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J. Yin, F.-S. X. Yu; Human Cathelicidin LL-37 Enhances High Glucose-Delayed Corneal Epithelial Wound Healing via Promoting Epidermal Growth Factor Receptor Signaling. Invest. Ophthalmol. Vis. Sci. 2009;50(13):3495.
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Patients with diabetes are at an increased risk for developing corneal complications and delayed wound healing. The human antimicrobial peptide LL-37 has been shown to play an important role in host defense against various microorganisms. This study investigated whether and how LL-37 enhances high glucose-delayed corneal epithelial wound healing.
Heparin-binding EGF-like growth factor (HB-EGF) shedding was assessed by measuring the release of alkaline phosphatase (AP) in a stable human corneal epithelial cell (HCEC) line that expresses HB-EGF with AP inserted in the heparin binding site. The activation of EGFR was analyzed by immunoprecipitation, and the phosphorylation of ERK and AKT (a major substrate of phosphatidylinositol 3'-kinase, PI3K) was analyzed by Western blotting. Epithelial wound healing was assessed by porcine corneal organ culture.
LL-37 induced the activation of EGFR, its downstream effectors ERK and AKT, in a dose dependent manner, probably via HB-EGF ectodomain shedding. LL-37 prolonged wound-induced EGFR signaling in HCECs. High glucose significantly delayed epithelial wound closure and disrupted the EGFR-mediated PI3K/AKT signaling in cultured porcine corneas. LL-37 reversed, at least partially, the delayed epithelial wound closure and averted the attenuated EGFR-PI3K-AKT signaling in the porcine corneas culture in high glucose.
The protective and regenerative activities of LL-37 support its therapeutic potential to promote epithelial wound healing and to prevent injury-associated infection in the cornea of diabetic patients.
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