INTRODUCTION
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,
