Cathelicidin promotes wound healing via EGFR; treatment for diabetic ulcers?

Invest Ophthalmol Vis Sci. 2009 Sep 24;

LL-37 Promotes High Glucose-Attenuated Epithelial Wound Healing via EGFR
Transactivation in Organ Cultured Corneas.
Yin J, Yu FS.
Kresge Eye Institute/Dept Ophthalmology, Wayne State University School
of Medicine, Detroit, United States.

Purpose: Diabetic patients are at a higher risk for delayed corneal
reepithelialization and infection. Previous studies indicated that high
glucose (HG) impairs epidermal growth factor receptor (EGFR) signaling
and attenuates ex vivo corneal epithelial wound healing. This study
investigated the effects of antimicrobial peptide LL-37 on HG-attenuated
corneal epithelial EGFR signaling and wound closure. Methods: Human
corneal epithelial cells (HCECs) were stimulated with LL-37.
Heparin-binding EGF-like growth factor (HB-EGF) shedding was assessed by
measuring the release of alkaline phosphatase (AP) in a stable HCEC line
expressing HB-EGF-AP. Activation of EGFR, phosphoinositide 3-kinase
(PI3K), and extracellular signal-regulated kinases 1/2 (ERK1/2) was
determined by Western Blotting. Corneal epithelial wound closure was
assessed in cultured HCECs and porcine corneas. LL-37 production was
determined by immune dot blot. Results: LL-37 induced HB-EGF-AP release
and EGFR activation in a dose-dependent manner. LL-37 prolonged EGFR
signaling in response to wounding. LL-37 enhanced the closure of a
scratch wound in cultured HCECs and partially rescued HG-attenuated
wound healing in an EGFR- and PI3K-dependent manner and restored
HG-impaired EGFR signaling in cultured porcine corneas. HG attenuated
wounding-induced LL-37 expression in cultured HCECs. Conclusions: LL-37
is a tonic factor promoting EGFR signaling and enhancing epithelial
wound healing in normal and high glucose conditions. With both
antimicrobial and regenerative capabilities, LL-37 may be a potential
therapeutic for diabetic keratopathy.

PMID: 19797203
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