Stress and wound healing

Abstract

Over the past decade it has become clear that stress can significantly slow wound healing: stressors ranging in magnitude and duration impair healing in humans and animals. For example, in humans, the chronic stress of caregiving as well as the relatively brief stress of academic examinations impedes healing. Similarly, restraint stress slows healing in mice. The interactive effects of glucocorticoids (e.g. cortisol and corticosterone) and proinflammatory cytokines [e.g. interleukin-1beta (IL-1beta), IL-1alpha, IL-6, IL-8, and tumor necrosis factor-alpha] are primary physiological mechanisms underlying the stress and healing connection. The effects of stress on healing have important implications in the context of surgery and naturally occurring wounds, particularly among at-risk and chronically ill populations. In research with clinical populations, greater attention to measurement of health behaviors is needed to better separate behavioral versus direct physiological effects of stress on healing. Recent evidence suggests that interventions designed to reduce stress and its concomitants (e.g., exercise, social support) can prevent stress-induced impairments in healing. Moreover, specific physiological mechanisms are associated with certain types of interventions. In future research, an increased focus on mechanisms will help to more clearly elucidate pathways linking stress and healing processes.

Fig. 1

Stages of wound healing. In healthy individuals, healing progresses sequentially through three overlapping phases: (1) inflammatory phase, (2) proliferative phase, and (3) remodeling phase. Stress can affect progression through these stages via multiple immune and neuroendocrine pathways. The current review focuses on the interactive role of glucocorticoids and cytokines (e.g. IL-8, IL-1α, IL-1β, IL-6, TNF-α, and IL-10). However, additional cytokines, chemokines, and growth factors are important to healing. These include CXC chemokine ligand 1 (CXCL1), CC chemokine ligand 2 (CCL2), granulocyte-macrophage colony-stimulating factor (GM-CSF), monocyte chemotactic protein-1 (MCP-1), macrophage inflammatory protien-1 alpha (MIP-lα), vascular endothelial growth factor (VEGF), transforming growth factor-β (TNF-β), keratinocyte growth factor (KGF), platelet-derived growth factor (PDGF), and basic fibroblast growth factor (bFGF) [for a broader review of physiological mechanisms relevant to wound healing, please see 73].

Fig. 2

Key findings linking stress and wound healing. PBLs = Peripheral blood leukocytes; LPS = lipopolysaccharide.

Fig. 3

Key findings linking stress and skin barrier recovery. n/a = Not available.