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The Outer Aspect of Our Inner Anxiety: The Skinny on Stress

July 2012 | Volume 11 | Issue 7 | Feature | 883 | Copyright © 2012

Jason Chouake and Adam Friedman


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The relationship between mind and skin is essential and undeniable. From their common ectodermal embryologic origin, the nervous system and skin remain interconnected and communicate throughout life. The skin is the first interface between environment, body, and mind from the moment we are born. Our sense of touch plays a fundamental role in social, cognitive, and physical development, and is a fundamental form of communication between mothers and infants. Oxytocin, a key hormonal regulator of positive social interactions,1 is produced through touch and sustained physical contact between infants and mothers.2 Skin is a highly innervated organ, and its afferent signals to the sensory cortex are relatively over-represented.3 In fact, the skin is integrated with and sensitive to the same signals and regulatory mechanisms produced by the hypothalamic- pituitary-adrenal (HPA) axis. Simple observations of emotional reactions, such as sweating due to fear or anxiety, elicit these innate connections, and are well known.4 The bidirectional relationship between psychological stress and certain skin diseases has been known for many years. Quality of life (QOL) can be negatively impacted by chronic skin disease, and patients with disfiguring skin disease may feel stigmatized, resulting in depression and other psychological morbidities. Conversely, a large number of skin diseases are exacerbated by psychological stress, including wound healing, psoriasis, and atopic dermatitis.5,6 Flares of psoriasis, and impaired wound healing are modulated by proinflammatory cytokines, which in turn are modulated by psychosocial stressors.7

Psychological stress (PS) induces the activation of the HPA axis and/or the sympathetic nervous system (SNS). The HPA is easily triggered by non-physical events. In response to psychological stress, the neuroendocrine system stimulates a series of adaptive responses involving multiple organ systems.8 Activation of the HPA results in the upregulation and release of key stress hormones. These include corticotropin releasing factor (CRF, CRH), adrenocorticotropic hormone (ACTH), and glucocorticoids. The release of these neuroendocrine mediators effects cellular and humoral immune responses.8 There are also direct nerve fiber connections between the SNS and the spleen and thymus. Other neuro-hormonal responses to stress include the activation of the sympathetic nervous system, with release of catecholamines. All lymphocytes express Β-adrenergic receptors, and catecholamines can alter the functional capacity of leukocyte subpopulations, as well as cytokine production and release.8,9 Stress has complex effects on both innate and acquired immunity; individual neuro-hormonal mediators can regulate multiple aspects of immune cell function. Both glucocorticoids and catecholamines induce the switch from Th1(cellular immunity) to a Th2 (humoral immunity) response, and suppress the secretion of proinflammatory cytokines. The inhibition of proinflammatory cytokines by neurohormones produced in the stress response is an important negative feedback loop that protects organisms from overactive inflammatory responses.

When psychological stress is perceived, the activation of the HPA is further translated into a skin stress response. In the skin, mast cells become the targets for stress triggered neurohormones as well as effectors of neurogenic inflammation in the skin.3 Skin cells are capable of generating the same neuroendocrine hormones, and crucial peptides that are produced in the HPA axis. The fully functional peripheral neuroendocrine axis within the skin is closely linked to the systemic neuro-endocrine axis.10 All skin cell lines (melanocytes, keratinocytes, fibroblasts, sebocytes, and mast cells) express CRF and CRF-receptors. Furthermore, the cutaneous transcription and translation of proopiomelanocortin (POMC) and POMC-derived peptides (ACTH, MSH, β-endorphins), has been confirmed in human melanocytes, keratinocytes, infiltrating immune cells, hair follicles, sweat glands, melanocytic nevi, and the walls of blood vessels.11 Normal human scalp hair follicles contain fully functional peripheral equivalents of the HPA axis and are capable of synthesizing cortisol and activating regulatory feedback loops.12 The intracutaneous neuroendocrine activities of the skin described here are complemented by the production of additional neurohormonal molecules (neurotrophins [NGF], substance P, prolactin [PRL], among others), which also play a role in inflammation and modulation of the secretory function of mast cells.

Increased levels of cortisol and epinephrine impair barrier function, and can delay wound healing. Stress induced elevation of epinephrine activates keratinocyte β2-adrenergic receptors (β2AR), resulting in the impairment of cell motility and wound re-epithelialization. Furthermore, burn wounds generate even greater levels of epinephrine, both locally and systemically, and therefore wound healing is doubly impacted. 13 These observations suggest a therapeutic role for beta-blockers and statin drugs in wound healing. In a recent retrospective review of 223 burn patients, aged 55 and older, the overall mortality in the statin user group was 4.3% (3 out of 70), while the overall mortality in non-statin users was 20.9% (32 out of 153).14 Topical statin drugs have also been shown to increase epitheliazation in ex-vivo mouse wounds,

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