationale for nerve growth factor and neuropeptide-based therapies already being explored for neurotrophic keratitis.

In vitro study using isolated fibroblasts — doesn't capture the complex corneal wound healing environment with multiple cell types, tear film factors, and immune cells. Only one neuropeptide (substance P) tested. No animal model or clinical validation of the proposed mechanism.