Diabetic Keratopathy, a sight-threatening corneal disease, comprises
several symptomatic conditions including delayed
epithelial wound healing, recurrent erosions, and sensory nerve (SN) neuropathy. We
investigated the role of neuropeptides in mediating corneal wound healing,
including epithelial wound closure and SN regeneration. Denervation
by Resiniferatoxin severely impaired corneal wound healing and markedly
up-regulated pro-inflammatory gene expression. Exogenous neuropeptides CGRP,
SP, and VIP partially reversed Resiniferatoxin’s effects, with VIP specifically
inducing IL-10 expression. Hence, we focused on VIP and observed that wounding
induced VIP and VIPR1 expression in normal (NL), but not diabetic (DM) mouse corneas.
Targeting VIPR1 in <em>NL</em> corneas attenuated corneal
wound healing, dampened wound-induced expression of neurotrophic factors, and
exacerbated inflammatory responses while exogenous VIP had the opposite effects in
DM corneas. Remarkably, wounding and diabetes
also affected the expression of Sonic Hedgehog
(SHH) in a VIP-dependent manner. Downregulating SHH expression
in NL corneas decreased, while exogenous SHH in DM corneas
increased the rates of corneal wound healing.
Furthermore, inhibition of SHH signaling dampened VIP-promoted corneal
wound healing. We conclude that VIP regulates epithelial wound he<a></a><a>aling,
inflammatory response, and nerve regeneration in the corneas in a</a> SHH-dependent manner, suggesting
a therapeutic potential for these molecules in treating diabetic keratopathy.
The Role of Neutrophils in Corneal Wound Healing in HO-2 Null Mice
