Reduced Innervation and Delayed Re-Innervation After Epithelial Wounding in Type 2 Diabetic Goto-Kakizaki Rats

Wang, Feng; Gao, Nan; Yin, Jia; Yu, Fei

doi:10.1016/j.ajpath.2012.08.029

Cited by 53 publications

(57 citation statements)

References 42 publications

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“…S13). This result is consistent with the inability of diabetic mice to regenerate neurons fully (29)(30)(31). There were no significant differences in the vascular density among the groups at day 21 (SI Appendix, Fig.…”

Section: High Peptide Hydrogel Outperforms a Clinically Approved Woundsupporting

confidence: 78%

Diabetic wound regeneration using peptide-modified hydrogels to target re-epithelialization

Xiao

Reis

Feric

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

127

156

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There is a clinical need for new, more effective treatments for chronic wounds in diabetic patients. Lack of epithelial cell migration is a hallmark of nonhealing wounds, and diabetes often involves endothelial dysfunction. Therefore, targeting re-epithelialization, which mainly involves keratinocytes, may improve therapeutic outcomes of current treatments. In this study, we present an integrin-binding prosurvival peptide derived from angiopoietin-1, QHREDGS (glutamine-histidine-arginine-glutamic acid-aspartic acid-glycine-serine), as a therapeutic candidate for diabetic wound treatments by demonstrating its efficacy in promoting the attachment, survival, and collective migration of human primary keratinocytes and the activation of protein kinase B Akt and MAPK p42/44 . The QHREDGS peptide, both as a soluble supplement and when immobilized in a substrate, protected keratinocytes against hydrogen peroxide stress in a dose-dependent manner. Collective migration of both normal and diabetic human keratinocytes was promoted on chitosan-collagen films with the immobilized QHREDGS peptide. The clinical relevance was demonstrated further by assessing the chitosan-collagen hydrogel with immobilized QHREDGS in full-thickness excisional wounds in a db/db diabetic mouse model; QHREDGS showed significantly accelerated and enhanced wound closure compared with a clinically approved collagen wound dressing, peptide-free hydrogel, or blank wound controls. The accelerated wound closure resulted primarily from faster re-epithelialization and increased formation of granulation tissue. There were no observable differences in blood vessel density or size within the wound; however, the total number of blood vessels was greater in the peptide-hydrogeltreated wounds. Together, these findings indicate that QHREDGS is a promising candidate for wound-healing interventions that enhance reepithelialization and the formation of granulation tissue.

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Section: High Peptide Hydrogel Outperforms a Clinically Approved Woundsupporting

confidence: 78%

Diabetic wound regeneration using peptide-modified hydrogels to target re-epithelialization

Xiao

Reis

Feric

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

127

156

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show abstract

“…26 In the literature, IL-1Ra was shown to either play a protective role against transthyretin-mediated axonal loss in a mouse model of familial amyloidotic polyneuropathy 55 or impair taste responses in the intact chorda tympani after nearby injury. 56 Our results indicate a supportive role of IL-1Ra in the DM cornea and corroborate the potential use of IL-1Ra in promoting sensory nerve regeneration in DM peripheral tissues.…”

Section: Il-1ra and Diabetic Cornea Wound Healingmentioning

confidence: 99%

“…26,27 Herein, we determined the role of IL-1Ra in corneal sensory nerve regeneration A: Infiltrating neutrophils stained by NIMP-R14. B: Infiltrating NK (T) cells stained by NK1.1.…”

Section: Role Of Il-1ra In Corneal Innervation and Nerve Regenerationmentioning

confidence: 99%

“…26 For staining of neutrophils or natural killer (NK) cells, fluorescein isothiocyanate conjugated antibodies (5 mg/mL) of NIMP-R14 (Hycult Biotech, Plymouth Meeting, PA) or NK1.1 (eBioscience, San Diego, CA) were incubated with the cornea, respectively. For nerve staining, an additional 2-day permeabilization was performed before incubation with TUJ1 antibody (2 mg/mL; Covance Research, Princeton, NJ).…”

Section: Whole Mount Confocal Microscopymentioning

confidence: 99%

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Targeting Imbalance between IL-1β and IL-1 Receptor Antagonist Ameliorates Delayed Epithelium Wound Healing in Diabetic Mouse Corneas

