Norepinephrine modulates the inflammatory and proliferative phases of wound healing.
ABSTRACT Injury results in the massive release of norepinephrine (NE) into the peripheral circulation. Recent investigations have demonstrated functional adrenoreceptors on the cellular mediators of cutaneous wound healing and NE-induced phenotypic alterations in immune cells have been demonstrated in vitro. Despite this, there is little description of how NE might alter the phases of wound healing in vivo. The purpose of this study was to compare cutaneous wound healing in norepinephrine-intact and norepinephrine-depleted mice.
Norepinephrine-depleted (NED) mice were generated by chemical axotomy with 6-hydroxydopamine and compared with norepinephrine-intact (NEI) animals (n = 6-12 per group, per time point). Using an excisional wound model, neutrophil recruitment was measured by myeloperoxidase assay. Macrophage recruitment and angiogenesis were measured by immunohistochemistry and re-epithelialization was determined histologically. The development of incisional wound disruption strength was determined over time. Finally, macrophage scavenger function was assessed by an in vitro latex bead phagocytosis assay.
Wounds from NEI mice demonstrated greater neutrophil infiltration than NED wounds (24, 72 hours; p < 0.05). Wound macrophage recruitment was initially higher in NEI animals (24 hours, p < 0.05), but was eventually surpassed by that of NED animals (120 hours, p < 0.05). Angiogenesis was decreased while re-epithelialization was accelerated in NEI animals (p < 0.05). Wound disruption strength and macrophage scavenger function were unaltered between NED and NEI mice.
Norepinephrine modulates the inflammatory and proliferative phases of wound healing in a temporally defined, cell-specific manner. By increasing recruitment of innate immune cells and expediting wound closure, norepinephrine appears to play a protective role in defense against infection.
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ABSTRACT: Keratinocyte migration is critical for wound re-epithelialization. Previous studies showed that epinephrine activates the beta2-adrengergic receptor (B2AR), impairing keratinocyte migration. Here, we investigated the keratinocyte catecholamine synthetic pathway in response to acute trauma. Cultured keratinocytes were scratch wounded and expression of the B2AR and catecholamine synthetic enzymes tyrosine hydroxylase (TH) and phenylethanolamine-N-methyltransferase (PNMT) were assayed. The binding affinity of the B2AR was measured. Wounding downregulated B2AR, TH, and PNMT expression, but pre-exposure to timolol, a beta-adrenergic receptor antagonist, delayed this effect. In wounded keratinocytes, B2AR binding affinity remained depressed even after its expression returned to pre-wounding levels. Keratinocyte derived norepinephrine increased after wounding. Norepinephrine impaired keratinocyte migration; this effect was abrogated with B2AR selective antagonist ICI-118,551 but not with B1AR selective antagonist bisoprolol. Finally, for clinical relevance, we determined that norepinephrine was present in freshly wounded skin, thus providing a potential mechanism for impaired healing by local B2AR activation in wound edge keratinocytes. Taken together, the data show that keratinocytes modulate catecholamine synthetic enzymes and release norepinephrine after scratch wounding. Norepinephrine appears to be a stress-related mediator that impairs keratinocyte migration through activation of the B2AR. Future therapeutic strategies evaluating modulation of norepinephrine related effects in the wound are warranted.Journal of Investigative Dermatology accepted article preview online, 10 March 2014; doi:10.1038/jid.2014.137.Journal of Investigative Dermatology 03/2014; 134(8). DOI:10.1038/jid.2014.137 · 6.37 Impact Factor
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ABSTRACT: Large full-thickness skin defects still represent a significant clinical problem for burn, plastic, and reconstructive surgeons. In fact, high morbidity and mortality in the acute phase, as well as functionally and cosmetically devastating scarring represent vexing problems that are far from being solved in a satisfactory way. Although a variety of biologic dressings and cultured skin substitutes, in particular cultured epithelial autografts, have contributed to improve short- and long-term outcomes of patients in the past, the authors hypothesize that only the bioengineering of near-natural autologous full-thickness skin grafts harbors the potential for a dimensional breakthrough. This review gives an insight into the development and characteristics of the autologous full-thickness skin grafts available for clinical application to date. In addition, recent scientific progress toward the bioengineering of dermoepidermal skin grafts which comprise a functional vasculature, pigmentation, neural elements, and skin appendages is discussed.European Journal of Pediatric Surgery 06/2014; 24(03). DOI:10.1055/s-0034-1376315 · 0.98 Impact Factor
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ABSTRACT: Pain is a primary symptom driving patients to seek physical therapy and its attenuation commonly defines a successful outcome. A large body of evidence is dedicated to elucidating the relationship between chronic stress and pain. A physiologic stress response may be evoked by fear or perceived threat to safety, status, or well-being, and elicits the secretion of sympathetic catecholamines (epinephrine and norepinepherine) and neuroendocrine hormones (cortisol) to promote survival and motivate success. Cortisol is a potent anti-inflammatory that functions to mobilize glucose reserves for energy and modulate inflammation. Cortisol may also facilitate the consolidation of fear-based memories for future survival and avoidance of danger. While short-term stress may be adaptive, maladaptive responses (such as magnification, rumination, or helplessness) to pain or non-pain-related stressors may intensify cortisol secretion and condition a sensitized physiologic stress response that is readily recruited. Ultimately, a prolonged or exaggerated stress response may perpetuate cortisol dysfunction, widespread inflammation, and pain. While stress may be unavoidable in life and challenges are inherent to success, humans have the capability to modify what they perceive as stressful and how they respond to it. Exaggerated psychological responses (eg: catastrophizing) following maladaptive cognitive appraisals of potential stressors as threatening may exacerbate cortisol secretion by facilitating fear-based activation of the amygdala. Coping, cognitive re-appraisal, or confrontation of stressors may minimize cortisol secretion and prevent chronic, recurrent pain. Given the parallel mechanisms underlying the physiologic effects of a maladaptive response to pain and non-pain-related stressors, physical therapists should consider screening for non-pain-related stress to facilitate treatment, prevent chronic disability, and improve quality of life.Physical Therapy 07/2014; 94(12). DOI:10.2522/ptj.20130597 · 3.25 Impact Factor