Adrenergic Signaling in Human Oral Keratinocytes and Wound Repair

Abstract

A supplemental appendix to this article is published electronically only at http://jdr.sagepub.com/supplemental. ABSTRACT Catecholamines are present in saliva, but their influence on oral epithelium is not understood. Because psychological stress increases salivary catecholamines and impairs oral mucosal wound healing, we sought to determine if epithelial adrenergic signaling could link these two findings. We found that cultured human oral keratinocytes (HOK) express the α 2B -and β 2 -adrenergic receptors (ARs). Exposure of HOK to either epinephrine or the β-AR agonist, isoproterenol, reduced migratory speed and decreased in vitro scratch wound healing. Incubation with the β-AR antagonist timolol reversed the catecholamine-induced effects, indicating that the observed response is mediated by β-AR. Epinephrine treatment decreased phosphorylation of the mitogen-activated protein kinases (MAPK) ERK1/2 and p38; these decreases were also reversed with timolol. Cultured HOK express enzymes of the epinephrine synthetic pathway, and generate epinephrine. These findings demonstrate that stress-induced elevations of salivary catecholamines signal through MAPK pathways, and result in impaired oral keratinocyte migration required for healing.

Differential Response of Dopamine Mediated by β-Adrenergic Receptors in Human Keratinocytes and Macrophages: Potential Implication in Wound Healing

“…Sivamani et al [26] have shown that the catecholamines released in the wound site decrease the keratinocyte migration mediated by ARs. It has also been described that the activation of β 2 -ARs leads to the in vitro and in vivo inhibition of keratinocytes migration [31, 32], and promotes the recruitment of polymorphonuclear cells by delaying the wound-healing process mediated by the increased IL-6 levels [33]. Furthermore, Shome et al [34] suggested that the neurotransmitter dopamine inhibits the VEGF-induced migration of murine mesenchymal progenitor cells to the wound site in vitro.…”

Stress-Induced Hormones Cortisol and Epinephrine Impair Wound Epithelization

“…3,6,11,12 Local cortisol and epinephrine synthesis impairs keratinocyte migration and ultimately delays epithelization. 3,5 HEKs and epidermis in vitro and ex vivo, along with porcine epidermis in vivo, express CYP11B1, an enzyme necessary for the cortisol production, and produce clinically relevant levels of cortisol.…”

“…Activation of b2AR decreases human keratinocyte migratory speed, delays healing of an in vitro scratch wound assay, impairs healing of an excisional human skin wound ex vivo, delays healing of acute surgical wounds in vivo, and results in impairment of oral mucosal wound healing. 5,[13][14][15][16][17] Similar to CYP11B1, the epidermal level of the epinephrine synthesizing enzyme PNMT is up-regulated during burn wound injury. Burn wounding of skin induces local epidermal generation of epinephrine by up-regulation of the enzyme, PNMT, required for epinephrine synthesis in the peri-wound epidermis.…”

“…Two novel topical treatments, which are typically used to improve cardiovascular health, are proposed to improve wound healing: statins and beta-blockers. 5,9,19 Additionally, topical treatment with metyrapone, an inhibitor of CYP11B1, enhanced keratinocyte migration and wound epithelization.…”

“…Stress-induced hormones glucocorticoids (GCs) and catecholamines have been shown to interfere with keratinocytes ability to migrate during the normal wound healing process. 3,[5][6][7][8] Therefore, a potential therapeutic approach may be blocking the enzymes and/or receptors necessary for the local production and function of stress hormones.…”