Yan

Gao

Sun

et al. 2016

The American Journal of Pathology

Self Cite

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fanxq@sh163. net.Patients with diabetes mellitus often develop corneal complications and delayed wound healing. How diabetes might alter acute inflammatory responses to tissue injury, leading to delayed wound healing, remains mostly elusive. Using a streptozotocin-induced type I diabetes mellitus mice and corneal epithelium-debridement wound model, we discovered that although wounding induced marked expression of IL-1b and the secreted form of IL-1 receptor antagonist (sIL-1Ra), diabetes suppressed the expressions of sIL-1Ra but not IL-1b in healing epithelia and both in whole cornea. In normoglycemic mice, IL-1b or sIL-1Ra blockade delayed wound healing and influenced each other's expression. In diabetic mice, in addition to delayed reepithelization, diabetes weakened phosphatidylinositol 3-kinaseeAkt signaling, caused cell apoptosis, diminished cell proliferation, suppressed neutrophil and natural killer cell infiltrations, and impaired sensory nerve reinnervation in healing mouse corneas. Local administration of recombinant IL-1Ra partially, but significantly, reversed these pathological changes in the diabetic corneas. CXCL10 was a downstream chemokine of IL-1beIL-1Ra, and exogenous CXCL10 alleviated delayed wound healing in the diabetic, but attenuated it in the normal corneas. In conclusion, the suppressed early innate/inflammatory responses instigated by the imbalance between IL-1b and IL-1Ra is an underlying cause for delayed wound healing in the diabetic corneas. Local application of IL-1Ra accelerates reepithelialization and may be used to treat chronic corneal and potential skin wounds of diabetic patients. (Am J Pathol 2016 http://dx

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“…Corneal nerve fibers exert important trophic influences and contribute to the maintenance of corneal epithelium homeostasis, whereas the dysfunction of corneal innervation produces an impairment of corneal epithelial wound healing, known as neurotrophic keratitis, as caused by for instance herpetic viral infections, trigeminal nerve damage, or diabetes (27)(28)(29). Although tear fluid impairment is also involved (30), the neurotrophic deficits may play a major role in the pathogenesis of diabetic keratopathy, as the density of corneal nerve fibers and corneal sensation decreased in diabetic patients (31)(32)(33).…”

mentioning

confidence: 99%

Substance P Promotes Diabetic Corneal Epithelial Wound Healing Through Molecular Mechanisms Mediated via the Neurokinin-1 Receptor

et al. 2014

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Substance P (SP) is a neuropeptide, predominantly released from sensory nerve fibers, with a potentially protective role in diabetic corneal epithelial wound healing. However, the molecular mechanism remains unclear. We investigated the protective mechanism of SP against hyperglycemia-induced corneal epithelial wound healing defects, using type 1 diabetic mice and high glucose–treated corneal epithelial cells. Hyperglycemia induced delayed corneal epithelial wound healing, accompanied by attenuated corneal sensation, mitochondrial dysfunction, and impairments of Akt, epidermal growth factor receptor (EGFR), and Sirt1 activation, as well as decreased reactive oxygen species (ROS) scavenging capacity. However, SP application promoted epithelial wound healing, recovery of corneal sensation, improvement of mitochondrial function, and reactivation of Akt, EGFR, and Sirt1, as well as increased ROS scavenging capacity, in both diabetic mouse corneal epithelium and high glucose–treated corneal epithelial cells. The promotion of SP on diabetic corneal epithelial healing was completely abolished by a neurokinin-1 (NK-1) receptor antagonist. Moreover, the subconjunctival injection of NK-1 receptor antagonist also caused diabetic corneal pathological changes in normal mice. In conclusion, the results suggest that SP-NK-1 receptor signaling plays a critical role in the maintenance of corneal epithelium homeostasis, and that SP signaling through the NK-1 receptor contributes to the promotion of diabetic corneal epithelial wound healing by rescued activation of Akt, EGFR, and Sirt1, improvement of mitochondrial function, and increased ROS scavenging capacity.

show abstract

Reduced Innervation and Delayed Re-Innervation After Epithelial Wounding in Type 2 Diabetic Goto-Kakizaki Rats

Cited by 53 publications

References 42 publications

Diabetic wound regeneration using peptide-modified hydrogels to target re-epithelialization

Diabetic wound regeneration using peptide-modified hydrogels to target re-epithelialization

Targeting Imbalance between IL-1β and IL-1 Receptor Antagonist Ameliorates Delayed Epithelium Wound Healing in Diabetic Mouse Corneas

Substance P Promotes Diabetic Corneal Epithelial Wound Healing Through Molecular Mechanisms Mediated via the Neurokinin-1 Receptor

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